title: Carbonic anhydrase inhibitors: benzenesulfonamides incorporating cyanoacrylamide moieties are low nanomolar/subnanomolar inhibitors of the tumor-associated isoforms IX and XII.
abstract: A series of benzenesulfonamides incorporating cyanoacrylamide moieties (tyrphostine analogues) have been obtained by reaction of sulfanilamide with ethylcyanoacetate followed by condensation with aromatic/heterocyclic aldehydes, isothiocyanates or diazonium salts. The new compounds have been investigated as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4. 2.1.1), and more specifically against the cytosolic human (h) isoforms hCA I and II, as well as the transmembrane, tumor-associated ones CA IX and XII, which are validated antitumor targets. Most of the new benzenesulfonamides were low nanomolar or subnanomolar CA IX/XII inhibitors whereas they were less effective as inhibitors of CA I and II. The structure-activity relationship for this class of effective CA inhibitors is also discussed. Generally, electron donating groups in the starting aldehyde reagent favored CA IX and XII inhibition, whereas halogeno, methoxy and dimethylamino moieties led to very potent CA XII inhibitors.
authors.affiliation: Department of Pharmaceutical Chemistry, College of Pharmacy, Salman Bin Abdulaziz University, PO Box 173, Alkharj 11942, Saudi Arabia. alafeefy@hotmail.com
authors.forename: Ahmed M
authors.initials: AM
authors.lastname: Alafeefy
authors.forename: Semra
authors.initials: S
authors.lastname: Isik
authors.forename: Hatem A
authors.initials: HA
authors.lastname: Abdel-Aziz
authors.forename: Abdelkader E
authors.initials: AE
authors.lastname: Ashour
authors.forename: Daniela
authors.initials: D
authors.lastname: Vullo
authors.forename: Nabila A
authors.initials: NA
authors.lastname: Al-Jaber
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D020106:Acrylamide / Q000737:chemistry*; D000951:Antigens, Neoplasm / Q000737:chemistry* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D002256:Carbonic Anhydrases / Q000737:chemistry* / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D007700:Kinetics; D009369:Neoplasms / Q000201:enzymology*; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D000096926:Benzenesulfonamides
chemical_list: D020106:Acrylamide; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors; D002256:Carbonic Anhydrases; D013449:Sulfonamides; D000096926:Benzenesulfonamides; C089226:CA9 protein, human; C477378:carbonic anhydrase XII