Chemical synthesis and tyrosinase inhibitory activity of rhododendrol glycosides

Abstract

The concise synthesis of rhododendrol glycosides 3-8, which are novel derivatives of (+)-epirhododendrin (1) and (-)-rhododendrin (2), has been achieved in six steps from benzaldehyde 9. The key reactions include aldol condensation and trichloroacetimidate glycosylation. From biological studies, it has been determined that synthetic derivatives of 1 and 2 possess potent tyrosinase inhibitory activity. Particularly, the inhibitory activity of cellobioside 8 (IC50=1.51μM) is six times higher than that of kojic acid. The R-epimers (4, 6, and 8) possessed more potent activity than the corresponding S-epimers (3, 5, and 7), indicating that tyrosinase inhibitory activity is significantly governed by stereochemistry of rhododendrol glycosides.

Rhododendrol glycosides as stereospecific tyrosinase inhibitors

“…When only 1 equiv of 16 was used in this step, an acetylated derivative of 16 was detected as a major product. 23 The b facial attack of acceptor 16 was probably blocked because the oxocarbenium intermediate generated from 25 was sterically hindered. 36 Although several alternative modifications, such as a change of Lewis acid and the application of Koenigs-Knorr conditions were explored, the glycosylation could not be further optimized.…”

“…33 IC 50 of the mixture of 1 and 2 could not be estimated within 100 lM. 23 Accordingly, tyrosinase inhibitory activity was significantly improved by the introduction of a hydroxy group at C-2 0 . In particular, the activity of 4 containing the R-stereogenic center at C-2 was two-fold higher than that of 3.…”

“…[18][19][20][21][22] Thus, it was envisaged that the transformation of the monophenol structures of 1 and 2 into the corresponding resorcinols might lead to novel, effective, and hydrophilic tyrosinase inhibitors. 23 Herein, we describe concise syntheses of rhododendrols 3-12 as well as an evaluation of their tyrosinase inhibitory activities. Benzaldehyde derivative 13, 24 which was prepared from commercially available 2,4-dihydroxybenzaldehyde, was converted to enone 14 through aldol condensation 25 with acetone in 94% yield (Scheme 1).…”

Synthesis and pharmacological evaluation of glycosides of resveratrol, pterostilbene, and piceatannol

“…There have been several reports on the biologically active glycosides. [36][37][38] Both quercetin 3-␤-glucoside and quercetin 4 -␤glucoside have been reported to show inhibitory action on cancer cell proliferation. 36 Iwadate et al…”

“…reported that two epimers of rhododendrol 2-␤-glucoside exerted efficient tyrosinase inhibitory activity stronger than kojic acid, and that the Repimer had higher activity than the S-epimer. 37 It has been reported that the N-acetylglucosamine analog of oleanolic acid showed high anticancer activity, which was about three times stronger than that of the aglycone (i.e., oleanolic acid). 38 To clarify the efficiency of glycosylation for the physiological and pharmacological activities of stilbenes, we examined several in vitro bioassays of stilbenes and their glycosides.…”