Language：English   Publisher：(一社)日本癌治療学会  

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BACKGROUND: Boron neutron capture therapy (BNCT) is a precise particle radiation therapy known for its unique cellular targeting ability. The development of innovative boron carriers is crucial for the advancement of BNCT technologies. Our previous study demonstrated the potential of PBC-IP administered via convection-enhanced delivery (CED) in an F98 rat glioma model. This approach significantly extended rat survival in neutron irradiation experiments, with half achieving long-term survival, akin to a cure, in a rat brain tumor model. Our commitment to clinical applicability has spurred additional nonclinical pharmacodynamic research, including an investigation into the effects of cannula position and the time elapsed post-CED administration. METHODS: In comprehensive in vivo experiments conducted on an F98 rat brain tumor model, we meticulously examined the boron distribution and neutron irradiation experiments at various sites and multiple time intervals following CED administration. RESULTS: The PBC-IP showed substantial efficacy for BNCT, revealing minimal differences in tumor boron concentration between central and peripheral CED administration, although a gradual decline in intratumoral boron concentration post-administration was observed. Therapeutic efficacy remained robust, particularly when employing cannula insertion at the tumor margin, compared to central injections. Even delayed neutron irradiation showed notable effectiveness, albeit with a slightly reduced survival period. These findings underscore the robust clinical potential of CED-administered PBC-IP in the treatment of malignant gliomas, offering adaptability across an array of treatment protocols. CONCLUSIONS: This study represents a significant leap forward in the quest to enhance BNCT for the management of malignant gliomas, opening promising avenues for clinical translation.

DOI： 10.1093/noajnl/vdae062

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Publishing type：Research paper (scientific journal)   Publisher：American Chemical Society (ACS)  

DOI： 10.1021/acs.molpharmaceut.3c00726

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.inoche.2023.111318

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.bmc.2023.117463

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Language：English   Publisher：(一社)日本癌治療学会  

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Language：English   Publisher：(一社)日本癌治療学会  

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Language：English   Publishing type：Research paper (scientific journal)  

High-grade gliomas present a significant challenge in neuro-oncology because of their aggressive nature and resistance to current therapies. Boron neutron capture therapy (BNCT) is a potential treatment method; however, the boron used by the carrier compounds-such as 4-borono-L-phenylalanine (L-BPA)-have limitations. This study evaluated the use of boron-conjugated 4-iodophenylbutanamide (BC-IP), a novel boron compound in BNCT, for the treatment of glioma. Using in vitro drug exposure experiments and in vivo studies, we compared BC-IP and BPA, with a focus on boron uptake and retention characteristics. The results showed that although BC-IP had a lower boron uptake than BPA, it exhibited superior retention. Furthermore, despite lower boron accumulation in tumors, BNCT mediated by BC-IP showed significant survival improvement in glioma-bearing rats compared to controls (not treated animals and neutrons only). These results suggest that BC-IP, with its unique properties, may be an alternative boron carrier for BNCT. Further research is required to optimize this potential treatment modality, which could significantly contribute to advancing the treatment of high-grade gliomas.

DOI： 10.3390/biology12091240

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Language：English   Publisher：(一社)日本癌学会  

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Language：English   Publishing type：Research paper (scientific journal)  

Boron neutron capture therapy (BNCT) has been applied for clinical trials on glioblastoma patients since 1950s, however, the low survival rate under the treatments has hampered the widespread use of BNCT. In this study, we developed a novel boron agent, PBC-IP, which consists of three functional groups: FRα-targeting, 10B resource (twelve 10B atoms in the molecule), and albumin-binding moieties. PBC-IP was selectively taken up by glioma cell lines such as C6, F98, and U87MG cells and accumulated 10- to 20-fold higher than L-4‑boronophenylalanine (BPA). PBC-IP administrated intravenously to the human glioblastoma (U87MG) xenograft model showed higher boron accumulation in tumors (29.8 μg [10B]/g at 6 h) than BPA (9.6 μg [10B]/g at 3 h) at a 25 mg [10B]/kg dose, effectively suppressing tumor growth after thermal neutron irradiation. PBC-IP administrated via convection-enhanced delivery (CED) accumulated in the F98 glioma orthotopic rat model, achieving 26.5 μg [10B]/g in tumors with tumor/normal (T/N) brain and tumor/blood (T/B) boron ratios of 37.8 and 94.6, respectively, 3 h after CED. Survival at 180 days after BNCT was 50% in the PBC-IP group and 70% in the combined BPA and PBC-IP groups, with no residual brain tumors.

DOI： 10.1016/j.jconrel.2023.06.022

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Publishing type：Research paper (scientific journal)   Publisher：American Chemical Society (ACS)  

DOI： 10.1021/acs.analchem.2c05818

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Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

Integrin αvβ3 is more highly expressed in high-grade glioma cells than in normal tissues. In this study, a novel boron-10 carrier containing maleimide-functionalized closo-dodecaborate (MID), serum albumin as a drug delivery system, and cyclic arginine-glycine-aspartate (cRGD) that can target integrin αvβ3 was developed. The efficacy of boron neutron capture therapy (BNCT) targeting integrin αvβ3 in glioma cells in the brain of rats using a cRGD-functionalized MID-albumin conjugate (cRGD-MID-AC) was evaluated. F98 glioma cells exposed to boronophenylalanine (BPA), cRGD-MID-AC, and cRGD + MID were used for cellular uptake and neutron-irradiation experiments. An F98 glioma-bearing rat brain tumor model was used for biodistribution and neutron-irradiation experiments after BPA or cRGD-MID-AC administration. BNCT using cRGD-MID-AC had a sufficient cell-killing effect in vitro, similar to that with BNCT using BPA. In biodistribution experiments, cRGD-MID-AC accumulated in the brain tumor, with the highest boron concentration observed 8 h after administration. Significant differences were observed between the untreated group and BNCT using cRGD-MID-AC groups in the in vivo neutron-irradiation experiments through the log-rank test. Long-term survivors were observed only in BNCT using cRGD-MID-AC groups 8 h after intravenous administration. These findings suggest that BNCT with cRGD-MID-AC is highly selective against gliomas through a mechanism that is different from that of BNCT with BPA.

DOI： 10.3390/biology12030377

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Publishing type：Research paper (scientific journal)   Publisher：Royal Society of Chemistry (RSC)  

The bridged diazatricycloundecane sp³-rich scaffold was synthesized via gold(I)-catalysed Conia-ene reaction. The electron-donating property of the siloxymethyl group on the alkyne 1 gave 6-endo-dig cyclization, whereas the ethoxy carbonyl group...

DOI： 10.1039/d3ob01534c

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Language：English   Publisher：(一社)日本癌治療学会  

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Publishing type：Research paper (scientific journal)   Publisher：American Chemical Society (ACS)  

DOI： 10.1021/acsomega.2c05042

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.bmcl.2022.128869

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Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

Background: BNCT (Boron Neutron Capture Therapy) is a tumor-selective particle radiotherapy that combines preferential boron accumulation in tumors and neutron irradiation. Although p-boronophenylalanine (BPA) has been clinically used, new boron compounds are needed for the advancement of BNCT. Based on previous studies in colon tumor-bearing mice, in this study, we evaluated MID:BSA (maleimide-functionalized closo-dodecaborate conjugated to bovine serum albumin) biodistribution and MID:BSA/BNCT therapeutic effect on tumors and associated radiotoxicity in the hamster cheek pouch oral cancer model. Methods: Biodistribution studies were performed at 30 mg B/kg and 15 mg B/kg (12 h and 19 h post-administration). MID:BSA/BNCT (15 mg B/kg, 19 h) was performed at three different absorbed doses to precancerous tissue. Results: MID:BSA 30 mg B/kg protocol induced high BSA toxicity. MID:BSA 15 mg B/kg injected at a slow rate was well-tolerated and reached therapeutically useful boron concentration values in the tumor and tumor/normal tissue ratios. The 19 h protocol exhibited significantly lower boron concentration values in blood. MID:BSA/BNCT exhibited a significant tumor response vs. the control group with no significant radiotoxicity. Conclusions: MID:BSA/BNCT would be therapeutically useful to treat oral cancer. BSA toxicity is a consideration when injecting a compound conjugated to BSA and depends on the animal model studied.

DOI： 10.3390/life12071082

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Language：Japanese   Publisher：日本DDS学会  

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Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1002/cctc.202200077

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/cctc.202200077

Language：English   Publishing type：Research paper (scientific journal)  

Introduction Boron neutron capture therapy (BNCT) is a biologically targeted, cell-selective particle irradiation therapy that utilizes the nuclear capture reaction of boron and neutron. Recently, accelerator neutron generators have been used in clinical settings, and expectations for developing new boron compounds are growing. Methods and Results In this study, we focused on serum albumin, a well-known drug delivery system, and developed maleimide-functionalized closo-dodecaborate albumin conjugate (MID-AC) as a boron carrying system for BNCT. Our biodistribution experiment involved F98 glioma-bearing rat brain tumor models systemically administered with MID-AC and demonstrated accumulation and long retention of boron. Our BNCT study with MID-AC observed statistically significant prolongation of the survival rate compared to the control groups, with results comparable to BNCT study with boronophenylalanine (BPA) which is the standard use of in clinical settings. Each median survival time was as follows: untreated control group; 24.5 days, neutron-irradiated control group; 24.5 days, neutron irradiation following 2.5 h after termination of intravenous administration (i.v.) of BPA; 31.5 days, and neutron irradiation following 2.5 or 24 h after termination of i.v. of MID-AC; 33.5 or 33.0 days, respectively. The biological effectiveness factor of MID-AC for F98 rat glioma was estimated based on these survival times and found to be higher to 12. This tendency was confirmed in BNCT 24 h after MID-AC administration. Conclusion MID-AC induces an efficient boron neutron capture reaction because the albumin contained in MID-AC is retained in the tumor and has a considerable potential to become an effective delivery system for BNCT in treating high-grade gliomas.

DOI： 10.1007/s10637-021-01201-7

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Language：Japanese   Publisher：(公社)日本薬学会  

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Language：English   Publishing type：Research paper (scientific journal)  

Intracellular photocatalytic-proximity labeling (iPPL) was developed to profile protein-protein interactions in the microenvironment of living cells. Acriflavine was found to be an efficient cell-membrane-permeable photocatalyst for introduction into the genetically HaloTag-fused protein of interest for iPPL with a radical labeling reagent, 1-methyl-4-arylurazole. iPPL was applied to the histone-associated protein H2B in HaloTag-H2B expressing HEK293FT cells. The proteins directly interacting with histones and RNA-binding proteins were selectively labeled in the intracellular environment, suggesting that the iPPL method has a smaller labeling radius (CA. 6 nm) than the BioID and APEX methods.

DOI： 10.1039/d1cc05764b

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Publishing type：Research paper (scientific journal)   Publisher：Royal Society of Chemistry (RSC)  

Curcumin derivatives B and N developed as disaggregation agents of amyloid β (Aβ) fibrils significantly rescued locomotion dysfunction in an Aβ-expressing <italic>Drosophila</italic> model of Alzheimer's disease.

DOI： 10.1039/d1cc07000b

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Publishing type：Research paper (scientific journal)   Publisher：Royal Society of Chemistry (RSC)  

A curcumin derivative conjugated with Gd-DO3A (Gd-DO3A-Comp.B) was developed to significantly inhibit the amyloid-β (Aβ) aggregation and detect the fibril growth by <italic>T</italic>₁-weighted MR imaging.

DOI： 10.1039/d2ra00614f

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Radiation therapy is one of standard treatment for malignant glioma after surgery. The microenvironment after irradiation is considered not to be suitable for the survival of tumor cells (tumor bed effect). This study investigated whether the effect of changes in the microenvironment of parenchymal brain tissue caused by radiotherapy affect the recurrence and progression of glioma. 65-Gy irradiation had been applied to the right hemisphere of Fisher rats. After 3 months from irradiation, we extracted RNA and protein from the irradiated rat brain. To study effects of proteins extracted from the brains, we performed WST-8 assay and tube formation assay in vitro. Cytokine production were investigated for qPCR. Additionally, we transplanted glioma cell into the irradiated and sham animals and the median survival time of F98 transplanted rats was also examined in vivo. Immunohistochemical analyses and invasiveness of implanted tumor were evaluated. X-ray irradiation promoted the secretion of cytokines such as CXCL12, VEGF-A, TGF-β1 and TNFα from the irradiated brain. Proteins extracted from the irradiated brain promoted the proliferation and angiogenic activity of F98 glioma cells. Glioma cells implanted in the irradiated brains showed significantly high proliferation, angiogenesis and invasive ability, and the post-irradiation F98 tumor-implanted rats showed a shorter median survival time compared to the Sham-irradiation group. The current study suggests that the microenvironment around the brain tissue in the chronic phase after exposure to X-ray radiation becomes suitable for glioma cell growth and invasion.

DOI： 10.1038/s41598-021-01475-0

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Other Link： https://www.nature.com/articles/s41598-021-01475-0

Publishing type：Research paper (scientific journal)   Publisher：American Chemical Society (ACS)  

DOI： 10.1021/acs.bioconjchem.1c00431

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Language：English   Publishing type：Research paper (scientific journal)  

Full-length pharmaceutical antibodies, trastuzumab and rituximab, were chemically modified into Quenchbody, a fluorescent immunosensor, using a two-step reaction: (1) selective tyrosine residue modification of antibody complementarity determining regions (CDRs), and (2) introduction of fluorescent dye molecules by Cu-free click reaction. Without the need for genetic manipulation and time-consuming examination of protein expression conditions, the antibody-dye combination with good antigen response efficiency was examined in a simple two-hour operation.

DOI： 10.1039/d1cc03231c

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.bmc.2021.116357

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Language：English   Publishing type：Research paper (scientific journal)  

A novel sp3 carbon-rich tricyclic 3D scaffold-based peptide mimetic compound library was constructed to target protein-protein interactions. Tricyclic framework 7 was synthesized from 9-azabicyclo[3,3,1]nonan-3-one (11) via a gold(I)-catalyzed Conia-ene reaction. The electron-donating group on the pendant alkyne of cyclization precursor 12 b-e was the key to forming 6-endo-dig cyclized product 7 with complete regioselectivity. Using the synthetic strategy for regioselective construction of bridged tricyclic framework 7, a diazatricyclododecene 3D-scaffold 8 a, which enables the introduction of substituents into the scaffold to mimic amino acid side chains, was designed and synthesized. The peptide mimetics 21 a-u were synthesized via step-by-step installation of three substituents on diazatricyclododecene scaffold 8 a. Compounds 21 a-h were synthesized as α-helix peptide mimics of hydrophobic ZZxxZ and ZxxZZ sequences (Z=Leu or Phe) and subjected to cell-based assays: antiproliferative activity, HIF-1 transcriptional activity which is considered to affect cancer malignancy, and antiviral activity against rabies virus. Compound 21 a showed the strongest inhibitory activity of HIF-1 transcriptional activity (IC50 =4.1±0.8 μM), whereas compounds 21 a-g showed antiviral activity with IC50 values of 4.2-12.4 μM, suggesting that the 3D-scaffold 8 a has potential as a versatile peptide mimic skeleton.

