4‑Hydroxy-3-nitro-5-ureido-benzenesulfonamides Selectively Target the Tumor-Associated Carbonic Anhydrase Isoforms IX and XII Showing Hypoxia-Enhanced Antiproliferative 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 bioreductive prodrugs. Here, new selective CA IX/XII inhibitors,
as analogues of the antitumor phase II drug SLC-0111 are described,
namely ureido-substituted benzenesulfonamides appended with a nitro-aromatic
moiety to yield an antiproliferative 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 toward
the development of hypoxia-activated antitumor CAIs.