RESUMEN
A series of 2-substituted-1,3,4-thiadiazole-5-sulfamides was prepared and assayed as inhibitors of several carbonic anhydrase (CA, EC 4.2.1.1) isoforms, the cytosolic CA I and II, the membrane-associated CA IV and the mitochondrial CA VA and VB. The new compounds showed weak inhibitory activity against hCA I (K(I)s of 102 nM-7.42 microM), hCA II (K(I)s of 0.54-7.42 microM) and hCA IV (K(I)s of 4.32-10.05 microM) but were low nanomolar inhibitors of hCA VA and hCA VB, with inhibition constants in the range of 4.2-32 nM and 1.3-74 nM, respectively. Furthermore, the selectivity ratios for inhibiting the mitochondrial enzymes over CA II were in the range of 67.5-415, making these sulfamides the first selective CA VA/VB inhibitors.
Asunto(s)
Anhidrasa Carbónica II/química , Anhidrasa Carbónica IV/química , Anhidrasa Carbónica I/química , Inhibidores de Anhidrasa Carbónica/síntesis química , Inhibidores de Anhidrasa Carbónica/farmacología , Anhidrasa Carbónica V/química , Tiadiazoles/síntesis química , Tiadiazoles/farmacología , Química Farmacéutica/métodos , Citosol/enzimología , Citosol/metabolismo , Diseño de Fármacos , Humanos , Isoenzimas , Cinética , Mitocondrias/enzimología , Modelos Biológicos , Modelos QuímicosRESUMEN
A series of glycosyl-thioureido sulfonamides incorporating glucosamine, galactosamine, and mannosamine tails, and sulfanilamide, halogenosulfanilamide, and metanilamide heads was synthesized. Many of the new compounds showed micromolar-submicromolar affinity for the inhibition of the cytosolic isoforms I and II of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1), but low nanomolar binding to the tumor-associated isozymes, CA IX and XII. The selectivity ratios for the inhibition of the tumor-associated over the cytosolic isozymes were in the range of 107-955 for the most selective such inhibitors.