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 (hCA 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 hCA IX and XII.
They showed promising results (hCA IX: KI = 15.9–67.6 nM, hCA XII: KI = 16.7–65.7 nM). Particularly, SH7s demonstrated outstanding activity (KIs = 15.9 nM for hCA IX and 55.2 nM for hCA 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 GI50 (MG-MID) value of 3.5 μM and a subpanel
GI50 (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.