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1.
Dihydrolipoamide dehydrogenase (LADH) from Trypanosoma cruzi was inactivated by treatment with myeloperoxidase (MPO)-dependent systems. With MPO/H2O2/NaCl, LADH lipoamide reductase and diaphorase activities significantly decreased as a function of incubation time. Iodide, bromide, thiocyanide and chloride effectively supplemented the MPO/H2O2 system, KI and NaCl being the most and the least effective supplements, respectively. LADH inactivation by MPO/H2O2/NaCl and by NaOCl was similarly prevented by thiol compounds such as GSH, L-cysteine, N-acetylcysteine, penicillamine and N-(2-mercaptopropionyl-glycine) in agreement with the role of HOCl in LADH inactivation by MPO/H2O2/NaCl. LADH was also inactivated by MPO/NADH/halide, MPO/H2O2/NaNO2 and MPO/NADH/NaNO2 systems. Catalase prevented the action of the NADH-dependent systems, thus supporting H2O2 production by NADH-supplemented LADH. MPO inhibitors (4-aminobenzoic acid hydrazide, and isoniazid), GSH, L-cysteine, L-methionine and L-tryptophan prevented LADH inactivation by MPO/H2O2/NaNO2. Other MPO systems inactivating LADH were (a) MPO/H2O2/chlorpromazine; (b) MPO/H2O2/monophenolic systems, including L-tyrosine, serotonin and acetaminophen and (c) MPO/H2O2/di- and polyphenolic systems, including norepinephrine, catechol, nordihydroguaiaretic acid, caffeic acid, quercetin and catechin. Comparison of the above effects and those previously reported with pig myocardial LADH indicates that both enzymes were similarly affected by the MPO-dependent systems, allowance being made for T. cruzi LADH diaphorase inactivation and the greater sensitivity of its LADH lipoamide reductase activity towards the MPO/H2O2/NaCl system and NaOCl. 相似文献
2.
Hypochlorous acid (HOCl) and N-chloramines are produced by myeloperoxidase (MPO) as part of the immune response to destroy invading pathogens. However, MPO also plays a detrimental role in inflammatory pathologies, including atherosclerosis, as inappropriate production of oxidants, including HOCl and N-chloramines, causes damage to host tissue. Low molecular mass thiol compounds, including glutathione (GSH) and methionine (Met), have demonstrated efficacy in scavenging MPO-derived oxidants, which prevents oxidative damage in vitro and ex vivo. Selenium species typically have greater reactivity toward oxidants compared to the analogous sulfur compounds, and are known to be efficient scavengers of HOCl and other hypohalous acids produced by MPO. In this study, we examined the efficacy of a number of sulfur and selenium compounds to scavenge a range of biologically relevant N-chloramines and oxidants produced by both isolated MPO and activated neutrophils and characterized the resulting selenium-derived oxidation products in each case. A dose-dependent decrease in the concentration of each N-chloramine was observed on addition of the sulfur compounds (cysteine, methionine) and selenium compounds (selenomethionine, methylselenocysteine, 1,4-anhydro-4-seleno-L-talitol, 1,5-anhydro-5-selenogulitol) studied. In general, selenomethionine was the most reactive with N-chloramines (k2 0.8–3.4×103 M–1 s–1) with 1,5-anhydro-5-selenogulitol and 1,4-anhydro-4-seleno-L-talitol (k2 1.1–6.8×102 M–1 s–1) showing lower reactivity. This resulted in the formation of the respective selenoxides as the primary oxidation products. The selenium compounds demonstrated greater ability to remove protein N-chloramines compared to the analogous sulfur compounds. These reactions may have implications for preventing cellular damage in vivo, particularly under chronic inflammatory conditions. 相似文献
3.
