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51.
T. Abdulkadir Çoban Şükrü Beydemir İlhami Gülçin Deniz Ekinci 《Journal of enzyme inhibition and medicinal chemistry》2013,28(2):266-270
The ethanol is a widely consumed as sedative-hypnotic drug throughout the world. In this study, the effects of ethanol were investigated on carbonic anhydrase (CA) enzyme activities both in vitro in human erythrocyte and in vivo in Sprague-Dawley rat erythrocyte. For in vitro study, the human carbonic anhydrase-I (HCA-I) and -II (HCA-II) are purified by Sepharose 4B–L-tyrosine-sulphanilamide affinity chromatography. In vivo CA enzyme activity was determined colorimetrically by using CO2-hydration method of Wilbur and Anderson. Rat blood samples were taken from each rat before and after the ethanol administration at different times (1 h, 3 h, and 5 h). Rat erythrocyte CA activity was significantly inhibited by pharmacological dosage of the ethanol (2 mL.kg? 1) for up to 3 h (p < 0.001) following intraperitoneally administration. The ethanol showed in vitro inhibitory effects on HCA-I and HCA-II hydratase activity, determined by colorimetrically using the CO2-hydratase method. The inhibitor concentrations causing up to 50% inhibition (IC50) were 2.09 M for HCA-I (r2:0.9273) and 1.83 M for HCA-II (r2:9749). In conclusion, it was demonstrated that carbonic anhydrase enzyme in erythrocytes was significantly inhibited by the ethanol both in in vitro and in vivo. 相似文献
52.
《Journal of enzyme inhibition and medicinal chemistry》2013,28(5):749-753
A carbonic anhydrase (CA, EC 4.2.1.1) from red blood cells of pigeons (Columba livia var. domestica), clCA, was purified to homogeneity. Its kinetic parameters for the CO2 hydration reaction were measured. With a kcat/Km of 1.1?×?108 M?1 s?1, and a kcat of 1.3?×?106 s?1, clCA has a high activity, similar to that of the human isoform hCA II. A group of 25 aromatic/heterocyclic sulfonamides incorporating the sulfanilamide, homosulfanilamide, benzene-1,3-disulfonamide, and acetazolamide scaffolds showed variable inhibitory activity against the pigeon enzyme, with KIs in the range of 1.9–3460?nM. Red blood cells of pigeons, like those of ostriches, contain thus just one CA isoform, unlike the blood of mammals, which normally contain two isoforms, one of low (CA I-like) and one of very high activity (CA II-like). However, from the sulfonamide inhibition viewpoint, the pigeon enzyme was more similar to hCA II than to the ostrich enzyme. 相似文献
53.
54.
《Journal of enzyme inhibition and medicinal chemistry》2013,28(6):906-911
AbstractDiatom genome sequences clearly reveal the presence of different systems for HCO3? uptake. Carbon-concentrating mechanisms (CCM) based on HCO3? transport and a plastid-localized carbonic anhydrase (CA, EC 4.2.1.1) appear to be more probable than the others because CAs have been identified in the genome of many diatoms. CAs are key enzymes involved in the acquisition of inorganic carbon for photosynthesis in phytoplankton, as they catalyze efficiently the interconversion between carbon dioxide and bicarbonate. Five genetically distinct classes of CAs exist, α-, β-, γ-, δ- and ζ and all of them are metalloenzymes. Recently we investigated for the first time the catalytic activity and inhibition of the δ-class CA from the marine diatom Thalassiosira weissflogii, named TweCA. This enzyme is an efficient catalyst for the CO2 hydration and its inhibition profile with sulfonamide/sulfamate and anions have also been investigated. Here, we report the detailed biochemical characterization and chemico-physical properties of the δ-CA of T. weissflogii. The δ-CA encoding gene was cloned and expressed in Artic Express cells and the recombinant protein purified to homogeneity. Interesting to note that TweCA has no intrinsic esterase activity with 4-nitrophenyl acetate (pNpA) as substrate although the phylogenetic analysis showed that δ-CAs are closer to the α-CAs than to the other classes of such enzymes. 相似文献
55.
Mahmood- Ul-Hassan Zahid H. Chohan Andrea Scozzafava Claudiu T. Supuran 《Journal of enzyme inhibition and medicinal chemistry》2013,28(3):263-267
Schiff's bases were obtained from aromatic/heterocyclic sulfonamides and amino-sulfonamide derivatives, such as sulfanilamide, homosulfanilamide, 4-aminoethyl-benzenesulfonamide and 5-amino-1,3,4-thiadiazole-2-sulfonamide. Metal complexes of some of these Schiff's bases, incorporating Zn(II), Co(II), Ni(II) and Cu(II) ions, were also prepared and tested as inhibitors of the zinc enzyme carbonic anhydrase (CA), and more specifically the red blood cell isozymes I and II. The Schiff's bases behaved as medium potency CA I and CA II inhibitors, whereas their metal complexes showed a highly enhanced potency, with several low nanomolar CA II inhibitors detected. 相似文献
56.
