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在医学化学中搜索新药的重要候选者。其中，许多含氮的螺旋体化合物表现出有趣的生物学活性。例如，TAN1251a，b，c和d具有独特的结构特征，具有1,4-二唑烷基环状[3.2.1]辛烷环系统和螺旋环环己酮，从thomii ra-89中分离出来，由thomii ra-89与thomii Industries分离出来，展示了与胆碱能的凝固性和抑制剂的糖尿病性刺激性构元的刺激性。 ed_ <50>分别为8.0和10.0 nm的值。 TAN1251A也被称为选择性毒蕈碱M_1亚型受体拮抗剂。由于具有吸引人的生物学活性及其独特的结构特征，我们研究了为合成TAN1251化合物的新策略，在这种策略中，我们认为，我们认为可以通过使用过度价值的碘含量的二次胺的含量芳族氧化物来实现碳氮键形成，以产生螺旋环。通过采用上述合成策略，我们成功地合成了光学纯的（ - ） - tan 1251 a，c和d.securinine，从Secuneinega suffruticasa分离出来，是另一种具有生物活性的氮气活性氮气化的弹药。该生物碱已在俄罗斯临床上用作中枢神经系统刺激药物，并已被证明是GABA受体受体复合物的GABA供电部位的立体特异性拮抗剂。 Viroallosecurinine是Securinine的映射生物碱，也从Securinega Virosa的叶子中分离出，作为一种细胞毒性生物碱，其MIC为PS为0.48μg/ml。铜绿和葡萄球菌。金黄色葡萄酒。由于MIC/MBC的产率小于1。在仔细研究反应条件后，我们可以通过使用环核酸和viroallosecurinine来建立第一个映射性手性手性，通过使用环环（RCM）作为关键反应来建立第一个映射的螺旋氨酸和viroallosecurinine的合成，因此可以建立第一个映射的乙酸和viroallosecurinine合成。较少的