title: 5- and 6-membered (thio)lactones are prodrug type carbonic anhydrase inhibitors.
abstract: The inhibition of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1) with (thio)coumarins has been recently reported (Maresca et al., J. Am. Chem. Soc. 2009, 131, 3057). Here we demonstrate that a series of γ- and δ-(thio)lactones also act as mechanism based, prodrug type CA inhibitors, similar to the (thio)coumarins. Through the esterase activity of CA, these compounds are hydrolyzed in situ to the corresponding hydroxy/keto/mercapto acids which thereafter act as inhibitors. CA isoforms I and IX were efficiently inhibited by simple such compounds, with K(I)s in the range of 0.92-19.1μM, whereas CA II was not inhibited at all. Isoform-selective CA inhibitors which spare the ubiquitous off-target CA II may have interesting applications for example for selectively inhibiting the tumor-associated CA IX, a validated anticancer target.
authors.affiliation: Università degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, I-50019 Sesto Fiorentino, Firenze, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Carta
authors.forename: Alfonso
authors.initials: A
authors.lastname: Maresca
authors.forename: Andrea
authors.initials: A
authors.lastname: Scozzafava
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003374:Coumarins / Q000737:chemistry; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D007783:Lactones / Q000737:chemistry / Q000494:pharmacology*; D008956:Models, Chemical; D009369:Neoplasms / Q000188:drug therapy; D011355:Prodrugs / Q000494:pharmacology; D020033:Protein Isoforms
chemical_list: D000970:Antineoplastic Agents; D002257:Carbonic Anhydrase Inhibitors; D003374:Coumarins; D004791:Enzyme Inhibitors; D007783:Lactones; D011355:Prodrugs; D020033:Protein Isoforms; C030123:coumarin