Department of Drug Chemistry and Technologies, Sapienza University of Rome, Laboratory Affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Piazzale Aldo Moro 5, I-00185 Roma, Italy.
Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, United States.
Eur J Med Chem. 2018 May 25;152:283-297. doi: 10.1016/j.ejmech.2018.04.042. Epub 2018 Apr 25.
We designed new 3-arylthio- and 3-aroyl-1H-indole derivatives 3-22 bearing a heterocyclic ring at position 5, 6 or 7 of the indole nucleus. The 6- and 7-heterocyclyl-1H-indoles showed potent inhibition of tubulin polymerization, binding of colchicine to tubulin and growth of MCF-7 cancer cells. Compounds 13 and 19 inhibited a panel of cancer cells and the NCI/ADR-RES multidrug resistant cell line at low nanomolar concentrations. Compound 13 at 50 nM induced 77% G2/M in HeLa cells, and at 20 nM caused 50% stable arrest of mitosis. As an inhibitor of HepG2 cells (IC = 20 nM), 13 was 4-fold superior to 19. Compound 13 was a potent inhibitor of the human U87MG glioblastoma cells at nanomolar concentrations, being nearly one order of magnitude superior to previously reported arylthioindoles. The present results highlight 13 as a robust scaffold for the design of new anticancer agents.
我们设计了新的 3-芳基硫代-和 3-芳基-1H-吲哚衍生物 3-22，它们在吲哚核的 5、6 或 7 位带有杂环。6-和 7-杂环基-1H-吲哚表现出对微管蛋白聚合的强烈抑制作用、与微管蛋白结合的秋水仙素和 MCF-7 癌细胞的生长。化合物 13 和 19 在低纳摩尔浓度下抑制了一系列癌细胞和 NCI/ADR-RES 多药耐药细胞系。化合物 13 在 50 nM 时诱导 HeLa 细胞中 77%的 G2/M，在 20 nM 时导致有丝分裂的 50%稳定停滞。作为 HepG2 细胞的抑制剂（IC=20 nM），13 比 19 强 4 倍。化合物 13 对纳摩尔浓度的人 U87MG 神经胶质瘤细胞具有很强的抑制作用，几乎比以前报道的芳基硫代吲哚高一个数量级。目前的结果突出了 13 作为设计新型抗癌药物的强大支架。
