Insight on novel sulfamoylphenyl pyrazole derivatives as anticancer carbonic anhydrase inhibitors.

Abstract

As another part continue for our previous study, variable substituted pyrazoles bearing sulfamoylphenyl moiety were synthesized and screened against two cancer related human carbonic anhydrase (hCA) isoforms and acetazolamide (AAZ) used as a reference standard. Some compounds as 4e and 6c manifested a promising inhibitory activity against both isoforms (K_I = 0.072, 0.081 and 0.073, 0.095 µM), respectively. While others as 4a and 5e showed inhibitory activity against hCA IX only (K_I = 0.062, 0.04 µM) or against hCA XII only as compound 5b (K_I = 0.106 µM) compared to AAZ (K_I = 0.065, 0.046 µM), respectively. Also, the anticancer efficacy against 60 cancer cell lines for the target compounds was assessed, and the most promising ones were 4d and 5a-d. Further investigation of the anticancer activity of 5b on MCF-7 cell line explored (IC₅₀ = 5.21 µM) compared to doxorubicin (IC₅₀ = 11.58 µM). Moreover, compound 5b was exposed to cell cycle analysis and apoptotic assay on MCF-7 breast cancer cell line under both normal and hypoxic conditions at its IC₅₀ concentration with elevation of total apoptotic cells % in MCF-7 relative to the control cells; respectively. Finally, molecular modelling simulations rationalized the in vitro testing results.