7-(3-Benzyloxypropyl)apigenin, A Novel Cytotoxic Flavone Derivative

In recent years, there has been a resurgence of scientific interest in flavonoids, which is due to the association of these compounds with a wide range of health promoting effects. Among those, much of the interest in flavonoids has recently been focused on their anticancer properties. Different mechanisms have been linked to flavonoidmediated cytotoxicity, including their antioxidant activities, their effects on signal transduction pathways involved in cell proliferation and angiogenesis, as well as their modulation of aromatase activity, a key enzyme involved in estrogen biosynthesis, and the enzymes required for metabolic activation of procarcinogens and the detoxification of carcinogens. Even though multiple mechanisms account for flavonoidinduced cytotoxicity, disruption of the signal transduction pathway for cell proliferation by inhibition of the cyclindependent kinases (CDKs) has drawn special attention since the discovery of a synthetic flavonoid flavopiridol as a potent anticancer agent. Flavopiridol demonstrated potent in vitro inhibition of all cyclin-dependent kinases (CDKs) tested (CDKs 1, 2, 4 and 7), and clearly blocked cell cycle progression at the G1/S and G2/M boundaries. However, in spite of flavopiridol’s potent activity, two major challenges remain: more potent and specific inhibition of the kinase targets. The crystal structure of the flavopiridol analogue, deschloroflavopiridol, co-crystallized with CDK2, reveals the key hydrogen bonds. In comparison with the other CDK2 inhibitors, desflavopiridol has additional hydrogen bonds around the C8-substituent (Fig. 1). As a result, in order to enhance the selectivity and binding affinity of the flavopiridol analogues against the target kinase, structural modifications at the C2 and C8 positions of the flavone core have been extensively pursued. However, little effort has been made to modify other positions of the flavone scaffold such as the most reactive nearby O7 position. In our previous virtual screening study against CDK2, we found a possible hydrophobic binding pocket composed of Phe80 and Phe146 inside the ATPbinding site (yellow ellipse, Fig. 2). Intriguingly, docking study of several flavonoid derivatives suggested that flavonoids with O7-substituent with optimum chain length would probably fit into this pocket (Fig. 2) to show increases in both selectivity and binding affinity against CDK2. Thus, in this study, we designed a flexible propyloxybenzyl linker which would locate its terminal aromatic ring in the proposed hydrophobic pocket. Also, an oxygen atom placed in the middle of the propyloxybenzyl linker is expected to have a dual role: formation of an additional hydrogen bonding interaction with backnone NH of Asp145 and enhancement of the solubility of the flavonoid. For the synthesis of the title compound, commercially available apigenin was initially used as a starting material, but alkylation under basic conditions usually provided dialkylated product at the 7-O and 4-O positions (data not shown). Thus, the synthetic plan was changed to regioselective alkylation of flavanone naringenin (1, Fig. 3) followed