Carbonic anhydrase inhibitors: thioxolone versus sulfonamides for obtaining isozyme-selective inhibitors?
Inhibition of 13 mammalian isoforms of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1), CA I-XV, with thioxolone (6-hydroxy-1,3-benzoxathiol-2-one) and two sulfonamides was investigated. Thioxolone was inefficient for generating isozyme-selective inhibitors, since except for CA I which is inhibited in the nanomolar range (K(I) of 91 nM), the remaining 12 isoforms were inhibited with a very flat profile (K(I)s in the range of only 4.93-9.04 microM). In contrast to thioxolone, 3,5-dichloro-4-hydroxybenzenesulfonamide as well as the clinically used heterocyclic sulfonamide acetazolamide showed K(I)s in the range of 58 nM-78.6 microM and 2.5 nM-200 microM, respectively, against the 13 investigated mammalian CAs. The sulfonamide zinc-binding group is thus superior to the thiol one for generating CA inhibitors with a varied and sometimes isozyme-selective inhibition profile against the mammalian enzymes.
Innocenti
Alessio
A
Università degli Studi di Firenze, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Room 188, Via della Lastruccia 3, 50019 Sesto Fiorentino (Florence), Italy.
Maresca
Alfonso
A
Scozzafava
Andrea
A
Supuran
Claudiu T
CT
D000818:Animals; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D002256:Carbonic Anhydrases / Q000737:chemistry*; D020134:Catalytic Domain; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D006801:Humans; D007527:Isoenzymes; D007700:Kinetics; D007783:Lactones / Q000138:chemical synthesis / Q000494:pharmacology*; D051379:Mice; D008956:Models, Chemical; D020033:Protein Isoforms; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000494:pharmacology*
D002257:Carbonic Anhydrase Inhibitors; D007527:Isoenzymes; D007783:Lactones; D020033:Protein Isoforms; D013449:Sulfonamides; C009474:thioxolone; D002256:Carbonic Anhydrases