Dipartimento Scienze del Farmaco, Università degli Studi di Sassari, Via Muroni 23/a, 07100 Sassari, Italy.
Eur J Med Chem. 2011 Sep;46(9):4151-67. doi: 10.1016/j.ejmech.2011.06.018. Epub 2011 Jul 8.
During a screening for compounds that could act against Mycobacterium tuberculosis, a series of new cellular antiproliferative agents was identified. The most cytotoxic molecules were evaluated against a panel of human cell lines derived from hematological and solid human tumors. In particular, (E)-2-(1H-benzo[d] [1,2,3]triazol-1-yl)-3-(4-methoxyphenyl)acrylonitrile (1) was found to be of a potency comparable to etoposide and greater than 6-mercaptopurine in all cell lines tested. Accordingly, a synthesis of a new series of (E)-2-(5,6-dichloro-1H-benzo[d] [1,2,3]triazol-1-yl)-3-(4-R-phenyl)acrylonitriles was conducted in order to extend the studies of structure-activity relationship (SAR) for this class of molecules. With the aim to evaluate if 3-aryl-2-[1H-benzotriazol-1-yl]acrylonitriles were able to act like tubulin binding agents, the effects on cell cycle distribution of the most active compounds (1, 2a, 3 and 4) were analyzed in K562 cells. A detailed molecular modeling study of the putative binding mode of this series of compounds on tubulin is also reported.
在筛选能够对抗结核分枝杆菌的化合物期间，发现了一系列新的细胞增殖抑制剂。评估了最具细胞毒性的分子对来自血液学和实体人类肿瘤的人类细胞系的面板。特别是，（E）-2-（1H-苯并[d] [1,2,3]三唑-1-基）-3-（4-甲氧基苯基）丙烯腈（1）被发现具有与依托泊苷相当的效力，并且在所有测试的细胞系中均大于 6-巯基嘌呤。因此，进行了一系列新的（E）-2-（5,6-二氯-1H-苯并[d] [1,2,3]三唑-1-基）-3-（4-R-苯基）丙烯腈的合成，以扩展此类分子的构效关系（SAR）研究。为了评估 3-芳基-2-[1H-苯并三唑-1-基]丙烯腈是否能够像微管结合剂一样起作用，分析了最活性化合物（1、2a、3 和 4）对 K562 细胞的细胞周期分布的影响。还报告了该系列化合物与微管结合的可能结合模式的详细分子建模研究。
