4-(Pyrazolyl)benzenesulfonamide Ureas as Carbonic Anhydrases Inhibitors and Hypoxia-Mediated Chemo-Sensitizing Agents in Colorectal Cancer Cells
Wagdy M. Eldehna, Mohamed Farès, Alessandro Bonardi, Moscos Avgenikos, Fady Baselious, Matthias Schmidt, Tarfah Al‐Warhi, Hatem A. Abdel‐Aziz, Robert C. Rennert, Thomas S. Peat, Claudiu T. Supuran, Ludger A. Wessjohann, Hany S. Ibrahim
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.