Synthesis and biological evaluation of indole-2-carbohydrazides and thiazolidinyl-indole-2-carboxamides as potent tubulin polymerization inhibitors

• Published in: Computational biology and chemistry 2019-06, Vol.80, p.512-523
• Main Authors: Kazan, Fusun, Yagci, Z. Begum, Bai, Ruoli, Ozkirimli, Elif, Hamel, Ernest, Ozkirimli, Sumru
• Format: Article
• Language: English
• Subjects: Anticancer activity; Indole-2-carbohydrazides; Molecular docking; Thiazolidinyl-indole; Tubulin polymerization
• ISSN: 1476-9271; 1476-928X
• DOI: 10.1016/j.compbiolchem.2019.05.002

[Display omitted] •Novel indole-2-carbohydrazides (5,6) and indole-2-carboxamides (7,8) were synthesized.•5a and 6b showed antiproliferative properties at nanomolar concentration.•6 g and 6f showed high potential as tubulin polymerization inhibitors.•Binding modes of 6 g and 6f were identified via molecular docking simulations.•Synthesized compounds may serve as scaffolds for novel anticancer chemotherapeutics. A new series of N’-(substituted phenyl)-5-chloro/iodo-3-phenyl-1H-indole-2-carbohydrazide (5, 6) and N-[2-(substituted phenyl)-4-oxo-1,3-thiazolidin-3-yl]-5-iodo/chloro-3-phenyl-1H-indole-2-carboxamide (7, 8) derivatives were synthesized and evaluated for their anticancer properties. Compounds 5a and 6b, selected as prototypes by the National Cancer Institute for screening against the full panel of 60 human tumor cell lines at a minimum of five concentrations at 10-fold dilutions, demonstrated remarkable antiproliferative activity against leukemia, non-small cell lung cancer, colon cancer, central nervous system (CNS) cancer, melanoma, ovarian cancer, renal cancer, and breast cancer (MCF-7) cell lines with GI50 values < 0.4 μM. A subset of the compounds was then tested for their potential to inhibit tubulin polymerization. Compounds 6f and 6g showed significant cytotoxicity at the nM level on MCF-7 cells and exhibited significant inhibitory activity on tubulin assembly and colchicine binding at about the same level as combretastatin A-4. Finally, docking calculations were performed to identify the binding mode of these compounds. Group 5 and 6 compounds interacted with the colchicine binding site through hydrophobic interactions similar to those of colchicine. These compounds with antiproliferative activity at high nanomolar concentration can serve as scaffolds for the design of novel microtubule targeting agents.