Novel coumarins and benzocoumarins acting as isoform-selective inhibitors against the tumor-associated carbonic anhydrase IX

Abstract

A series of coumarins and benzocoumarins incorporating methyl and hydroxyl moieties in the heterocyclic ring were investigated for the inhibition of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1). These coumarins were very weak or ineffective as inhibitors of the housekeeping, offtarget isoforms CA I and II, but showed effective, submicromolar inhibition of the transmembrane, tumor-associated isoforms CA IX and to a slightly less extent, CA XII. The nature and position of the groups substituting the coumarin ring influenced CA inhibitory properties. 4-Methyl-5,7-dihydroydroxycoumarin showed K I s 4200 mM against CA I and II, of 0.19 mM against CA IX and of 6.4 mM against CA XII, being thus a selective, efficient inhibitor for the tumor-associated over cytosolic CA isoforms. These compounds are interesting leads for designing isoform-selective enzyme inhibitors.

Design, synthesis and biological evaluation ofN-(5-methyl-isoxazol-3-yl/1,3,4-thiadiazol-2-yl)-4-(3-substitutedphenylureido) benzenesulfonamides as human carbonic anhydrase isoenzymes I, II, VII and XII inhibitors

“…All the synthesized compounds (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26) were studied for the inhibition of four CA isozymes of human origin, i.e. hCA I, hCA II, hCA VII and hCA XII ( Table 1).…”

“…The inhibition constants were obtained by non-linear least-squares methods using the ChengPrusoff equation, and represent the mean from at least three different determinations. The human isoforms hCA I, II, VII and XII were recombinant enzymes produced as described earlier in our laboratory [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] .…”

The effects of some bromophenols on human carbonic anhydrase isoenzymes

“…CA inhibitors (CAIs) are clinically used as diuretics and antiglaucoma drugs. In addition, CAIs could have potential as antiobesity, anti-cancer and anti-infective drugs [22][23][24][25] . Naturally occurring bromophenols are important in synthetic organic chemistry and medicinal chemistry.…”

Carbonic anhydrase inhibitors: guaiacol and catechol derivatives effectively inhibit certain human carbonic anhydrase isoenzymes (hCA I, II, IX and XII)

“…Additionally, it has lately emerged that CAIs could have potential as anticancer, anti-obesity and anti-infective drugs. Most often, CAIs have been investigated with the classical CA inhibitors belonging to the sulphonamide/sulphamates class, but other chemo-types have also been explored, such as boronic acids, metal-complexing anions and similar small molecules, and phenols 1,[19][20][21][22][23][24] . These sulphonamides are clinically used, as antiglaucoma agents, and also for the therapy of other diseases, such as increased intracranial pressure, neuromuscular pathologies and various neurological disorders, such as epilepsy, hypokalaemia, tardive dyskinesia, genetic hemiplegic migraine and ataxia, essential tremor and Parkinsons disease, and mountain sickness.…”