Institut Curie, Centre de Recherche, 26 rue d'Ulm, F-75005 Paris, France.
Eur J Med Chem. 2012 Aug;54:22-32. doi: 10.1016/j.ejmech.2012.04.017. Epub 2012 May 9.
To find new and better antivascular agents for cancer therapy, a series of combretastatin A4 (CA4) analogs were prepared from 1,3-diaryl-2-nitroprop-1-enes (6-12) obtained in a two-step synthesis from appropriate arylaldehydes and 2-aryl-1-nitroethanes (4 or 5). Treatment of these 1,3-diaryl-2-nitroprop-1-enes 6-12 by sodium azide in DMSO yielded the targeted compounds. The synthesized 1,2,3-triazoles disubstituted in 4- and 5-positions by one benzyl group and one aryl nucleus have also been tested for biological activities involved in antivascular action. It was found that several new compounds exhibited interesting biological activities in the nanomolar or low micromolar range, in terms of rounding up of endothelial cells, inhibition of tubulin polymerization, and cytotoxicity on B16 melanoma cancer cells. In silico docking studies of 11 and 19 within the active site of tubulin were also carried out in order to rationalize the inhibitory properties of these compounds and further understand their inhibition mechanism. In vivo evaluation of compounds 11 and 19 in mice bearing colon 26 carcinoma indicated modest anticancer activity.
为了寻找新的、更好的癌症治疗抗血管生成药物，我们从适当的芳基醛和 2-芳基-1-硝基乙烷（4 或 5）合成的两步法中获得的 1,3-二芳基-2-硝基-1-丙烯（6-12）中制备了一系列 combretastatin A4（CA4）类似物。将这些 1,3-二芳基-2-硝基-1-丙烯 6-12 通过叠氮化钠在 DMSO 中处理，得到目标化合物。还测试了用一个苄基和一个芳核取代 4-和 5-位的合成的 1,2,3-三唑在抗血管生成作用方面的生物活性。结果发现，一些新化合物在纳米摩尔或低微摩尔范围内表现出有趣的生物活性，表现在内皮细胞圆化、微管蛋白聚合抑制和对 B16 黑色素瘤癌细胞的细胞毒性方面。还对 11 和 19 在微管蛋白活性部位的体内对接研究进行了计算机模拟，以合理化这些化合物的抑制特性，并进一步了解它们的抑制机制。在携带结肠 26 癌的小鼠体内对化合物 11 和 19 的评价表明，它们具有适度的抗癌活性。
