Efficient Enantioselectine Total Synthesis of Bioactiae natual Products
| Project/Area Number |
12672061
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Chemical pharmacy
|
|---|
| Research Institution | Kitasato University |
|---|
Principal Investigator |
SUNAZAKA Toshiahi Kitasato University, Kitasato University, Kitasato Institute for life Science, Associate Professor (30226592)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
大村 智 北里大学, 北里研究所, 所長 (90050426)
|
|---|
| Project Period (FY) |
2000 – 2002
|
| Project Status |
Completed (Fiscal Year 2002)
|
| 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)
|
|---|
| 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 |
|---|
| 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.
|
Report
(4 results)
Research Products
(19 results)
-
-
-
-
-
[Journal Article] A Short Total Synthesis of (+)-Madindoline A and B2002
Author(s)
Sunazuka, T., Hirose, T., Shirahata, T., Yamamoto, D., Harigaya, Y., Kuwajima, I., Omura., S.
-
Journal Title
Organic Letters. 4
Pages: 501-503
Description
「研究成果報告書概要(欧文)」より
Related Report
-
[Journal Article] The First Total Synthesis of (±)Arisugacin A, A Potent, Orally Inhibitor of Acetylcholinesterase2002
Author(s)
Sunazuka, T., Handa, M., Nagai, K., Shirahata, T., Otoguro, K., Harigaya, Y., Kuwajima, I., Omura, S.
-
Journal Title
Organic Letters. 4
Pages: 367-369
Description
「研究成果報告書概要(欧文)」より
Related Report
-
-
-
[Journal Article] Convergent Synthesis of Arisugacin Skekleton and Their Acetylcholinesterase Inhibitor2001
Author(s)
Sunazuka, T., Handa, M., Nagai, K., Kimura, R., Shirahata, T., Tian, Z-M., Otoguro, K., Harigaya, Y., Omura, S.
-
Journal Title
J.Antibiotics. 54
Pages: 382-385
Description
「研究成果報告書概要(欧文)」より
Related Report
-
[Journal Article] Otoguro, K., Harigaya, Y., and Omura, S.2001
Author(s)
Sunazuka, T., Handa, M., Nagai, K., Kimura, R., Shirahata, T., Tian, Z-M.
-
Journal Title
Determination of Absolute Stereochemistries of Arisugacin F, and Territrem B 54
Pages: 386-391
Description
「研究成果報告書概要(欧文)」より
Related Report
-
-
-
-
[Journal Article] Total Synthesis of (+)-Madindoline A and (-)-Madindoline B, Potent Inhibitors of Interleukin 62000
Author(s)
Sunazuka, T., Hirose, T., Shirahata, T., Harigaya, Y., Hayashi, M., Komiyama, K., Omura, S.
-
Journal Title
J.Am.Chem.Soc. 122
Pages: 2122-2123
Description
「研究成果報告書概要(欧文)」より
Related Report
-
-
-
-
-
