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Synthetic Studies on Nitrogen-containing Spiro Compounds by Means of Aromatic Oxidation in Medicinal Chemistry

药物化学中芳香氧化合成含氮螺环化合物的研究

基本信息

批准号：
15590026
负责人：
HONDA Toshio
金额：
$ 2.3万
依托单位：
Faculty of Pharmaceutical Sciences, Hoshi University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2005
项目状态：
已结题

项目摘要

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 … More 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

含氮天然产物被认为是药物化学中寻找新药的重要候选物。其中，一些含氮的螺化合物表现出有趣的生物活性。例如，TAN1251A， B， C和D具有独特的结构特征，具有1,4-重氮双环[3.2.1]辛烷环体系和螺环环己酮，由武田工业从青霉RA-89中分离得到，具有胆碱能活性，ED_<50>值分别为8.0和10.0 nM，可抑制乙酰胆碱诱导的豚鼠回肠收缩。TAN1251A也被称为选择性毒蕈碱M_1亚型受体拮抗剂。由于TAN1251化合物具有良好的生物活性和独特的结构特征，我们研究了一种新的合成策略，我们认为可以通过高价碘试剂将…More仲胺进行分子内芳香族氧化来形成螺旋环。通过上述合成策略，我们成功地合成了光学纯净的(-)- tan 1251 a， C和D.Securinine是另一种具有生物活性的含氮螺旋体化合物，从Securinega suffruticasa中分离得到。该生物碱已在俄罗斯临床用作刺激中枢神经系统的药物，并已被证明在gabaa受体复合物的GABA结合位点作为立体特异性拮抗剂。Viroallosecurinine是securinine的非对映异构体生物碱，对铜绿假单胞菌和葡萄球菌的MIC均为0.48 μg/ml。葡萄球菌。由于MIC/MBC产率小于1，该生物碱被认为具有杀菌作用。经过对反应条件的仔细考察，我们首次建立了以闭合环复分解（RCM）为关键反应的非对映选择性手性合成securinine和viroallosecurinine。少