New 6- and 7-heterocyclyl-1H-indole derivatives as potent tubulin assembly and cancer cell growth inhibitors

3-Arylthio- and 3-aroyl-1H-indoles are potent inhibitors of tubulin polymerization and of cancer cell growth, by binding the colchicine site on β-tubulin. Several compounds of this class were more potent than colchicine, combretastatin A-4, vinblastine, and paclitaxel. Herein, we designed and synthesized new 3-arylthio- and 3-aroyl-1H-indole derivatives by shifting the heterocyclic ring from 2 to 5, 6 or 7 positions 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. 6-(Thiophen-3-yl)-3-((3,4,5-trimethoxyphenyl)thio)-1H-indole and 6-(thiophen-2-yl)-3-((3,4,5-trimethoxyphenyl)thio)-1H-indole inhibited a panel of cancer cells and the NCI/ADR-RES multidrug resistant cell line at low nanomolar concentrations. Thiophen-3-yl derivative at 50 nM induced 77% G2/M in HeLa cells, and at 20 nM caused 50% stable arrest of mitosis. Furthermore, the same compound was a potent inhibitor of the human U87MG glioblastoma cells at nanomolar concentrations, being nearly one order of magnitude superior to previously reported arylthioindoles.