title: Carbonic anhydrase inhibitors: inhibition of cytosolic/tumor-associated carbonic anhydrase isozymes I, II, and IX with benzo[b]thiophene 1,1-dioxide sulfonamides.
abstract: A series of selected benzo[b]thiophene-5- and 6-sulfonamide derivatives previously reported to show cytotoxic activity and some others newly synthesized has been tested for the interactions with several CA isozymes, some of which are known to be involved in tumorigenesis (hCA IX), whereas others are ubiquitously found in many normal tissues (the cytosolic isoforms hCA I and II). The unsubstituted sulfonamides inhibited hCA I with inhibition constants in the range of 63-138 nM, hCA II with inhibition constants in the range of 6.3-8.8 nM, and hCA IX with inhibition constants in the range of 2.8-15 nM, being thus more active than clinically used inhibitors such as acetazolamide, methazolamide, ethoxzolamide, dichlorophenamide or indisulam (E 7070). Some of these derivatives also showed some selectivity for the inhibition of the tumor-associated (hCA IX) over the cytosolic isozyme hCA II. Although these derivatives may act on many targets other than the CAs (such as the NADH oxidase) or may induce apoptosis by accumulation of reactive oxygen species, it is quite important to try to decipher as many as possible of the potential mechanisms that lead to derivatives with potent antitumor activity in order to develop novel therapeutic strategies for the management of cancer.
authors.affiliation: Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Room 188, Via della Lastruccia 3, 50019 Sesto Fiorentino (Florence), Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Innocenti
authors.forename: Raquel
authors.initials: R
authors.lastname: Villar
authors.forename: Victor
authors.initials: V
authors.lastname: Martinez-Merino
authors.forename: María J
authors.initials: MJ
authors.lastname: Gil
authors.forename: Andrea
authors.initials: A
authors.lastname: Scozzafava
authors.forename: Daniela
authors.initials: D
authors.lastname: Vullo
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D000951:Antigens, Neoplasm / Q000187:drug effects; D024401:Carbonic Anhydrase I / Q000037:antagonists & inhibitors; D024402:Carbonic Anhydrase II / Q000037:antagonists & inhibitors; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D002256:Carbonic Anhydrases / Q000187:drug effects; D003600:Cytosol / Q000201:enzymology; D006801:Humans; D009363:Neoplasm Proteins / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000951:Antigens, Neoplasm; D002257:Carbonic Anhydrase Inhibitors; D009363:Neoplasm Proteins; D024401:Carbonic Anhydrase I; D024402:Carbonic Anhydrase II; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases