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寻找药物化学新药的重要候选物，其中许多含氮螺环化合物具有独特的结构，例如TAN1251A、B、C和D。具有 1,4-二氮杂双环[3.2.1]辛烷环系统和螺环环己酮的特征，从青霉中分离出来Takeda Industries 的 RA-89 具有胆碱能活性，可抑制乙酰胆碱诱导的豚鼠回肠收缩，ED_<50> 值分别为 8.0 和 10.0 nM TAN1251A 也被称为选择性毒蕈碱 M_1 亚型受体拮抗剂。由于其有吸引力的生物活性及其独特的结构特征，我们研究开发了一种新的合成策略。 TAN1251化合物，我们认为可以通过使用高价碘试剂对仲胺进行分子内芳香氧化来形成碳氮键以生成螺环，通过应用上述合成策略，我们成功地实现了简单的合成。光学纯 (-)-TAN 1251 A、C 和 D.Securinine，从 Securinega suffruticasa 中分离出来，是另一种生物学上的这种生物碱已在俄罗斯临床上用作中枢神经系统刺激药物，并已被证明可作为 GABAA 受体复合物（一种非对映异构生物碱）的 GABA 结合位点的立体特异性拮抗剂。叶秋碱，也从 Securinega virosa 的叶子中分离出来，是一种细胞毒性生物碱，其 MIC 为 0.48 μg/ml，对铜绿假单胞菌和金黄色葡萄球菌具有杀菌作用，因为 MIC/MBC 的产率小于 1。经过仔细研究反应条件，我们可以建立第一个非对映选择性手性合成叶秋碱和病毒亚叶秋碱。采用闭环复分解（RCM）作为关键反应。