DOI： 10.1002/chem.202101440

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier Ltd  

The Suzuki-Miyaura cross-coupling of 3,4-disubstituted 5-bromoisoxazoles 1 at the C5 position has successfully proceeded in the presence of Pd2(dba)3 and P(t-Bu)3·HBF4 catalysts to give the corresponding trisubstituted isoxazoles 3 in good to high yields while suppressing the formation of ketone 4 as a byproduct. The use of bulky phosphine ligand P(t-Bu)3·HBF4 is essential for the current transformation, and the formation of ketone 4, which was a major product in the previous report, was able to be suppressed under the current conditions.

DOI： 10.1016/j.tetlet.2021.153185

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：John Wiley and Sons Inc  

Lactams are cyclic amides that are indispensable as drugs and as drug candidates. Conventional lactamization includes acid-mediated and coupling-agent-mediated approaches that suffer from narrow substrate scope, much waste, and/or high cost. Inexpensive, less-wasteful approaches mediated by highly electrophilic reagents are attractive, but there is an imminent risk of side reactions. Herein, a methods using highly electrophilic triphosgene in a microflow reactor that accomplishes rapid (0.5–10 s), mild, inexpensive, and less-wasteful lactamization are described. Methods A and B, which use N-methylmorpholine and N-methylimidazole, respectively, were developed. Various lactams and a cyclic peptide containing acid- and/or heat-labile functional groups were synthesized in good to high yields without the need for tedious purification. Undesired reactions were successfully suppressed, and the risk of handling triphosgene was minimized by the use of microflow technology.

DOI： 10.1002/chem.202100059

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Language：English   Publishing type：Research paper (scientific journal)  

While electrophilic reagents for histidine labeling have been developed, we report an umpolung strategy for histidine functionalization. A nucleophilic small molecule, 1-methyl-4-arylurazole, selectively labeled histidine under singlet oxygen (1O2) generation conditions. Rapid histidine labeling can be applied for instant protein labeling. Utilizing the short diffusion distance of 1O2 and a technique to localize the 1O2 generator, a photocatalyst in close proximity to the ligand-binding site, we demonstrated antibody Fc-selective labeling on magnetic beads functionalized with a ruthenium photocatalyst and Fc ligand, ApA. Three histidine residues located around the ApA binding site were identified as labeling sites by liquid chromatography-mass spectrometry analysis. This result suggests that 1O2-mediated histidine labeling can be applied to a proximity labeling reaction on the nanometer scale.

DOI： 10.1021/jacs.1c01626

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Publishing type：Research paper (scientific journal)   Publisher：Informa {UK} Limited  

DOI： 10.1080/13543776.2021.1874345

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Publishing type：Research paper (scientific journal)   Publisher：Royal Society of Chemistry ({RSC})  

DOI： 10.1039/D0OB02544E

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

Bis(carboranyl)amides 1,1'-µ-(CH2NH(O)C(CH2)n-1,2-C2B10H11)2 (n = 0, 1) were prepared by the reactions of the corresponding carboranyl acyl chlorides with ethylenediamine. Crystal molecular structure of 1,1'-µ-(CH2NH(O)C-1,2-C2B10H11)2 was determined by single crystal X-ray diffraction. Treatment of bis(carboranyl)amides 1,1'-µ-(CH2NH(O)C(CH2)n-1,2-C2B10H11)2 with ammonium or cesium fluoride results in partial deboronation of the ortho-carborane cages to the nidocarborane ones with formation of [7,7'(8')-µ-(CH2NH(O)C(CH2)n-7,8-C2B9H11)2]2-. The attempted reaction of [7,7'(8')-µ-(CH2NH(O)CCH2-7,8-C2B9H11)2]2- with GdCl3 in 1,2-dimethoxy- ethane did not give the expected metallacarborane. The stability of different conformations of Gd-containing metallacarboranes has been estimated by quantum-chemical calculations using [3,3-µ-DME-3,30- Gd(1,2-C2B9H11)2]- as a model. It was found that in the most stable conformation the CH groups of the dicarbollide ligands are in anti,anti-orientation with respect to the DME ligand, while any rotation of the dicarbollide ligand reduces the stability of the system. This makes it possible to rationalize the design of carborane ligands for the synthesis of gadolinium metallacarboranes on their base.

DOI： 10.3390/molecules26051321

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Publishing type：Research paper (scientific journal)  

DOI： 10.3390/catal10111321

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Publishing type：Research paper (scientific journal)   Publisher：American Chemical Society ({ACS})  

DOI： 10.1021/acs.oprd.0c00174

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Publishing type：Research paper (scientific journal)   Publisher：American Chemical Society ({ACS})  

DOI： 10.1021/acs.molpharmaceut.0c00478

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Publishing type：Research paper (scientific journal)   Publisher：Pharmaceutical Society of Japan  

DOI： 10.1248/cpb.c20-00434

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Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1002/cpps.108

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/cpps.108

Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

Inhibition of nicotinamide phosphoribosyltransferase (NAMPT) is an attractive therapeutic strategy for targeting cancer metabolism. So far, many potent NAMPT inhibitors have been developed and shown to bind to two unique tunnel-shaped cavities existing adjacent to each active site of a NAMPT homodimer. However, cytotoxicities and resistances to NAMPT inhibitors have become apparent. Therefore, there remains an urgent need to develop effective and safe NAMPT inhibitors. Thus, we designed and synthesized two close structural analogues of NAMPT inhibitors, azaindole–piperidine (3a)- and azaindole–piperazine (3b)-motif compounds, which were modified from the well-known NAMPT inhibitor FK866 (1). Notably, 3a displayed considerably stronger enzyme inhibitory activity and cellular potency than did 3b and 1. The main reason for this phenomenon was revealed to be due to apparent electronic repulsion between the replaced nitrogen atom (N1) of piperazine in 3b and the Nδ atom of His191 in NAMPT by our in silico binding mode analyses. Indeed, 3b had a lower binding affinity score than did 3a and 1, although these inhibitors took similar stable chair conformations in the tunnel region. Taken together, these observations indicate that the electrostatic enthalpy potential rather than entropy effects inside the tunnel cavity has a significant impact on the different binding affinity of 3a from that of 3b in the disparate enzymatic and cellular potencies. Thus, it is better to avoid or minimize interactions with His191 in designing further effective NAMPT inhibitors.

DOI： 10.3390/molecules25163633

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Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1002/anie.202002106

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Language：English   Publishing type：Research paper (scientific journal)  

Photodynamic therapy (PDT) is a non-invasive, selective, and cost-effective cancer therapy. We previously reported that thiophene-based organic D-π-A sensitizers consist of an electron-donating (D) moiety, a π-conjugated bridge (π) moiety, and an electron-accepting (A) moiety, and are readily accessible and stable templates for photosensitizers that could be used in PDT. In addition, acrylic acid acceptor-containing photosensitizers exert a high level of phototoxicity. This study was an investigation into 1) the possibility of increasing phototoxicity by introducing another carboxyl group or by replacing a carboxyl group with a pyridinium group, and 2) the importance of an alkene in the acrylic acid acceptor for phototoxicity. A review of the design, synthesis, and evaluation of sensitizers revealed that neither dicarboxylic acid nor pyridinium photosensitizers enhance phototoxicity. An evaluation of a photosensitizer without an alkene in the acrylic acid moiety revealed that the alkene was not indispensable in the pursuit of phototoxicity. The obtained results provided new insight into the design of ideal D-π-A photosensitizers for PDT.

DOI： 10.1016/j.bmc.2020.115558

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Publishing type：Research paper (scientific journal)   Publisher：{MDPI} {AG}  

DOI： 10.3390/cells9071615

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Chemical Society ({ACS})  

Targeting less abundant amino acid residues on the protein surface may realize site-selective protein modification of natural proteins. The relative hydrophobicity of tyrosine combined with the π-π stacking tendency of the aromatic rings results in generally low accessibility. In this study, site-selective protein modification was achieved by targeting surface-exposed tyrosine residues without using a genetic encoding system. Tyrosine residues were modified with N-methylated luminol derivative under single-electron transfer (SET) reaction conditions. Horseradish peroxidase (HRP)-catalyzed SET and electrochemically activated SET modified surface-exposed tyrosine residues selectively. N-Methylated luminol derivative modified tyrosine residues more efficiently than 4-arylurazole under tyrosine click conditions using HRP and electrochemistry. Tyrosine residues that are evolutionarily exposed only in the complementarity-determining region (CDR) of an antibody were selectively modified by tyrosine click reactions. CDR-modified antibodies were applied to in vivo imaging and antibody-drug conjugated (ADC).

DOI： 10.1021/acs.bioconjchem.0c00120

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Publishing type：Research paper (scientific journal)   Publisher：American Chemical Society ({ACS})  

DOI： 10.1021/acs.orglett.0c00910

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s10876-020-01773-z

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.apradiso.2019.109011

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.bbrc.2020.01.031

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1246/bcsj.20190270

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Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1002/asia.201901586

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Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1002/asia.201901429

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.matlet.2019.126832

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Language：English   Publishing type：Research paper (scientific journal)  

HIF-1 is regarded as a promising target for the drugs used in cancer chemotherapy, and creating readily accessible templates for the development of synthetic drug candidates that could inhibit HIF-1 transcriptional activity is an important pursuit. In this study, indeno[2,1-c]pyrazolones were designed as readily available synthetic inhibitors of HIF-1 transcriptional activity. Nine compounds were synthesized in 4-5 steps from commercially available starting materials. In evaluations of the ability to inhibit the hypoxia-induced transcriptional activity of HIF-1, compound 3c showed a higher level compared with that of known inhibitor, YC-1. The compound 3c suppressed HIF-1α protein accumulation without affecting the levels of HIF-1α mRNA.

DOI： 10.1016/j.bmc.2019.115207

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Publishing type：Research paper (scientific journal)   Publisher：Royal Society of Chemistry ({RSC})  

DOI： 10.1039/D0CC01403F

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Publishing type：Research paper (scientific journal)   Publisher：Royal Society of Chemistry ({RSC})  

DOI： 10.1039/C9OB02066G

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Publishing type：Research paper (scientific journal)   Publisher：Royal Society of Chemistry ({RSC})  

DOI： 10.1039/D0OB02027C

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Royal Society of Chemistry ({RSC})  

A laccase-catalysed tyrosine click reaction proceeded between the tyrosine modification reagent N-methyl luminol and tyrosine residues in peptides/proteins. Laccase-catalysed tyrosine-specific modification under mild reaction conditions (shaking at 37 °C) was more efficient than previously reported tyrosine click reactions using hemin, horseradish peroxidase (HRP) or electrochemistry.

DOI： 10.1039/D0OB00650E

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ROYAL SOC CHEMISTRY  

Tumor-binding peptides such as human epidermal growth factor receptor 2 (HER2)-binding peptides are attractive therapeutic and diagnostic options for cancer. However, the HER2-binding peptides (HBPs) developed thus far are susceptible to proteolysis and lose their affinity to HER2 in vivo. In this report, a method to create a HER2-binding fluctuation-regulated affinity protein (HBP-FLAP) consisting of a fibronectin type III domain (FN3) scaffold with a structurally immobilized HBP is presented. HBPs were selected by phage-library screening and grafted onto FN3 to create FN3-HBPs, and the HBP-FLAP with the highest affinity (HBP sequence: YCAHNM) was identified after affinity maturation of the grafted HBP. HBP-FLAP containing the YCAHNM peptide showed increased proteolysis-resistance, binding to HER2 with a dissociation constant (K-D) of 58 nM in ELISA and 287 nM in biolayer interferometry and specifically detects HER2-expressing cancer cells. In addition, HBP-FLAP clearly delineated HER2-expressing tumors with a half-life of 6 h after intravenous injection into tumor-bearing mice. FN3-based FLAP is an excellent platform for developing target-binding small proteins for clinical applications.

DOI： 10.1039/D0RA00427H

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Publishing type：Research paper (scientific journal)   Publisher：Royal Society of Chemistry ({RSC})  

<p>G-quadruplex-proximity protein labeling was performed using a hemin-parallel G-quadruplex (G4) complex. A tyrosine labeling reaction was accelerated in close proximity to the hemin with enhanced peroxidase activity by binding to parallel G4.</p>

DOI： 10.1039/D0CC02571B

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Publishing type：Research paper (scientific journal)   Publisher：Royal Society of Chemistry ({RSC})  

DOI： 10.1039/D0CC02921A

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Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1002/chem.201903531

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

<jats:p>Chemical labeling of proteins with synthetic low-molecular-weight probes is an important technique in chemical biology. To achieve this, it is necessary to use chemical reactions that proceed rapidly under physiological conditions (i.e., aqueous solvent, pH, low concentration, and low temperature) so that protein denaturation does not occur. The radical reaction satisfies such demands of protein labeling, and protein labeling using the biomimetic radical reaction has recently attracted attention. The biomimetic radical reaction enables selective labeling of the C-terminus, tyrosine, and tryptophan, which is difficult to achieve with conventional electrophilic protein labeling. In addition, as the radical reaction proceeds selectively in close proximity to the catalyst, it can be applied to the analysis of protein–protein interactions. In this review, recent trends in protein labeling using biomimetic radical reactions are discussed.</jats:p>

DOI： 10.3390/molecules24213980

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Publishing type：Research paper (scientific journal)   Publisher：Japan Society of Applied Physics  

DOI： 10.7567/1882-0786/ab4a5d

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Other Link： http://iopscience.iop.org/article/10.7567/1882-0786/ab4a5d/pdf

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.bmc.2019.05.013

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Language：English   Publishing type：Research paper (scientific journal)  

© 2018, Springer-Verlag GmbH Germany, part of Springer Nature. Folic acid (FA) has high affinity for the folate receptor (FR), which is limited expressed in normal human tissues, but over-expressed in several tumor cells, including glioblastoma cells. In the present work, a novel pteroyl–closo-dodecaborate conjugate (PBC) was developed, in which the pteroyl group interacts with FR, and the efficacy of boron neutron capture therapy (BNCT) using PBC was investigated. Thus, in vitro and in vivo studies were performed using F98 rat glioma cells and F98 glioma-bearing rats. For the in vivo study, boronophenylalanine (BPA) was intravenously administered, while PBC was administered by convection-enhanced delivery (CED)—a method for direct local drug infusion into the brain of rats. Furthermore, a combination of PBC administered by CED and BPA administered by intravenous (i.v.) injection was also investigated. In the biodistribution experiment, PBC administration at 6 h after CED termination showed the highest cellular boron concentrations (64.6 ± 29.6 µg B/g). Median survival time (MST) of untreated controls was 23.0 days (range 21–24 days). MST of rats administered PBC (CED) followed by neutron irradiation was 31 days (range 26–36 days), which was similar to that of rats administered i.v. BPA (30 days; range 25–37 days). Moreover, the combination group [PBC (CED) and i.v. BPA] showed the longest MST (38 days; range 28–40 days). It is concluded that a significant MST increase was noted in the survival time of the combination group of PBC (CED) and i.v. BPA compared to that in the single-boron agent groups. These findings suggest that the combination use of PBC (CED) has additional effects.

