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

Abstract

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.

Serotonin type-3 receptor antagonists selectively kill melanoma cells through classical apoptosis, microtubule depolymerisation, ERK activation, and NF-κB downregulation

“…Indole-3-carboxylic acid and arylthioindole derivatives have been widely used as potent inhibitors of tubulin polymerisation and cancer cell growth (La Regina et al 2018;Duan et al 2016). Given the similarity in structure of OND and TRO to these compounds, it was hypothesized that one possible mechanism of action could be through inhibition of tubulin polymerisation.…”

Synthesis, spectral analysis and in vitro cytotoxicity of diorganotin (IV) complexes derived from indole‐3‐butyric hydrazide

“…[25][26][27][28][29][30][31][32][33][34] Indoles are widely distributed heterocyclic compounds having medicinal importance e.g.-Tryptophan, a natural occurring essential amino acid which is used as precursor for auxin (indole-3-acetic acid-IAA), a plant regulating hormone and used as secondary metabolites, vincristine and vindesine, natural indole alkaloids is used in treatment of leukemia and as antitumor agent, brassinin which is used against microorganism and mitomycin is natural antibiotic used as anticancer and DNA cross linking agents. [35][36][37][38][39] Keeping in view the medicinal and biological activities of indole hydrazides and the impending application of organotins, here we join both the moieties in the search for designing biologically active candidates that could belligerently work against microbes and have some potential application in pharmacology. In the present study, we have synthesized diorganotin (IV) complexes of indole-3-butyric hydrazide.…”

In Silico Exploration of Novel Tubulin Inhibitors: A Combination of Docking and Molecular Dynamics Simulations, Pharmacophore Modeling, and Virtual Screening

“…The GH score method was used to evaluate the discriminative ability of the pharmacophore model in distinguishing active compounds from the inactive compounds from a testing set database including 20 known tubulin inhibitors and 600 inactive molecules [ 3 , 12 , 22 – 25 ]. The GH analysis by computing parameters such as total hits (Ht), active hits (Ha), enrichment factor ( E ), and goodness of hit score (GH) were performed ( Table 1 ).…”