| Project/Area Number |
12672061
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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 | Kitasato University |
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Principal Investigator |
SUNAZAKA Toshiahi Kitasato University, Kitasato University, Kitasato Institute for life Science, Associate Professor (30226592)
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| Co-Investigator(Kenkyū-buntansha) |
大村 智 北里大学, 北里研究所, 所長 (90050426)
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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 |
¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2002: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2001: ¥800,000 (Direct Cost: ¥800,000)
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| Keywords | Natunal Products / Madindoline / IL-6 / Ligand / Stereoselectire / Enantioselective / Absolute Stereochemistry / Structor Determination / IL-6 / リガンド / 大量合成 / 生物活性 / 絶対構造決定 / 全合成 / 効率的 / エナンチオ制御 / 生物活性天然物 / 鍵化学物質 |
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| Research Abstract |
Our search for new inhibitors of IL-6 activity has recently led to the isolation of madindolines A and B from Streptomyces nitrosporeus K93-0711. The structures of these compounds were initially deduced by extensive spectroscopic analysis to be 3a-hydroxyfuroindoline ring connected at nitrogen via a methylene bridge to a cyclopentene-1, 3-dione ring. Madindoline A is a stereoisomer of B at the C-2' position. Unfortunately, the original culture of the Streptomyces no longer produces these natural products.
The first total synthesis of madindoline A has been succeeded by the stereoselective aldol reaction (A), ring-closing metathesis (B), reductive N-alkylation (C), and asymmetric oxidative ring-closing of indole (D) to determine its absolute stereochemistry. Moreover, we have developed more efficient total synthesis (second generation) by stereoselective acylation of ester 3 in coordination with 3a-hydroxyfuroindoline moiety as the chiral ligand (E), and the intramolecular acylation of allylsilane 4 (F) (19% yield over 9 steps) (Scheme 1). We have found that [^3H]-madindoline A binds to gp-130, selectively. Synthetic madindoline A markedly inhibited osteoclastogenesis in vitro and bone resorption in ovariectomized mice in vivo.
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