title: Dithiocarbamates strongly inhibit carbonic anhydrases and show antiglaucoma action in vivo.
abstract: A series of dithiocarbamates were prepared by reaction of primary/secondary amines with carbon disulfide in the presence of bases. These compounds were tested for the inhibition of four human (h) isoforms of the zinc enzyme carbonic anhydrase, CA (EC 4.2.1.1), hCA I, II, IX, and XII, involved in pathologies such as glaucoma (CA II and XII) or cancer (CA IX). Several low nanomolar inhibitors targeting these CAs were detected. The X-ray crystal structure of the hCA II adduct with morpholine dithiocarbamate evidenced the inhibition mechanism of these compounds, which coordinate to the metal ion through a sulfur atom from the dithiocarbamate zinc-binding function. Some dithiocarbamates showed an effective intraocular pressure lowering activity in an animal model of glucoma.
authors.affiliation: Laboratorio di Chimica Bioinorganica, Polo Scientifico, Università degli Studi di Firenze, Room 188, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Carta
authors.forename: Mayank
authors.initials: M
authors.lastname: Aggarwal
authors.forename: Alfonso
authors.initials: A
authors.lastname: Maresca
authors.forename: Andrea
authors.initials: A
authors.lastname: Scozzafava
authors.forename: Robert
authors.initials: R
authors.lastname: McKenna
authors.forename: Emanuela
authors.initials: E
authors.lastname: Masini
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D000818:Animals; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D005901:Glaucoma / Q000188:drug therapy* / Q000201:enzymology; D006801:Humans; D007429:Intraocular Pressure / Q000187:drug effects; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D009369:Neoplasms / Q000201:enzymology; D011487:Protein Conformation; D011817:Rabbits; D013329:Structure-Activity Relationship; D013859:Thiocarbamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D007527:Isoenzymes; D013859:Thiocarbamates