Inhibition of human glutathione S-transferases by curcumin and analogues.
Glutathione S-transferases (GSTs) are important phase II drug-metabolizing enzymes that play a major role in protecting cells from the toxic insults of electrophilic compounds. Curcumin, a promising chemotherapeutic agent, inhibits human GSTA1-1, GSTM1-1, and GSTP1-1 isoenzymes. In the present study, the effect of three series of curcumin analogues, 2,6-dibenzylidenecyclohexanone (A series), 2,5-dibenzylidenecyclopentanone (B series), and 1,4-pentadiene-3-one (C series) substituted analogues (n = 34), on these three human GST isoenzymes, and on human and rat liver cytosolic GSTs, was investigated using 1-chloro-2,4-dinitrobenzene (CDNB) as a substrate. Most of the 34 curcumin analogues showed less potent inhibitory activities towards GSTA1-1, GSTM1-1, and GSTP1-1 than the parent curcumin. Compounds B14 and C10 were the most potent inhibitors of GSTA1-1 and human liver cytosolic GSTs, with IC(50) values of 0.2-0.6 microM. The most potent inhibitors of GSTM1-1 were C1, C3 and C10, with IC(50) values of 0.2-0.7 microM. Similarly, GSTP1-1 was predominantly strongly inhibited by compounds of the C series C0, C1, C2 C10 and A0, with IC(50) values of 0.4-4.6 microM. Compounds in the B series showed no significant inhibition of GSTP1-1. Molecular Operating Environment (MOE) program-based quantitative structure-activity relationship (QSAR) analyses have also suggested the relevance of Van der Waals surface area and compound lipophilicity factors for the inhibition of GSTA1-1 and GSTM1-1 and partial charge factors for GSTP1-1. These results may be useful in the design and synthesis of curcumin analogues with either more or less potency for GST inhibition.
Division of Molecular Toxicology, Leiden/Amsterdam Center for Drug Research, Department of Pharmacochemistry, Vrije Universiteit, De Boelelaan 1083, Amsterdam, the Netherlands.
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Vermeulen
D000818:Animals; D003474:Curcumin / Q000494:pharmacology*; D004137:Dinitrochlorobenzene; D051549:Glutathione S-Transferase pi / Q000037:antagonists & inhibitors*; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors*; D006801:Humans; D020128:Inhibitory Concentration 50; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008099:Liver / Q000378:metabolism*; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D051381:Rats
D003474:Curcumin; D004137:Dinitrochlorobenzene; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D007527:Isoenzymes; C484555:GSTA1 protein, human; C496556:GSTP1 protein, human