2. Academic Validation
  3. Novel Indole-Pyrazole Hybrids as Potential Tubulin-Targeting Agents; Synthesis, antiproliferative evaluation, and molecular modeling studies

Novel Indole-Pyrazole Hybrids as Potential Tubulin-Targeting Agents; Synthesis, antiproliferative evaluation, and molecular modeling studies

  • J Mol Struct. 2023 Aug 5;1285:135477. doi: 10.1016/j.molstruc.2023.135477.
Mohammed Hawash 1 2,  Sezen Guntekin Ergun 3 4,  Deniz Cansen Kahraman 3,  Abdurrahman Olgac 1,  Ernest Hamel 5,  Rengul Cetin-Atalay 3,  Sultan Nacak Baytas 1
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, 06330, Ankara, Turkey.
  • 2 Department of Pharmacy, Faculty of Medicine and Health Sciences, An-Najah National University, 00970, Nablus, Palestine.
  • 3 Cancer Systems Biology Laboratory, Graduate School of Informatics, Middle East Technical University, 06800, Ankara, Turkey.
  • 4 Department of Medical Biology, Hacettepe University, 06100, Ankara, Turkey.
  • 5 Molecular Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702, USA.
PMID: 37234266 DOI: 10.1016/j.molstruc.2023.135477
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 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.

Keywords

cancer; hepatocellular carcinoma; indole-pyrazole; tubulin polymerization inhibitor.

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