DOI： 10.1007/s00411-018-0765-2

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.bmc.2019.01.036

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Publishing type：Research paper (scientific journal)   Publisher：Royal Society of Chemistry ({RSC})  

DOI： 10.1039/C9CC05231C

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Publishing type：Research paper (scientific journal)  

© 2019 Society of Synthetic Organic Chemistry. All rights reserved. The chemical labeling of proteins with synthetic small compound is an important technique in chemical biology. To achieve reliable bioconjugation. rapid reactions in aqueous under physiological pH and mild temperature are required. In the attempt to covalently label native proteins, various biorthogonal chemical reactions targeting not only nucleophilic amino acid residues such as lysine and cysteine, but also tyrosine, tryptophan, methionine, N-and C-terminal positions have been developed. The radical protein labeling reaction proceeds rapidly even in intracellular and physiological environment, and high reactivity of radical species enables local reaction control on the nanometer scale. In this paper, we introduce our recent studies on the labeling of protein tyrosine residues via single electron transfer initiated radical reaction, especially using ruthenium photocatalyst. We found the protein labeling at tyrosine residues with small compounds such as N-acyl-N,N-phenylenediamine and l-methyl-4-aryl-urazole under the reaction condition using ruthenium photocatalyst and visible light irradiation. Target-selective labeling using ligand-conju-gated ruthenium photocatalysts, and target-selective-purification and labeling from protein mixture using catalyst-functionalized affinity beads were achieved.

DOI： 10.5059/yukigoseikyokaishi.77.463

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Publishing type：Research paper (scientific journal)   Publisher：Royal Society of Chemistry ({RSC})  

DOI： 10.1039/C9OB00584F

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Publishing type：Research paper (scientific journal)  

© 2019 The Royal Society of Chemistry. Raman spectroscopic measurements and theoretical calculation revealed that the Raman bands corresponding to the B-H stretching vibrations of two types of simple icosahedral boron clusters, ortho-carborane 3 and closo-dodecaborate 4 appeared at approximately 2450-2700 cm-1, and did not overlap with those of cellular components. Although ortho-carborane 3 possesses a possible property as a Raman probe, it was difficult to measure Raman imaging in the cell due to its poor water solubility. In fact, ortho-carborane derivative 6, which internally has an alkyne moiety, exhibited very weak Raman signals of the CC stretching and the B-H stretching vibrations were barely detected at a 400 ppm boron concentration in HeLa cells. In contrast, closo-dodecaborate derivatives such as BSH (5) were found to be a potential Raman imaging probe cluster for target molecules in the cell. BSH-conjugated cholesterol 7 (BSH-Chol) was synthesized and used in Raman imaging in cells. Raman imaging and spectral analysis revealed that BSH-based Raman tags provide a versatile platform for quantitative Raman imaging.

DOI： 10.1039/C9RA04228H

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Royal Society of Chemistry ({RSC})  

<p>Isoxazolyl-4-carboxylic acids underwent rhodium(<sc>iii</sc>)-catalysed carboxylate-directed C–H functionalizations with internal alkynes to produce pyranoisoxazolones, isoquinolines, and 5-alkenylisoxazoles controlled by oxidants.</p>

DOI： 10.1039/c9cc03283e

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DOI： 10.1016/j.bmc.2018.12.006

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DOI： 10.1021/acsomega.8b03114

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Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1002/asia.201801488

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DOI： 10.1002/chem.201886564

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier {BV}  

DOI： 10.1016/j.bmcl.2018.07.025

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Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1002/anie.201803549

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Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1002/ange.201803549

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier {BV}  

DOI： 10.1016/j.jorganchem.2018.02.026

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier {BV}  

DOI： 10.1016/j.tetlet.2018.02.020

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Publishing type：Research paper (scientific journal)   Publisher：American Chemical Society ({ACS})  

DOI： 10.1021/acs.orglett.7b03760

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DOI： 10.3390/molecules23092194

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Publishing type：Research paper (scientific journal)  

© 2018 IUPAC & De Gruyter. Maleimide-functionalized closo-dodecaborate (MID) and isothiocyanate-functionalized closo-dodecaborate (ISD) were synthesized from closo-dodecaborate via ring opening reaction of 1,4-dioxane-closo-dedecaborate complex 1 with ammonia. MID was found to possess highest conjugation efficacy to bovine serum albumin among three closo-dodecaborate derivatives, MID, ISD, and 1. The conjugation reaction of MID to human serum albumin (HSA) proceeded under PBS buffer conditions (pH 7.4). Boron distribution studies in colon 26 tumor-bearing mice revealed that HSA-MID was highly accumulated in tumor (23 ppm B), whereas boron concentrations in other organs such as liver, kidney and spleen were low (3~8 ppm B).

DOI： 10.1515/pac-2017-1104

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Publishing type：Research paper (scientific journal)   Publisher：Royal Society of Chemistry ({RSC})  

<p>Reactive oxygen species (ROS) and radical species generated by oxidative single-electron transfer (SET) catalysts induce local environmental oxidative reactions, resulting in protein inactivation and labelling in proximity to the catalysts.</p>

DOI： 10.1039/C8OB01484A

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Publishing type：Research paper (scientific journal)   Publisher：Royal Society of Chemistry ({RSC})  

DOI： 10.1039/C8CC02891E

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Publishing type：Research paper (scientific journal)  

© Georg Thieme Verlag Stuttgart New York. Fused-ring systems containing heterocycles are attractive templates for drug discovery. Biologically active 6-5-5+6 fused-ring systems that possess heterocycles are available, but these require a relatively large number of synthetic steps for preparation. Therefore, pyrazolofuropyrazine was designed as a 6-5-5+6 ring system template that incorporates ready accessibility for drug discovery. Pyrazolofuropyrazines were successfully constructed in only a few steps via one-pot S N Ar reaction/intramolecular C-H direct arylation. As a drug candidate, pyrazolofuropyrazine has earned a favorable LogP, although significant biological activity has yet to be established; the ready accessibility of pyrazolofuropyrazine template, however, offers an opportunity for the rapid development of promising new drug candidates.

DOI： 10.1055/s-0036-1591885

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Publishing type：Research paper (scientific journal)   Publisher：Wiley-Blackwell  

DOI： 10.1002/ejoc.201700789

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Publishing type：Research paper (scientific journal)   Publisher：Wiley-Blackwell  

DOI： 10.1002/ejic.201701118

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Publishing type：Research paper (scientific journal)   Publisher：Wiley-Blackwell  

DOI： 10.1002/ejic.201701117

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Subcellular localization of a photosensitizer is known to determine the therapeutic efficacy of photodynamic therapy (PDT). Cell membrane is an optimal target that promises an effective treatment outcome. OBJECTIVES: We previously developed a novel photosensitizer named porphyrus envelope (PE) by combining hemagglutinating virus of Japan envelope (HVJ-E) with lipidated protoporphyrin IX (PpIX lipid). In the current study, the cellular localization of PE and its ability to induce multiple anti-tumor effect were characterized. MATERIALS AND METHODS: The localization and uptake of PpIX lipid in cells were evaluated with confocal laser scanning microscopy and a cell-based fluorescent assay, respectively. The ability of PE to suppress the migration and proliferation of cancer cells was assessed using a scratch-wound assay. The synergistic effect of PDT and HVJ-E treatment was evaluated using an in vitro experiment with PC-3 cells. RESULTS: PE localized along the cell membrane and PpIX lipid accumulated selectively in the prostate cancer cells within 10min. Also, PE maintained the ability to undergo fusion and induce cancer cell death even after light irradiation at the dose for PDT. Incubation with PE resulted in delayed migratory and proliferative activity of PC-3 cells. PE-mediated PDT was twice as effective when cells were further incubated with PE following PDT. CONCLUSIONS: PE allows rapid drug delivery targeting the cell membrane. Because the cytotoxicity of HVJ-E was maintained, synergistic effect of HVJ-E and the photochemical reactions resulted in highly effective killing of prostate cancer cells in vitro and thus represents a promising treatment for prostate cancer.

DOI： 10.1016/j.pdpdt.2017.10.017

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Georg Thieme Verlag  

Functionalized isoxazoles are important as pharmaceuticals and agrochemicals. Generally, electrophilic aromatic substitution or generation of carbanions/electrophilic trapping approach is used to introduce functional groups into unsubstituted heteroaromatics. However, these approaches have not been simple to apply to unsubstituted isoxazoles due to their poor nucleophilicity and instability under basic conditions. Recently several approaches have been reported to overcome these problems. This review summarizes the functionalization of isoxazoles, including SEAr reactions and C-H direct arylations, towards the step-by-step multifunctionalization of isoxazoles. 1 Introduction 2 SEAr Reaction of Isoxazoles 3 Preparation of Isoxazolyl Anions and Their Use for the Synthesis of Functionalized Isoxazoles 4 Other C-C and C-N Bond Formations of Isoxazoles 5 Transition-Metal-Catalyzed C-H Direct Functionalization of Isoxazoles 6 Step-by-Step Multifunctionalization of Isoxazoles 7 Summary and Outlook.

DOI： 10.1055/s-0036-1588784

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Publishing type：Research paper (scientific journal)   Publisher：Wiley-Blackwell  

DOI： 10.1002/cbic.201700043

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Publishing type：Research paper (scientific journal)   Publisher：Wiley-Blackwell  

DOI： 10.1002/cbic.201600649

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japan Society for Laser Surgery and Medicine  

<p>Photodynamic therapy (PDT), which utilizes laser light and photosensitizer (PS), is now arising as a potential modality for minimally invasive prostate cancer therapy due to its cancer selectivity. However, cancer selectivity and drug accumulation efficiency have to be enhanced to eliminate unwanted side effects and to shorten the time requirement for shielding from light. Therefore, to accomplish high accumulation and selective delivery, we have focused on the drug delivering system of replication-deficient Sendai virus particle, hemagglutinating virus of Japan envelope (HVJ-E). We are currently investigating the therapeutic effectiveness of PDT with a novel photosensitizer named porphyrus envelope, which can be created by combining HVJ-E and PS called protoporphyrin IX (PpIX). This paper will discuss about the drug delivering mechanism of this novel photosensitizer.</p>

DOI： 10.2530/jslsm.jslsm-37_0028

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Publishing type：Research paper (scientific journal)  

© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim In this study, synthetically readily accessible, thiophene-based organic D–π–A sensitizers exerted high phototoxicity and are valuable as sensitizer templates for use in photodynamic therapy (PDT). Evaluation of the antitumor activity of our previously synthesized D–π–A sensitizers under photoirradiation revealed their potent phototoxicity. The structural requirements of the D–π–A sensitizer for phototoxicity were elucidated with the rapid synthesis of structurally simplified analogues and evaluation of their antitumor activity under photoirradiation. Our developed sensitizers mainly accumulated in mitochondria and damaged cancer cells through both Type I and Type II mechanisms. The developed new template could be useful in the future development of sensitizers that could fulfil the requirements for PDT.

DOI： 10.1002/ejoc.201701019

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Publishing type：Research paper (scientific journal)   Publisher：Royal Society of Chemistry ({RSC})  

DOI： 10.1039/C7CC01595J

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier {BV}  

DOI： 10.1016/j.jconrel.2016.07.017

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Language：Japanese   Publisher：(NPO)日本レーザー医学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：International Institute of Anticancer Research  

BACKGROUND: Malignant pleural mesothelioma (MPM) is a refractory cancer of the pleura caused by asbestos exposure. MPM is difficult to treat because it easily disseminates. Boron neutron capture therapy (BNCT) is a radiotherapy in which cancer cells that selectively take up (10)Boron-containing compounds are destroyed, and normal cells are uninjured. Hyaluronan (HA) is a ligand of cluster of differentiation 44 (CD44), that is expressed on MPM cells. MATERIALS AND METHODS: In order to enhance BNCT for MPM tumors, we developed a novel HA-containing (10)B (sodium borocaptate: BSH) formulation (HA-BND-S). We examined the efficacy of HA-BND-S using MPM cells and a mouse MPM model. RESULTS: HA-BND-S preferentially bound MPM cells dose-dependently, and increased the cytotoxicity of BNCT compared to BSH in vitro. HA-BND-S administration significantly increased the survival of MPM tumor-bearing mice compared to BSH at the same (10)B dosage in BNCT. CONCLUSION: Modifying BSH with HA is a promising strategy for enhancing the efficacy of BNCT for therapy of MPM.

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DOI： 10.1021/acs.chemrev.6b00342

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DOI： 10.1038/ncomms13491

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：International Phototherapy Association  

Background and Aims: There is an urgent need to develop an efficient strategy for the treatment of drug-resistant prostate cancer. Photodynamic therapy (PDT), in which low incident levels of laser energy are used to activate a photosensitizer taken up by tumor cells, is expected as a novel therapy for the treatment of prostate cancer because of the minimal invasive nature of PDT. The present study was designed to assess the efficacy of a novel vector approach combined with a conventional porphyrin-based photosensitizer.Materials and Methods: Our group focused on a non-viral vector (hemagglutinating virus of Japan envelope; HVJ-E) combined with protoporphyrin IX (PpIX) lipid, termed the porphyrus envelope (PE). It has been previously confirmed that HVJ-E has drug-delivering properties and can induce cancer-specific cell death. The PE (HVJ-E contained in PpIX lipid) was developed as a novel photosensitizer. In this study, the antitumor and PDT efficacy of the PE against hormoneantagonistic human prostate cancer cells (PC-3) were evaluated.Results and Conclusions: Our results demonstrated that, under specific circumstances, PDT using the PE was very effective against PC-3 cells. A novel therapy for drug-resistant prostate cancer based on this vector approach is eagerly anticipated.

