Design, synthesis and biological evaluation of novel naphthoquinone-4-aminobenzensulfonamide/carboxamide derivatives as proteasome inhibitors


Uysal Ş. , Soyer Z. , Saylam M., Tarikogullari A., Yilmaz S. , Kirmizibayrak P.

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol.209, 2021 (Journal Indexed in SCI) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 209
  • Publication Date: 2021
  • Doi Number: 10.1016/j.ejmech.2020.112890
  • Title of Journal : EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
  • Keywords: Proteasome inhibitor, Antiproliferative activity, Naphthoquinone, Sulfonamide/carboxamide, Molecular docking, Synthesis, 20S PROTEASOME, GENETIC ALGORITHM, UBIQUITIN, CANCER, GENERATION, RESOLUTION, PARTICLE, SERIES

Abstract

A series of novel 4-aminobenzensulfonamide/carboxamide derivatives bearing naphthoquinone pharmacophore were designed, sythesized and evaluated for their proteasome inhibitory and anti-proliferative activities against human breast cancer cell line (MCF-7). The structures of the synthesized compounds were confirmed by spectral and elemental analyses. The proteasome inhibitory activity studies were carried out using cell-based assay. The antiproteasomal activity results revealed that most of the compounds exhibited inhibitory activity with different percentages against the caspase-like (C-L, beta 1 subunit), trypsin-like (T-L, beta 2 subunit) and chymotrypsin-like (ChT-L, beta 5 subunit) activities of proteasome. Among the tested compounds, compound 14 bearing 5-chloro-2-pyridyl ring on the nitrogen atom of sulfonamide group is the most active compound in the series and displayed higher inhibition with IC50 values of 9.90 +/- 0.61, 44.83 +/- 4.23 and 22.27 +/- 0.15 mu M against ChT-L, C-L and T-L activities of proteasome compared to the lead compound PI-083 (IC50 = 12.47 +/- 0.21, 53.12 +/- 2.56 and 26.37 +/- 0.5 mu M), respectively. The antiproliferative activity was also determined by MTT (3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide) assay in vitro. According to the antiproliferative activity results, all of the compounds exhibited cell growth inhibitory activity in a range of IC50 = 1.72 +/- 0.14-20.8 +/- 0.5 mu M and compounds 13 and 28 were found to be the most active compounds with IC50 values of 1.79 +/- 0.21 and 1.72 +/- 0.14 mu M, respectively. Furthermore, molecular modeling studies were carried out for the compounds 13, 14 and 28 to investigate the ligand-enzyme binding interactions. (c) 2020 Elsevier Masson SAS. All rights reserved.