| Project/Area Number |
10470463
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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 |
Chemical pharmacy
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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) |
首藤 紘一 国立医薬品, 食品衛生研究所, 医薬品医療機器審査センター長(研究職)
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| Project Period (FY) |
1998 – 2000
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| Project Status |
Completed (Fiscal Year 2000)
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| Budget Amount *help |
¥9,300,000 (Direct Cost: ¥9,300,000)
Fiscal Year 2000: ¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 1999: ¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 1998: ¥3,600,000 (Direct Cost: ¥3,600,000)
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| Keywords | benzolactam / teleocidin / phorbol ester / signal transduction / molecular Design / receptor / hydrophbic interaction / boron cluster / ベンゾラクタム / 発癌プロモーター |
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| Research Abstract |
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. (-)-Benzolactam-V8-310, which we have been synthesized, reproduces well the active conformation and activities of teleocidins. In this project, 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 PKCδ with phorbol 13-acetate. On the basis of these investigation, we designed new PKC agonists having 7-membered lactam moiety and hydroxymethyl group. The compounds showed significant PKC agonistic activity, with inhibition constants of low nanomolar order. We also developed a new hydrophobic pharmacophore, carborane (dicarba-closo-dodecaborane), and applied in design of the PKC agonist. The compound with carborane as a hydrophobic component on benzolactam sleleton, showed potent affinity for PKC.The results lead us to design and synthesis of the other receptor ligands with carborane as a hydrophobic pharmacophore. Designed synthetic retinoids and estrogens with carborane showed significant agonistic activities, compared with native ligands.
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