| 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)
玉村 啓和 京都大学, 薬学研究科, 講師 (80217182)
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| Project Period (FY) |
1998 – 2001
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| Project Status |
Completed (Fiscal Year 2001)
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| Budget Amount *help |
¥10,600,000 (Direct Cost: ¥10,600,000)
Fiscal Year 2001: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2000: ¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 1999: ¥2,400,000 (Direct Cost: ¥2,400,000)
Fiscal Year 1998: ¥4,700,000 (Direct Cost: ¥4,700,000)
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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 / ペプチドイソスター / ゲノム情報集約型ライブラリー / 立体配座固定 / αVβ3インテグリン拮抗剤剤 / 癌 / アルツハイマー型痴呆症 / エイズ / 有機亜鉛-銅複合試薬 / ペプチドリード医薬品 / Ru-触媒メタセシス閉環反応 / グローバル配座固定 / HIVプロテアーゼ阻害剤 / 抗腫瘍活性 / β-secretase / マラリア / 多剤耐性HIV型プロテアーゼ / Plasmepsin II / aza-Payne転位反応 / 基質遷移状態模倣型酵素阻害剤 / オレフィンメタセシス閉環反応 / (E)-Alkcnc型dipcptidcisostcrc / 非天然型アミノ酸誘導体 / 基質遷移状態ミミック構造 / 遷移金属触媒 / ボンベシンアンタゴニスト / ケモカインアンタゴニスト |
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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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