A series of compounds containing the sulfonamide scaffold were synthesized andscreened for their in vitro anticancer activity against a representative panel of human cancer cell lines, leading to the identification ofN-(2-methyl-1H-indol-5-yl)-1-naphthalenesulfonamide (8e) as a compound showing a remarkable activity across the panel, with IC50 values in the nanomolar-to-low micromolar range. Cell cycle distribution analysis revealed that 8e promoted a severe G2/M arrest, which was followed by cellular senescence as indicated by the detection of senescence-associated beta-galactosidase (SA-beta-gal) in 8e-treated cells. Prolonged 8e treatment also led to the onset of apoptosis, in correlation with the detection of increased Caspase 3/7 activities. Despite increasinggamma-H2A.X levels, a well-established readout for DNA double-strand breaks, in vitro DNA binding studies with 8e did not support interaction with DNA. In agreement with this, 8e failed to activate the cellular DNA damage checkpoint. Importantly, tubulin staining showed that 8e promoted a severe disorganization of microtubules and mitotic spindle formation was not detected in 8e-treated cells. Accordingly, 8e inhibited tubulin polymerization in vitro in a dose-dependent manner andwas also able to robustly inhibit cancer cell motility. Docking analysis revealed a compatible interaction with the colchicine-binding site of tubulin. Remarkably, thesecellular effects were reversible since disruption of treatment resulted in the reorganization of microtubules, cell cycle re-entry and loss of senescent markers. Collectively, our data suggest that this compound may be a promising new anticancer agent capable of both reducing cancer cell growth and motility.

中文翻译：

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N-（2-甲基-吲哚-1H-5-基）-1-萘磺酰胺：一种新型可逆的抗有丝分裂剂，可抑制癌细胞的运动。

合成了一系列含有磺酰胺骨架的化合物，并筛选了其对人癌细胞系代表性细胞的体外抗癌活性，从而鉴定了N-（2-甲基-1H-吲哚-5-基）-1-萘磺酰胺（8e）作为化合物在整个面板上均显示出显着的活性，IC50值在纳摩尔至低微摩尔范围内。细胞周期分布分析表明，8e促进了严重的G2 / M阻滞，随后检测到8e处理过的细胞中与衰老相关的β-半乳糖苷酶（SA-β-gal），表明细胞发生了衰老。延长的8e治疗还导致凋亡的发生，与Caspase 3/7活性增加的检测有关。尽管γ-H2A.X水平增加，但DNA双链断裂的公认读数，用8e进行的体外DNA结合研究不支持与DNA的相互作用。与此相符，8e无法激活细胞DNA损伤检查点。重要的是，微管蛋白染色显示8e促进了微管的严重混乱，并且在8e处理的细胞中未检测到有丝分裂纺锤体的形成。因此，8e在体外以剂量依赖性方式抑制微管蛋白聚合，并且还能够强烈抑制癌细胞的运动性。对接分析显示与微管蛋白的秋水仙碱结合位点相容的相互作用。值得注意的是，这些细胞作用是可逆的，因为治疗的中断导致微管的重组，细胞周期的重新进入和衰老标记的丧失。总的来说，