Sulfonate Derivatives of Naphtho[2,3-<i>b</i>]thiophen-4(9<i>H</i>)-one and 9(10<i>H</i>)-Anthracenone as Highly Active Antimicrotubule Agents. Synthesis, Antiproliferative Activity, and Inhibition of Tubulin Polymerization
作者:Anne Zuse、Peter Schmidt、Silke Baasner、Konrad J. Böhm、Klaus Müller、Matthias Gerlach、Eckhard G. Günther、Eberhard Unger、Helge Prinz
DOI:10.1021/jm0708984
日期:2007.11.1
Benzenesulfonate derivatives of naphtho[2,3-b]thiophen-4(9H)-one and 9(10H)-anthracenone were prepared and found to inhibit microtubule formation by an in vitro tubulin polymerization assay. Several analogues showed potent cytotoxic activity in an assay based on K562 leukemia cells with IC50 values of <100 nM. The methylamino analogue 14i was the most active compound in this assay (14i, IC50 K562:
制备了萘并[2,3-b]噻吩-4(9H)-一和9(10H)-蒽酮的苯磺酸酯衍生物,并通过体外微管蛋白聚合试验发现抑制微管形成。在基于K562白血病细胞的测定中,IC50值小于100 nM的几种类似物显示出强大的细胞毒性活性。甲基氨基类似物14i是该测定法中活性最高的化合物(14i,IC50 K562:0.05μM)。此外,还针对一组12种肿瘤细胞系(包括多重耐药性表型)评估了所选化合物的抗增殖活性。所有抗性细胞系均对这些化合物敏感。浓度依赖性流式细胞术研究表明,用选定化合物处理的KB / HeLa细胞被阻滞在细胞周期的G2 / M期。在比赛实验中 这些化合物从微管蛋白的结合位点强烈取代了放射性标记的秋水仙碱,显示出的IC50值低于秋水仙碱。结果表明,抗增殖活性与微管蛋白聚合的抑制有关。