2005 Fiscal Year Final Research Report Summary
Development of novel protein phosphatase inhibitors based on fostriecin
| Project/Area Number |
16590083
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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 |
Drug development chemistry
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| Research Institution | Osaka University |
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Principal Investigator |
MIYASHITA Kazuyuki Osaka University, Graduate School of Pharmaceutical Sciences, Associate Professor, 薬学研究科, 助教授 (10166168)
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| Co-Investigator(Kenkyū-buntansha) |
IMANISHI Takeshi Osaka University, Graduate School of Pharmaceutical Sciences, Professor, 薬学研究科, 教授 (40028866)
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| Project Period (FY) |
2004 – 2005
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| Keywords | Fostriecin / Leustroducsin / Protein phosphatase / Total synthesis / Structure-activity relationship |
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| Research Abstract |
We have already succeeded to synthesize an antitumor antibiotic, fostriecin, stereoselectively. A characteristic feature of our synthesis is highly convergent, in which fostriecin was separated into three segments A (an unsaturated lactone moiety), B (a polyalcohol moiety containing a series of stereogenic centers) and C (a triene moiety). Because of the characteristic feature, this synthetic strategy is highly versatile and would be applicable to synthesize not only fostriecin but also other fostriecin family natural products and various unnatural analogues. Applying our synthesis, we planned to synthesize leustroducsin B which shows protein phosphatase 2A specific inhibitory activity, like fostriecin, and some analogues such as a hybrid of fostriecin and leustroducsin, and also planned to study a structure-activity relationship of protein phosphatase inhibition.
Regarding the total synthesis of leustroducsin B, we have successfully synthesized a key intermediate having a carbon skeleton of leustroducsin B. Some analogues focusing on the triene moiety of fostriecin and on the aminoethyl substituent of leustroducsin B were also synthesized stereoselectively, and employed to study structure-activity relationship of protein phosphatase inhibition. As a consequence, it was found that the aminoethyl moiety of leustroducsin was not in relation with the activity, but the triene moiety was suggested to play a significant role in specific inhibition against protein phosphatase 2A.
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