通过干扰微管蛋白动力学导致细胞凋亡的药物，例如长春花碱和紫杉醇，是一类重要的化疗药物。不幸的是，这些化合物是多药耐药性（MDR）泵的底物，使癌细胞对这些化疗药物产生耐药性。吲哚磺酰胺家族的微管蛋白抑制剂不被 MDR 泵排除，并且具有有前途的活性特征，尽管它们的高亲脂性是其临床使用的药代动力学限制。在这里，我们提出了一个新的 N-吲哚基-3,4,5-三甲氧基苯磺酰胺衍生物家族，其在吲哚系统的 1 和 3 位以及磺酰胺氮上进行了修饰。我们针对 HeLa 细胞合成并筛选了 34 种新型吲哚苯磺酰胺类药物。最有效的衍生物（1.7-109 nM）针对广泛的癌细胞系进行了测试，结果表明取代的苯磺酰胺类似物具有最高的效力。重要的是，这些化合物对非致瘤细胞仅具有中等毒性，表明存在治疗指数。与已知的临床抗微管蛋白药物一致，这些化合物将细胞周期阻滞在 G2/M 期。从机制上讲，它们通过在 M 停滞期间发生的 caspase 3/7 激活诱导细胞凋亡。磺酰胺氮上的取代基似乎决定了不同的机制结果和细胞命运。这些结果表明，这些化合物根据桥取代基的不同而发挥不同的作用，因此使它们作为机制探针以及进一步开发的潜在药物非常有趣。版权所有 © 2024 作者。由 Elsevier Masson SAS 出版。保留所有权利。

Agents that cause apoptotic cell death by interfering with tubulin dynamics, such as vinblastine and paclitaxel, are an important class of chemotherapeutics. Unfortunately, these compounds are substrates for multidrug resistance (MDR) pumps, allowing cancer cells to gain resistance to these chemotherapeutics. The indolesulfonamide family of tubulin inhibitors are not excluded by MDR pumps and have a promising activity profile, although their high lipophilicity is a pharmacokinetic limitation for their clinical use. Here we present a new family of N-indolyl-3,4,5-trimethoxybenzenesulfonamide derivatives with modifications on the indole system at positions 1 and 3 and on the sulfonamide nitrogen. We synthesized and screened against HeLa cells 34 novel indolic benzenesulfonamides. The most potent derivatives (1.7-109 nM) were tested against a broad panel of cancer cell lines, which revealed that substituted benzenesulfonamides analogs had highest potency. Importantly, these compounds were only moderately toxic to non-tumorigenic cells, suggesting the presence of a therapeutic index. Consistent with known clinical anti-tubulin agents, these compounds arrested the cell cycle at G2/M phase. Mechanistically, they induced apoptosis via caspase 3/7 activation, which occurred during M arrest. The substituents on the sulfonamide nitrogen appeared to determine different mechanistic results and cell fates. These results suggest that the compounds act differently depending on the bridge substituents, thus making them very interesting as mechanistic probes as well as potential drugs for further development.Copyright © 2024 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.