Abstract

2- or 4-Substituted 3-N-benzyltriazolylmethyl-13α-oestrone derivatives were synthesised via bromination of ring A and subsequent microwave-assisted, Pd-catalysed C(sp²)–P couplings. The antiproliferative activities of the newly synthesised brominated and phosphonated compounds against a panel of human cancer cell lines (A2780, MCF-7, MDA-MB 231) were investigated by means of MTT assays. The most potent compound, the 3-N-benzyltriazolylmethyl-4-bromo-13α-oestrone derivative exerted substantial selective cell growth-inhibitory activity against A2780 cell line with a submicromolar IC₅₀ value. Computational calculations reveal strong interactions of the 4-bromo derivative with both colchicine and taxoid binding sites of tubulin. Disturbance of tubulin function has been confirmed by photometric polymerisation assay.

摘要

通过环A的溴化和随后的微波辅助，Pd催化的C（sp ²）-P偶联，合成了2-或4-取代的3- N-苄基三唑基甲基-13α-雌酮衍生物。通过MTT试验研究了新合成的溴化和膦化化合物对一组人类癌细胞系（A2780，MCF-7，MDA-MB 231）的抗增殖活性。最有效的化合物3- N-苄基三唑基甲基-4-溴-13α-雌酮衍生物具有亚微摩尔IC _50，对A2780细胞系具有明显的选择性细胞生长抑制活性。值。计算结果表明4-溴衍生物与微管蛋白的秋水仙碱和紫杉醇结合位点有很强的相互作用。通过光度聚合测定法已证实微管蛋白功能紊乱。