4-(Pyrazolyl)benzenesulfonamide Ureas as Carbonic Anhydrases Inhibitors and Hypoxia-Mediated Chemo-Sensitizing Agents in Colorectal Cancer Cells.

Hypoxia in tumors contributes to chemotherapy resistance, worsened by acidosis driven by carbonic anhydrases (CA IX and XII). Targeting these enzymes can mitigate acidosis, thus enhancing tumor sensitivity to cytotoxic drugs. Herein, novel 4-(pyrazolyl)benzenesulfonamide ureas () were developed and evaluated for their inhibitory activity against CA IX and XII. They showed promising results (CA IX: = 15.9-67.6 nM, CA XII: = 16.7-65.7 nM). Particularly, demonstrated outstanding activity (s = 15.9 nM for CA IX and 55.2 nM for CA XII) and minimal off-target kinase inhibition over a panel of 258 kinases. In NCI anticancer screening, exhibited broad-spectrum activity with an effective growth inhibition full panel GI (MG-MID) value of 3.5 μM and a subpanel GI (MG-MID) range of 2.4-6.3 μM. Furthermore, enhanced the efficacy of Taxol and 5-fluorouracil in cotreatment regimens under hypoxic conditions in HCT-116 colorectal cancer cells, indicating its potential as a promising anticancer agent.