Lead identification of conformationally restricted β-lactam type combretastatin analogues: Synthesis, antiproliferative activity and tubulin targeting effects
作者:Miriam Carr、Lisa M. Greene、Andrew J.S. Knox、David G. Lloyd、Daniela M. Zisterer、Mary J. Meegan
DOI:10.1016/j.ejmech.2010.09.033
日期:2010.12
The synthesis and study of the structure–activity relationships of a series of rigid analogues of combretastatin A-4 are described which contain the 1,4-diaryl-2-azetidinone (β-lactam) ring system in place of the usual ethylene bridge present in the natural combretastatin stilbene products. The 1,4-diaryl-2-azetidinones are unsubstituted at C-3, or contain methyl substituent(s) at C-3. The most potent
描述了一系列康布雷他汀A-4刚性类似物的合成和结构-活性关系的研究,这些类似物包含1,4-二芳基-2-氮杂环丁酮(β-内酰胺)环系统,代替了现有的乙烯桥在天然康美他汀二苯乙烯产品中。1,4-二芳基-2-氮杂环丁酮在C-3处未被取代,或在C-3处含有一个或多个甲基取代基。当针对MCF-7和MDA-MB-231人乳腺癌细胞系进行评估时,最有效的化合物12d和12e在纳摩尔浓度下显示出抗增殖活性。12d通过抑制微管蛋白聚合和随后的G 2发挥抗有丝分裂作用/ M抑制人MDA-MB-231乳腺癌细胞的细胞周期,其活性与CA-4相似。这些新的β-内酰胺化合物被认为是潜在的有用的支架,可用于进一步开发靶向微管蛋白的抗肿瘤剂。