Molecular design of melanogenesis-controlled agents having the dihydroresveratrol skeleton

<p>Introduction</p><p> Dihydroresveratrol glucoside (1) was isolated from Camelia oleifera (theaceae) which has been used as ingredients of edible oil and cosmetics. This glucoside has a resorcinol moiety that is frequently found in the structure of potent melanogenesis inhibitors. Despite containing the resorcinol motif, there has been no report on the total synthesis of1 or its development towards the identification of novel anti-melanogenesis agent. Therefore, we performed total synthesis of 1, chemical synthesis of derivatives 2-6, and the evaluation of their activity against melanogenesis observed in B16F0 melanoma cell culture. </p><p>Results and discussion </p><p> Aglycon 7 was synthesized from commercially available benzaldehydes via Wittig reaction as a key step. Glycosylation of 7 using imidate 8 as the glucosyl donor and trifluoromethanesulfonate (TMSOTf) as the Lewis acid at low temperature afforded glucoside 9 (Scheme 1). Natural product 1 was synthesized for the first time by the removal of all the protective groups in glucoside 9. According to the similar route, xyloside 2 was synthesized from aglycon 7 and xylosyl imidate 10. </p><p>Glucoside 1 and xyloside 2 were purified by preparative PR-HPLC and their biological activity was evaluated using B16F0 melamoma cells. Natural glucoside 1 is a potent melanogenesis inhibitor in this melanoma cells (approximately 40 fold more potent than kojic acid). In contrast, synthetic xyloside 2 stimulates melanogenesis, significantly. </p><p> Next, chemical synthesis and biological evaluation of disaccharides 3 and 4 were performed to develop novel hydrophilic melanogenesis-controlled agents. Cellobioside 3 was synthesized from aglycon 7 and cellobiosyl donor 12. Likewise, xylobioside 4 was synthesized from aglycon 7 and xylobiosyl donor 14that was prepared from a mixture of xylooligosaccharides. Surprisingly, both disaccharides act as melanogenesis activators. </p><p>These results suggested that a single hydroxymethyl group in the mono-glycoside substituent of dihydroresveratrols is responsible for inhibition or activation of melanogenesis. Further investigation for clarifying the molecular logic of the dihydroresveratrol glycosides against melanogenesis is underway by chemical approaches.</p>