Solid-Phase Synthesis of a Combinatorial Methylated (+/-)-Epigallocatechin Gallate Library and the Growth-Inhibitory Effects of these Compounds on Melanoma B16 Cells

We report on the solid-phase synthesis of a combinatorial methylated (+/-)-epigallocatechin gallate (EGCG) library and its biological evaluation. Epigallocatechin gallate (EGCG) and its methylated derivatives, which are members of the catechin family, exhibit various anti-cancer effects. The solid-phase synthesis of methylated EGCG involves the preparation of the alpha-acyloxyketone by the coupling of a solid-supported aldehyde with a ketone and an acid. The subsequent release and reductive etherification reaction of the solid-supported alpha-acyloxyketone provide the protected EGCG in good total yields. Sixty-four methylated EGCGs were successfully prepared. The growth-inhibitory effects of the methylated EGCG library were also examined. Although methylation of EGCG generally causes reduced growth inhibition, the growth-inhibitory effect of 7-OMe EGCGs was comparable to that of EGCG. The 7-OMe EGCGs are attractive drug candidates because of their enhanced bioavailability.