| Project/Area Number |
12307052
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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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 | The University of Tokyo |
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Principal Investigator |
FUKUYAMA Tohru The University of Tokyo Graduate School of Pharmaceutical Sciences, Professor, 大学院・薬学研究科, 教授 (10272486)
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| Co-Investigator(Kenkyū-buntansha) |
KAN Toshiyuki The University of Tokyo Graduate School of Pharmaceutical Sciences, Research Associate, 大学院・薬学研究科, 助手 (10221904)
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| Project Period (FY) |
2000 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥26,300,000 (Direct Cost: ¥22,100,000、Indirect Cost: ¥4,200,000)
Fiscal Year 2002: ¥9,100,000 (Direct Cost: ¥7,000,000、Indirect Cost: ¥2,100,000)
Fiscal Year 2001: ¥9,100,000 (Direct Cost: ¥7,000,000、Indirect Cost: ¥2,100,000)
Fiscal Year 2000: ¥8,100,000 (Direct Cost: ¥8,100,000)
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| Keywords | Ecteinascidin 743 / antitumor / anticancer drug / total synthesis / natural scarcity / tetrahydroisoquinoline / Ugi's 4CC reaction / Heck reaction / 抗ガン剤 / 立体選択的 / セグメント / UGIの連結反応 / 類縁体 / 10員環チオエーテル化 / 大量供給 / ピペラジン / テトラヒドロイソキノリン / 光学活性イミノエステル / 不斉アミノヒドロキシル化 / 環化反応 |
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| Research Abstract |
Ecteinascidin 743 (Et 743) is an extremely potent antitumor agent isolated from a marine tunicate, Ecteinascidia turbinata. Based on promising results in phase II clinical trials, Et 743 is likely to become the first anticancer drug among marine natural products. The novelty of its structure, the remarkable biological activities, and its natural scarcity have made it an attractive target for total synthesis. We accomplished an efficient total synthesis of Et 743 that would potentially lead to the development of a practical synthesis of this important compound. The synthesis was started from a large scale preparation of left and right segment. These two segments were efficiently coupled by the Ugi's 4CC reaction, and transformed into the cyclic enamide via diketopiperazine. Intramolecular Heck reaction of the enamide proceeded smoothly to give the bicyclo[3.3.1] skeleton. Construction of B-ring was performed by the phenol-aldehyde cyclization, giving the desired pentacyclic compound. After conversion to the sulfur-containing ten-membered lactone, construction of tetrahydroisoquinoline moiety was afforded ecteinascidin 743.
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