title: Ureido-substituted benzenesulfonamides potently inhibit carbonic anhydrase IX and show antimetastatic activity in a model of breast cancer metastasis.
abstract: 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.
authors.affiliation: Laboratorio di Chimica Bioinorganica, Rm. 188, Polo Scientifico, Università degli Studi di Firenze, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Pacchiano
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Carta
authors.forename: Paul C
authors.initials: PC
authors.lastname: McDonald
authors.forename: Yuanmei
authors.initials: Y
authors.lastname: Lou
authors.forename: Daniela
authors.initials: D
authors.lastname: Vullo
authors.forename: Andrea
authors.initials: A
authors.lastname: Scozzafava
authors.forename: Shoukat
authors.initials: S
authors.lastname: Dedhar
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001555:Benzene Derivatives / Q000138:chemical synthesis* / Q000494:pharmacology; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000378:metabolism*; D020134:Catalytic Domain; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000473:pathology*; D051379:Mice; D008958:Models, Molecular; D009362:Neoplasm Metastasis; D009578:Nitrobenzenes / Q000138:chemical synthesis / Q000494:pharmacology; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D001555:Benzene Derivatives; D007527:Isoenzymes; D009578:Nitrobenzenes; D013449:Sulfonamides; D014508:Urea; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases