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., ...Daha Fazla

Journal of Molecular Structure, cilt.1285, 2023 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 1285
  • Basım Tarihi: 2023
  • Doi Numarası: 10.1016/j.molstruc.2023.135477
  • Dergi Adı: Journal of Molecular Structure
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, Chemical Abstracts Core, INSPEC
  • Anahtar Kelimeler: Cancer, Hepatocellular carcinoma, Indole-pyrazole, Tubulin polymerization inhibitor
  • Orta Doğu Teknik Üniversitesi Adresli: Evet

Özet

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.