Inhibition of human glutathione S-transferases by curcumin and analogues

1. 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.

2. 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.

3. 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 IC₅₀ values of 0.2–0.6 μM. The most potent inhibitors of GSTM1-1 were C1, C3 and C10, with IC₅₀ values of 0.2–0.7 μM. Similarly, GSTP1-1 was predominantly strongly inhibited by compounds of the C series C0, C1, C2 C10 and A0, with IC₅₀ values of 0.4–4.6 μM. Compounds in the B series showed no significant inhibition of GSTP1-1.

4. 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.