The powerful oxidant HOCl (hypochlorous acid and its corresponding anion, −OCl) generated by the myeloperoxidase (MPO)–H2O2–Cl− system of activated leukocytes is strongly associated with multiple human inflammatory diseases; consequently there is considerable interest in inhibition of this enzyme. Nitroxides are established antioxidants of low toxicity that can attenuate oxidation in animal models, with this ascribed to superoxide dismutase or radical-scavenging activities. We have shown (M.D. Rees et al., Biochem. J. 421, 79–86, 2009) that nitroxides, including 4-amino-TEMPO (4-amino-2,2,6,6-tetramethylpiperidin-1-yloxyl radical), are potent inhibitors of HOCl formation by isolated MPO and activated neutrophils, with IC50 values of ~1 and ~6 µM respectively. The utility of tetramethyl-substituted nitroxides is, however, limited by their rapid reduction by biological reductants. The corresponding tetraethyl-substituted nitroxides have, however, been reported to be less susceptible to reduction. In this study we show that the tetraethyl species were reduced less rapidly than the tetramethyl species by both human plasma (89–99% decreased rate of reduction) and activated human neutrophils (62–75% decreased rate). The tetraethyl-substituted nitroxides retained their ability to inhibit HOCl production by MPO and activated neutrophils with IC50 values in the low-micromolar range; in some cases inhibition was enhanced compared to tetramethyl substitution. Nitroxides with rigid structures (fused oxaspiro rings) were, however, inactive. Overall, these data indicate that tetraethyl-substituted nitroxides are potent inhibitors of oxidant formation by MPO, with longer plasma and cellular half-lives compared to the tetramethyl species, potentially allowing lower doses to be employed. 相似文献
4.
Martina Paumann-Page Paul G. Furtmüller Stefan Hofbauer Louise N. Paton Christian Obinger Anthony J. Kettle 《Archives of biochemistry and biophysics》2013
Human myeloperoxidase (MPO) uses hydrogen peroxide generated by the oxidative burst of neutrophils to produce an array of antimicrobial oxidants. During this process MPO is irreversibly inactivated. This study focused on the unknown role of hydrogen peroxide in this process. When treated with low concentrations of H2O2 in the absence of reducing substrates, there was a rapid loss of up to 35% of its peroxidase activity. Inactivation is proposed to occur via oxidation reactions of Compound I with the prosthetic group or amino acid residues. At higher concentrations hydrogen peroxide acts as a suicide substrate with a rate constant of inactivation of 3.9 × 10−3 s−1. Treatment of MPO with high H2O2 concentrations resulted in complete inactivation, Compound III formation, destruction of the heme groups, release of their iron, and detachment of the small polypeptide chain of MPO. Ten of the protein’s methionine residues were oxidized and the thermal stability of the protein decreased. Inactivation by high concentrations of H2O2 is proposed to occur via the generation of reactive oxidants when H2O2 reacts with Compound III. These mechanisms of inactivation may occur inside neutrophil phagosomes when reducing substrates for MPO become limiting and could be exploited when designing pharmacological inhibitors. 相似文献
5.
Using MALDI-TOF mass spectrometry, we have shown that leukocytic myeloperoxidase (MPO) in the presence of its substrates (H2O2 and Br?) does not induce any changes in saturated 1,2-dipalmitoyl-sn-glycero-3-phosphocholine. Incubation of liposomes prepared from mono-unsaturated phosphatidylcholine (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine) with the (MPO + H2O2 + Br?) system resulted in formation of bromohydrins as the main products. 1-Palmitoyl-2-hydroxy-sn-glycero-3-phosphocholine (lysophosphatidylcholine) was the main product of the reaction of polyunsaturated phosphatidylcholine (1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine) with the (MPO + H2O2 + Br?) system. The formation of lysophospholipids as well as of bromohydrins was not observed when the enzyme or one of its substrates (H2O2 or Br?) was absent from the incubation medium, or if an inhibitor of MPO (sodium azide) or hypobromite scavengers (taurine or methionine) were added. Thus, it can be postulated that the formation of bromohydrins as well as lysophospholipids by the (MPO + H2O2 + Br?) system results from reactions of hypobromite formed during MPO catalysis with double bonds of acyl chains of phosphatidylcholine. Such destructive processes may take place in vivo in membrane-or lipoprotein-associated unsaturated lipids in centers of inflammation. 相似文献
6.