DOI： 10.5978/islsm.16-OR-05

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Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.bmcl.2016.11.009

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley Online Library  

DOI： 10.1002/anie.201602416

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Publishing type：Research paper (scientific journal)  

DOI： 10.1002/anie.201608039

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Taylor \& Francis  

DOI： 10.1517/13543776.2016.1146252

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Publishing type：Research paper (scientific journal)  

DOI： 10.1039/C6OB02391F

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier {BV}  

The protoporphyron (PPIX)-lipid (PL-C17) liposomes were successfully prepared from the corresponding micelles by post-inserted method. Both the PL-C17 micelles and liposomes were distributed in plasma membrane and cytoplasm after incubation of the cells with PL-C17 liposomes for 1 h. They translocated from plasma membrane into a certain organelle in the cells after incubation in the photosensitizer-free medium. Higher photo-cytotoxicity was observed in the PL-C17 micelles and liposomes localized in plasma membrane in comparison with those localized in the cytoplasm under light irradiation. The LDH assay revealed that cytopathic damages of the plasma membrane were observed in the PL-C17 micelles and liposomes highly localized in plasma membrane. The fluorescent intensity of the calcein-encapsulating DOPC liposomes post-inserted with PL-C17 increased after light irradiation, suggesting that the membrane disruption is possibly caused by oxidation of membrane lipids with ROS generated from photosensitizers and affects the photo-cytotoxicity in PDT.

DOI： 10.1016/j.bmc.2015.11.001

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier {BV}  

DOI： 10.1016/j.jorganchem.2015.05.029

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

To understand the mechanism of cell death induced by boron neutron capture reaction (BNCR), we performed proteome analyses of human squamous tumor SAS cells after BNCR. Cells were irradiated with thermal neutron beam at KUR after incubation under boronophenylalanine (BPA)(+) and BPA(-) conditions. BNCR mainly induced typical apoptosis in SAS cells 24 h post-irradiation. Proteomic analysis in SAS cells suggested that proteins functioning in endoplasmic reticulum, DNA repair, and RNA processing showed dynamic changes at early phase after BNCR and could be involved in the regulation of cellular response to BNCR. We found that the BNCR induces fragments of endoplasmic reticulum-localized lymphoid-restricted protein (LRMP). The fragmentation of LRMP was also observed in the rat tumor graft model 20 hours after BNCf treatment carried out at the National Nuclear Center of the Republic of Kazakhstan. These data suggest that dynamic changes of LRMP could be involved during cellular response to BNCR. (C) 2015 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.apradiso.2015.08.001

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Publishing type：Research paper (scientific journal)   Publisher：Elsevier {BV}  

DOI： 10.1016/j.bmcl.2015.04.088

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Publishing type：Research paper (scientific journal)   Publisher：Wiley Online Library  

DOI： 10.1002/tcr.201402100

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Publishing type：Research paper (scientific journal)  

DOI： 10.3769/radioisotopes.64.47

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Publishing type：Research paper (scientific journal)   Publisher：ACS Publications  

DOI： 10.1021/acschembio.5b00440

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Language：English   Publishing type：Research paper (international conference proceedings)   Publisher：SPIE-INT SOC OPTICAL ENGINEERING  

Traditional treatment options for prostate cancer are insufficient to cure advanced drug-resistant prostate cancer. Thus, as an alternative form of cancer therapy, photodynamic therapy (PDT) has become the main subject of intense investigation as a possible treatment modality. In this study, ultraviolet-inactivated viral vector, called hemagglutinating virus of Japan envelope (HVJ-E) was utilized to establish an effective delivery system for photosensitizer. Lipidated protoporphyrin IX (PpIX lipid) was inserted in HVJ-E by centrifugation to create a new drug delivering system that allows selective accumulation of photosensitizers in cancer cells. To study in vitro drug release mechanism of porphyrus envelope, the ultra-high voltage electron microscope tomography was applied. Next, to evaluate the photodynamic efficiency of porphyrus envelope for hormone antagonistic prostate cancer cells (PC-3), uptake of porphyrus envelope derived PpIX lipid and PpIX induced from exogenously administered precursor of 5-aminolevulinic acid hydrochloride (5-ALA) were compared by measuring fluorescence intensity of PpIX. Finally, to evaluate the efficacy of porphyrus envelope-PDT, laser light at a wavelength of 405 nm was irradiated to PC-3 cells. As a result, incorporation of porphyrus envelope-derived PpIX lipid occurred via membrane fusion, giving the highest fluorescence intensity when compared to 5-ALA-induced PpIX. Also, results from PDT experiment revealed the 28.6 x 10(3)-fold and 206-fold increase in therapeutic efficacy when compared to those of PDT using 5-ALA induced PpIX and PpIX lipid, respectively. Our findings suggest how porphyrus envelope can induce efficient accumulation of PpIX lipid, which can enhance the therapeutic efficacy of PDT against hormone antagonistic prostate cancer.

DOI： 10.1117/12.2080692

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© 2014 American Chemical Society. Ligand-directed Ru(bpy)3 photocatalysts induce chromophore-assisted light inactivation (CALI) of target proteins under visible light irradiation in vitro and within cells. Here, histidine, methionine, and tryptophan residues were oxidized by the singlet oxygen (1O2) generated by Ru(bpy)3 with light. The addition of a tyrosyl radical trapper (TRT), such as N'-acyl-N,N-dimethyl phenylenediamine, inhibited peptide/protein oxidation and induced labeling on the tyrosine residue. This mechanistic study suggests that TRT scavenges 1O2, concomitant with the coupling reaction to the tyrosyl radical generated by Ru(bpy)3. Both CALI and labeling can be regulated by the Ru(bpy)3 photocatalysts in the absence or presence of TRT. Ligand-conjugated Ru(bpy)3 photocatalysts (local environmental single-electron transfer catalysts: LSCs) were used not only for target-selective protein labeling, but also for protein knockdown by CALI.

DOI： 10.1021/bc500518t

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DOI： 10.1515/pac-2014-0911

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Publishing type：Research paper (scientific journal)   Publisher：ACS Publications  

DOI： 10.1021/acs.jmedchem.5b00035

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Publishing type：Research paper (scientific journal)   Publisher：Royal Society of Chemistry  

DOI： 10.1039/c5nj00856e

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Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.bmcl.2014.12.005

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Publishing type：Research paper (scientific journal)   Publisher：{\copyright} Georg Thieme Verlag  

DOI： 10.1055/s-0034-1380462

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Publishing type：Research paper (scientific journal)  

Background: In the clinic, it is often very difficult to treat drug-resistant advanced prostate cancer by conventional treatments. Photodynamic therapy (PDT) is a minimally invasive treatment that takes advantage of photochemical reactions between a photosensitizer and light. On the basis of several of its key characteristics, PDT is considered to be a promising novel method for treating drug-resistant prostate cancer. Objectives: For effective treatment of drug-resistant prostate cancer, we developed a novel agent termed porphyrus envelope, which was produced from PpIX lipid and hemagglutinating virus of Japan envelope (HVJ-E). Materials and methods: We inserted PpIX lipid into HVJ-E by centrifugation, and used the resultant porphyrus envelope in PDT of two drug-resistant prostate cancer cell lines, PC-3 and PC-3-DR. Results: Porphyrus envelope enhanced uptake of PpIX, and cytotoxicity of PDT, relative to free PpIX lipid or PpIX induced by 5-ALA. Conclusion: PDT using porphyrus envelope has potential as a method for treating drug-resistant prostate cancer. © 2013.

DOI： 10.1016/j.pdpdt.2013.10.001

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Language：English   Publishing type：Research paper (scientific journal)  

INTRODUCTION: We previously demonstrated that a family predisposed to lung cancer harbored a V843I substitution in the epidermal growth factor receptor (EGFR) protein. We report here the further characterization of this mutant EGFR protein in the context of tumorigenicity and resistance to tyrosine kinase inhibitors (TKIs) of EGFR activity. METHODS: Phosphorylation of EGFR and downstream signaling proteins of lung adenocarcinoma cell lines with EGFR mutations was assayed by flow cytometry. Susceptibility to TKIs of these cell lines, with or without suppression of mutant EGFR expression by small inhibitory RNA (siRNA), was investigated using a cellular viability assay. Furthermore, protein modeling was used to predict TKI binding to EGFR protein carrying the V843I mutation. RESULTS: Phosphorylation of EGFR and downstream signaling proteins was elevated upon transfection with an EGFR gene with the V843I. Although the cell line with V843I + L858R demonstrated resistance to EGFR-TKIs, the cells became susceptible to TKIs upon incubation with siRNA specific for the V843I allele. The structural analysis suggested that TKI binding to EGFR would be sterically hindered by Arg841 in the double-mutant (V843I + L858R) EGFR. CONCLUSIONS: The V843I mutation contributes to tumorigenesis by promoting phosphorylation of EGFR and its downstream signaling proteins. This mutation also appears to provide resistance to EGFR-TKIs through structural modification of EGFR. These features are comparable with those in EGFR T790M mutation, suggesting that cases with germ-line V843I or T790M mutations could be categorized as a class of familial lung cancer syndrome with resistance to EGFR-TKIs.

DOI： 10.1097/JTO.0000000000000241

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Language：Japanese   Publishing type：Research paper (scientific journal)  

CiNii Books

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Publishing type：Research paper (scientific journal)  

DOI： 10.1039/c3dt52828f

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DOI： 10.1016/j.bmc.2014.07.003

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DOI： 10.1039/c4cc04344h

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Society of Photopolymer Science and Technology  

CiNii Books

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Publishing type：Research paper (scientific journal)  

DOI： 10.1039/c4cc01283f

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Language：Japanese   Publisher：(公社)日本薬学会  

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DOI： 10.4155/FMC.13.48

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DOI： 10.1016/j.bmc.2012.12.039

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DOI： 10.1016/j.jorganchem.2013.04.007

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DOI： 10.1248/yakushi.13-00222-F

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DOI： 10.1016/j.bmcl.2012.11.081

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DOI： 10.1002/anie.201303831

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DOI： 10.1002/cmdc.201200502

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DOI： 10.1021/ml3004632

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Language：English   Publishing type：Research paper (scientific journal)  

Mercaptoundecahydrododecaborate (BSH)-encapsulating 10% distearoyl boron lipid (DSBL) liposomes were developed as a boron delivery vehicle for neutron capture therapy. The current approach is unique because the liposome shell itself possesses cytocidal potential in addition to its encapsulated agents. BSH-encapsulating 10% DSBL liposomes have high boron content (B/P ratio: 2.6) that enables us to prepare liposome solution with 5000 ppm boron concentration. BSH-encapsulating 10% DSBL liposomes displayed excellent boron delivery efficacy to tumor: boron concentrations reached 174, 93, and 32 ppm at doses of 50, 30, and 15 mg B/kg, respectively. Magnescope was also encapsulated in the 10% DSBL liposomes and the real-time biodistribution of the Magnescope-encapsulating DSBL liposomes was measured in a living body using MRI. Significant antitumor effect was observed in mice injected with BSH-encapsulating 10% DSBL liposomes even at the dose of 15 mg B/kg; the tumor completely disappeared three weeks after thermal neutron irradiation ((1.5-1.8) × 10(12) neutrons/cm(2)). The current results enabled us to reduce the total dose of liposomes to less than one-fifth compared with that of the BSH-encapsulating liposomes without reducing the efficacy of boron neutron capture therapy (BNCT).

DOI： 10.1021/bc300527n

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DOI： 10.1055/s-0031-1290376

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DOI： 10.1039/c2md20134h

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DOI： 10.1021/ja211092q

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DOI： 10.1016/j.bmcl.2012.06.084

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DOI： 10.1117/1.JBO.17.7.078002

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DOI： 10.1351/PAC-CON-11-11-03

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DOI： 10.1039/c1ob06500a

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DOI： 10.1002/chem.201102710

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DOI： 10.1016/j.tetlet.2010.11.082

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DOI： 10.1039/c1ob05952a

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DOI： 10.1021/ic2002095

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DOI： 10.1071/CH11295

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DOI： 10.1002/hc.20670

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Publishing type：Research paper (scientific journal)   Publisher：Taylor \& Francis  

DOI： 10.1517/13543776.2011.547477

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DOI： 10.1016/j.apradiso.2011.04.004

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Language：English   Publishing type：Research paper (scientific journal)  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

closo-Dodecaborate lipid liposomes were developed as new vehicles for boron delivery system (BDS) of neutron capture therapy. The current approach is unique because the liposome shell itself possesses cytocidal potential in combination with neutron irradiation. The liposomes composed of closo-dodecaborate lipids DSBL and DPBL displayed high cytotoxicity with thermal neutron irradiation. The closo-dodecaborate lipid liposomes were taken up into the cytoplasm by endocytosis without degradation of the liposomes. Boron concentration of 22.7 ppm in tumor was achieved by injection with DSBL-25% PEG liposomes at 20 mg B/kg. Promising BNCT effects were observed in the mice injected with DSBL-25% PEG liposomes: the tumor growth was significantly suppressed after thermal neutron irradiation (1.8 x 10(12) neutrons/cm(2)). (c) 2010 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.bmc.2010.03.050

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DOI： 10.1039/c0md00115e

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DOI： 10.1021/ja104739t

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DOI： 10.1021/ja9109055

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DOI： 10.1002/cmdc.201000112

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DOI： 10.1016/j.bmcl.2009.12.037

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DOI： 10.1002/chem.200901532

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

A series of 4-anilinoquinazolines with C-C multiple bond substitutions at the 6-position were synthesized and investigated for their potential to inhibit epidermal growth factor receptor (EGFR) tyrosine kinase activity. Among the compounds synthesized, alkyne 6d and allenes 7d and 7f significantly inhibited EGFR tyrosine kinase activity. These compounds inhibited EGF-mediated phosphorylation of EGFR in A431 cells, resulting in cell-cycle arrest and apoptosis induction. The C-C multiple bonds substituted at the C-6 position of the anilinoquinazoline framework were essential for the significant inhibitory activity. Compounds with long carbon chains (n = 3-6), such as 6c-f, 7c-f, 11, and 12, displayed prolonged inhibitory activity. (C) 2009 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.bmc.2009.11.035

