Inhibition of Human Glutathione Transferase P1-1 by Novel Benzazole Derivatives

Musdal, Yaman; Bolelli, Tugba Ertan-; Bolelli, Kayhan; Yılmaz, Serap; Ceyhan, Deniz; Hegazy, Usama M.; Mannervik, Bengt; Aksoy, Yasemin

doi:10.5505/tjb.2012.97759

Cited by 3 publications

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“…In this study, newly synthesized 2‐substituted‐5‐(4‐nitro/aminophenylsulfonamido)benzoxazole derivatives were screened for in vitro inhibition of hGST P1‐1. Among all of the tested compounds, 2‐(4‐chlorobenzyl)‐5‐(4‐nitrophenyl‐sulfonamido)benzoxazole ( 5 f ) exhibited the most potent inhibitory activity for hGST P1‐1, with an IC 50 value of 10.2 μ M ) 41. According to inhibitor activity results given in Table 1, compound 2‐(4‐ethylbenzyl)‐5‐(4‐aminophenylsulfonamido) benzoxazole ( 6 c ) displayed no inhibitory activity toward hGST P1‐1 due to the lack of electron‐withdrawing effect of the amino group at the α‐carbon atom of the phenyl ring attached to the sulfonyl group.…”

Section: Resultsmentioning

confidence: 99%

“…IC 50 values of the compounds were determined by regression analysis using GraphPad Prism software version 4.0. Among the all tested compounds, 5 f 2‐(4‐chlorobenzyl)‐5‐(4‐nitrophenylsulfonamido)benzoxazole was found as the most potent inhibitor for hGST P1–1, with an IC 50 value of ∼10 μ M 41 (Table 1).…”

Section: Methodsmentioning

confidence: 99%

“…The reaction system contained 5 % ethanol (from the CDNB stock solution), but the solvent had a negligible inhibitory effect on enzyme activity. The enzymatic reaction was obtained by subtracting the nonenzymatic rate from the rate measured in the presence of enzyme 41…”

Section: Methodsmentioning

confidence: 99%

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Synthesis and Biological Evaluation of 2‐Substituted‐5‐(4‐nitrophenylsulfonamido)benzoxazoles as Human GST P1‐1 Inhibitors, and Description of the Binding Site Features

et al. 2014

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Glutathione-S-transferases (GSTs) are enzymes involved in cellular detoxification by catalyzing the nucleophilic attack of glutathione (GSH) on the electrophilic center of numerous of toxic compounds and xenobiotics, including chemotherapeutic drugs. Human GST P1-1, which is known as the most prevalent isoform of the mammalian cytosolic GSTs, is overexpressed in many cancers and contributes to multidrug resistance by directly conjugating to chemotherapeutics. It is suggested that this resistance is related to the high expression of GST P1-1 in cancers, thereby contributing to resistance to chemotherapy. In addition, GSTs exhibit sulfonamidase activity, thereby catalyzing the GSH-mediated hydrolysis of sulfonamide bonds. Such reactions are of interest as potential tumor-directed prodrug activation strategies. Herein we report the design and synthesis of some novel sulfonamide-containing benzoxazoles, which are able to inhibit human GST P1-1. Among the tested compounds, 2-(4-chlorobenzyl)-5-(4-nitrophenylsulfonamido)benzoxazole (5 f) was found as the most active hGST P1-1 inhibitor, with an IC50 value of 10.2 μM, showing potency similar to that of the reference drug ethacrynic acid. Molecular docking studies performed with CDocker revealed that the newly synthesized 2-substituted-5-(4-nitrophenylsulfonamido)benzoxazoles act as catalytic inhibitors of hGST P1-1 by binding to the H-site and generating conjugates with GSH to form S-(4-nitrophenyl)GSH (GS-BN complex) via nucleophilic aromatic substitution reaction. The 4-nitrobenzenesulfonamido moiety at position 5 of the benzoxazole ring is essential for binding to the H-site and for the formation of the GST-mediated GSH conjugate.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Synthesis and Biological Evaluation of 2‐Substituted‐5‐(4‐nitrophenylsulfonamido)benzoxazoles as Human GST P1‐1 Inhibitors, and Description of the Binding Site Features

et al. 2014

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“…However, the IC 50 value for the alkaloids was high as compared to other GST inhibitors namely, hematin (3.16 μg/ml), tributyltin bromide (2.2 μg/ml) and for S-hexylglutathione (7.8 μg/ml) [ 31 ]. The difference can be ascribed to the fact that this was a mixture and not pure compounds.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of hematopoietic prostaglandin D2 Synthase (H-PGDS) by an alkaloid extract from Combretum molle