Hypochlorous acid (HOCl), an oxidant produced by myeloperoxidase (MPO), induces protein and lipid oxidation, which is implicated in the pathogenesis of atherosclerosis. Individuals with mildly elevated bilirubin concentrations (i.e., Gilbert syndrome; GS) are protected from atherosclerosis, cardiovascular disease, and related mortality. We aimed to investigate whether exogenous/endogenous unconjugated bilirubin (UCB), at physiological concentrations, can protect proteins/lipids from oxidation induced by reagent and enzymatically generated HOCl. Serum/plasma samples supplemented with exogenous UCB (≤250 µM) were assessed for their susceptibility to HOCl and MPO/H2O2/Cl− oxidation, by measuring chloramine, protein carbonyl, and malondialdehyde (MDA) formation. Serum/plasma samples from hyperbilirubinemic Gunn rats and humans with GS were also exposed to MPO/H2O2/Cl− to: (1) validate in vitro data and (2) determine the relevance of endogenously elevated UCB in preventing protein and lipid oxidation. Exogenous UCB dose-dependently (P<0.05) inhibited HOCl and MPO/H2O2/Cl−-induced chloramine formation. Albumin-bound UCB efficiently and specifically (3.9–125 µM; P<0.05) scavenged taurine, glycine, and N-α-acetyllysine chloramines. These results were translated into Gunn rat and GS serum/plasma, which showed significantly (P<0.01) reduced chloramine formation after MPO-induced oxidation. Protein carbonyl and MDA formation was also reduced after MPO oxidation in plasma supplemented with UCB (P<0.05; 25 and 50 µM, respectively). Significant inhibition of protein and lipid oxidation was demonstrated within the physiological range of UCB, providing a hypothetical link to protection from atherosclerosis in hyperbilirubinemic individuals. These data demonstrate a novel and physiologically relevant mechanism whereby UCB could inhibit protein and lipid modification by quenching chloramines induced by MPO-induced HOCl. 相似文献
7.
We explored the behaviour of a series of phenolic acids used as enhancers or inhibitors of luminol chemiluminescence by three different methods to determine if behaviour was associated with phenolic acid structure and redox character. All the phenolic acids inhibited chemiluminescence when hexacyanoferrate(III) was reacted with the phenolic acids before adding luminol. The redox character of these compounds was clearly related to structure. When hexacyanoferrate(III)-luminol-O2 chemiluminescence was initiated by phenolic acid-luminol mixtures some phenolic acids behaved as enhancers of chemiluminescence, and others as inhibitors. We propose a mechanism to explain these findings. We found direct relationships between the redox character of the phenolic acids and the enhancement or inhibition of the chemiluminescence of the luminol–H2O2–peroxidase system and we propose mechanism to explain these phenomena. 相似文献
8.
Ghassan J. Maghzal Katie M. Cergol Sudhir R. Shengule Cacang Suarna Darren Newington Anthony J. Kettle Richard J. Payne Roland Stocker 《The Journal of biological chemistry》2014,289(9):5580-5595
Oxidants derived from myeloperoxidase (MPO) contribute to inflammatory diseases. In vivo MPO activity is commonly assessed by the accumulation of 3-chlorotyrosine (3-Cl-Tyr), although 3-Cl-Tyr is formed at low yield and is subject to metabolism. Here we show that MPO activity can be assessed using hydroethidine (HE), a probe commonly employed for the detection of superoxide. Using LC/MS/MS, 1H NMR, and two-dimensional NOESY, we identified 2-chloroethidium (2-Cl-E+) as a specific product when HE was exposed to hypochlorous acid (HOCl), chloramines, MPO/H2O2/chloride, and activated human neutrophils. The rate constant for HOCl-mediated conversion of HE to 2-Cl-E+ was estimated to be 1.5 × 105
m−1s−1. To investigate the utility of 2-Cl-E+ to assess MPO activity in vivo, HE was injected into wild-type and MPO-deficient (Mpo−/−) mice with established peritonitis or localized arterial inflammation, and tissue levels of 2-Cl-E+ and 3-Cl-Tyr were then determined by LC/MS/MS. In wild-type mice, 2-Cl-E+ and 3-Cl-Tyr were detected readily in the peritonitis model, whereas in the arterial inflammation model 2-Cl-E+ was present at comparatively lower concentrations (17 versus 0.3 pmol/mg of protein), and 3-Cl-Tyr could not be detected. Similar to the situation with 3-Cl-Tyr, tissue levels of 2-Cl-E+ were decreased substantially in Mpo−/− mice, indicative of the specificity of the assay. In the arterial inflammation model, 2-Cl-E+ was absent from non-inflamed arteries and blood, suggesting that HE oxidation occurred locally in the inflamed artery. Our data suggest that the conversion of exogenous HE to 2-Cl-E+ may be a useful selective and sensitive marker for MPO activity in addition to 3-Cl-Tyr. 相似文献
9.
