4-Hydroxy-3-nitro-5-ureido-benzenesulfonamides selectively target the tumor-associated carbonic anhydrase isoforms IX and XII showing hypoxia-enhanced anti-proliferative profiles.

Human carbonic anhydrases (CA, EC, 4.2.1.1) IX and XII are overexpressed in cancer cells as adaptive response to hypoxia and acidic conditions characteristic of many tumors. In addition, hypoxia facilitates the activity of specific oxido-reductases that may be exploited to selectively activate bio-reductive prodrugs. Here, new selective CA IX/XII inhibitors, as analogues of the anti-tumor phase II drug SLC-0111 are described, namely ureido-substituted benzenesulfonamides appended with a nitro-aromatic moiety to yield an anti-proliferative action increased by hypoxia. These compounds were screened for the inhibition of the ubiquitous hCA I/II and the target hCA IX/XII. Six X-ray crystallographies with CA II and IX/mimic allowed for the rationalization of the compounds inhibitory activity. The effects of some such compounds on the viability of HT-29, MDA-MB-231 and PC-3 human cancer cell lines in both normoxic and hypoxic conditions were examined, providing the initiation towards the development of hypoxia-activated anti-tumor CAIs.