Inhibition of human glutathione transferase P1-1 by novel benzazole Derivatives

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

doi:10.5505/tjb.2012.30301

Cited by 10 publications

(4 citation statements)

References 31 publications

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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[1718] 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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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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“…Benzamide derivatives including XT5 were found to have in vitro anticancer effects [38]. In our previous study, XT5 was suggested as a novel molecule that has apoptotic effects on imatinib sensitive and resistant K562 cells [39].…”

Section: Introductionmentioning

confidence: 99%

Fluorescence labelled XT5 modified nano-capsules enable highly sensitive myeloma cells detection

Dizaji¹,

Kohneshahri²,

Gafil³

et al. 2022

Nanotechnology

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Accurate diagnosis of cancer cells in early stages plays an important role in reliable therapeutic strategies. In this study, we aimed to develop fluorescence-conjugated polymer carrying nanocapsules (NCs) which is highly selective for myeloma cancer cells. To gain specific targeting properties, NCs, XT5 molecules (a benzamide derivative) which shows high affinity properties against protease-activated receptor-1 (PAR1), that overexpressed in myeloma cancer cells, was used. For this purpose, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[carboxy(polyethylene glycol)-2000]-carboxylic acid (DSPE-PEG2000-COOH) molecules, as a main encapsulation material, was conjugated to XT5 molecules due to esterification reaction using N,N'-dicyclohexylcarbodiimide (DCC) as a coupling agent. The synthesized DSPE-PEG2000-COO-XT5 was characterized by using FT-IR and 1H NMR spectroscopies and results indicated that XT5 molecules were successfully conjugated to DSPE-PEG2000-COOH. Poly(fluorene-alt-benzothiadiazole) (PFBT) conjugated polymer was encapsulated with DSPE-PEG2000-COO-XT5 due to dissolving in THF and ultra-sonication in an aqueous solution, respectively. The morphological properties, UV-vis absorbance, and emission properties of obtained conjugated polymer encapsulated DSPE-PEG2000-COO-XT5 (CPDP-XT5) NCs was determined by utilizing scanning electron microscopy (SEM), UV-vis spectroscopy, and fluorescent spectroscopy, respectively. Cytotoxicity properties of CPDP-XT5 was evaluated by performing MTT assay on RPMI 8226 myeloma cell lines. Cell viability results confirmed that XT5 molecules were successfully conjugated to DSPE-PEG2000-COOH. Specific targeting properties of CPDP-XT5 NCs and XT5-free NCs (CPDP NCs) were investigated on RPMI 8226 myeloma cell lines by utilizing fluorescent microscopy and results indicated that CPDP-XT5 NCs shows significantly high affinity in comparison to CPDP NCs against the cells. Homology modeling and molecular docking properties of XT5 molecules were evaluated and simulation results confirmed our results.

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“…Some of the benzoxazole and benzamide compounds, which were previously synthesized in our laboratory, showed strong inhibitory activity for human DNA Topoisomerases and Glutathione S-Transferases and also anticancer effects observed on various cell cultures [12][13][14][15][16][17][18][19][20]. These findings encouraged us to search for the new anticancer target NK1R by comparing their activities with the well-known NK1R antagonist aprepitant.…”

Section: Introductionmentioning

confidence: 99%

“…Over the last decade our group have been working on the drug design studies on the new anticancer active compounds by using both computational techniques and experimental work such as synthesis and activity studies [12][13][14][15][16][17][18][19][20]. Some of the benzoxazole and benzamide compounds, which were previously synthesized in our laboratory, showed strong inhibitory activity for human DNA Topoisomerases and Glutathione S-Transferases and also anticancer effects observed on various cell cultures [12][13][14][15][16][17][18][19][20].…”

Section: Introductionmentioning

confidence: 99%

Possible Mechanism of Action of Neurokinin-1 Receptors (NK1R) Antagonists

Ozturk¹,

Akı-Yalçın²,

Ertan-Bolelli³

et al. 2017

JPP

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Abstract:Recently, NK1R (Neurokinin-1 receptors) take attention as new and promising target in anticancer drug development area. It has been proved that non-peptide NK1R antagonists L-733,060, aprepitant and L-732,138 inhibited tumor growth in several cancer cell lines. For the development of novel NK1R antagonists as antitumor agents, heterocyclic compounds which were previously synthesized by our team, tested for their cytotoxic activities in several cancer cell lines in this study. Among the tested compounds, a benzothiazole derivative BSN-009 inhibited colon cancer cell lines growth by 57.53% by comparing the activity to the control drug aprepitant. Molecular modeling studies such as molecular docking and pharmacophore generation were performed with known NK1R antagonists and BSN-009 by using Discovery Studio 3.5 in order to explain their binding modes to NK1R. BSN-009 may be a good anticancer drug candidate as a possible NK1R antagonist and is worthy to carry on the anticancer studies.

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Inhibition of human glutathione transferase P1-1 by novel benzazole Derivatives

Cited by 10 publications

References 31 publications

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

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

Fluorescence labelled XT5 modified nano-capsules enable highly sensitive myeloma cells detection

Possible Mechanism of Action of Neurokinin-1 Receptors (NK1R) Antagonists

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