RT Journal Article SR Electronic T1 In Vitro Cytotoxic Activity of Novel Protoflavone Analogs – Selectivity Towards a Multidrug Resistant Cancer Cell Line JF Anticancer Research JO Anticancer Res FD International Institute of Anticancer Research SP 2863 OP 2869 VO 32 IS 7 A1 B. DANKO A1 A. MARTINS A1 D.W. CHUANG A1 H.C. WANG A1 L. AMARAL A1 J. MOLNÁR A1 F.R. CHANG A1 Y.C. WU A1 A. HUNYADI YR 2012 UL http://ar.iiarjournals.org/content/32/7/2863.abstract AB Background: Protoapigenone (PA), a natural flavonoid possessing an unusual p-quinol moiety on its B ring, is a prospective novel lead compound against cancer currently in development, together with WYC0209, a potent synthetic PA analog. Structure activity relationships (SAR) concerning different 1’-O-alkyl side-chains were also studied on two sets of derivatives. Materials and Methods: Fifteen 1’-O-alkyl protoflavone derivatives were synthesized from genkwanin or 4’-hydroxy-6-methylflavone, thirteen of which are new compounds. All compounds were tested for their cytotoxic effect on four human cancer cell lines, such as HepG2 and Hep3B (hepatic), A549 (lung) and MDA-MB-231 (breast) cell lines, with doxorubicin as a positive control. All compounds, as well as PA, WYC0209 and fourteen of their previously reported analogs were also tested on a multidrug-resistant (MDR) sub-cell line of L5178 mouse T-cell lymphoma and on its parental counterpart (PAR). Results: In general, derivatives bearing a free hydroxyl group at C-1’ exerted the strongest activities, while C-1’-substituted compounds were found to be much weaker. Derivatives of 6-methylflavone exhibited mild, but statistically significant selectivity towards the MDR cell line. Conclusion: The results are in agreement with our previous findings for fundamental SAR of 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 exhibit resistance to protoflavones by ABCB1 efflux pump overexpression.