Pyrazole-sulfonamide scaffold featuring dual-tail strategy as apoptosis inducers in colon cancer. Design, synthesis, biological, and docking studies

Abstract Dual-tail strategy has been successfully utilized in the development of novel carbonic anhydrase IX inhibitors. Herein we adopted this approach in the design and synthesis of a series of novel pyridine sulfonamide-pyrazole hybrid scaffold mimicking dual-tail inhibitors of carbonic anhydrase IX. A library of 15 compounds was synthesized and assessed for their potential cytotoxic effects against colorectal cancer cells. Compounds 3, and 11 induced potential cytotoxic effects against the three cancer cell lines (HCT-116, HT-29, and SW-620) with IC50s’ of 45.88, 28.27, and 16.57 uM, 25.01, 8.997, and 3.275 uM respectively on the three used cell lines. Both compounds induced cellular apoptosis on HCT-116 and SW-620 cells, while compound 3 induced necrosis as well. In addition, both compounds induced cell cycle arrest on G0/G1, and S phases. Also, compound 11 showed potential autophagy induction on both colon cancer cell lines (HCT-116, and HT-29), and a little bit on metastatic type. The migration rates of HCT-116 and the metastatic one SW-620 were reduced by both compounds. Finally, Compounds 3 and 11 were docked into the active site of CA IX and the obtained results were confirmed by evaluating the in vitro inhibitory activity for both compounds.