《Bioorganic & medicinal chemistry letters》2014,24(12):2758-2763
In the present study, a series of fifteen α-tetralone (3,4-dihydro-2H-naphthalen-1-one) derivatives were synthesised and evaluated as inhibitors of recombinant human monoamine oxidase (MAO) A and B. The α-tetralone derivatives examined are structurally related to a series of chromone (1-benzopyran-4-one) derivatives which has previously been shown to act as MAO-B inhibitors. The results document that the α-tetralones are highly potent MAO-B inhibitors with all compounds exhibiting IC50 values in the nanomolar range (<78 nM). Although most compounds are selective inhibitors of MAO-B, the α-tetralones are also potent MAO-A inhibitors with ten compounds exhibiting IC50 values in the nanomolar range (<792 nM). The most potent MAO-B inhibitor, 6-(3-iodobenzyloxy)-3,4-dihydro-2H-naphthalen-1-one, exhibits an IC50 value of 4.5 nM with a 287-fold selectivity for MAO-B over the MAO-A isoform, while the most potent MAO-A inhibitor, 6-(3-cyanobenzyloxy)-3,4-dihydro-2H-naphthalen-1-one, exhibits an IC50 value of 24 nM with a 3.25-fold selectivity for MAO-A. Analyses of the structure–activity relationships for MAO inhibition show that substitution on the C6 position of the α-tetralone moiety is a requirement for MAO-A and MAO-B inhibition, and that a benzyloxy substituent on this position is more favourable for MAO-A inhibition than phenylethoxy and phenylpropoxy substitution. For MAO-B inhibition, alkyl and halogen substituents on the meta and para positions of the benzyloxy ring enhance inhibitory potency. It may be concluded that α-tetralone derivatives are promising leads for design of therapies for Parkinson’s disease and depression. 相似文献
10.
Díaz-Viciedo R Hortelano S Girón N Massó JM Rodriguez B Villar A de Las Heras B 《Biochemical and biophysical research communications》2008,369(2):761-766
Fractionation of a petroleum ether extract of Helianthus annuus L. led to the isolation of three diterpene acids: grandiflorolic, kaurenoic and trachylobanoic acids. These compounds were studied for potential anti-inflammatory activity on the generation of inflammatory mediators in lipopolysaccharide (LPS)-activated RAW 264.7 macrophages. At non-toxic concentrations, these compounds reduced, in a concentration-dependent manner nitric oxide (NO), prostaglandin E2 (PGE2) and tumor necrosis factor (TNF-α) production, as well as expression of inducible nitric oxide synthase (NOS-2) and cyclooxygenase-2 (COX-2).All diterpenoids displayed significant in vivo anti-inflammatory activity and suppressed the 12-O-tetradecanoylphorbol-13-acetate (TPA)-mouse ear edema. In addition, inhibition of myeloperoxidase (MPO) activity, an index of cellular infiltration, was observed.In summary, our results suggest that the inhibition of the expression of NOS-2, COX-2 and the release of inflammatory cytokines, is responsible for the anti-inflammatory effects of the diterpenoids isolated from H. annuus L. which likely contributes to the pharmacological action of sunflower. 相似文献
11.
Diabetes is one of the most popular worldwide diseases, regulated by the defects in insulin secretion, insulin action, or both. The overexpression of protein tyrosine phosphatase 1B (PTP1B) was found to down-regulate the insulin-receptor activation. PTP1B has been known as a strategy for the treatment of diabetes via the regulation of insulin signal transduction pathway. Herein, we investigated the PTP1B inhibitors isolated from natural sources. The chemical investigation of Selaginella tamariscina (Beauv.) Spring revealed seven unsaturated alkynyl phenols 1–7, four new selaginellins T–W 1–4 together with three known compounds 5–7 isolated from the aerial parts. The structures of the isolates were determined by spectroscopic techniques (1D/2D-NMR, MS, and CD). The inhibitory effects of these isolates on the PTP1B enzyme activity were investigated. Among them, compounds 2–7 significantly exhibited the inhibitory effects with the IC50 values ranging from 4.8 to 15.9 μM. Compound 1 moderately displayed the inhibitory activity with an IC50 of 57.9 μM. Furthermore, active compounds were discovered from their kinetic and molecular docking analysis. The results revealed that compounds 2 and 4–7 were mixed-competitive inhibitors, whereas compound 3 was a non-competitive inhibitor. This data confirm that these compounds exhibited potential inhibitory effect on the PTP1B enzyme activity. 相似文献
12.
