Development of nimesulide analogs as a dual inhibitor targeting tubulin and HSP27 for treatment of female cancers

Abstract

In drug repurposing paradigm, medicines that are already used to treat specific disease can also treat alternative ones. Recently, nimesulide was reported as an antitumor agent, beside its anti-inflammatory effect. Tubulin and heat shock protein 27 (HSP27) are attractive targets for the discovery of anticancer therapy because both are up regulated in cancer cells. In this regard, this study aims to develop nimesulide skeleton, synthesize, characterize, and biologically evaluate the new nimesulide analogs as anticancer agents through the inhibition of tubulin and HSP27 functions. The synthesized agents were characterized by 1H NMR, 13C NMR, IR, melting point and both endothermic and exothermic DSC analysis. The molecular weight was confirmed using GC–MS technique. N-(3-((2,5-dichlorobenzyl)oxy)-4-(N-methylmethylsulfonamido)phenyl)-4-iodobenzamide (agent L4) structure was confirmed using X-ray crystallographic analysis. The ligands adopt triclinic crystal with a = 8.194(14) Å, b = 10.75(3) Å, c = 14.21(2) Å and space group of P-1. Western blot analysis was used to express the presence of the dual proteins on the harvested SKOV3 and SKBR3 cell lines. The anticancer effect of nimesulide analogs was studied using MTT assay on SKOV3 and SKBR3 cell lines as a surrogate model for ovarian cancer, and breast cancer respectively. The present results indicated that the developed nimesulide analogs elicited cytotoxicity against SKOV3 and SKBR3 cell lines in turn cell cycle arrest, in the concentration range between 0.23–2.02 µM and 0.50–3.73 µM respectively. This study concluded that nimesulide analogues are potent promising agents for the repurposing of nimesulide as future chemotherapy for female cancers.