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

Abstract

High Resolution Image Download MS PowerPoint Slide Hypoxia in tumors contributes to chemotherapy resistance, worsened by acidosis driven by carbonic anhydrases ( h CA IX and XII). Targeting these enzymes can mitigate acidosis, thus enhancing tumor sensitivity to cytotoxic drugs. Herein, novel 4-(pyrazolyl)benzenesulfonamide ureas ( SH7a–t ) were developed and evaluated for their inhibitory activity against h CA IX and XII. They showed promising results ( h CA IX: K I = 15.9–67.6 nM, h CA XII: K I = 16.7–65.7 nM). Particularly, SH7s demonstrated outstanding activity ( K I s = 15.9 nM for h CA IX and 55.2 nM for h CA XII) and minimal off-target kinase inhibition over a panel of 258 kinases. In NCI anticancer screening, SH7s exhibited broad-spectrum activity with an effective growth inhibition full panel GI 50 (MG-MID) value of 3.5 μM and a subpanel GI 50 (MG-MID) range of 2.4–6.3 μM. Furthermore, SH7s 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.