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DOI： 10.1016/j.heares.2010.08.015

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Language：Japanese   Publisher：The Pharmaceutical Society of Japan  

The cell-killing effect of boron neutron capture therapy (BNCT) is due to the nuclear reaction of two essentially nontoxic species, boron-10 (¹⁰B) and thermal neutrons, whose destructive effect is well observed in boron-loaded tissues. High accumulation and selective delivery of boron into tumor tissue are the most important requirements to achieve efficient neutron capture therapy of cancers. This review focuses on liposomal boron delivery system (BDS) as a recent promising approach that meet these requirements for BNCT. BDS involves two strategies: (1) encapsulation of boron in the aqueous core of liposomes and (2) accumulation of boron in the liposomal bilayer. In this review, recent development of liposomal boron delivery system is summarized.<br>

DOI： 10.1248/yakushi.130.1687

CiNii Books

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Other Link： https://jlc.jst.go.jp/DN/JALC/00359735769?from=CiNii

Publishing type：Research paper (scientific journal)  

DOI： 10.1039/c005032f

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Language：Japanese   Publisher：THE JAPAN SOCIETY OF DRUG DELIVERY SYSTEM  

The cell-killing effect of boron neutron capture therapy (BNCT) is due to the nuclear reaction of two essentially nontoxic species, boron-10 (¹⁰B) and thermal neutrons, whose destructive effect is well observed in boron-loaded tissues. Therefore, the high accumulation and selective delivery of ¹⁰B into the tumor tissue are the most important requirements to achieve efficient neutron capture therapy for cancer. BNCT has been applied clinically for the treatment of malignant brain tumors, malignant melanoma, head and neck cancer, and hepatoma using two boron compounds:sodium borocaptate (¹⁰BSH) and L-p-boronophenylalamine (L-¹⁰BPA). These low molecule compounds are easily cleared from the cancer cells and blood, therefore, high accumulation and selective delivery of boron compounds into tumor tissues are most important to achieve effective BNCT and to avoid damage of adjacent healthy cells. Recently, much attention has been focused on liposomal drug delivery system as an attractive intelligent technology of targeting and controlled release of ¹⁰B compounds.<BR>In this review, recent development of liposomal boron delivery system is summarized.

DOI： 10.2745/dds.25.474

CiNii Books

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Other Link： https://jlc.jst.go.jp/DN/JALC/00358080945?from=CiNii

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DOI： 10.1016/j.canlet.2010.03.010

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DOI： 10.1039/c0nj00046a

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

A new method that utilizes the click cycloaddition reaction to functionalize B(12)H(11)SH(2-) (BSH) with organic molecules was investigated. S,S-Dipropargyl-SB(12)H(11)(-) (1) and S-propargyl-SB(12)H(11)(2-) (4) were prepared from [(CH(3))(4)N](2)B(12)H(11)SH and [(CH(3))(4)N](2)B(12)H(11)S(CH(2))(2)CN (2) with propargyl bromide, respectively. Compound 1 or 4 reacted with various azides with mediation by Cu(II) ascorbate to give the corresponding bis-triazolo BSH derivatives (1-) or monotriazole BSH derivatives (2-), respectively, in excellent yields. The click cycloaddition reaction is very useful not only for the synthesis of various BSH-containing organic compounds for boron neutron capture therapy (BNCT) but also for the visualization of boron clusters in cells. We succeeded in the click cycloaddition reaction of compound 1 with Alexa Fluor 488 azide dye and found that 1 accumulated not in the cytoplasm but in the nuclei of HeLa cells.

DOI： 10.1021/ic902033c

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

A series of 1-[4-(N-benzylamino)phenyl]-3-phenylurea derivatives 2a-r were synthesized as HIF-1 alpha inhibitors. Among the compounds synthesized, compound 2k was found to be a potent inhibitor against HIF-1 alpha accumulation under hypoxic condition and inhibited the hypoxia-induced HIF-1 transcriptional activity in HEK293 cells (IC(50) = 7.2 mu M). Furthermore, compound 2k suppressed the hypoxia-induced secretion of VEGF in HeLa cells (IC(50) = 15 mu M). (C) 2009 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.bmcl.2009.04.122

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

High accumulation and selective delivery of boron into tumor tissues are the most important requirements to achieve efficient neutron capture therapy of cancers. We focused on liposomal boron delivery system in order to achieve a large amount of boron delivery to tumor. We synthesized the double-tailed boron cluster lipid 4c according to our reported procedure with modification. Size distribution of liposomes prepared from the boron cluster lipid 4c, DMPC, PEG-DSPE, and cholesterol was determined as 100 nm in diameter by an electrophoretic light scattering spectrophotometer. A high level of 1013 concentration (22 ppm) was observed in tumor tissue at 24 h after the administration of boron liposomes. (C) 2009 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.apradiso.2009.03.091

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ROYAL SOC CHEMISTRY  

Boron-conjugated 4-anilinoquinazolines were designed and synthesized as inhibitors of EGFR tyrosine kinase with possible covalent bond interactions between the boron atom and the nucleophilic groups of the EGFR kinase domain. Among the compounds synthesized, compounds 6c, 7b, and 7d reduced the EGF-mediated phosphorylation of EGFR tyrosine kinase and its downstream kinases including ERK and Akt in A431 cells. The cell growth was inhibited by these compounds through arrest of G1 cell cycle, which induced apoptosis. A time-dependent in vitro preincubation assay demonstrated the irreversible inhibition of compound 7d against EGFR tyrosine kinase. Quantum mechanical docking simulation revealed that the boronic acid moiety of compound 7d formed a covalent B-O bond with Asp800 in addition to hydrogen bonds with Asp800 and Cys797, which may cause the prolonged inhibition of compound 7d toward EGFR tyrosine kinase.

DOI： 10.1039/b909504g

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

A series of boron peptides 11, 13, 15 and 17 were designed and synthesized as proteasome inhibitors based on the structure of Belactosin C. Matteson homologation was a key step in the synthesis of the boron peptides. Compounds 11a and 13 showed significant inhibition of 20S proteasome chymotrypsin-like (beta 5) activity (IC(50) = 0.28 and 0.51 mu M, respectively). Furthermore, like PS-341, compound 11a increased the G2/M cell distribution. A biparametric cytofluorimetric analysis with FITC-labeled annexin V and propidium iodide showed induction of apoptosis by compound 11a at &gt;1 mu M concentrations of compound. (C) 2009 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.bmcl.2009.04.103

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

o-Carboranyl aminoalcohols were synthesized using a standard Mannich reaction, and were tested for their anticancer properties using an in vitro test for CT26 cancer cells. The polar periphery of the aminoalcohols benefited from the high boron uptake in CT26 cancer cells with low toxicity, indicating their potential as BNCT agents. (C) 2009 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tetlet.2009.03.207

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Language：English   Publishing type：Part of collection (book)   Publisher：ELSEVIER ACADEMIC PRESS INC  

Tumor cell destruction in boron neutron capture therapy (BNCT) is due to the nuclear reaction between B-10 and thermal neutrons. The thermal neutrons have an energy of 0.025 eV, clearly below the threshold energy required to ionize tissue components. However, neutron capture by B-10 produces lithium ion and helium (alpha-partictes), which are high linear energy transfer (LET) particles, and dissipate their kinetic energy before traveling one cell diameter (5-9 mu m) in biological tissues, ensuring their potential for precise cell killing. BNCT has been applied clinically for the treatment of malignant brain tumors, malignant melanoma, head and neck cancer, and hepatoma using two boron compounds: sodium borocaptate ((Na2B12H11SH)-B-10; (Na2BSH)-B-10) and L-P-boronophenylalanine (L-(10)BPA). These low molecular weight compounds are cleared easily from the cancer cells and blood. Therefore, high accumulation and selective delivery of boron compounds into tumor tissues are most important to achieve effective BNCT and to avoid damage of adjacent healthy cells. Much attention has been focused on the liposomal drug delivery system (DDS) as an attractive, intelligent technology of targeting and controlled release of B-10 compounds. Two approaches have been investigated for incorporation of B-10 into liposomes: (1) encapsulation of B-10 compounds into liposomes and (2) incorporation of B-10-conjugated lipids into the liposomal bilayer. Our laboratory has developed boron ion cluster lipids for application of the latter approach. In this chapter, our boron lipid liposome approaches as well as recent developments of the liposomal boron delivery system are summarized.

DOI： 10.1016/S0076-6879(09)65010-2

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Royal Society of Chemistry  

N-Benzylanilines were designed and synthesized as vascular endothelial growth factor ( VEGF)-2 inhibitors using de novo drug design systems based on the X-ray structure of VEGFR-2 kinase domain. Among compounds synthesized, compound 3 showed the most potent inhibitory activity toward VEGFR-2 (KDR) tyrosine kinase and its IC(50) value was 0.57 mu M.

DOI： 10.1039/B719959G

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Publishing type：Research paper (scientific journal)   Publisher：{\copyright} Georg Thieme Verlag Stuttgart{\textperiodcentered} New York  

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Publisher：Springer  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

A series of indenopyrazoles 8 and 9 were designed and synthesized as EGFR tyrosine kinase inhibitors by in silico high-throughput screening. Compounds 8b and 8d showed significant inhibition of A431 cell growth (GI(50) = 0.062 and 0.057 mu M, respectively). Compounds 8b and 9a showed inhibitory activity toward both EGFR and VEGFR-2 (KDR) tyrosine kinases, whereas 8d inhibited VEGFR-2 tyrosine kinase, exclusively. (C) 2007 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.bmcl.2007.10.084

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Synthesis, structural characterization, and biological activity studies of o-carborane-substituted 1,3,5-triazines (9-12) containing polar functional groups such as methoxyethyl and t-butoxycarbonylmethyl amine units are described. De-methylation of di(methoxyethyl)amine functionalized triazines 9 and 10 resulted in the production of di(hydroxyethyl)amine derivatives 13 and 14. NNIR (H-1 and C-13) and X-ray crystallographic studies confirmed the structures derived from the sequential o-carborane substitution on the 1,3,5-triazine core. Preliminary in vitro studies revealed that compounds 9, 10, 13, and 14, despite their low cytotoxicity, accumulated at high levels in B-16 melanoma cells. (c) 2007 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tetlet.2007.10.145

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ROYAL SOC CHEMISTRY  

Mono- and 1,3-disubstituted allenes were synthesized from the corresponding propargylamines via palladium-catalysed hydride-transfer reaction. In the current transformation, propargylic amines can be handled as allenyl anion equivalents and introduced into various electrophiles to be transformed into allenes under palladium-catalyzed conditions.

DOI： 10.1039/b718298h

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：PHARMACEUTICAL SOC JAPAN  

Boron neutron capture therapy (BNCT) is a binary cancer treatment based on the nuclear reaction of two essentially nontoxic species, B-10 and thermal neutrons. High accumulation and selective delivery of boron into tumor tissue are the most important requirements to achieve efficient neutron capture therapy of cancers. This review focuses on the liposomal boron delivery system (BDS) as a recent promising approach that meets these requirements for BNCT. BDS involves two strategies: (1) encapsulation of boron in the aqueous core of liposomes and (2) accumulation of boron in the liposomal bilayer. Various boronated liposomes have been developed and significant boron accumulation into tumor tissue with high tumor/blood boron ratios has been achieved by BDS.

DOI： 10.1248/yakushi.128.193

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-V C H VERLAG GMBH  

A series of allenic quinazolines were synthesized as receptor tyrosine kinase inhibitors by using a simple protocol for palladium-catalyzed allene transformation. Among the compounds synthesized, two allenic 4-anilinoquinazolines selectively suppressed epidermal growth factor receptor (EGFR) tyrosine kinase activity in vitro. According to immunoblot analysis, the allenic quinazolines inhibited the EGF-mediated phosphorylation of EGFR and its downstream kinases in A431 cells. Furthermore, one of these allenic quinazolines decreased the proliferation of A437 cells through the induction of cell-cycle arrest and apoptosis.

DOI： 10.1002/cmdc.200800073

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Addition-cyclization of chloroform to ortho-alkynylaldimines proceeded in the presence of PdCl(2)(PPh(3))(2)/dppe or Pd(2)dba(3)center dot CHCl(3)/ dppe at 100 degrees C to afford the corresponding 1-(trichloromethyl)-1,2-dihydi-oisoquinolines in good to high yields. (c) 2008 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tetlet.2008.02.156

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMEDICAL RESEARCH PRESS LTD  

Based on studies of hypophosphatasia, which is a systemic skeletal disorder resulting from tissue-nonspecific alkaline phosphatase (TNSALP) deficiency, TNSALP was suggested to be indispensable for bone mineralization. Recently, we demonstrated that there was a significant difference in bone mineral density (BMD) among haplotypes, which was lowest among TNSALP (787T [Tyr246Tyr]) homozygotes, highest among TNSALP (787T &gt; C [Tyr246His]) homozygotes, and intermediate among heterozygotes. To analyze protein translated from the TNSALP gene 787T &gt; C, we performed the biosynthesis of TNSALPs using TNSALP cDNA expression vectors. TNSALP (787T) and TNSALP (787T &gt; C) were synthesized similarly as a high-mannose-type 66-kDa form, becoming an 80-kDa form. Expression of the human 787T &gt; C TNSALP gene using the cultured mouse marrow stromal cell line ST2 demonstrated that the protein translated from 787T &gt; C exhibited an ALP-specific activity similarly to that of 787T. Interestingly, the Km value for TNSALP in ST2 cells transfected with the 787T &gt; C TNSALP gene was decreased significantly compared to that of cells carrying the 787T gene (P &lt; 0.01). These results suggest that the significant difference in Km values between the proteins translated from 787T &gt; C and 787T may contribute to regulatory effects on bone metabolism.

