The carbonic anhydrase (CA, EC 4.2.1.1.) isozymes I and II are cytosolic, ubiquitous enzymes; differently isoforms IX and XII are transmembrane and tumor-associated, that show a restricted expression in normal tissues. CA IX/XII are now proposed as novel therapeutic antitumor targets. The report of the X-ray crystal structure of CA IX, which is a dimeric protein with a quaternary structure not evidenced earlier for this family of enzymes, allows for structure-based drug design campaigns of inhibitors against this novel antitumor target. Indeed, it has been known for some time that aromatic/heterocyclic sulfonamides have good affinity for this isoform, but generally they do not show specificity for the inhibition of the tumor-associated isoform versus the remaining CA isozymes (CA I-VII, and XII-XV) found in mammals. Recently, we reported a series of arylsulfonamides, synthesized and investigated for the inhibition of some selected human carbonic anhydrase (h CA) isoforms. The studied compounds showed significant inhibitory effects in the nanomolar range toward druggable isoforms (hCA VII, hCA IX, and hCA XIV), whereas they generally exhibited significant selectivity over hCA I and hCA II, that are ubiquitous and considered off-target isoforms. Studies on structure-affinity relationships for this series of 1-(cyclo)alkylisoquinolines containing a sulfonamide, function considered a key feature for inhibiting CA, have been performed and suggested a key role for alkoxy substituents in CA inhibition [1]. Moreover, derivatives with different C-1 substituents on isoquinoline scaffold were synthesized to verify as this moiety controls both inhibitory potency and selectivity. Some derivatives showed potent hCA IX and hCA XIV inhibitory effects at nanomolar concentrations as well as low affinity for the ubiquitous hCA II. Moreover, reported X-ray crystal structure of one of these derivatives in complex with dominant human isoform II, have confirmed the sulfonamide--zinc interactions. Finally, the results of docking experiments suggested the hypothetic interactions in the catalytic binding site for the most active and selective hCA IX and hCA XIV inhibitor [2]. Those cited studies were carried out on racemic mixture of arylsulfonamide derivatives but a different level of activity or specificity of action of the two enantiomers was to be expected. Therefore, in order to elucidate the enantio-pharmacological profile of the more potent 3,4-dihydroisoquinoline-2(1H)-sulfonamides, we performed a comparison of column performances in direct enantio-separation of 1-methyl and 1-fenyl-substituted isoquinoline analogs. using high performance chromatography (HPLC). The differences between the selectivities of the columns chosen for this study were compared and optimized to yield the best resolution. [1] Gitto R, Damiano FM, Mader P, De Luca L, Ferro S, Supuran CT, Vullo D, Brynda J, Rezáčová P, Chimirri A. J Med Chem. 2012, Apr 26;55(8):3891-9. [2] Gitto R, Agnello S, Ferro S, De Luca L, Vullo D, Brynda J, Mader P, Supuran CT, Chimirri A. J Med Chem. 2010 Mar 25;53(6):2401-8.

COMPARATIVE STUDY ON CHIRAL SEPARATION OF 3,4-DIHYDROISOQUINOLINE-2(1H)-SULFONAMIDE DERIVATIVES AS POTENT CARBONIC ANYDRASE INHIBITORS

RIZZO, Milena;RONSISVALLE, SIMONE;
2013

Abstract

The carbonic anhydrase (CA, EC 4.2.1.1.) isozymes I and II are cytosolic, ubiquitous enzymes; differently isoforms IX and XII are transmembrane and tumor-associated, that show a restricted expression in normal tissues. CA IX/XII are now proposed as novel therapeutic antitumor targets. The report of the X-ray crystal structure of CA IX, which is a dimeric protein with a quaternary structure not evidenced earlier for this family of enzymes, allows for structure-based drug design campaigns of inhibitors against this novel antitumor target. Indeed, it has been known for some time that aromatic/heterocyclic sulfonamides have good affinity for this isoform, but generally they do not show specificity for the inhibition of the tumor-associated isoform versus the remaining CA isozymes (CA I-VII, and XII-XV) found in mammals. Recently, we reported a series of arylsulfonamides, synthesized and investigated for the inhibition of some selected human carbonic anhydrase (h CA) isoforms. The studied compounds showed significant inhibitory effects in the nanomolar range toward druggable isoforms (hCA VII, hCA IX, and hCA XIV), whereas they generally exhibited significant selectivity over hCA I and hCA II, that are ubiquitous and considered off-target isoforms. Studies on structure-affinity relationships for this series of 1-(cyclo)alkylisoquinolines containing a sulfonamide, function considered a key feature for inhibiting CA, have been performed and suggested a key role for alkoxy substituents in CA inhibition [1]. Moreover, derivatives with different C-1 substituents on isoquinoline scaffold were synthesized to verify as this moiety controls both inhibitory potency and selectivity. Some derivatives showed potent hCA IX and hCA XIV inhibitory effects at nanomolar concentrations as well as low affinity for the ubiquitous hCA II. Moreover, reported X-ray crystal structure of one of these derivatives in complex with dominant human isoform II, have confirmed the sulfonamide--zinc interactions. Finally, the results of docking experiments suggested the hypothetic interactions in the catalytic binding site for the most active and selective hCA IX and hCA XIV inhibitor [2]. Those cited studies were carried out on racemic mixture of arylsulfonamide derivatives but a different level of activity or specificity of action of the two enantiomers was to be expected. Therefore, in order to elucidate the enantio-pharmacological profile of the more potent 3,4-dihydroisoquinoline-2(1H)-sulfonamides, we performed a comparison of column performances in direct enantio-separation of 1-methyl and 1-fenyl-substituted isoquinoline analogs. using high performance chromatography (HPLC). The differences between the selectivities of the columns chosen for this study were compared and optimized to yield the best resolution. [1] Gitto R, Damiano FM, Mader P, De Luca L, Ferro S, Supuran CT, Vullo D, Brynda J, Rezáčová P, Chimirri A. J Med Chem. 2012, Apr 26;55(8):3891-9. [2] Gitto R, Agnello S, Ferro S, De Luca L, Vullo D, Brynda J, Mader P, Supuran CT, Chimirri A. J Med Chem. 2010 Mar 25;53(6):2401-8.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11769/107306
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