In this work, the effects of H2O2 at concentrations of 10?8–10?2 mol/l on the neutrophil ability to generate reactive oxygen and chlorine species (ROCS) and to secrete myeloperoxidase (MPO) were studied, as well as the H2O2 damaging action on neutrophils. It was found that H2O2 at concentrations of 2 × 10?3–10?2 mol/l led to disturbances of neutrophil membrane barrier properties and to a lactate dehydrogenase release. Incubation of neutrophils with an addition of 10?4–10?7 mol/l H2O2 was accompanied by an increase of the cell ability to generate ROCS during phagocytosis and a decrease of neutrophil ability to secrete MPO and ROCS into the extracellular medium during adhesion. Mechanisms of the H2O2 action are coupled with arachidonic acid metabolism. Inhibition of the 5-lipoxygenase or cyclooxygenase metabolism pathways produced an enhancement of the H2O2 destructive effect. Block of 5-lipoxygenase pathway led to elimination of the H2O2 action on MPO and ROCS secretion and to an enhancement of the H2O2 effect on the neutrophil ability to generate ROCS during phagocytosis. The obtained data indicate a high blood neutrophil resistance to the H2O2 destructive action and confirm the H2O2 regulatory role with respect to the neutrophil functions. 相似文献
13.
A key function of neutrophil myeloperoxidase (MPO) is the synthesis of hypochlorous acid (HOCl), a potent oxidizing agent that plays a cytotoxic role against invading bacteria and viruses at inflammatory sites and in phagosomes. MPO displayed a chlorinating activity preferably at acidic pH but at neutral pH MPO catalyzes mainly reactions of the peroxidase cycle. In the present work effects of tyrosine on the chlorinating activity of MPO were studied. At pH 7.4 we detected an increased HOCl production in the presence of tyrosine not only by the MPO-H2O2-Cl- system but also in suspensions of zymosan-activated neutrophils. An excess of H2O2 is known to cause an accumulation of compound II of MPO blocking the generation of HOCl at neutral pH. As evidenced by spectral changes, tyrosine-induced activation of MPO to synthesize HOCl was due to the ability of tyrosine to reduce compound II back to the native state, thus accelerating the enzyme turnover. MPO-induced oxidation of tyrosine is relevant to what can be in vivo; we detected MPO-catalyzed formation of dityrosine in the presence of plasma under experimental conditions when tyrosine concentration was about three magnitudes of order less than the Cl− concentration. At acidic pH formation of compound II was impaired in the presence of chloride and dityrosine couldn't be detected in plasma. In conclusion, the ability of tyrosine to increase the chlorinating activity of MPO at neutral pH and enhanced values of H2O2 may be very effective for the specific enhancement of HOCl production under acute inflammation. 相似文献
14.
《Bioorganic & medicinal chemistry letters》2014,24(1):90-95
A series of novel schiff base derivatives (H1–H20) containing pyrazine and triazole moiety have been designed and synthesized, and their biological activities were also evaluated as potential inhibitors of β-ketoacyl-acyl carrier protein synthase III (FabH). These compounds were assayed for antibacterial activity against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Bacillus subtilis and Bacillus amyloliquefaciens and selected compounds among them were tested for their Escherichia coli FabH inhibitory activity. Based on the biological data, compound H17 showed the most potent antibacterial activity with MIC values of 0.39–1.56 μg/mL against the tested bacterial strains and exhibited the most potent E. coli FabH inhibitory activity with IC50 of 5.2 μM, being better than the positive control Kanamycin B with IC50 of 6.3 μM. Furthermore, docking simulation was performed to position compound H17 into the E. coli FabH active site to determine the probable binding conformation. This study indicated that compound H17 has demonstrated significant E. coli FabH inhibitory activity as a potential antibacterial agent and provides valuable information for the design of E. coli FabH inhibitors. 相似文献
15.
