Synthesis and Assessment of the Enantioselectivity in Antitumor Activity of a Library of Novel Chiral Flavone Derivatives

Abstract

Nature represents a rich source of bioactive compounds, with flavones emerging as privileged scaffolds owing to their multiple biological activities. Their antitumor potential arises from their ability to modulate pathways implicated in cancer progression and multidrug resistance, but structural modifications are often required to improve their pharmacokinetic properties and target selectivity. Incorporating chiral moieties, such as amino acids, may improve their potency and selectivity. Herein, we report the stereoselective synthesis of 32 new chiral derivatives of flavones (CDFs) obtained by coupling four commercial flavones with the enantiomerically pure amino esters and amino acids of tryptophan and tyrosine. Overall, the amino ester derivatives showed greater antiproliferative activity than their parent flavones against four cancer cell lines. 6HF-DTrp (14) and 7HF-DTrp (18) demonstrated micromolar equipotent inhibition with IC50 <21 µM against all cell lines. Most CDFs preferentially affected cancer cells over nontumor HPAEpiC cells, particularly 7HF-DTrp (18), which displayed selectivity indices above 6. Metabolic assays exposed heterogeneous effects on glucose consumption and lactate production, suggesting that CDF-induced cytotoxicity depends on the metabolic flexibility of each tumor phenotype rather than a universal mechanism. Furthermore, in vitro and in silico studies suggest potential P-glycoprotein (P-gp) inhibitory activity for 6HF-DTrp (14) and 7HF-DTrp (18).