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


Hawash M., Ergun S. G., KAHRAMAN D. C., OLĞAÇ A., Hamel E., Cetin-Atalay R., ...More

JOURNAL OF MOLECULAR STRUCTURE, vol.1285, 2023 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 1285
  • Publication Date: 2023
  • Doi Number: 10.1016/j.molstruc.2023.135477
  • Journal Name: JOURNAL OF MOLECULAR STRUCTURE
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, Chemical Abstracts Core, Chimica, Compendex, INSPEC
  • Keywords: Indole-pyrazole, Cancer, Hepatocellular carcinoma, Tubulin polymerization inhibitor
  • Gazi University Affiliated: Yes

Abstract

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 mu M. Compound 18 also exhibited moderate inhibitory activity against tubulin polymerization (IC50 = 19 mu M). 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.(c) 2023 Elsevier B.V. All rights reserved.