A novel 2-(aryl)-6-morpholin-4-yl(or 4-methylpiperazin-1-yl)-1H-benzimidazole derivatives were designed and expeditiously synthesized starting from 5-morpholin-4-yl(or 4-methylpiperazin-1-yl)-2-nitroaniline with various aldehydes which were preliminarily screened for in vitro antioxidant activities and glucosidase inhibitors. The benzimidazoles were effectively synthesized by a rapid ‘onepot’ nitro reductive cyclization reaction using sodium hydrosulfite as a reagent. All reactions were conducted using both the microwave and conventional methods to compare yields and reaction times. Antioxidant activities of the synthesized compounds were clarified using various in vitro antioxidant assays including Cupric Reducing Antioxidant Capacity (CUPRAC, ranging from 5.511 to 19.703 mM Trolox/mg compound) and Ferric Reducing Antioxidant Power (FRAP) (1.141–12.943 mM FeSO4·7H2O/mg compound) assays. Also, the radical scavenging activities of these compounds were assayed using ABTS+ and DPPH methods. The results showed that all compounds exhibited very high scavenging activity. These synthesized compounds were then evaluated for their α-glucosidase inhibitory potential and seven compounds demonstrated an inhibitory potential much better than the standard acarbose. Herein, we will provide details of the structure activity relationship of the benzimidazole analog for the potency. 相似文献
16.
Bo Li Tongmeng Jiang Hui Liu Zhikang Miao Depeng Fang Li Zheng Jinmin Zhao 《Journal of cellular physiology》2019,234(1):561-571
Recent studies have shown that andrographolide (AP) has the potential to be developed as a drug for therapy for osteoarthritis (OA). However, the role of AP in attenuating the progression of OA is still unknown. We hypothesized that its therapeutic effect may be associated with its antioxidant potential. In this study, we investigated the therapeutic effect of AP on chondrocytes injured by H2O2 and the association with the oxidation-related signaling pathways through the detection of cell proliferation, cell viability, the expression of oxidative stress-specific genes (Sod1, Cat, and malonaldehyde [Mda]) and proteins (superoxide dismutase [SOD], catalase [CAT]) after a culture period of 3 and 5 days, respectively. Further exploration of the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) messenger RNA and protein was also performed. The results showed that 0.625 µg/ml and 2.5 µg/ml of AP decreased oxidative stress injury of chondrocytes by increasing cell proliferation reduced by H2O2 and antioxidant enzyme activity, including SOD and CAT. Inflammation factors, such as matrix metallopeptidase 13 (Mmp13), tissue inhibitor of metalloproteinase 1 (Timp1), and interleukin-6 (Il6), were downregulated in the H2O2 group with AP, demonstrating a decrease in the progression of OA. Pathway analyses identified that the kelch-like ECH-associated protein 1 (Keap1)–Nrf2–antioxidant response element (Are) pathway is an important mediator in AP therapy on H2O2-induced OA. This study indicates that AP exerts protection effects on oxidative stress via activation of the Keap1–Nrf2–Are pathway in chondrocytes injured by H2O2, which may be promising for the therapy of OA. 相似文献
17.
《Bioorganic & medicinal chemistry》2016,24(6):1402-1407
A series of heterocyclic benzenesulfonamides incorporating 2-mercapto-3H-quinazolin-4-one tails were prepared by condensation of substituted anthranilic acids with 4-isothiocyanato-benzenesulfonamide. These sulfonamides were investigated as inhibitors of the human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms hCA I and II (cytosolic isozymes), as well as hCA IX and XII (trans-membrane, tumor-associated enzymes). They acted as medium potency inhibitors of hCA I (KIs of 81.0–3084 nM), being highly effective as hCA II (KIs in the range of 0.25–10.8 nM), IX (KIs of 3.7–50.4 nM) and XII (KIs of 0.60–52.9 nM) inhibitors. These compounds should thus be of interest as preclinical candidates in pathologies in which the activity of these enzymes should be inhibited, such as glaucoma (CA II and XII as targets) or some tumors in which the activity of three isoforms (CA II, IX and XII) is dysregulated. 相似文献
18.
