Dehydroepiandrosterone‐α‐2‐Deoxyglucoside Exhibits Enhanced Anticancer Effects in MCF‐7 Breast Cancer Cells and Inhibits Glucose‐6‐Phosphate Dehydrogenase Activity

In the pentose phosphate pathway, dehydroepiandrosterone (DHEA) uncompetitively inhibits glucose‐6‐phosphate dehydrogenase (G6PD), reducing NADPH production and increasing oxidative stress, which can influence the onset and/or progression of several diseases, including cancer. 2‐Deoxy‐D‐glucose (2‐DG), a glucose mimetic, competes with glucose for cellular uptake, inhibiting glycolysis and competing with glucose‐6‐phosphate (G‐6‐P) for G6PD activity. In this study, we report that DHEA‐α‐2‐DG ( 5 ), an α‐covalent conjugate of DHEA and 2‐DG, exhibits better anticancer activity than DHEA, 2‐DG, DHEA +2‐DG, and polydatin in MCF‐7 cells, and reduces NADPH/NADP + ratio in cellular assays. In vitro enzyme kinetics and molecular docking studies showed that 5 uncompetitively inhibits human G6PD activity and binds to the structural NADP + site but not to the catalytic NADP + site. Further combining 5 with the FDA‐approved drug tamoxifen enhanced its cytotoxicity against MCF‐7 cells, suggesting that it could serve as a candidate for combination of drug strategies.