多样性导向合成螺环吲哚类天然产物及其初步活性的评价

Diversity-oriented syntheses of natural-like dispirooxindole derivatives and their preliminary activity evaluation

目的探索多样性导向合成类天然产物的方法,寻找具潜在药理活性的分子。方法利用各种靛红衍生物与氨基酸衍生物原位生成亚胺叶立德,在温和条件下与取代苄基-2-苯基噁唑酮发生具有区域选择性和立体选择性的1,3-偶极环化反应,一锅法生成连接噁唑酮、螺环吲哚-四氢吡咯、吡咯里西啶和吡咯并噻唑的结构复杂的类天然产物;利用计算机辅助药物设计方法鉴定潜在的靶点和已合成化合物的ADMET性质,并进行细胞活性筛选。结果建立了一种快速有效构建复杂类天然产物库的方法,经过基于计算机辅助药物设计和体外筛选的方法得到一个具有潜在抗肿瘤活性的先导化合物。结论所用方法对寻找和发现具有药理活性的先导化合物具较好的可行性。

OBJECTIVE To explore Diversity - oriented synthesis of natural - like dispirooxindole derivatives and find potential pharmacological compounds. METHODS Natural - like products with oxazolones - grafted spirooxindole - pylTolidine, pyrrolizidines and pyrrolothiazoles were prepared using regio - and stereoselectively via 1,3 - dipolar cyeloaddition of substituted benzylidene - 2 - phenyloxazolone under mild conditions with azomethine ylides, which were generated in situ by a decarboxylative route from a common set of diverse isatins and amino acid derivatives. In silico drug discovery and computational methods were used to identify potential tar- gets and the ADMET properties of synthetic compounds library. And a screening for cytotoxic activities against a spectrum of cell - lines was performed. RESULTS An effective method to rapidly construct a chemical library of hybrid heterocycles was established and a good lead compound for subsequent optimization was found. CONCLUSION This method is a feasible way to find potential pharmaco- logical lead compounds.