In vitro cytotoxic activity of novel protoflavone analogs-selectivity against a multi-drug resistant cancer cell line

Protoapigenone (PA), a natural flavonoid possessing an unusual p-quinol moiety on its B ring, is a prospective novel anticancer lead compound currently in development, together with WYC0209, a potent synthetic PA analog. Previously, an increased cytotoxicity was found when a 3–4 carbon long aliphatic side-chain was present at C-1' for analogs of PA, while this was not the case when WYC0209 derivatives expressed the same moiety. Fifteen 1'-O-alkyl protoflavone derivatives were synthesized from genkwanin or 4'-hydroxy-6-methylflavone, thirteen of which are new compounds. All compounds, as well as PA, WYC0209 and fourteen of their previously reported analogs were also tested on a multi-drug resistant sub-cell line (MDR) of L5178 mouse T-cell lymphoma and on its parental counterpart (PAR). In general, derivatives expressing a free hydroxyl group at C-1' exerted the strongest activities, while C-1' substituted compounds were found much weaker. Derivatives of 6-methylflavone showed mild, but statistically significant selectivity against the MDR cell line. The results are in agreement with our previous findings for fundamental structure-activity relationships on protoflavones. 6-methylated protoflavones may serve as valuable leads for developing selective compounds against MDR cancer. Identical activity of other derivatives on the PAR and MDR cell lines suggests that cancer cells cannot confer resistance to protoflavones by ABCB1 efflux pump over-expression.