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

• DOI: 10.1021/jm101541x
• Publication Date: 2011-03-02T07:04:33Z
• Authors: Fabio Pacchiano; Fabrizio Carta; Paul C. McDonald; Yuanmei Lou; Daniela Vullo; Andrea Scozzafava; Shoukat Dedhar; Claudiu T. Supuran
• Keywords: Models, Molecular; 0301 basic medicine; Sulfonamides; Mammary Neoplasms, Experimental; Antineoplastic Agents; 3. Good health; Isoenzymes; Mice; Structure-Activity Relationship; 03 medical and health sciences; Carbonic Anhydrase IX; Breast tumor metastasis; ureidobenzenesulfonamides; Antigens, Neoplasm; Catalytic Domain; Benzene Derivatives; Animals; Humans; Urea; Female; Neoplasm Metastasis; Carbonic Anhydrase IX; Nitrobenzenes; Carbonic Anhydrases; Protein Binding

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 I and 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 IX/XII inhibitors also showing good selectivity for the transmembrane over the cytosolic isoforms have been discovered. One of them, 4-{[(3'-nitrophenyl)carbamoyl]amino}benzenesulfonamide, significantly inhibited the formation of metastases 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.