DOI： 10.2220/biomedres.29.213

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Language：Japanese   Publisher：The Japanese Society of Hematology  

DOI： 10.11406/rinketsu.49.294

CiNii Books

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Other Link： http://search.jamas.or.jp/link/ui/2008238080

Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

CuBr-catalyzed homologation of alk-1-ynes 1 with paraformaldehyde and N,N-diisopropylamine (or N,N-dicyclohexylamine) was accelerated by microwave irradiation at 150 degrees C to afford the corresponding allenes 2 in good to high yields in 1-10 min. Bisalkynes 5 and 7 were also converted to the corresponding bisallenes 6 and 8 in 63% and 61% yields, respectively, under the current condition. (C) 2008 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tetlet.2008.10.019

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JOHN WILEY & SONS INC  

The phase-vanishing (PV) method is based on spontaneous reaction controlled by diffusion of reagents into fluorous media, such as perfluorohexanes (FC-72) and polyperfluoroethers. Thus, the original PV reaction utilizes a triphasic test tube method composed of a bottom reagent phase, a middle fluorous phase, and a top substrate phase. In such a triphasic system, the fluorous phase acts as a liquid membrane to transport the bottom reagents to the top organic phase containing substrates. In the end, the bottom layer disappears and two phases remain. Since the first demonstration of the PV method by bromination of alkenes with molecular bromine, a number of applications have been developed thus far. These include halogenation of alcohols with SOBr(2) and PBr(3), demethylation of methoxyarenes with BBr(3), cyclopropanation of alkenes by CH(2)I(2)-AlEt(3), and Friedel-Crafts acylation of aromatic compounds with SnCl(4). A fluorous triphasic U-tube method is effective for chlorination of alcohols based on lighter (less dense) reagents such as SOCl(2), and PCl(3). A system using a solution containing reagents as a bottom phase is useful for oxidation with m-CPBA, which may be defined as a new category for the "extractive PW method. Recent advances include a "quadraphasic" PV method, in which an aqueous 11 scavenger 11 phase is added to the original triphasic PV method to remove acidic by-products. (c) 2008 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 8: 351-363; 2008: Published online in Wiley InterScience (www.interscience.wiley.com) DOI 10.1002/tcr.20161

DOI： 10.1002/tcr.20161

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Language：Japanese   Publishing type：Research paper (international conference proceedings)  

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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Language：English   Publishing type：Research paper (scientific journal)  

High accumulation and selective delivery of boron into tumor tissues are the most important requirements to achieve efficient neutron capture therapy of cancers. We focused on liposomal boron delivery system to achieve a large amount of boron delivery to tumor. We succeeded in the synthesis of the double-tailed boron cluster lipids 4a-c and 5a-c, which has a B12H 11S-moiety as a hydrophilic function, by S-alkylation of B 12H11SH with bromoacetyl and chloroacetocarbamate derivatives of diacylglycerols. Size distribution of liposomes prepared from the boron cluster lipid 4b, dimyristoylphosphatidylcholine, polyethyleneglycol- conjugated distearoylphosphatidylethanolamine, and cholesterol was determined as 100 nm in diameter by an electrophoretic light scattering spectrophotometer. Calcein-encapsulation experiments revealed that these boronated liposomes are stable at 37°C in fetal bovine serum solution for 24 h. © 2008 Humana Press Inc.

DOI： 10.1007/s12030-008-9000-6

Scopus

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Dodecaborate-conjugated cholesterols 3a-c were synthesized for liposomal boron delivery systems in neutron capture therapy. The current synthesis is based on the S-alkylation protocol of the cyanoethyl-protected BSH with alkyl halides. The dodecaborate-conjugated cholesterol 3a liposome, which was prepared from dimyristoylphosphatidylcholine (DMPC), cholesterol, dodecaborate-conjugated cholesterol 3a, and polyethyleneglycol-conjugated distearoylphosphatidylethanolamine (PEG-DSPE) (1:0.5:0.5:0.1), exhibited higher cytotoxicity than BSH at the same boron concentration and IC50 values of the 3a liposome and BSH toward colon 26 cells were estimated as 25 and 78 ppm of boron concentration, respectively. (c) 2007 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tetlet.2007.03.043

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

[GRAPHIC]
We succeeded in the synthesis of the double-tailed boron cluster lipids 4a-c and 5a-c, which have a B12H11S moiety as a hydrophilic function, by S-alkylation of B12H11SH (BSH) with bromoacetyl and chloroacetocarbamate derivatives of diacylglycerols for a liposomal boron delivery system on neutron capture therapy. Calcein encapsulation experiments revealed that the liposomes, prepared from the boron cluster lipid 4b, DMPC, PEG-DSPE, and cholesterol, are stable at 37 degrees C in FBS solution for 24 h.

DOI： 10.1021/ol062840+

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

The nido-carborane lipid 2 as a double-tailed boron lipid was synthesized from heptadecanol in five steps. The lipid 2 formed stable liposomes at 25% molar ratio toward DSPC with cholesterol. Transferrin was able to be introduced on the surface of boron liposomes (Tf(+)-PEG-CL liposomes) by the coupling of transferrin to the PEG-CO2H moieties of Tf(-)-PEG-CL liposomes. The biodistribution of Tf(+)-PEG-CL liposomes, in which I-125-tyraminyl inulins were encapsulated, showed that Tf(+)- PEG-CL liposomes accumulated in tumor tissues and stayed there for a sufficiently long time to increase tumor/blood concentration ratio, although Tf(-)-PEG-CL liposomes were gradually released from tumor tissues with time. A boron concentration of 22 ppm in tumor tissues was achieved by the injection of Tf(+)-PEG-CL liposomes at 7.2 mg/kg body weight boron in tumor-bearing mice. After neutron irradiation, the average survival rate of mice not treated with Tf(+)-PEG-CL liposomes was 21 days, whereas that of the treated mice was 31 days. Longer survival rates were observed in the mice treated with Tf(+)-PEG-CL liposomes; one of them even survived for 52 days after BNCT.

DOI： 10.1021/bc060064k

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Publishing type：Research paper (scientific journal)   Publisher：Nihon Yakugakkai  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Allenic quinazolines 13a-h were designed as mimics of Tarceva, which is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, and synthesized from the corresponding 4-(iodoanilino)quinazolines or 4-(iodophenoxy)quinazolines with N,N-dicyclohexylprop-2-ynylamine by the Sonogashira coupling followed by palladium-catalyzed hydride-transfer reaction. Cell growth inhibition of 13a-h toward A431, Kato III, SKBR3, and HepG2 was examined. Among the compounds synthesized, 13a showed a similar cell growth inhibition to Tarceva. Moreover, 13d and 13h exhibited a specific growth inhibition toward Kato III cells (IC50 = 12 and 4.7 mu M, respectively), although a significant inhibition toward other three cell lines was not observed at a 100 mu M concentration of compounds. (c) 2006 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tetlet.2006.02.043

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：GEORG THIEME VERLAG KG  

A method for synthesizing o-carborane substituted tetrahydroisoquinolines containing a polar functional group such as sulfonic or phosphoric acid on the nitrogen atom of the piperidine ring, starting from N-(2-arylethyl)sulfamic acid or 2-arylethylamidophosphate, is described. In vitro studies showed that the desired compounds 7a and 10b accumulate to high levels in B-16 melanoma cells despite low cytotoxicity.

DOI： 10.1055/s-2006-926222

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-V C H VERLAG GMBH  

A series of boronic acid containing cis-stilbenes as potent inhibitors of tubulin polymerization was synthesized by the introduction of boronic acid as an acceptor-type functional group into the aromatic ring B of the combretastatin framework. High cell-growth inhibition was observed with boron compounds 13c and 13d, in which a hydroxy group on the aromatic ring B of combretastatin A-4 was replaced with boronic acid; IC50 values toward B-16 and 1-87 cell lines are 0.48-2.1 mu M. Compounds 13 c and 13d exhibited significant inhibitory activity toward tubulin Polymerization (IC50=21-22 mu M). The carboxylic acid derivative 17, which con be considered as a mimic of boronic acid 13c, did not show significant inhibition of cell growth or tubulin polymerization. According to the FACScan analysis using Jurkat cells, apoptosis was induced after incubation for 8 h with 73 c at a concentration of &gt;10(-8) M. Growth inhibitory experiments against a panel of 39 human cancer cell lines revealed 13c to inhibit growth differently than combretastatin A-4; the correlation coefficient (r) between the two compounds was 0.553 in the COMPARE analysis.

DOI： 10.1002/cmdc.200600068

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

One-pot allene synthesis from aryl iodides 1 and propargyldicyclohexylamine 2 proceeded in the presence of Pd-2(dba)(3)(CHCl3)-C-. Catalyst (2-5 mol %), 1,2-bis(diphenylphosphino)carborane 5 (10 mol %), Cul (15 mol %), and Et3N (150 mol %) to give the corresponding allenes 4 in good to high yields. Electron-deficient bidentate phosphines, such as 1,2-bis(diphenylphosphino)carborane 5 and (C6F5)(2)PC2H4P(C6F5)(2), play the role of a dual mode ligand for both the Sonogashira coupling and hydride-transfer reactions.

DOI： 10.1021/ol060538v

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

A series of benzamidines and benzamides was synthesized as selective inhibitors of vascular endothelial growth factor receptor (VEGFR) tyrosine kinases, and tested for inhibitory activity toward autophosphorylation by the enzyme assay. Selective inhibition of VEGFR-2 tyrosine kinase was observed in the salicylic amide 4e and the anthranilic amidine 5a, and their percent inhibitions of VEGFR-2 tyrosine kinase were 44-60% at a 10 mu M concentration of compounds. The salicylic amide 4a showed inhibition of both VEGFR-1 and VEGFR-2 tyrosine kinases at a 10 mu M concentration. (c) 2006 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.bmcl.2006.07.075

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The palladium-catalyzed allene transformation reaction from propargylic amines proceeded in the presence of Pd-2(dba)(3)(HCl3)-H-. (5 mol %) and (C6F5)(2)PC2H4P(C6F5)(2) (10 mol %) in CHCl3 at room temperature to give the corresponding allenes in good to high yields. Dicyclohexyl groups substituted on the nitrogen of propargylic amines were found to be effective for the current transformation and the conjugated ene-allenes 4 were synthesized from the corresponding propargylic amines 3 under mild conditions. (c) 2005 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tetlet.2005.09.169

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

p-Boronophenylalanine (BPA) conjugated Gd-DTPA complex (3) was synthesized from the active methyne compound 6, the allylic carbonate 7, and BPA by the palladium-catalyzed allylation reaction followed by the DCC coupling reaction. The in vivo biodistribution of complex 3 was evaluated by prompt gamma-ray analysis and alpha-autoradiography using the tumor-bearing rats. High accumulation of gadolinium was observed in the kidney and the %ID values were 0.17 and 0.088 at 20 and 60 min after injection of 3, respectively. The accumulation was also observed in the tumor and the %ID values were 0.010 and 0.0025 at 20 and 60 min after injection, respectively. The visualization experiment of boron distribution in the tumor-bearing rat by alpha-autoradiography indicates that boron was accumulated in the tumor and the intestines at 20 min after injection. (C) 2004 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.bmc.2004.10.046

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC BONE & MINERAL RES  

Polymorphisms of the TNSALP gene have not previously been studied as a possible determinant for variations in BMD or as a predisposing genetic factor for osteoporosis. This study showed a significantly higher association between the 787T &gt; C (Tyr246His) TNSALP gene and BMD among 501 postmenopausal women. Furthermore, the effects of amino acid substitution on the catalytic property of the protein translated from the 787T &gt; C gene were examined.
Introduction: Alkaline phosphatase (ALP) is present mainly on the cell membrane in various tissues and hydrolyzes a variety of monophosphate esters into inorganic phosphoric acid and alcohol. Human ALPs are classified into four types: tissue-nonspecific, intestinal, placental, and germ cell types. Based on studies of hypophosphatasia, which is a systemic skeletal disorder resulting from a tissue-nonspecific ALP (TNSALP) deficiency, TNSALP was suggested to be indispensable for bone mineralization.
Materials and Methods: We explored the possibility that the TNSALP gene may contribute to age-related bone loss in humans by examining the association between TNSALP gene polymorphisms and BMD in 501 Japanese postmenopausal women. To analyze the protein translated from the TNSALP gene associated with BMD, we constructed a TNSALP cDNA expression plasmid.
Results: We genotyped two single nucleotide polymorphisms (787T &gt; C[Tyr246His] and 876A &gt; G[Pro275Pro]), which proved to be in complete linkage disequilibrium. There was a significant difference in BMD and the BMD score adjusted for age and body weight (Z score) among haplotypes (p = 0.041), which was lowest among 787T/876A homozygotes, highest among 787T &gt; C/876A &gt; G homozygotes, and intermediate among heterozygotes. In subgroups divided by age, haplotypes were significantly associated with BMD in older postmenopausal women (&gt; 74 years; p = 0.001), but not in younger postmenopausal women (&lt; 74 years; p = 0.964). Expression of the 787T &gt; C TNSALP gene using COS-1 cells showed that the protein translated from 787T &gt; C had ALP-specific activity similar to that of 787T. Interestingly, the K-m value for TNSALP in cells transfected with the 787T &gt; C TNSALP gene was decreased significantly compared with that of cells bearing the 787T gene, reflecting the higher affinity.
Conclusions: These results suggest that variation in TNSALP may be an important determinant of age-related bone loss in humans and that the phosphate metabolism pathway may provide a novel target for the prevention and treatment of osteoporosis.

DOI： 10.1359/JBMR.041229

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

Propargylic diisopropylamines containing heterocycles, which were prepared readily from heterocyclic bromides and propargyldiisopropylamine by the Sonogashira coupling reaction, underwent the allene transformation reaction in the presence of Pd-2(dba)(3)(CHCl3)-C-. catalyst (2.5 mol %) and 1,2-bis [bis(pentafluorophenyl)phosphino] ethane (10 mol %) at 100 degrees C in CHCl3, giving the corresponding heterocyclic allenes in good to high yields via the palladium-catalyzed hydride-transfer reaction.

DOI： 10.1021/jo0479664

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

The benzamides 1 and the benzamidines 2-3 were synthesized as the mimics of 4-anilinoquinazolines, which possess inhibition of epidermal growth factor receptor (EGER) tyrosine kinase, and tested for cytotoxicity toward A431 and inhibitory activity toward autophosphorylation by the enzyme assay. High cell growth inhibition was observed in a series of the cyclic benzamides 3: the IC50 values are 0.09-0.32 mM. The benzamidines 3a and 3b exhibited high inhibition of EGER tyrosine kinase at a 1.0 muM concentration, although the benzamides 1 and the benzamidines 2 did not show significant kinase inhibition at a 10 muM concentration. (C) 2004 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.bmcl.2004.02.001

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ROYAL SOC CHEMISTRY  

The nido-carborane lipid 2, which has a double-tailed moiety, was synthesized from heptadecanol in 5 steps. Analysis in a transmission electron microscope by negative staining with uranyl acetate showed that the lipid 2 formed a stable vesicle in which calcein was encapsulated. The lipid 2 was incorporated into distearoylphosphatidylcholine ( DSPC) liposomes at a very high concentration.

