2005 Fiscal Year Final Research Report Summary
Synthetic Studies on Nitrogen-containing Spiro Compounds by Means of Aromatic Oxidation in Medicinal Chemistry
Project/Area Number |
15590026
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Single-year Grants |
Section | 一般 |
Research Field |
Chemical pharmacy
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Research Institution | Faculty of Pharmaceutical Sciences, Hoshi University |
Principal Investigator |
HONDA Toshio Hoshi University, Faculty of Pharmaceutical Sciences, Professor, 薬学部, 教授 (70089788)
|
Co-Investigator(Kenkyū-buntansha) |
KATOH Miho Hoshi University, Faculty of Pharmaceutical Sciences, Research Associate, 薬学部, 助手 (40350219)
HONDA Toshio Hoshi University, Faculty of Pharmaceutical Sciences, Professor (70089788)
|
Project Period (FY) |
2003 – 2005
|
Keywords | nitrogen spiro-compounds / hyper-valent iodine reagent / (-)-TAN1251 series of compounds / ring-closing metathesis / viroallosecurinine / securinine / aromatic oxidation / biologically active compounds |
Research Abstract |
Nitrogen-containing natural products were recognized to be important candidates for searching new drugs in medicinal chemistry. Among them, a number of nitrogen-containing spiro-compounds exhibit interesting biological activities. For example, TAN1251A, B, C and D, having unique structural features with a 1,4-diazabicyclo[3.2.1]octane ring system and a spirocyclic cyclohexanone, isolated from a Penicillium thomii RA-89 by Takeda Industries, exhibit cholinergic activity and inhibit the acetylcholine-induced contraction of Guinea-pig ileum with ED_<50> values of 8.0 and 10.0 nM, respectively. TAN1251A is also known as a selective muscarinic M_1 subtype receptor antagonist. Due to the attractive biological activities and also their unique structural features, we investigated to develop a novel strategy for the synthesis of TAN1251 compounds, in which we thought that the carbon-nitrogen bond formation to generate a spirocyclic ring could be achieved by intramolecular aromatic oxidation of
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secondary amine using hypervalent iodine reagent. By applying the above synthetic strategy, we have succeeded in a facile synthesis of optically pure (-)-TAN 1251 A, C, and D. Securinine, isolated from Securinega suffruticasa, was another biologically active nitrogen-containing spiro-compound. This alkaloid has been clinically used in Russia as a CNS stimulating drug, and has been shown to act as a stereospecific antagonist at the GABA biding site of the GABAA-receptor complex. Viroallosecurinine, a diastereoisomeric alkaloid of securinine, was also isolated from the leaves of Securinega virosa as a cytotoxic alkaloid exhibiting a MIC of 0.48 μg/ml for Ps. aeruginosa and Staph. aureus. This alkaloid is recognized to be bactericidal since the yields of MIC/MBC were less than 1. After careful investigation of reaction conditions, we could establish the first diastereoselective chiral synthesis of securinine and viroallosecurinine by employing ring-closing metathesis (RCM) as the key reaction. Less
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Research Products
(14 results)