| Project/Area Number |
17590019
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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 | Meiji Pharmaceutical University |
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Principal Investigator |
KAWASAKI Tomomi Meiji Pharmaceutical University, Professor, 薬学部, 教授 (70161304)
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| Co-Investigator(Kenkyū-buntansha) |
SATOH Mitsutoshi Toho University, School of Pharmaceutical Sciences, Associate Professor, 薬学部, 助教授 (60231346)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2005: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Keywords | phenserine / acetylcholine esterase / amauromine / asymmetric reaction / pyrrolo-indole / Claisen rearrangement / structure-activity-relationship / Ugi reaction / フィゾスチグミン / 酵素阻害活性 |
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| Research Abstract |
We have developed our methodology of stereoselective and efficient domino reactions into synthesis of biologically active pyrrolo-indole compounds such as phenserine derivatives (acetylcholine esterase inhibitor) and amauromine (antihypertensive),
1. Phenserine derivatives with a variety of substituents at 3a-site and on phenylcarbamoyl moiety were prepared by the tandem olefination, isomerization and Claisen rearrangement of 2-allyloxyindolin-3-ones followed by reductive cyclization as the key-steps. The asymmetric syntheses of phenserine derivatives have been also accomplished efficiently. As its further application to construction of 3a-oxyganated phenserine, we have achieved the total synthesis 3a-hydroxypyrrolo-indole, alline.
2. The evaluation of these compounds as choline esterase (ChE) inhibitor was assessed against human AChE and BChE in vitro, alongside and compared to the activity of phenserine. Some of these tested compounds have shown the selectively moderate anti-AChE activity, but lacked anti-BChE activity.
3. We have achieved the total syntheses of fructigenine A and verrucofortine as the amauromine analogues using Ugi reaction of pyrrolo-indole imine with isonitrile and the corresponding amino acid followed by cyclization-epimerization as the key-process. The bioactive test of other type of phenserine derivatives and synthesis of amauromine and its analogues are now in progress.
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