Antitubulin effects of aminobenzothiophene-substituted triethylated chromones
Antitubulin effects of aminobenzothiophene-substituted triethylated chromones
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氨基苯并噻吩取代的三乙基色酮的抗微管蛋白作用
DOI：
10.1016/j.bmcl.2017.04.055
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发表时间：
2017
影响因子：
2.7
通讯作者：
Nakagawa-Goto Kyoko
中科院分区：
文献类型：
--
作者：
Kobayashi Yukiko;Saito Yohei;Goto Masuo;Nakagawa-Goto Kyoko
在我们对 2-(苯并[b]噻吩-3′-基)-6,8,8-三乙基去链杜莫汀 B (TEDB-TB) 系列的持续研究过程中，我们设计并合成了九种氨基-TEDB-TB 衍生物，以改善药物特性、确定结构活性关系并发现新型抗微管蛋白药物。在所有新合成的氨基-TEDB-TB中，5'-和6'-氨基衍生物6和7对五种人类肿瘤细胞系（包括过度表达P-gp的MDR亚系）表现出显着的抗增殖活性。 0.50–1.01 µM 的 IC50 值比之前报道的羟基-TEDB-TB 好 3–6 倍。化合物6和7抑制微管蛋白聚合，诱导间期微管解聚和多纺锤体形成，并导致细胞停滞在中期。在所有化合物中，化合物 7 在药学上得分最高，LogP 2.11，在生物学上得分最高，具有更强的抗增殖活性和诱导细胞周期停滞于中期。
In the course of our continuing studies on the 2-(benzo[b]thiophene-3′-yl)-6,8,8-triethyldesmosdumotin B (TEDB-TB) series, we designed and synthesized nine amino-TEDB-TB derivatives to improve pharmaceutical properties, identify structure activity relationships, and discover novel antitubulin agents. Among all newly synthesized amino-TEDB-TBs, the 5′- and 6′-amino derivatives,6and7, exhibited significant antiproliferative activity against five human tumor cell lines, including an MDR subline overexpressing P-gp. The IC50values of 0.50–1.01 µM were 3–6 times better than those of previously reported hydroxy-TEDB-TBs. Compounds6and7inhibited tubulin polymerization, induced both depolymerization of interphase microtubules and multiple spindle formations, and caused cell arrest at prometaphase. Among all compounds, compound7scored best pharmaceutically with LogP 2.11 and biologically with greater antiproliferative activity and induction of cell cycle arrest at prometaphase.