Structure-activity relationships of flavonoid-induced cytotoxicity on human leukemia cells

The aim of this study was to identify structure elements in flavonoids that are associated with enhanced cytotoxic activity. We determined the cytotoxicity (EC(50)) of 23 different flavonoids, including O-methylated and glucuronidated metabolites, on the human leukemia cell line Jurkat E6-1 by analyzing cell death triggered after 24 and 48 h. By comparing the cytotoxicity of selected molecules that differ in only one structure element, we identified several structure-function relationships associated with enhanced cytotoxicity, including the presence of a 2-3 double bond, the presence of a 4-carbonyl group and ortho- compared to meta-hydroxylation in the B ring. Molecules with a 3-hydroxyl group exhibited significantly lower cytotoxicity than their non-hydroxylated counterparts. O-Methylation and glucuronidation were associated with a significant increase in cytotoxicity, suggesting that metabolites found in vivo are more active than unmodified flavonoids. We identified the solubility maximum of the tested flavonoids in culture medium and found a negative correlation between maximum solubility and cytotoxicity. The results of our study may help to identify novel flavonoid structures with optimized cytotoxic activity to be tested for anti-cancer treatment.