7,8-disubstituted- but not 6,7-disubstituted coumarins selectively inhibit the transmembrane, tumor-associated carbonic anhydrase isoforms IX and XII over the cytosolic ones I and II in the low nanomolar/subnanomolar range.
Two series of disubstituted coumarins incorporating ether and acetyl/propionyl moieties in positions 6,7- and 7,8- of the heterocyclic ring were synthesized investigated for the inhibition of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1). All these coumarins were very weak or ineffective as inhibitors of the housekeeping, offtarget isoforms CA I and II. The 6,7-disubstituted series showed ineffective inhibition also for the transmembrane tumor-associated isoforms CA IX and XII, whereas the corresponding isomeric 7,8-disubstituted coumarins showed nanomolar/subnanomolar inhibition of CA IX/XII. The nature and position of the groups substituting the coumarin ring in the 7,8-positions greatly influenced CA inhibitory properties, with C1-C4 alkyl ethers being the most effective inhibitors.
Università degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Sesto Fiorentino (Firenze), Italy.
Alfonso
A
Maresca
Andrea
A
Scozzafava
Claudiu T
CT
Supuran
D000951:Antigens, Neoplasm / Q000737:chemistry* / Q000378:metabolism; D024401:Carbonic Anhydrase I / Q000737:chemistry / Q000378:metabolism; D024402:Carbonic Anhydrase II / Q000737:chemistry / Q000378:metabolism; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002256:Carbonic Anhydrases / Q000737:chemistry* / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D003374:Coumarins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D009369:Neoplasms / Q000378:metabolism; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship
D000951:Antigens, Neoplasm; D002257:Carbonic Anhydrase Inhibitors; D003374:Coumarins; D020033:Protein Isoforms; D024401:Carbonic Anhydrase I; D024402:Carbonic Anhydrase II; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; C477378:carbonic anhydrase XII