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

Objective: Glutathione transferases (GST) are multifunctional enzymes involved in detoxication, drug resistance, cell signaling and apoptosis. The inhibitory effects of novel benzazole derivatives were tested on human GST P1-1 to find new agents for overcoming drug resistance in cancer cells. Methods: GST P1-1 was heterogously expressed in E. coli strain XL-1 Blue and purified using S-hexylglutathione-Sepharose 6B affinity chromatography. The effect of 33 potential inhibitors on enzymatic activity was assayed spectrophotometrically with 1-chloro-2,4-dinitrobenzene (CDNB) as well as with the alternative substrate phenethyl isothiocyanate (PEITC). Results: Compound-18 (N-[2-(4-chloro-benzyl)-benzooxazol-5-yl]-4- nitro-benzenesulfonamide) was the most potent inhibitor found with an IC 50 value of approximately 10 µM with respect to CDNB and a somewhat less strong inhibitor (45 % inhibition at 40 µM) with PEITC as substrate. Compound-18 showed mixed inhibition with GSH and uncompetitive inhibition with CDNB with the K i values 6.3 ± 0.7 µM and 11.8 ± 3.4 µM, respectively. Conclusion: Compound-18 is a potent inhibitor of GST P1-1. It may serve as a lead for further chemical modifications for increased potency. Additional studies will elucidate the effects of the inhibitor on cancer cells.