Ureido-Substituted Benzenesulfonamides Potently Inhibit Carbonic Anhydrase IX and Show Antimetastatic Activity in a Model of Breast Cancer Metastasis

A series of ureido-substituted benzenesulfonamides was prepared that showed a very interesting profile for the inhibition of several human carbonic anhydrases (hCAs, EC 4.2.1.1), such as hCAs land II (cytosolic: isoforms) and hCAs IX and XII (transmembrane, tumor-associated enzymes). Excellent inhibition of all these isoforms has been observed with various members of the series, depending on the substitution pattern of the urea moiety. Several low nanomolar CA DC/XII inhibitors also showing good selectivity for the transmembrane over the cytosolic isoforms have been discovered. One of them, 4-{[(3'-nitrophenyl)carbamoyl] amino}benzene sulfonamide, significantly inhibited the formation of inetastases by the highly aggressive 4T1 mammary tumor cells at pharmacologic concentrations of 45 mg/kg constituting an interesting candidate for the development of conceptually novel antimetastatic drugs.