Purpose:The over-expression of glutathion S-transferase Pi (GSTπ) in tumors and inhibitory effect of GSTπ to JNK are two possible causes of the development of drug-resistance in chemotherapy. This research is to develop a novel pH-controlled NO donor to inhibit GSTπ(and to activate the JNK/c-Jun pathway (omit “to induce apoptosis”).Methods:Four 4-Aryl-1,3,2-oxathiazolylium-5-olate (OZO) derivatives with varying aryl para-substitutions (–H, –CF3, –Cl, and –OCH3) were synthesized. Anticancer activity was determined by MTS assay. GST activity was measured with spectrophotometry using 1-chlro-2,4-dinitrobenzene (CDNB) and GSH as substrates. (omit “Apoptosis was evaluated by annexin V staining and flow cytometry”). c-Jun N-terminal kinase 1 (JNK1) association with GSTπ and activation of c-Jun were evaluated with immunoprecipitation and western blot.Results:OZO derivatives showed anticancer effect against leukemia and breast cancer cells by MTS assay. The relative potency of their anticancer effects is OZO-H > OZO-Cl, OZO-OMe > OZO-CF3. The anticancer activity of these compounds was correlated with their inhibition of GST activity in cancer cells. The immunoprecipitaion result showed that the treatment of OZO-H released JNK1 from GSTπ-JNK1 complex. Consequently, the treatment of OZO-H in cancer cells induced JNK1 phophorylation and activated c-Jun in cancer cells.Conclusion:OZO-H is a novel GST inhibitor to release JNK1 for activation of JNK/c-Jun pathway (original is “c-Jun to trigger apoptosis in cancer cells”). It provides a new class of GST target compound for anticancer therapy.