In our previous experiments, a natural cinnamic acid derivative, graviquinone (1) was synthesized through the hypervalent iodine-catalyzed oxidative de-aromatization of p-coumaric acid methyl ester. Graviquinone proved to be a potent anticancer compound, similarly to the p-quinol flavonoid protoapigenone, expressing the same pharmacophore in its B-ring. Considering the promising pharmacological activity of 1’-O-alkyl protoflavones,[1] the aim of the present study was to prepare a set of substituted graviquinone analogs, and to study their in vitro antitumor potential.
As a first step, various esters (methyl, ethyl, butyl, i-propyl) of p-coumaric acid were prepared with the corresponding alcohol and cc. sulfuric acid. The esters were then dissolved in acetonitrile:R-OH mixtures (9:1, v/v), and oxidation was performed with hypervalent iodine reagent PIDA or PIFA, to obtain compounds 1-12. All compounds were purified with the help of combined chromatographic methods (Flash, HPLC), and their structures were confirmed by NMR spectroscopy.
The anticancer activity of the derivatives was investigated on a susceptible/multi-drug resistant mouse lymphoma cell line pair and on a human gynecological cancer cell line panel (HeLa, SiHa, MCF-7, MDA-MB-231). The compounds could efficiently bypass resistance conferred by the ABCB1 transporter. On the mouse lymphoma cell lines, 1 and 4 exerted very strong antiproliferative activity with sub-micromolar IC50 values, while compound 3 was the most effective on the human cell lines with IC50 values ranging from 1.7 to 5.8 µM.
Acknowledgements
This work was supported by the National Research, Development and Innovation Office, Hungary (NKFIH; K119770). A.H. acknowledges the János Bolyai fellowship of the Hungarian Academy of Sciences and the Kálmán Szász Prize.
References
1Hunyadi A et al., PLoS ONE 6, 2011, e23922