DOI： 10.1039/b406141a

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：GEORG THIEME VERLAG KG  

A convenient method for o-carborane-substituted piperidines is described. Product compounds 5a, 5b, 5d, and 5e were found accumulate in B-16 melanoma cells with a significantly high level, although with low cytotoxicity.

DOI： 10.1055/s-2004-829544

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

The reaction of the ortho-alkynylarylimines 1 with allyltributylstannane and allyl chloride in the presence of allyipalladium chloride dimer (5 mol %) and Cu(OAC)(2) (20 mol %) in CH(3)CN at 50 degreesC gave the 1,4-diallyl-1,2-dihydroisoquinolines 2 in good yields. Most probably, the reaction proceeds through tandem bis-allylation of the imine-alkyne functional groups with bis-pi-allylpalladium. (C) 2004 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tetlet.2004.08.008

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

DOI： 10.1021/ja039175+

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

The benzamides 1 and the benzamidines 2 as well as the cyclic benzamidines 3 were designed and synthesized as the mimics of 4-anilinoquinazolines for an inhibitor of EGFR tyrosine kinase. The specific inhibitions of EGFR tyrosine kinase were observed in the benzamides 1c and 1d, and the benzamidine 2a, whereas the specific inhibitions of v-Src kinase were observed in the benzamide 1j and the benzamidine 2d at a 10 mug/mL concentration of compounds. The cyclic benzamidines 3a and 3b showed potent kinase inhibition of EGFR at a 1.0 mug/mL concentration. According to the docking simulation using the X-ray structure of EGFR kinase domain in complex with erlotimb, the LigScore2 scoring function value of erlotimb was calculated as 5.61, whereas that of the benzamide 1c was 5.05. In a similar manner, the LigScore2 value of the cyclic benzamidine 3a was calculated as 5.10. (C) 2004 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.bmc.2004.04.030

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-V C H VERLAG GMBH  

A series of aminoboronic acids was synthesized abased on the structure of lavendustin pharmocophore 1. Their inhibitory activities against the epidermal growth-factor receptor (EGFR) and vascular endothelial growth-factor receptor-1 (VEGFR-1, Flt-1) protein tyrosine kinases, and various protein kinases, PKA, PKC, PTK, and eEF2K were evaluated. Selective inhibition activities were observed in a series of aminoboronic acids. 4-Methoxy-3-((2-methoxyphenylamino)methyl)phenylboronic acid 10 inhibited EGFR tyrosine kinase, whereas 4-(2,5-dihydroxybenzylamino)phenyl boronic acid 72 inhibited Flt-1 protein kinase, although lavendustin pharmacophore 1 inhibited both EGFR and Flt-1 kinases at a compound concentration of 1.0 mug mL(-1). The selective inhibition of EGFR by 70 is considered to be due to the substitution of the dihydroxy groups on the benzyl moiety for a boronic acid group at the para position, whereas the selective inhibition of Flt-1 by 12 is due to the substitution of the carboxyl group on the aniline moiety in the lavendustin pharmacophore 1 for a boronic acid group.

DOI： 10.1002/cbic.200300748

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

A perfluorohexane layer regulates the rate of reagent transport in the bromination and chlorination of alcohols. A fluorous triphasic U-tube method is effective for lighter reagents; the thionyl chloride layer (yellow) vanishes, and the chlorides are obtained from the right top organic layer in the chlorination of alcohols.

DOI： 10.1021/ol034060w

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JOHN WILEY & SONS LTD  

Our objective was to design and synthesize substituted o-carboranes carrying the 1,3,5-s-triazine units as potential boron neutron capture therapy agents. The preliminary results indicated that selective substitution was successful, and the structural AB(2) (mono-o-carboranyl-1,3,5-s-triazine) or A(2)B (bis-o-carboranyl-1,3,5-s-triazine) type was used as the starting point for the generation of biologically active species. In the first series, the influence of the structural changes in the central core unit was investigated. Thus, a procedure for the sequential, selective derivatization of cyanuric chloride that allows for the incorporation of o-carborane was elucidated. As a result, a variety of mono-, di-, and tri-substituted triazines were produced in good yield. In the second series, the effect of additional amine substituents on the 1,3,5-s-triazine was studied. Copyright (C) 2003 John Wiley Sons, Ltd.

DOI： 10.1002/aoc.483

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Publishing type：Research paper (scientific journal)   Publisher：Wiley Online Library  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

The tandem nucleophilic allylation-alkoxyallylation reaction of the alkynylaldehydes 3 with ally] chloride and allyltributylstannane proceeded very smoothly in the presence of catalytic amounts of allylpalladium chloride dimer in THE at room temperature to give the corresponding 5-exo-dig products 4 as the major product in good to high yields along with 6-endo-dig products 5 as the minor product. (C) 2002 Elsevier Science Ltd. All rights reserved.

DOI： 10.1016/S0040-4039(02)01604-0

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

The three-component aminoallylation reaction of the activated olefins 2, with the phthalimide la and allyl chloride proceeded very smoothly in the presence of Pd(2)dba(3)-CHCl3 (5 mol %)/P(4-FC6H4)(3) (40 mol %) and CS2CO3 (3 equiv against 2) in dichloromethane at room temperature to give the corresponding aminoallylated products, N-pent-4-enylphthalimides 3, in 58-99% yields. The reaction of oxazolidinone 1b also proceeded very smoothly to give N-(2,2-dicyano-1-phenylpent-4-enyl)oxazolidinone in a quantitative yield; however, the Tsuji-Trost-type allylation products 4 were obtained in the case of dibenzylamine, N-tosylaniline, and pyrrolidin-2-one. Further, 2 underwent cycloaddition with N-tosylvinylaziridine 9a in the presence of Pd(2)dba(3)-CHCl3 (5 mol %)/P(4-FC6H4)3 (40 mol %) in THF at room temperature, giving the corresponding pyrrolidines 11 in 69-99% yields.

DOI： 10.1021/jo025747h

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

A convenient method for o-carborane-substituted tetrahydroisoquinolines (THIQ) is described; in particular, compound 8c accumulates in B-16 melanoma cells with a significantly high level although its cytotoxicity is significantly low. (C) 2002 Elsevier Science Ltd. All rights reserved.

DOI： 10.1016/S0040-4039(02)01034-1

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CHEMICAL SOC JAPAN  

The reaction of the allylic halides 5-9 having an aldehyde or an imine moiety in the molecule with allyltributylstannane proceeded smoothly in the presence of Pd-2.dba(3)-CHCl3 (5 mol%) in DMF or THF, giving the corresponding heterocycles 10-14 in good to high yields. The Stille coupling product was not obtained under these reaction conditions.

DOI： 10.1246/cl.2002.158

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-V C H VERLAG GMBH  

The synthesis and biological evaluation of two ortho-carborane derivatives which contain a 5,6,7-trimethoxyindole (TMI) unit for use in boron neutron capture therapy is described. The TMI moiety is known to be the DNA-binding part of the highly potent anticancer agent duocarmycin A. The ortho-carborane derivatives were prepared from amino alkynes which were bound to a protected TMI carboxylic acid. Addition of decaborane(14) to the alkyne triple bond with subsequent removal of the tert-butoxy-carbonyl (Boc) and benzyl protecting groups gave the desired product. Boron uptake from the ortho-carborane derivatives into B-16 melanoma cells was higher and faster than that observed with L-p-boronophenylalanine (BPA), which is in use in the clinic.

DOI： 10.1002/1439-7633(20020301)3:2/3<219::AID-CBIC219>3.0.CO;2-#

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

DOI： 10.1021/ja027965y

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE SA  

Reactions of [(eta (6)-arene)RuCl2](2) (1) (eta (6)-arene = p-cymene (1a), 1,3,5-Me3C6H3 (1b), 1,2,3-Me3C6H3 (1c) 1,2,3-Me4C6H2(1d), 1,2,3,5-Me4C6H2 (1e) and C6Me6 (1f)) or [Cp*MCl2](2) (M = Rh (2), Ir (3); Cp* = C5Me5) with 4-isocyanoazobenzene (RNC) and 4,4'-diisocyanoazobenzene (CN-R-NC) gave mononuclear and dinuclear complexes, [(eta (6)-arene)Ru(CNC6H4N=NC6H5)Cl-2] (4a-f). [Cp*M(CNC6H4N=NC6H5)Cl-2] (5: M = Rh; 6: M = Ir), [{(eta (6) -arene)RuCl2}(2){mu -CNC6H4N=NC6H4NC}] (8a-f) and [(Cp*MCl2)(2)(mu -CNC6H4N=NC6H4NC)}] (9: M = Rh; 10: M = Ir), respectively. It was confirmed by X-ray analyses of 4a and 5 that these complexes have trans-forms for the -N=N- moieties. Reaction of [Cp*Rh(dppf)(MeCN)](PF6)(2) (dppf = 1,1'-bis (diphenylphosphino)ferrocene) with 4-isocyanoazobenzene gave [Cp*Rh(dppf)(CNC6H4N=NC6H5)](PF6)(2) (7), confirmed by X-ray analysis. Complex 8b reacted with Ag(CF3SO3), giving a rectangular tetranuclear complex 11b, [{(eta (6)-1,3,5-Me3C6H3)Ru(mu -Cl}(4)(mu -CNC6H4N=NC6H4NC)(2)](CF3SO3)(4) bridged by four Cl atoms and two mu -diisocyanoazobenzene ligands. Photochemical reactions of the ruthenium complexes (4 and 8) led to the decomposition of the complexes, whereas those of 5, 7, 9 and 10 underwent a trans-to-cis isomerization. In the electrochemical reactions the reductive waves about -1.50 V for 4 and -1.44 V for 8 are due to the reduction of azo group, [-N=N-] [-N=N-]2 -. The irreversible oxidative waves at ca. 0.87 V for the 4 and at ca. 0.85 V for 8 came from the oxidation of Ru(II) Ru(III). (C) 2001 Elsevier Science B.V. All rights reserved.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

DOI： 10.1021/ja011716c

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DOI： 10.1016/S0968-0896(01)00061-X

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

The reaction of certain activated alkenes 3 with allyltributylstannane (4) and allyl chloride (5a) in the presence of palladium catalyst gave the bis-allylation products, 1,7-octadiene derivatives 6a-k, in good to high yields. The reaction of certain imines 9 with 4 and 5a under similar conditions as above afforded the bis-allylated amines, N-allyl-N-3-butene-1-amine derivatives 10a-f, in good to high yields. The bis-allylation reactions most probably proceed through bis-pi -allylpalladium intermediate 2. The above intermolecular bisallylation was extended to the intramolecular reaction. The reaction of 8-chloro-2,6-octadienyltributylstannane (17a) with activated alkenes 3 gave a mixture of regioisomeric cycloadducts, [8+2] and [4+2] cycloaddition products. The regioisomeric ratio was dependent on solvent and the electron density at the P-position of activated alkenes. In general, the [8+2] cycloadducts 18 were obtained predominantly in CH2Cl2, whereas the [4+2] adducts 24 and 25 were produced predominantly in DMF. The reaction of 7-chloro-2,8-nonadienyltributylstannane (17b) with activated alkenes gave selectively the [9+2] cycloadducts 19 and 22: the regioisomeric [5+2] and [7+2] adducts were not obtained at all. The reaction of 10-chloro-2,8-decadienyltributylstannane (17c) with activated alkene 3a afforded the [10+2] cycloadducts 20 and 23 in low yields. The mechanism on the intramolecular bis-allylation reaction is discussed.

DOI： 10.1021/ja002931g

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DOI： 10.1002/1439-7633(20010504)2:5<326::AID-CBIC326>3.3.CO;2-P

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-V C H VERLAG GMBH  

DOI： 10.1002/1521-3773(20010903)40:17<3208::AID-ANIE3208>3.0.CO;2-U

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

DOI： 10.1021/ja003718n

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

The reaction of the activated olefins 1 with the allylic carbonate 2, having a hydroxy group at the terminus of the carbon chain, in the presence of catalytic amounts of Pd(2)dba(3)(.)CHCl(3);l and dppe in THF at room temperature gave the corresponding cycloaddition products, tetrahydrofuran derivatives 5, in good to very high yields. The diastereoselectivities (trans/cis ratios) of the products were in the range of ca. 60-70/40-30. The reaction of 1 with the hydroxy allylic carbonate 3 in the presence of catalytic amounts of Pd(2)dba(3)(.)CHCl(3) and (o-tolyl)(3)P in THF at 50 degreesC afforded the corresponding cycloaddition products, tetrahydropyran derivatives 6, in good to high yields. The trans/cis ratios of the products were in the range of ca. 0-40/99-80. The reaction of la with the hydroxy allylic carbonate 4 needed higher reaction temperatures (similar to 100 degreesC) to give the cycloaddition product, the oxepane 7a, in 31% yield with low diastereoselectivity. Next, catalytic asymmetric syntheses of tetrahydrofuran and -pyran derivatives were carried out. With the Trost ligand 15, good to high ees were accomplished in the cycloaddition, although the diastereoselectivities were of low level. With the Hayashi ligand 16, good to high ees were also achieved in the cycloaddition. The absolute stereochemistries of the major enantiomers of 51, 5m, and 6d were determined unambiguously by X-ray crystallographic analysis: trans-(2R,4R)-51, cis-(2S,4R)-51, 4R-5m, trans(2S,4S)-6d, and cis-(2R,4S)-6d were major enantiomers. Based upon the absolute stereochemistries of the major enantiomers, the mechanism of catalytic asymmetric induction in the cycloaddition reaction is discussed.

DOI： 10.1021/jo0158332

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

The polymer-supported chiral pi-allylpalladium catalyst 8 was applied to the asymmetric allylation reaction of imines 9 with allyltributylstannane. The catalyst was very stable and could be reused several times with high catalytic activity, although the enantioselectivity was not necessarily high. (C) 1999 Elsevier Science Ltd. All rights reserved.

DOI： 10.1016/S0040-4039(99)02032-8

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DOI： 10.1021/ja9940165

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Pharmaceutical Society of Japan  

The evaluation of the Gd-carborane complex 2 as an MR imaging and boron carrier agent was carried out in vivo using tumor-bearing Donryu rats, MRI, ICP-AES, and α-autoradiography. The MR imaging revealed that the carborane Gd-DTPA 2 was metabolized slower in the body than Gd-DTPA 1. The results of the ICP-AES method indicated that compound 2 was incorporated into normal tissues and metabolized quickly, whereas it was not accumulated into tumor or brain tissue. The α-autoradiography showed that a high level of boron was obtained in the internal organs and in the necrosis of tumor tissue.

