Abstract

Searching for improved indolesulfonamides with higher polarities, 45 new analogues with modifications on the sulfonamide nitrogen, the methoxyaniline, and/or the indole 3-position were synthesised. They show submicromolar to nanomolar antiproliferative IC₅₀ values against four human tumour cell lines and they are not P-glycoprotein substrates as their potencies against HeLa cells did not improve upon cotreatment with multidrug resistance (MDR) inhibitors. The compounds inhibit tubulin polymerisation in vitro and in cells, thus causing a mitotic arrest followed by apoptosis as shown by cell cycle distribution studies. Molecular modelling studies indicate binding at the colchicine site. Methylated sulfonamides were more potent than those with large and polar substitutions. Amide, formyl, or nitrile groups at the indole 3-position provided drug-like properties for reduced toxicity, with Polar Surface Areas (PSA) above a desirable 75 Ų. Nitriles 15 and 16 are potent polar analogues and represent an interesting class of new antimitotics.

摘要

为了寻找具有更高极性的改进的吲哚磺酰胺，合成了 45 种对磺酰胺氮、甲氧基苯胺和/或吲哚 3 位进行修饰的新类似物。它们对四种人类肿瘤细胞系显示出亚微摩尔至纳摩尔的抗增殖 IC ₅₀值，并且它们不是 P-糖蛋白底物，因为它们对 HeLa 细胞的效力在与多药耐药 (MDR) 抑制剂共同治疗后没有提高。这些化合物在体外抑制微管蛋白聚合并在细胞中，从而导致有丝分裂停滞，然后是细胞周期分布研究显示的细胞凋亡。分子建模研究表明在秋水仙碱位点结合。甲基化磺胺类药物比那些具有大的极性取代物的药物更有效。吲哚 3 位的酰胺、甲酰基或腈基团提供类似药物的特性以降低毒性，极性表面积 (PSA) 高于理想的 75 Å ²。腈类15和16是有效的极性类似物，代表了一类有趣的新型抗有丝分裂剂。