| Project/Area Number |
07557377
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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 | 展開研究 |
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| Research Field |
医薬分子機能学
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| Research Institution | University of Tokyo |
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Principal Investigator |
ENDO Yasuyuki University of Tokyo, Graduate School of Pharmaceutical Sciences, Associate Professor, 大学院・薬学系研究科, 助教授 (80126002)
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| Co-Investigator(Kenkyū-buntansha) |
KAGECHIKA Hiroyuki University of Tokyo, Graduate School of Pharmaceutical Sciences, Research Associ, 大学院・薬学系研究科, 助手 (20177348)
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| Project Period (FY) |
1995 – 1997
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| Project Status |
Completed (Fiscal Year 1997)
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| Budget Amount *help |
¥2,700,000 (Direct Cost: ¥2,700,000)
Fiscal Year 1997: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 1996: ¥1,500,000 (Direct Cost: ¥1,500,000)
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| Keywords | tumor promoter / anti-HIV compound / molecular design / chemical synthesis / protein kinase C / teleocidin / steroid / 医薬品化学 / 有機合成化学 / 立体配座 / 発癌プロモーター / 核磁気共鳴スペクトル |
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| Research Abstract |
Development of chemotherapy against human immunodeficiency virus (HIV) is currently a challenging problem. Though 12-O-tetradecanoylphorbol-13-acetate(TPA) has anti-HIV activity, it is not suitable for use in vivo as it is too toxic. However, prostratin has been reported as an anti-HIV cytoprotective phorbol with protein kinase C (PKC) binding activity and without apparent tumor promotion activity. Teleocidins are well-known TPA-type tumor promoters. The discovery of prostratin prompted us to investigate the anti-HIV activity of teleocidins. We havefound the anti-HIV activity of teleocidin and of designed molecules that reproduce the stereochemistry of teleocidins.
Phorbol esters (TPA) and teleocidins are known to be potent tumor promoters and to activate protein kinase C (PKC) by binding competitively to the enzyme. The relationship between the chemical structures and the activities of these compounds has attracted much attention because of the marked structural dissimilarities. (-) -B
… More
enzolactam-V8-310 which is a potent anti-HIV compound with the highest selectivity index among the teleocidin-related derivatives examined, reproduces the active conformation and the other biological activities of teleocidins. We have performed the synthesis of benzolactams with hydrophobic substituents at various positions. Structure-activity data indicate that the existence of a hydrophobic region between C-2 and C-9 and the steric factor at C-8 play critical roles in the appearance of biological activities. We also simulated the docking of these teleocidin-type benzolactam molecules to the cys2 domain structure observed in the crystalline complex of PKCd with phorbol 13-acetate. Teleocidins and benzolactams fitted well into the same cavity as phorbol-13-acetate. 0f the three functional groups hydrogen-honding to the protein, two hydrogen-bonded with protein atoms in cmmon with phorbol 13-acetate, but the third one hydrogen-bonded with a different protein atom from that in the case of phorbol-13-acetale. The model explains well the remarkable difference in activity between (-) -BL-V8-310 and its analog having a bulky substituent at C-8. Less
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