Inhibitors of glutathione S-transferases as therapeutic agents

Schultz, Mary; Dutta, Seema; Tew, Kenneth D.

doi:10.1016/s0169-409x(97)00029-x

Cited by 138 publications

(63 citation statements)

References 65 publications

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“…Many anticancer drugs are substrates for the GST and thus they can be conjugated with the GSH and efficiently extruded from the cell by specific export pumps (2)(3)(4)(5). Therefore, the overexpression of GSTs in the tumor cell lines, in particular of GSTP1-1, is responsible for their resistance to certain chemotherapeutic drugs (6,7). Recently, it has been suggested the GSTs are involved in cell protection against apoptotic signals by inhibiting the stress-signaling cascade mediated by ASK1-JNK (8).…”

Section: Introductionmentioning

confidence: 99%

“…The former (ethacrynic acid) binds to the H-site but has low affinity for the enzyme, and conjugated with GSH, it is easily excreted from the cell. Moreover, phase I clinical trials have shown severe toxicity of ethacrynic acid, including diuresis, metabolic abnormalities, and myelosuppression (7). The latter (TER 199) is a glutathione peptidomimetic which rapidly enters cells, and being a prodrug, is activated by the intracellular esterases.…”

Section: Introductionmentioning

confidence: 99%

“…The latter (TER 199) is a glutathione peptidomimetic which rapidly enters cells, and being a prodrug, is activated by the intracellular esterases. A different class of cytotoxic GSH analogues consists of molecules that do not inhibit GST but take advantage of its catalytic power to be activated (7,19). An example is TER 286, whose structure has the GST binding capacity of a GSH-peptidomimetic molecule.…”

Section: Introductionmentioning

confidence: 99%

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Proapoptotic Activity of New Glutathione S-Transferase Inhibitors

Turella¹,

et al. 2005

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Selected 7-nitro-2,1,3-benzoxadiazole derivatives have been recently found very efficient inhibitors of glutathione Stransferase (GST) P1-1, 5 an enzyme which displays antiapoptotic activity and is also involved in the cellular resistance to anticancer drugs. These new inhibitors are not tripeptide glutathione-peptidomimetic molecules and display lipophylic properties suitable for crossing the plasma membrane. In the present work, we show the strong cytotoxic activity of these compounds in the following four different cell lines: K562

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Proapoptotic Activity of New Glutathione S-Transferase Inhibitors

Turella¹,

et al. 2005

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“…8,9) Inhibition of GST has been proposed to improve prognosis in patients during cancer chemotherapy, and can be applied as adjuvant in antiparasitic chemotherapy and as antiparasitic drugs. 10,11) In our continuing effort to discover bioactive natural products from plant and marine sources, we discovered that the crude ethanolic extract of C. bonduc exhibited concentration-dependent GST inhibitory activity with an IC 50 value of 83 mg/ml. Based on this activity, we performed bioassay-guided fractionations on this crude extract to isolate natural products exhibiting GST inhibitory activity.…”

