Carbonic anhydrase inhibitors. Inhibition of transmembrane isoforms IX, XII, and XIV with less investigated anions including trithiocarbonate and dithiocarbamate.
An inhibition study of the transmembrane carbonic anhydrase (CA, EC 4.2.1.1) isoforms IX, XII (tumor-associated), and XIV with anions such as stannate(IV), selenate(VI), tellurate(VI), perosmate(VIII), persulfate, pyrophosphate(V), pyrovanadate(V), tetraborate, persulfate, perrhenate(VII), perrutenate(VII), selenocyanate, iminodisulfonate, fluorosulfate, and trithiocarbonate is reported. Selenate, perosmate, and pyrophosphate were ineffective inhibitors, whereas most of these anions inhibited the three enzymes in the millimolar-submillimolar range. Trithiocarbonate and diethyldithiocarbamate were the best CA IX inhibitors (K(I)s of 1.4-9.7microM), but trithiocarbonate showed less affinity for CA XII and XIV (K(I)s of 0.12-0.66mM). N,N-Diethyldithiocarbamate was a low micromolar inhibitor also against CA XII and XIV (K(I)s of 1.0-1.1microM), suggesting that this new zinc-binding group (CS2-) may lead to efficient inhibitors targeting transmembrane CAs.
Università degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, I-50019 Sesto Fiorentino (Firenze), Italy.
Alessio
A
Innocenti
Andrea
A
Scozzafava
Claudiu T
CT
Supuran
D000838:Anions / Q000737:chemistry*; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D002256:Carbonic Anhydrases / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D006801:Humans; D017434:Protein Structure, Tertiary; D013859:Thiocarbamates / Q000737:chemistry* / Q000494:pharmacology; D013871:Thiones / Q000737:chemistry* / Q000494:pharmacology
D000838:Anions; D000951:Antigens, Neoplasm; D002257:Carbonic Anhydrase Inhibitors; D013859:Thiocarbamates; D013871:Thiones; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; C477378:carbonic anhydrase XII; C466621:carbonic anhydrase XIV; C013321:trithiocarbonic acid