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DOI： 10.1016/S0040-4039(00)00284-7

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CHEMICAL SOC JAPAN  

Enantiomerically pure L-BPA (4-borono-L-phenylalanine) was synthesized from L-tyrosine or 4-iodo-L-phenylalanine derivatives using the palladium-catalyzed cross-coupling reaction of pinacolborane (2,3-dimethyl-2,3-butanediolatoboron). Cbz-Tyr(Nf)-OBzl (2b) underwent the cross-coupling reaction with pinacolborane (1) in the presence of [PdCl2(PPh3)(2)] catalyst to give N-benzyloxycarbonyl-3-(2,3-dimethyl-2,3-butanediolatoboryl)-L-phenylalanine benzyl ester (3a) in 58% yield. The reaction of the 4-iodo-L-phenylalanine derivatives, such as N-benzyloxycarbonyl-3-iodo-L-phenylalanine benzyl ester (2c), N,N-dibenzyl-4-iodo-L-phenylalanine benzyl ester (2d), (4S)-3-benzyloxycarbonyl-4-(4-iodobenzyl)-5-oxazolidinone (2e), and (4S)-3-1-butyroxycarbonyl-4-(4-iodobenzy)-5-oxazolidinone (2f), with 1 proceeded very smoothly in the presence of [PdCl2(dppf)] catalyst, giving N-benzyloxycarbonyl-4-(2,3-dimethyl-2,3-butanediolatoboryl)-L-phenylalanine benzyl ester (3a), N,N-dibenzyl-4-(2,3-dimethyl-2,3-butanediolatoboryl)-L-phenylalanine benzyl ester (3b), (4S)-3-benzyloxycarbonyl-4-[3-(2,3-dimethyl-2,3-butanediolatoboryl)benzyl]-5-oxazolidinone (3c), and (4S)-3-butyloxycarbonyl-4-[4-(2,3-dimethyl-2,3-butanediolatoboryl)benzyl]-5-oxazolidinone (3d), respectively, in high yields. Deprotection of 3a-d gave enantiomerically pure L-BPA in high total yields.

DOI： 10.1246/bcsj.73.231

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

DOI： 10.1021/ja992117x

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DOI： 10.1002/(SICI)1522-2594(199907)42:1<32::AID-MRM6>3.0.CO;2-5

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DOI： 10.1016/S0022-328X(98)00922-X

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：INST ORGANIC CHEM AND BIOCHEM  

Stannyl- and silyl-ortho-carboranes serve as an ortho-carborane carbanion equivalents in the addition reaction to aldehydes. The reaction of (tributylstannyl)-ortho-carborane 2 with aldehydes 4 in the presence of palladium(0) catalysts gave the corresponding (ortho-carboranyl) carbinols 5 in good to high yields. The reaction of (trimethylsilyl) -ortho-carborane 3 with aldehydes 4 in the presence of tetrabutylammonium fluoride (TBAF) gave the corresponding (ortho-carboranyl) carbinols 5 in high yields. Furthermore, (trimethylsilyl)-ortho-carborane 3 underwent a facile [3+2] annulation reaction with various alpha,beta-unsaturated enals and enones in the presence of tetrabutylammonium fluoride, giving the corresponding five-membered carboracyclic products 14 in good to high yields.

DOI： 10.1135/cccc19990829

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DOI： 10.1021/jo9901081

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE SA  

Five-carboxylate DTPA derivatives (5 and 10) were synthesized via the palladium-catalyzed reaction of allyl ethyl carbonate 9 with diethylenetriamine-N-ethoxycarbonyl acetic-N,N',N ",N "-tetraacetic acid hexaethyl ester 7. This method can be applied to the synthesis of a Gd-carborane complex. The reaction of the hexaethyl ester 7 with carboranyl allyl carbonate 13a proceeded very smoothly under Pd(dba)(2)/2dppe catalyst (10 mol%) in THF at 50 degrees C, giving the C-C bond formation product 14 in 74% yield. Hydrolysis of the ethyl esters in 14 was carried out with UOH in aqueous methanol followed by treatment with diluted hydrochloric acid (IN) to afford the corresponding pentaacid 15 in 68% yield. Treatment of the carborane containing DTPA derivative 15 with gadolinium(III) chloride hexahydrate gave the desired Gd-DTPA carborane complex 16 in quantitative yield. (C) 1999 Elsevier Science S.A. All rights reserved.

DOI： 10.1016/S0022-328X(99)00049-2

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

A 1,2-dicarba-closo-dodecaboranyl derivative (8) and its disodium salt (9) were prepared from 4-aminobenzoic acid (1). The water solubility and the biological data (toxicity and cell-uptake) of the disodium salt (9) were identified to be enough for clinical trial. (C) 1999 Elsevier Science Ltd. All rights reserved.

DOI： 10.1016/S0040-4039(99)00853-9

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Publishing type：Research paper (scientific journal)  

DOI： 10.1021/jo9903306

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DOI： 10.1021/ja980959a

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

The addition of o-carborane (1) to aldehydes 2 proceeded very smoothly in the presence of aqueous tetrabutylammonium fluoride (TBAF; 3 equiv) at room temperature, giving the corresponding carbinols 3 in high yields. The TBAF-mediated reaction was applied to the intramolecular cycloaddition of o-carboranyl aldehydes and ketones 4, and the corresponding five-, six-, and seven-membered carboracycles were obtained in good-to-high yields. Further, [3 + 2] annulation between o-carborane (dianionic C-2 synthons) and alpha,beta-unsaturated aldehydes and ketones (dicationic C-3 synthons) proceeded very smoothly in the presence of TBAF to give the corresponding five-membered carbocycles in good-to-high yields. Detailed mechanistic studies revealed that the [3 + 2] annulation proceeded through kinetically controlled 1,2-addition and thermodynamically controlled 1,4-addition.

DOI： 10.1021/ja973832e

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DOI： 10.1021/jo980818r

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DOI： 10.1021/ja973540d

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DOI： 10.1021/jo981719g

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-V C H VERLAG GMBH  

DOI： 10.1002/anie.199703671

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DOI： 10.1021/jo962130p

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DOI： 10.1021/ja971599e

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

3-(0-Carboranylhydroxymethyl)-7-isopropylazulene sodium carboxylate (1) and 3-(o-carboranylmethyl)-7-isopropylazulene sodium sulfonate (2) were synthesized from the palladium-catalyzed addition reaction of 1-carboranyltributylstannnane (4) to azulene aldehydes (3 and 9). Although the water solubility of 1 was of the order of 10(-6) M, that of 2 was bf the order of 10(-3) M and was enough for clinical use. The cytotoxicity of 1 (IC50) toward B-16 melanoma cells was of the order of 10(-5) M, whereas that of 2 was of the order of 10(-4) M. This value was close to that of BPA (similar to 9 x 10(-3) M) which is utilized for clinical use. The boron uptake by B-16 cells was 0.17 mu g of B/10(6) cells for 1 and 0.25 mu g of B/10(6) cells for 2. It is clear that compound 2 accumulates in B-16 melanoma cells with a significantly high level although it is highly water soluble and its cytotoxicity is significantly low.

DOI： 10.1021/jm970023x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

The reaction of allylstannanes 1 with aldehydes 2 in THF was catalyzed by Pd(II) or Pt(II) complexes (10 mol %) either at room temperature or at reflux, giving the corresponding homoallylic alcohols 3 in high to good yields. Among the catalysts examined, PtCl2(PPh(3))(2) gave the best result. No only allyltribitylstannane but also methallyl- and crotyltributylstannane could be utilized in this transition metal catalyzed reaction. Detailed mechanistic studies of the Pd(II)-catalyzed allylation, using NMR spectroscopy, revealed that the bis-pi-allylpalladium complex is a key intermediate for the catalytic cycle and it exhibits nucleophilic reactivity. The nucleophilic reactivity of the intermediate is in marked contrast to the electrophilic reactivity of ordinary pi-allylpalladium complexes (pi-allylPdX, X = OAc, halogen, OCO(2)R, etc.). The addition of allyl-, crotyl-, and methallylstannanes to various imines 4 proceeded very smoothly to give the corresponding allylated products (homoallylic amines 5) in good to high yields. The reactivities of allylstannanes to imines were higher than those to aldehydes under the catalytic conditions, although it is known that the reactivity of allylstannanes to aldehydes is higher than that to imines under the Lewis acid promoted condition. Imines were chemoselectively allylated in the presence of aldehydes and the highest selectivities were obtained using pi-allylpalladium chloride dimer 11 as a catalyst.

DOI： 10.1021/ja9608858

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ROYAL SOC CHEMISTRY  

Imines are allylated chemoselectively in the presence of aldehydes using allylstannanes with pi-allylpalladium chloride dimer catalyst.

DOI： 10.1039/cc9960001459

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CHEMICAL SOC JAPAN  

Trimethylsilyl-o-carborane serves as o-carborane carbanion upon fluoride ion promoted reaction with carbonyl compounds. Thus, in the presence of tetrabutylammonium fluoride, trimethylsilyl-o-carborane undergoes facile, unprecedented, carbodesilylation with aromatic and aliphatic aldehydes.

DOI： 10.1246/cl.1996.791

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Language：English   Publisher：AMER CHEMICAL SOC  

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DOI： 10.1039/c39950001273

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

Netropsin and distamycin A analogues containing o-carborane framework, 4a-c and 5a-c, respectively, were synthesized to investigate DNA binding sequence of these molecules. Cascade type polyols were attached to the carboranes in certain cases; 4b and 5b had the diol unit and 4c and 5c possessed the tetraol unit, whereas 4a and 5a had no hydroxy group. MPE . Fe(II) footprinting on the 216 base pair Pvu I/ Bam HI restriction fragment from pBLUESCRIPT KS(+1-) (bp 2958) indicated that 4a and 5a bound only slightly to the DNA fragment, whereas 4b and 5b bearing two hydroxy groups bound to the A,T-rich base pairs. The compounds containing four; hydroxy groups 4c and 5c bound most selectively to the DNA fragments. In general, the compounds 5 containing three pyrrole rings in their molecules bound to the DNA more selectively than the corresponding two pyrrole ring-bearing compounds 4.

DOI： 10.1021/jo00116a018

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DOI： 10.1039/c39940002581

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC JNL-COMP SUBSCRIPTIONS  

DOI： 10.1006/jmrb.1993.1032

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DOI： 10.1039/c39930001201

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CHEMICAL SOC JAPAN  

A p-boronophenylalanine (BPA) derivative, that is ca. thousand times more water-soluble and is incorporated with higher tumour/normal cell ratio than BPA itself, has been synthesized.

DOI： 10.1246/cl.1993.465

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DOI： 10.1021/jm00067a021

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Language：Japanese   Publisher：Symposium on the chemistry of natural products  

Several new methods for the synthesis of boron-10 carriers have been developed for boron neutron capture therapy (BNCT). Two new methods for the synthesis of nucleosides having arylboronic moiety have been developed (Scheme 1 and 2). Chemistry of o-carborane has been studied since it is a nice candidate for BNCT in order to deliver sufficient quantity of boron atoms to tumor cells. The carbon-carbon bond formation reaction to o-carboranes proceeding under essentially neutral conditions has been accomplished for the first time (Scheme 3). o-Carboranes having a cascade type of polyglycerols 5 have been synthesized since o-carborane itself has strong lipophilic nature which causes a serious problem for the design of its derivatives (Scheme 4). The water solubility of 6 and 7 is 0.67M and 5.44M, respectively. Nucleoside derivatives having o-carborane moiety have been synthesized via palladium catalyzed coupling reaction and o-carborane formation reaction with decaborane-14 (Scheme 5). The biological activity of 11a, and 11b have been examined in vitro using B16 melanoma cells and TIG-I-20 Fibroblast cells. The boron atom is selectively concentrated in B16 Melanoma cells (model of a cancer cell), compared with in Hybroblast cells (model of a normal cell).

DOI： 10.24496/tennenyuki.34.0_763

CiNii Books

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JOHN WILEY & SONS INC  

The carboranes containing uridine derivatives (9a, b, c), and purine base (8) were prepared by the reaction of decaborane with the corresponding acetylene precursors (3a, 3b, 2c and 5b, respectively).

DOI： 10.1002/hc.520030308

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

A practical method for the synthesis of polyols of a cascade type, as a water-solubilizing element of carborane derivatives for boron neutron capture therapy (BNCT), was developed. The carborane attached to the tetraol 6a was dissolved in water in a concentration of 5.44 M.

DOI： 10.1021/jo00028a010

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Publishing type：Research paper (scientific journal)  

DOI： 10.1039/c39920000157

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J-GLOBAL

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Language：Japanese   Publisher：(NPO)日本レーザー医学会  

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Language：Japanese   Publisher：(NPO)日本レーザー医学会  

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J-GLOBAL

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© 2018 The Pharmaceutical Society of Japan. The chemical labeling of proteins with synthetic probes is a key technique used in chemical biology, protein-based therapy, and material science. Much of the chemical labeling of native proteins, however, depends on the labeling of lysine and cysteine residues. While those methods have significantly contributed to native protein labeling, alternative methods that can modify different amino acid residues are still required. Herein we report the development of a novel methodology of tyrosine labeling, inspired by the luminol chemiluminescence reaction. Tyrosine residues are often exposed on a protein's surface and are thus expected to be good targets for protein functionalization. In our studies so far, we have found that 1) hemin oxidatively activates luminol derivatives as a catalyst, 2. N-methyl luminol derivative specifically forms a covalent bond with a tyrosine residue among the 20 kinds of natural amino acid residues, and 3) the efficiency of tyrosine labeling with N-methyl luminol derivative is markedly improved by using horseradish peroxidase (HRP) as a catalyst. We were able to use molecular oxygen as an oxidant under HRP/NADH conditions. By using these methods, the functionalization of purified proteins was carried out. Because N-methyl luminol derivative is an excellent protein labeling reagent that responds to the activation of peroxidase, this new method is expected to open doors to such biological applications as the signal amplification of HRP-conjugated antibodies and the detection of protein association in combination with peroxidase-tag technology.

DOI： 10.1248/yakushi.17-00186-1

Scopus

PubMed

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Language：Japanese   Publisher：日本DDS学会  

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