Novel indole-pyrazole hybrids as potential tubulin-targeting agents; Synthesis, antiproliferative evaluation, and molecular modeling studies

• Published in: Journal of molecular structure Vol. 1285; p. 135477
• Main Authors: Hawash, Mohammed, Ergun, Sezen Guntekin, Kahraman, Deniz Cansen, Olgac, Abdurrahman, Hamel, Ernest, Cetin-Atalay, Rengul, Baytas, Sultan Nacak
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 05.08.2023
• Subjects: Cancer; Hepatocellular carcinoma; Indole-pyrazole; Tubulin polymerization inhibitor; Hepatocellular carcinoma; Tubulin polymerization inhibitor; Indole-pyrazole; Cancer; indole-pyrazole; cancer; tubulin polymerization inhibitor; hepatocellular carcinoma
• ISSN: 0022-2860; 1872-8014
• DOI: 10.1016/j.molstruc.2023.135477

•Synthesis, characterization and biological evaluation of indole-pyrazole derivatives as anticancer agents.•Compounds 10, 11 and 18 showed potent activity against the hepatocellular cancer cell lines, with IC50 values in the range 0.6-4.3 µM.•Compound 18 showed significant inhibitory activity against tubulin polymerization with IC50 value of 19 µM.•The Molecular docking studies showed that pyrazole, indole, and methoxy sections of compound 18 forms hydrogen bonds with various amino acids in the colchicine binding site. Structurally diverse indole-3-pyrazole-5-carboxamide analogues (10-29) were designed, synthesized, and evaluated for their antiproliferative activity against three cancer cell lines (Huh7, MCF-7, and HCT116) using the sulforhodamine B assay. Some of the derivatives showed anticancer activities equal to or better than sorafenib against cancer cell lines. Compounds 18 showed potent activity against the hepatocellular cancer (HCC) cell lines, with IC50 values in the range 0.6-2.9 µM. Compound 18 also exhibited moderate inhibitory activity against tubulin polymerization (IC50 = 19 µM). Flow cytometric analysis of cultured cells treated with 18 also demonstrated that the compound caused cell cycle arrest at the G2/M phase in both Huh7 and Mahlavu cells and induced apoptotic cell death in HCC cells. Docking simulations were performed to determine possible modes of interaction between 18 and the colchicine site of tubulin and quantum mechanical calculations were performed to observe the electronic nature of 18 and to support docking results. [Display omitted]