Dupeyre Grégory, Chabot Guy G, Thoret Sylviane, Cachet Xavier, Seguin Johanne, Guénard Daniel, Tillequin François, Scherman Daniel, Koch Michel, Michel Sylvie
Université Paris 5, Faculté des Sciences Pharmaceutiques et Biologiques, UMR 8638 CNRS, Laboratoire de Pharmacognosie, France.
Bioorg Med Chem. 2006 Jul 1;14(13):4410-26. doi: 10.1016/j.bmc.2006.02.037. Epub 2006 Mar 10.
Combretastatin A-4 (CSA-4), a stilbene derivative, is a potent vascular disrupting agent (VDA) with the structural requirement of a cis-configuration to maintain a molecular geometry and a correct orientation of both phenyl groups. A series of indolic analogues of CSA-4 was synthesized by means of an efficient strategy. Six compounds (20b, 25b-27b, 32b, and 35b) were identified as potent inhibitors of tubulin polymerization and also displayed cytotoxic activities on B16 melanoma cells at a nanomolar level. Both activities were well correlated with the ability to induce morphological changes of EA.hy 926 endothelial cells. In conclusion, the cis-stilbene skeleton of CSA-4 could conveniently be replaced by the 3-aroylindolic moiety, thus avoiding any isomerization leading to inactive trans compounds.
康普瑞他汀A-4（CSA-4）是一种芪类衍生物，是一种有效的血管破坏剂（VDA），其结构要求为顺式构型以维持分子几何形状和两个苯基的正确取向。通过一种有效的策略合成了一系列CSA-4的吲哚类似物。六种化合物（20b、25b - 27b、32b和35b）被鉴定为微管蛋白聚合的有效抑制剂，并且在纳摩尔水平对B16黑色素瘤细胞也表现出细胞毒性活性。这两种活性都与诱导EA.hy 926内皮细胞形态变化的能力密切相关。总之，CSA-4的顺式芪骨架可以方便地被3-芳酰基吲哚部分取代，从而避免任何导致无活性反式化合物的异构化。
