| Project/Area Number |
10470491
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
医薬分子機能学
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| Research Institution | KYOTO UNIVERSITY |
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Principal Investigator |
FUJII Nobutaka Graduate School of Pharmaceutical Sciences, Kyoto University, Professor, 薬学研究科(研究院), 教授 (60109014)
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| Co-Investigator(Kenkyū-buntansha) |
IBUKA Toshiro Graduate School of Pharmaceutical Sciences, Kyoto University, Professor, 薬学研究科(研究院), 教授 (80025692)
OTAKA Akira Graduate School of Pharmaceutical Sciences, Kyoto University, Asoc. Professor, 薬学研究科(研究院), 助教授 (20201973)
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| Project Period (FY) |
1998 – 2001
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| Keywords | Stereoselective Synthesis / Aspartyl Protease / Substrate Transition State Mimic / aza-Payne Rearrangement / β-Secretase / HIV-protease / Organocopper Reagent / Alkene-type tipeptide isostere |
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| Research Abstract |
The four year research project has been focused on the development of stereoselective synthetic methods for peptide-lead drug discovery and its application for several peptidic drug candidates as follows :
1. One-flask reaction composed of aza-Payne rearrangement and consecutive epoxy-ring opening was developed for stereoselective synthesis of key substructure of substrate transition state-based protease inhibitors. The new method has been applied to the discovery of highly active HIV protease inhibitors even potent to multi-drug resistant HIV-1 virus clinical strains. The new method coupled with O'N-acyl transfer reaction and solid phase organic synthesis found the versatile utility to combinatorial chemistry and applied to structure activity-relationship study on β-secretase relevant to Alzheimer disease.
2. Theoretical and practical investigation on stereoselecive synthesis of alkene-type dipeptide isosteres and its application to biologically active peptides (bombesin, integrin antagonist, CXCR4 antagonist, nociceptin) met with the great achievements beyond the initial research plans, as follows :
1) Establishment of totally stereo-controlled synthetic process for (E)-alkene dipepitde isosteres, EADI, starting from amino acids and successful application to peptide-lead agonists ＆ antagonists.
2) Stereoselective synthesis of EADIs with trisubstituted-and tetrasubstituted alkenes based on organocopper chemistry.
3) Stereoselective synthesis of (Z)-fluoroalkene dipeitide isosteres based on organocopper mediated reduction oxidative alkylation.
4) Stereoselective synthesis of highly α-functionalised EADI based on anti-SN2' reaction by organozinc copper complex.
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