Chemical transformations of oxyresveratrol (trans-2,4,3',5'-tetrahydroxystilbene) into a potent tyrosinase inhibitor and a strong cytotoxic agent.
From oxyresveratrol (trans-2,4,3',5'-tetrahydroxystilbene 1), seven derivatives were prepared, including trans-2-methoxy-4,3',5'-trihydroxystilbene (2), trans-2,3'-dimethoxy-4,5'-dihydroxystilbene (3), trans-4,3'-dimethoxy-2,5'-dihydroxystilbene (4), trans-2,4,3',5'-tetramethoxystilbene (5) and cis-2,4,3',5'-tetramethoxystilbene (6), 2,4,3',5'-tetrahydroxybibenzyl (7), and 2,4,3',5'-tetramethoxybibenzyl (8). The tetrahydroxybibenzyl 7, a hydrogenation product of 1, exhibited more potent tyrosinase inhibitory activity than the parent compound, without cytotoxicity. A kinetic study revealed that 7 was a reversible and non-competitive inhibitor of mushroom tyrosinase with l-dopa as the substrate. Analysis of the K(i) values indicated that 7 has a slightly higher affinity to the enzyme than 1. Compound 6, a tetra-O-methylated analogue of 1 with cis-configuration, was deprived of inhibitory effect on the enzyme tyrosinase, but showed very strong cytotoxicity against the human cancer cells KB, BC, and NCI-H187, with potency comparable to those of the anticancer agents ellipticine and doxorubicin. Data on the tyrosinase inhibitory activity and cytotoxicity of 1-8 indicated that O methylation on stilbene 1 destroyed anti-tyrosinase activity but generated cytotoxicity. Thus, facile preparations of a potent tyrosinase inhibitor (7) and a strong cytotoxic agent (6) from the natural product 1 were achieved through simple chemical reactions.
Likhitwitayawuid
Kittisak
K
Department of Pharmacognosy, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand. Kittisak.L@chula.ac.th
Sornsute
Acom
A
Sritularak
Boonchoo
B
Ploypradith
Poonsakdi
P
D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007700:Kinetics; D014442:Monophenol Monooxygenase / Q000037:antagonists & inhibitors*; D010936:Plant Extracts / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D013267:Stilbenes / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity
D010936:Plant Extracts; D013267:Stilbenes; C034912:puag-haad; D014442:Monophenol Monooxygenase