mentioning

confidence: 99%

Glutathione S-Transferase Inhibiting Chemical Constituents of Caesalpinia bonduc

Udenigwe

Ata

Samarasekera

2007

CHEMICAL & PHARMACEUTICAL BULLETIN

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Caesalpinia bonduc L. (Fabaceae) is a medicinal plant predominantly distributed in the tropical and subtropical regions of Asia and the Caribbean. It is locally known as Nata Karanja (Hindi) in India and Kuburu in Sri Lanka, and possesses a lot of applications in folk medicines. For instance, its seed and bark extracts have been used as antihelmintic, anticancer, antimalarial, hypoglycemic, anti-inflammatory, antimicrobial, antirheumatic and antipyretic agents.1,2) Previous phytochemical investigations on C. bonduc and some other members of the family Fabaceae have resulted in the isolation of several cassane and norcassane furanoditerpenes.3-6) Some of these compounds were reported to exhibit inhibitory activity against interleukin-1 production 4) and growth inhibitory activity against malaria-causing Plasmodium falciparum. 5)The glutathione S-transferase (GST) system is a primary cellular mechanism protecting against cytotoxic and genotoxic stress. GST isoenzymes are phase II detoxification enzymes that catalyze the conjugation of cytotoxic agents to glutathione producing a less reactive, water-soluble chemical species.7) Physiological activities of these enzymes have been implicated in development of resistances by cancer cells and parasites towards chemotherapeutic agents and the body immune system, respectively. 8,9) Inhibition of GST has been proposed to improve prognosis in patients during cancer chemotherapy, and can be applied as adjuvant in antiparasitic chemotherapy and as antiparasitic drugs.10,11) In our continuing effort to discover bioactive natural products from plant and marine sources, we discovered that the crude ethanolic extract of C. bonduc exhibited concentration-dependent GST inhibitory activity with an IC 50 value of 83 mg/ml. Based on this activity, we performed bioassay-guided fractionations on this crude extract to isolate natural products exhibiting GST inhibitory activity. Consequently, we have successfully isolated a new sterol, 17-hydroxy-campesta-4,6-dien-3-one (1) as well as four known compounds, 13,14-seco-stigmasta-5,14-dien-3a-ol (2), 13,14-seco-stigmasta-9(11),14-dien-3a-ol (3), caesaldekarin J (4) and pipataline (5) as GST inhibitors. Spectroscopic methods were used to establish the structures of these new and known compounds. This paper describes the isolation and structure elucidation of these compounds as well as their GST inhibitory activity data. Three derivatives of compounds 2 and 3 were prepared to investigate the effects of the C-3 hydroxyl group and the C-5/C-6 double bond in 13,14-seco-steroids on GST inhibition. Inhibition of GST by compounds 1-5 and derivatives of 2 and 3 (2a, 3a, b) was compared with activity of sodium taurocholate, a standard steroidal GST inhibitor under similar assay conditions. This indicated that the newly isolated compounds have more or less same activity as that of the standard inhibitor. Nearly half a dozen of 13,14-seco-steroids have been reported in the literature, [12][13][14] and no comments on their biosynthetic origin have been p...

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“…This enzyme is involved in a variety of biological processes including detoxication of xenobiotics in cells [20][21][22] and thereby can decrease effects of drugs causing multidrug resistance. 22,23 Several heterocyclic compounds, 24,25 etacrinic acid derivatives 26 and some structural analogues of glutathione 27,28 have been described as reversible or irreversible inhibitors of GST. Some endogenous compounds such as bilirubin and bile salts are able to bind to GST and inhibit their activity.…”

Section: Introductionmentioning

confidence: 99%

Calix[4]arene-α-hydroxyphosphonic acids. Synthesis, stereochemistry, and inhibition of glutathione S-transferase

Cherenok¹,

Yushchenko²,

Tanchuk³

et al. 2012

Arkivoc

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A series of dipropoxy-, tripropoxy-and tetrapropoxycalix[4]arenes bearing one or two fragments of α-hydroxymethylphosphonic acid at the upper rim of the macrocycle was prepared by the reaction of the corresponding mono-and di-formylcalixarenes with sodium salts of dialkyl phosphites or with trialkyl (tristrimethylsilyl)phosphites followed by dealkylation (desilylation) of the ester derivatives. The conformations of the macrocyclic skeleton and the stereoisomeric forms of the compounds obtained were investigated by 1 H NMR. The resulting α-hydroxymethylphosphonic acids were found to be able to inhibit the activity of glutathione Stransferase in vitro.

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Inhibitors of glutathione S-transferases as therapeutic agents

Cited by 138 publications

References 65 publications

Proapoptotic Activity of New Glutathione S-Transferase Inhibitors

Proapoptotic Activity of New Glutathione S-Transferase Inhibitors

Glutathione S-Transferase Inhibiting Chemical Constituents of Caesalpinia bonduc

Calix[4]arene-α-hydroxyphosphonic acids. Synthesis, stereochemistry, and inhibition of glutathione S-transferase

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