Sutarnthip Reungprapavut Sudaratana R. Krungkrai Jerapan Krungkrai 《Journal of enzyme inhibition and medicinal chemistry》2013,28(3):249-256
Plasmodium falciparum is responsible for the majority of life-threatening cases of human malaria. The global emergence of drug-resistant malarial parasites necessitates identification and characterization of novel drug targets. Carbonic anhydrase (CA) is present at high levels in human red cells and in P. falciparum. Existence of at least three isozymes of the α class was demonstrated in P. falciparum and a rodent malarial parasite Plasmodium berghei. The major isozyme CA1 was purified and partially characterized from P. falciparum (PfCA1). A search of the malarial genome database yielded an open reading frame similar to the α-CAs from various organisms, including human. The primary amino acid sequence of the PfCA1 has 60% identity with a rodent parasite Plasmodium yoelii enzyme (PyCA). The single open reading frames encoded 235 and 252 amino acid proteins for PfCA1 and PyCA, respectively. The highly conserved active site residues were also found among organisms having α-CAs. The PfCA1 gene was cloned, sequenced and expressed in Escherichia coli. The purified recombinant PfCA1 enzyme was catalytically active. It was sensitive to acetazolamide and sulfanilamide inhibition. Kinetic properties of the recombinant PfCA1 revealed the authenticity to the wild type enzyme purified from P. falciparum in vitro culture. Furthermore, the PfCA1 inhibitors acetazolamide and sulfanilamide showed good antimalarial effect on the in vitro growth of P. falciparum. Our molecular tools developed for the recombinant enzyme expression will be useful for developing potential antimalarials directed at P. falciparum carbonic anhydrase. 相似文献
57.
《Journal of enzyme inhibition and medicinal chemistry》2013,28(2):224-228
AbstractThe new affinity gel reported in this study was prepared using EUPERGIT C250L as a chromatographic bed material, to which etylenediamine spacer arms were attached to prevent steric hindrance between the matrix and ligand, and to facilitate effective binding of the CA-specific ligand, of the aromatic sulfonamide type for the purification of α-carbonic anhydrases (Cas; EC 4.2.1.1). Indeed, the aminoethyl moieties of the affinity gel were derivatized by reaction with 4-isothiocyanatobenzenesulfonamide, with the formation of a thiourea-based gel, having inhibitory effects against CAs. Both bovine erythrocyte carbonic anhydrase BCA and human (h) erythrocyte CA isoforms I, II (hCA I and II) have been purified from hemolysates, by using this affinity gel. The greatest purification fold and column yields for BCA and for cytosolic (hCA I?+?II) enzymes were of 181-fold (21.07%) and 184-fold (9.49%), respectively. Maximum binding was achieved at 15?°C and I?=?0.3 ionic strength for α-carbonic anhydrases. 相似文献
58.
《Journal of enzyme inhibition and medicinal chemistry》2013,28(6):896-900
AbstractThe inhibition of two human cytosolic carbonic anhydrase (hCA, EC 4.2.1.1) isozymes I and II, with some 3,4-dihydroxypyrrolidine-2,5-dione and 3,5-dihydroxybenzoic acid derivatives, were investigated by using the esterase assay, with 4-nitrophenyl acetate (4-NPA) as substrate. Compounds 10–13 showed KI values in the range of 112.7–441.5?μM for hCA I and of 3.5–10.76?μM against hCA II, respectively. These hydroxyl group containing compounds generally were competitive inhibitors. Some hydroxyl group containing compounds investigated here showed effective hCA II inhibitory effects, in the same range as the clinically used sulfonamide acetazolamide, and might be used as leads for generating enzyme inhibitors possibly targeting other CA isoforms which have not been yet assayed for their interactions with such agents. 相似文献
59.
《Journal of enzyme inhibition and medicinal chemistry》2013,28(5):773-777
Abstract7-Amino-3,4-dihydro-1H-quinolin-2-one, a compound structurally similar to coumarins, recently discovered class of inhibitors of the α-carbonic anhydrases (CAs, EC 4.2.1.1) was investigated for its interaction with all human (h) CA isoforms, hCA I-XIV. The compound was not an inhibitor of the cytosolic, widespread isoform hCA II (KI?>?10?µM), was a weak inhibitor of hCA I, III, IV, VA, VI and XIII (KIs in the range of 0.90–9.5?µM) but effectively inhibited the cytosolic isoform hCA VII (KI of 480?nM) as well as the transmembrane isoforms hCA IX, XII and XIV (KIs in the range of 16.1–510?nM). Against many CA isoforms this lactam was a better inhibitor compared to the structurally similar 4-methyl-7-aminocoumarin, but unlike this compound, the lactam ring was not hydrolyzed and the inhibition was due to the intact bicyclic amino-quinolinone scaffold. Bicyclic lactams strucurally related to coumarins are thus a new class of CA inhibitors possessing however a distinct inhibition mechanism compared to the coumarins which undergo a hydrolysis of their lactone ring for generating the enzyme inhibitory species. 相似文献
60.
《Journal of enzyme inhibition and medicinal chemistry》2013,28(6):1010-1012
AbstractWe investigated a series of N-hydroxysulfamides obtained by Ferrier sulfamidoglycosylation for the inhibition of two bacterial carbonic anhydrases (CAs, EC 4.2.1.1) present in the pathogen Brucella suis. bsCA I was moderately inhibited by these compounds with inhibition constants ranging between 522 and 958?nM and no notable differences of activity between the acetylated or the corresponding deacetylated derivatives. The compounds incorporating two trans-acetates and the corresponding deprotected ones were the most effective inhibitors in the series. bsCA II was better inhibited, with inhibition constants ranging between 59.8 and 799?nM. The acetylated derivatives were generally better bsCA II inhibitors compared to the corresponding deacetylated compounds. Although these compounds were not highly isoform-selective CA inhibitors (CAIs) for the bacterial over the human CA isoforms, some of them possess inhibition profiles that make them interesting leads for obtaining better and more isoform-selective CAIs targeting bacterial enzymes. 相似文献