| Project/Area Number |
10672011
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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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 | Osaka University (1999)
Kyoto Pharmaceutical University (1998) |
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Principal Investigator |
AKAJI Kenichi Institute for Protein Research, Osaka University, Associate Professor, 蛋白質研究所, 助教授 (60142296)
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| Co-Investigator(Kenkyū-buntansha) |
木村 徹 京都薬科大学, 薬学部, 助手 (70204980)
藤原 洋一 京都薬科大学, 薬学部, 助手 (60199396)
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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 |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 1999: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 1998: ¥2,500,000 (Direct Cost: ¥2,500,000)
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| Keywords | solid pahse synthesis / coupling reaction / dolastatin 15 / CIP reagent / 固相上縮合 / 縮合剤 / Nメチルアミノ酸 / デブシペプチド |
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| Research Abstract |
Dolastatin 15 is a cytostatic depsipeptide isolated from the marine mollusk Dolabella auricularia by Pettit et. al. in 1989. Among the dolastatins, an unprecedented series of linear and cyclic antineoplastic and/or cytostatic peptide isolated from the Indian Ocean sea hare, dolastatin 15 as well as dolastatin 10 represent the two most important members because of the strong and selective activities.
For completing the synthesis of dolastatin 15, single step segment condensation between peptide fragment and nonpeptide fragment by the CIP/HOAt method was used, since activation at the Pro residue is resistance to isomerization. N, N-dimethylamino acid was incorporated in peptide fragment 2 since CIP-mediated activation is expected to be efficient enough for hindered couplings in solution. Pro, 2-hydroxyisovaleric acid (Hiva), and Phe was employed for the preparation of nonpeptide fragment. The Pyrrolidone ring of was constructed by the CIP-mediated coupling of Phe and Meldrum's ester employed as C2 unit. For the preparation of peptide fragment, CIP-mediated activation for the coupling of N-methylamino acid on solid support was selected as a preferable scheme to facilitate the practical synthesis of dolastatin 15. Thus, prior to the synthesis of dolastatin 15 according to the scheme, we evaluated CIP-mediated activation for its efficiency in preparing peptide sequence containing N-methylamino acids on solid support.
In conclusion, a convergent synthesis utilizing single step condensation of fragment and pyrrolidone fragment using CIP-HOAt as an efficient coupling reagent was achieved. The CIP-mediated reaction was also successfully applied for coupling of N-methylamino acid on solid support, demonstrating the first practical application of the solid-phase procedure for natural product synthesis
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