Abstract

Chalcone derivatives exhibit a broad range of biological activities, with antioxidant and cytotoxic properties among the most studied. Despite numerous reports on chalcones as cytotoxic, and potentially anticancer agents, very little is know on their actual mechanism of activity. Generally, chalcones are considered as antimitotic agents, which interfere with tubulin assembly.We have recently developed a new class of chalcones with high cytotoxic activity toward different tumor cell types in vitro and bearing potent anticancer properties. The objective of this study was to determine whether new chalcone derivatives are metabolized by phase II enzymes such as glutathione-S-transferases (GSTs), UDP-glucuronide transferases (GDTs) and sulfotransferases (SULFs). We also verified if our compounds inhibit GST activity in vitro. This was important given recent reports which showed that other chalcones are inhibitors of GST. We show here that chalcones do not appreciably inhibit GSTs activity (IC50 concentration about 50-300uM). In contrast, several biologically active chalcones derivatives are god substrates of GSTs and are efficiently conjugated with GSH, glucuronic acid as well as sulfate groups, as revealed by HPLC-DAD analysis. Incubation of tumor cells with chalcone derivatives decreased intracellular GSH level in a time-dependent manner. This can be associated with both non-enzymatic and GST-mediated conjugation with GSH but also co-transport of GSH and GSH conjugates by ABC transporters. As a result of this study, we determined structural determinants responsible for substrate properties of chalcone derivatives toward phase II enzymes such as GSTs, GDT and SULFs. Efficient conjugation with GSH by GSTs required enone moiety, whereas for conjugation with both glucuronic acid and sulfate group the presence of free hydroxyl group in chalcone molecule was essential. This allowed us to design new compounds with improved pharmacological properties and possibly better bioavailability.

Authors (11)