Moyo

Chimponda

Mukanganyama

2014

BMC Complement Altern Med

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BackgroundHematopoietic prostaglandin D2 synthase (H-PGDS, GST Sigma) is a member of the glutathione S-transferase super family of enzymes that catalyses the conjugation of electrophilic substances with reduced glutathione. The enzyme catalyses the conversion of PGH2 to PGD2 which mediates inflammatory responses. The inhibition of H-PGDS is of importance in alleviating damage to tissues due to unwarranted synthesis of PGD2. Combretum molle has been used in African ethno medicinal practices and has been shown to reduce fever and pain. The effect of C. molle alkaloid extract on H-PGDS was thus, investigated.MethodsH-PGDS was expressed in Escherichia coli XL1-Blue cells and purified using nickel immobilized metal affinity chromatography. The effect of C. molle alkaloid extract on H-PGDS activity was determined with 1-chloro-2, 4-dinitrobenzene (CDNB) as substrate. The effect of C. molle alkaloid extract with time on H-PGDS was determined. The mechanism of inhibition was then investigated using CDNB and glutathione (GSH) as substrates.ResultsA specific activity of 24 μmol/mg/min was obtained after H-PGDS had been purified. The alkaloid extract exhibited a 70% inhibition on H-PGDS with an IC50 of 13.7 μg/ml. C. molle alkaloid extract showed an uncompetitive inhibition of H-PGDS with Ki = 41 μg/ml towards GSH, and non-competitive inhibition towards CDNB with Ki = 7.7 μg/ml and Ki′ = 9.2 μg/ml.ConclusionThe data shows that C. molle alkaloid extract is a potent inhibitor of H-PGDS. This study thus supports the traditional use of the plant for inflammation.

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“…The inhibition studies using rat liver GST and human GST Pi-1 (hGSTP1) were carried out according to a previous method[ 16 ] with slight modifications[ 17 18 ] using 1-chloro-2,4-dinitrobenzene (CDNB) as substrate. Incubation mixtures (300 μL for rat liver GST, 200 μL for hGSTP1) contained 0.1 M potassium phosphate buffer (pH 6.5) and 0.001 M of GSH.…”

Section: Methodsmentioning

confidence: 99%

Effects of Curcuma xanthorrhiza extracts and their constituents on phase ii drug-metabolizing enzymes activity

Salleh¹,

Ismail²,

Halim³

2016

Phcog Res

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Background:Curcuma xanthorrhiza is a native Indonesian plant and traditionally utilized for a range of illness including liver damage, hypertension, diabetes, and cancer.Objective:The study determined the effects of C. xanthorrhiza extracts (ethanol and aqueous) and their constituents (curcumene and xanthorrhizol) on UDP-glucuronosyltransferase (UGT) and glutathione transferase (GST) activities.Materials and Methods:The inhibition studies were evaluated both in rat liver microsomes and in human recombinant UGT1A1 and UGT2B7 enzymes. p-nitrophenol and beetle luciferin were used as the probe substrates for UGT assay while 1-chloro-2,4-dinitrobenzene as the probe for GST assay. The concentrations of extracts studied ranged from 0.1 to 1000 μg/mL while for constituents ranged from 0.01 to 500 μM.Results:In rat liver microsomes, UGT activity was inhibited by the ethanol extract (IC50 =279.74 ± 16.33 μg/mL). Both UGT1A1 and UGT2B7 were inhibited by the ethanol and aqueous extracts with IC50 values ranging between 9.59–22.76 μg/mL and 110.71–526.65 μg/Ml, respectively. Rat liver GST and human GST Pi-1 were inhibited by ethanol and aqueous extracts, respectively (IC50 =255.00 ± 13.06 μg/mL and 580.80 ± 18.56 μg/mL). Xanthorrhizol was the better inhibitor of UGT1A1 (IC50 11.30 ± 0.27 μM) as compared to UGT2B7 while curcumene did not show any inhibition. For GST, both constituents did not show any inhibition.Conclusion:These findings suggest that C. xanthorrhiza have the potential to cause herb-drug interaction with drugs that are primarily metabolized by UGT and GST enzymes.SUMMARY Findings from this study would suggest which of Curcuma xanthorrhiza extracts and constituents that would have potential interactions with drugs which are highly metabolized by UGT and GST enzymes. Further clinical studies can then be designed if needed to evaluate the in vivo pharmacokinetic relevance of these interactions Abbreviations Used: BSA: Bovine serum albumin, CAM: Complementary and alternative medicine, cDNA: Complementary deoxyribonucleic acid, CDNB: 1-Chloro-2,4-dinitrobenzene, CuSO4.5H2O: Copper(II) sulfate pentahydrate, CXEE: Curcuma xanthorrhiza ethanol extract, CXAE: Curcuma xanthorrhiza aqueous extract, GC-MS: Gas chromatography-mass spectroscopy, GSH: Glutathione, GST: Glutathione S-transferase, KCl: Potassium chloride, min: Minutes, MgCl2: Magnesium chloride, mg/mL: Concentration (weight of test substance in milligrams per volume of test concentration), mM: Milimolar, Na2CO3: Sodium carbonate, NaOH: Sodium hydroxide, nmol: nanomol, NSAIDs: Non-steroidal antiinflammatory drug, p-NP: para-nitrophenol, RLU: Relative light unit, SEM: Standard error of mean, UDPGA: UDP-glucuronic acid, UGT: UDP-glucuronosyltransferase.

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Inhibition of Human Glutathione Transferase P1-1 by Novel Benzazole Derivatives

Cited by 3 publications

References 0 publications

Synthesis and Biological Evaluation of 2‐Substituted‐5‐(4‐nitrophenylsulfonamido)benzoxazoles as Human GST P1‐1 Inhibitors, and Description of the Binding Site Features

Synthesis and Biological Evaluation of 2‐Substituted‐5‐(4‐nitrophenylsulfonamido)benzoxazoles as Human GST P1‐1 Inhibitors, and Description of the Binding Site Features

Inhibition of hematopoietic prostaglandin D2 Synthase (H-PGDS) by an alkaloid extract from Combretum molle

Effects of Curcuma xanthorrhiza extracts and their constituents on phase ii drug-metabolizing enzymes activity

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