1997 Fiscal Year Final Research Report Summary
Design, Synthesis and Biological Activity of Anti-HIV Compounds Derived from Teleocidins
| 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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| Keywords | tumor promoter / anti-HIV compound / molecular design / chemical synthesis / protein kinase C / teleocidin / steroid |
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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
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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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Research Products
(14 results)
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[Publications] Endo, Y., Ohno, M., Hirano, M., Itai, A., Shudo, K,: "Synthesis, Conformation and Biological Activity of Teleocidin Mimics, Benzolactams.A Clarification of the Conformatioal Flexibility Problem in Structure-activity Studies of Teleocidins." J.Am.Chem.Soc.118. 1841-1855 (1996)
Description
「研究成果報告書概要(欧文)」より
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[Publications] Azuma, A,, Hashimoto, Y., Yamaguchi, M., Takehana, S., Ando, Y., lwasaki, S., Fukasawa, H., Endo, Y., Shudo, K.: "Photoaffinity Labeling and Affinity Sorbent Gels of Tumor promoter-Binding Protein (CN-TPBP)." Biol.Pharm.Bull. 20. 5-8 (1997)
Description
「研究成果報告書概要(欧文)」より
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[Publications] Endo, Y., Ohno, M., Takehana, S., Driedger, P.E., Stabel, S., Shudo, K.: "Role of the Hydrophobic Moiety of Tumor Promoters. Synthesis and Activity of Benzolactams with Alkyl Substituents at Various Positions." Chem.Pharm.Bull.45. 424-426 (1997)
Description
「研究成果報告書概要(欧文)」より
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[Publications] Itai, A., Matsuo, A., Mizutani, M., Tomioka, N,, Endo, Y., Shudo, K: "Advanced Docking of Two Teleocidin Congeners with the cys2 Domain of Protein Kinase Cdelta." Chem.Pharm.Bull.45. 573-575 (1997)
Description
「研究成果報告書概要(欧文)」より
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[Publications] Endo, Y,, Hirano, M., Driedger, P.E., Stabel, S., Shudo, K.: "A Novel Conformationa1 Consttrained Analogues of Diacylglycerol. Protein Kinase C Affinity of Simplified Compounds Based on 6-Membered Lactam Moiety." BioMed.Chem, Lett.7. 2997-3000 (1997)
Description
「研究成果報告書概要(欧文)」より
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[Publications] Endo, Y., Takehana, S., Ohno, M., Driedger, P,E., Stabel, S., Mizutani, M., Tomioka, N., Itai, A., Shudo, K.: "A Clarification of the Binding Mode of Teleocidin and Benzolactams to the Cys2 Domain of Protein Kinase Cdelta by Synthesis of Hydrophobically Modified, Teleocidin-mimicking Benzolactams and Computational Docking Simulation." J,Med.Chem.41, (in press). (1998)
Description
「研究成果報告書概要(欧文)」より