A direct correlation between cathepsin expression–cancer progression and elevated levels of cathepsins due to an imbalance in cellular inhibitors-cathepsins ratio in inflammatory diseases necessitates the work on the identification of potential inhibitors to cathepsins. In the present work we report the synthesis of some 2,3-dihydroquinazolin-4(1H)-ones followed by their evaluation as cysteine protease inhibitors in general and cathepsin B and cathepsin H inhibitors in particular. 2,3-Dihydroquinazolin-4(1H)-ones, synthesized by the condensation of anthranilamide and carbonyl compound in presence of PPA-SiO2 catalyst, were characterized by spectral analysis. The designed compounds were screened as inhibitors to proteolysis on endogenous protein substrates. Further, a distinct differential pattern of inhibition was obtained for cathepsins B and H. The inhibition was more to cathepsin B with Ki values in nanomolar range. However, cathepsin H was inhibited at micromolar concentration. Maximum inhibition was shown by compounds, 1e and 1f for cathepsin B and compounds 1c and 1f for cathepsin H. The synthesized compounds were established as reversible inhibitors of cathepsins B and H. The results were also compared with the energy of interaction between enzyme active site and compounds using iGemdock software. 相似文献
19.
Polymorphonuclear leukocyte (PMN)-derived myeloperoxidase (MPO) contributes to the pathophysiology of numerous systemic inflammatory disorders through: (1) direct peroxidation of targets and (2) production of strong oxidizing compounds, e.g., hypohalous acids, particularly hypochlorous acid, which furthers oxidant damage and contributes to the propagation of inflammation and tissue injury/dysfunction. Carbon monoxide-releasing molecules (CORMs) offer potent anti-inflammatory effects; however, the mechanism(s) of action is not fully understood. This study assessed the potential of MPO activity inhibition by a water-soluble CORM, CORM-3. To this end, we used in vitro assays to study CORM-3-dependent modulation of MPO activity with respect to: (1) the inhibition of MPO’s catalytic activity generally and (2) the specific inhibition of MPO’s peroxidation and halogenation (i.e., production of hypochlorous acid) reactions. Further, we employed primary human umbilical vein endothelial cells (HUVECs) to investigate MPO-dependent cellular activation and dysfunction by measuring intracellular oxidant stress (DHR-123 oxidation) and HUVEC permeability (flux of Texas red–dextran), respectively. The results indicate that CORM-3 significantly inhibits MPO activity as well as MPO’s peroxidation and hypohalous acid cycles specifically (p<0.05 vs uninhibited MPO). In addition, CORM-3 significantly decreases PMN homogenate- or rhMPO-induced intracellular DHR-123 oxidation in HUVECs and rhMPO-induced HUVEC monolayer permeability (p<0.05 vs untreated). In all assays the inactivated CORM-3 was significantly less effective than CORM-3 (p<0.05). Taken together our findings indicate that CORM-3 is a novel MPO inhibitor and mitigates inflammatory damage at least in part through a mechanism involving the inhibition of neutrophilic MPO activity. 相似文献
20.
Cemalettin Alp Deniz Ekinci Mehmet Serdar Gültekin Murat Şentürk Ertan Şahin Ömer İrfan Küfrevioğlu 《Bioorganic & medicinal chemistry》2010,18(12):4468-4474
Here we propose a novel one-pot synthesis of new tosyl-pyrrole derivatives. By means of the new developed method, pyrrole derivatives were synthesized at room temperature in a single step, and a useful method is proposed for the synthesis of similar compounds. Moreover, inhibitions of two human cytosolic carbonic anhydrase (hCA, EC 4.2.1.1) isozymes I and II by 1-tosyl-pyrrole and 1-tosyl-pyrrol-2-on derivatives were investigated. 1-Tosyl-pyrrole, 1-tosyl-1H-pyrrol-2(5H)-one, 5-hydroxy-1-tosyl-1H-pyrrol-2(5H)-one and 5-oxo-1-tosyl-2,5-dihydro-1H-pyrrol-2-yl acetate showed inhibitory action with Ki values in the range of 14.6–42.4 μM for hCA I and 0.53–37.5 μM for hCA II, respectively. All pyrrole derivatives were competitive inhibitors with 4-nitrophenylacetate as substrate. Some new synthesized pyrrole derivatives showed very 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 targeting other CA isoforms. 相似文献