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

• Published in: Chemistry, an Asian journal an Asian journal, 2010-10, Vol.5 (10), p.2231-2248
• Main Authors: Tanaka, Hiroshi, Yamanouchi, Maasa, Miyoshi, Haruko, Hirotsu, Keisuke, Tachibana, Hirofumi, Takahashi, Takashi
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - therapeutic use; Antineoplastic Agents - toxicity; Catechin - analogs & derivatives; Catechin - chemical synthesis; Catechin - therapeutic use; Catechin - toxicity; Cell Line, Tumor; combinatorial chemistry; Combinatorial Chemistry Techniques; Hydrogenation; Melanoma, Experimental - drug therapy; Methylation; Mice; microreactors; phytochemistry; receptors; Small Molecule Libraries - chemical synthesis; Small Molecule Libraries - therapeutic use; Small Molecule Libraries - toxicity; solid-phase synthesis
• ISSN: 1861-4728; 1861-471X
• DOI: 10.1002/asia.201000372

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 α‐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 α‐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. A brand new combine harvester: The solid‐phase synthesis of a combinatorial methylated (±)‐epigallocatechin gallate (EGCG) library is reported. Deprotection of the protected EGCG is achieved by utilizing a continuous‐flow hydrogenation reactor (H‐Cube). The growth‐inhibitory effects of the methylated EGCG library reveal that 7‐OMe EGCGs exhibit comparable biological activity to natural EGCG.