| Project/Area Number |
10557233
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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 | Osaka University |
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Principal Investigator |
KOBAYASHI Motomasa Professor, Graduate School of Pharmaceutical Sciences, Osaka University, 薬学研究科, 教授 (40116033)
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| Co-Investigator(Kenkyū-buntansha) |
AOKI Shunji Assistant Professor, Graduate School of Pharmaceutical Sciences, Osaka University, 薬学研究科, 助手 (60252699)
MURAKAMI Nobutoshi Associate Professor, Graduate School of Pharmaceutical Sciences, Osaka University, 薬学研究科, 助教授 (00210013)
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| Project Period (FY) |
1998 – 1999
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| Project Status |
Completed (Fiscal Year 1999)
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| Budget Amount *help |
¥12,500,000 (Direct Cost: ¥12,500,000)
Fiscal Year 1999: ¥3,800,000 (Direct Cost: ¥3,800,000)
Fiscal Year 1998: ¥8,700,000 (Direct Cost: ¥8,700,000)
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| Keywords | anti-tumor / cytotoxicity / callystatin A / arenastatin A / marine sponge / polyketide / structure activity relationship / depsipeptide / 細胞毒性 / araguspongine / P-glycoprotein / MRP |
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| Research Abstract |
As a part of our continuing programs aimed at search for new biologically active substances from marine organisms, we have engaged in creating new anti-tumor leads by utilizing extremely potent cytotoxic constituents as seed compounds. Recently, we isolated and characterized two new potent cytotoxic substances, callystatin A and arenastatin A, from marine sponges through bioassay-guided separation. In this research project, we have especially investigated on search for new anti-tumor leads by use of these two active substances and our outcome of this research is summarized as follows.
1. As for the cytotoxic polyketide callystatin A, we achieved the first total synthesis using asymmetric Evans aldol condensation and E-selective Wittig reaction as key reactions to confirm the absolute stereostructure presented by us. Syntheses and biological assessment of several derivatives disclosed that 5-R configuration and 8-ethyl residue, and β-hydroxy ketone function played a significantly important role in the potent cytotoxicity of callystatin A. Furthermore, α, β-unsaturated δ-lactone portion proved to be conclusive functional group for cytotoxicity.
2. With respect to cytotoxic depsipeptide arenastatin A, we had already clarified that this depsipeptide showed little anti-tumor activity in vivo. Hence, we synthesized three amide anlogues to reveal functional group metabolized in serum. Based on this finding, design for some analogues in expectation of stability in serum brought about a promising anti-tumor lead, 20-deoxoarenastatin A.
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