Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Eur J Med Chem. 2024 Jul 5;273:116509. doi: 10.1016/j.ejmech.2024.116509. Epub 2024 May 16.
A series of novel carbazole sulfonamide derivatives were synthesized and evaluated for antiproliferative activity. Among them, compounds 7 and 15 showed strong potency (IC values of 0.81-31.19 nM) against five different cancer cells including multidrug-resistant MCF7/ADR cells. Compound 15 displayed a high cancer cell selectivity (IC(L02)/average IC: SI = 7.7). The l-valine prodrug 7a and the phosphate prodrug 15a exerted rohust in vivo antitumor efficacies and accepted safety prolifes. Further mechanism studies revealed that 7 and 15 directly bind to the colchicine site in tubulin to block tubulin polymerization, promote microtubule fragmentation at the cellular level, and induce apoptosis with G2/M cell cycle arrest. These compounds also inhibit HEMC-1 cells migration and vascular tube formation. Additionally, compound 7 displayed a selective inhibition of Topo I. Collectively, these studies suggest that 7 and 15 represents a promising new generation of tubulin inhibitors for cancer treatment.
一系列新型咔唑磺酰胺衍生物被合成并评估其抗增殖活性。其中，化合物 7 和 15 对包括多药耐药 MCF7/ADR 细胞在内的五种不同癌细胞表现出很强的活性（IC 值为 0.81-31.19 nM）。化合物 15 表现出很高的癌细胞选择性（IC（L02）/平均 IC：SI=7.7）。L-缬氨酸前药 7a 和磷酸前药 15a 在体内显示出强大的抗肿瘤疗效和可接受的安全性。进一步的机制研究表明，7 和 15 直接与微管蛋白上的秋水仙碱结合位点结合，阻止微管蛋白聚合，在细胞水平促进微管的断裂，并诱导细胞周期 G2/M 期阻滞的细胞凋亡。这些化合物还抑制 HEMC-1 细胞的迁移和血管管腔形成。此外，化合物 7 显示出对拓扑异构酶 I 的选择性抑制作用。综上所述，这些研究表明 7 和 15 代表了一类有前途的新型微管抑制剂，可用于癌症治疗。
