Relationship between structure and antiproliferative, proapoptotic, and differentiation effects of flavonoids on...

The aim of this study was to reveal the relationships between structure elements of flavonoids and their antileukemic activity. The human leukemia cell line K562 as a model of blast crisis of chronic myeloid leukemia and a set of 18 different flavonoids from four flavonoid subfamilies were used for researching these relationships. Relationships between structure and antiproliferative, proapoptotic, and differentiation activities of flavonoids were estimated by pairwise comparative analysis of selected flavonoids that differ in one structure element. We found that C4 carbonyl and C2-C3 double bonds are critical structure elements for antileukemic activity of flavonoids. We also observed that the ortho-position of hydroxyl groups in the B ring of the flavonoid molecule has an advantage over other variants of B ring hydroxylation patterns. At the same time, flavonoids with a nonhydroxylated B ring were more effective. In the A ring, hydroxylation status of C5 is not critical for antileukemic activity of the flavonoids, whereas the appearance of the hydroxyl group in the C6 position of the flavonoid molecule significantly decreased the IC50 (inhibition concentration required for 50% cytotoxic effect) value. Glycosylation of flavonoids was associated with dramatically decreased activity. These data may help in the rational design of semisynthetic flavonoids with improved antileukemic activity.