Sonnerphenolic C (3), which was predicted in a redox product of epirhododendrin (1) isolated from Acer nikoense, was synthesized for the first time via the epimeric separation of benzylidene acetal intermediates as a key step. From a similar synthetic route, 1 was obtained concisely. As a result of their antioxidative evaluation, only 3 revealed potent activity. The redox transformation of 1 into 3 was achieved in the presence of tyrosinase and vitamin C. Moreover, 3 was identified in the decoction of A. nikoense by HPLC analysis with the effective use of synthesized 3. Thus, a novel naturally occurring antioxidant 3 was developed through the sequential flow including redox prediction, chemical synthesis, evaluation of the activity, and identification as the natural product.Download high-res image (65KB)Download full-size image

•Dihydroresveratrol cellobioside 3 was synthesized via the Schmidt glycosylation.•Xylobioside 4 was prepared from the corresponding xylooligosaccharides.•Both derivatives are potent melanogenesis activators of B16F0 melanoma cells.Dihydroresveratrol cellobioside and xylobioside, whose structures were designed based on that of the naturally occurring melanogenesis-controlling agent dihydroresveratrol glucoside, were synthesized via Schmidt glycosylation as the key step. Both analogues stimulated melanogenesis with efficacies comparable to that of 8-methoxypsoralen, a well-known melanogenesis activator. This suggests that diglycosyl modification of the 4’-OH on the dihydroresveratrol skeleton leads to the activation of melanogenesis, both with and without hydroxymethyl groups in the sugar moieties.

Rhododendrol derivatives 3–12 have been synthesized in six steps, including aldol condensation and/or trichloroacetimidate glycosylation as the key reactions. Each derivative showed effective inhibition of tyrosinase-catalyzed oxidation processes. In particular, a series of synthetic derivatives having an R-stereogenic center at C-2 proved to be more potent than their respective epimers. In addition, the glycosylation on the phenylbutanoid scaffold increased the difference in activity between the isomers. This suggests that the sugar moiety plays an important role in eliciting their potent inhibitory activity.

•Dihydroresveratrol glucoside 1 isolated from Camellia oleifera was synthesized.•Natural product 1 is a potent melanogenesis inhibitor in B16F0 melanoma cells.•In contrast, its xyloside derivative 2 synthesized, stimulates melanogenesis.•The sugar moiety is responsible for inhibition or activation of melanogenesis.Dihydroresveratrol glucoside 1 isolated from Camellia oleifera and its xyloside derivative 2 were synthesized for the first time in 5 steps from TBS-protected aldehyde 4. Natural product 1 is a potent melanogenesis inhibitor in B16F0 melanoma cells (approximately 40 fold more potent than kojic acid). In contrast, the synthetic product 2 stimulates melanogenesis, suggesting that a single hydroxymethyl group in the glycoside substituent of dihydroresveratrols is responsible for inhibition or activation of melanogenesis.

Bibenzyl glycosides 1–6 were synthesized from 2,4-dihydoxybenzaldehyde and xylose, glucose, cellobiose or maltose. The key steps in the synthesis were the Wittig reaction and trichloroacetimidate glycosylation. Tests for tyrosinase inhibitory activity showed that all were significantly active, indicating that they are unique hydrophilic tyrosinase inhibitors. Bibenzyl xyloside 2 is a particularly potent inhibitor (IC50 = 0.43 μM, 17 times higher than that of kojic acid). These results suggest that the hydrophilic cavity of tyrosinase might accommodate the bulky carbohydrate on the bibenzyl scaffold.Potent and hydrophilic tyrosinase inhibitors have been designed, on the basis of the bibenzyl glycoside scaffold.Figure optionsDownload full-size imageDownload as PowerPoint slideResearch highlights► Bibenzyl xyloside, glucoside, cellobioside and maltoside have been synthesized. ► The key steps were the Wittig reaction and trichloroacetimidate glycosylation. ► Tests for tyrosinase inhibitory activity showed that all were significantly active. ► Bibenzyl xyloside is a particularly potent inhibitor (IC50 = 0.43 μM). ► The bibenzyl glycosides are unique hydrophilic tyrosinase inhibitors.

•Benzaldehyde possessed tyrosinase inhibitory activity (IC50 = 31.0 μM).•Dixon plots indicated that it acts as a partial noncompetitive inhibitor.•In contrast, 4-penthylbenzaldehyde acts as a full and mixed type inhibitor.•Thus, 4-substituent may act as a tight hydrophobic cover on the catalytic center.Benzaldehyde inhibited the oxidation of 4-t-butylcatechol catalyzed by mushroom tyrosinase with an IC50 of 31.0 μM. The inhibition kinetics analyzed by Dixon plot indicated that it acts as a partial noncompetitive inhibitor. Further studies of several benzaldehydes, particularly those having a substitution at C-4, suggested that the partial inhibitory property diminished when using a bulk substituent. For example, 4-penthylbenzaldehyde showed a full and mixed type inhibition on diphenolase activity. Therefore, 4-substituted benzaldehyde on the aromatic ring primarily reflected the rate of product formation as it may act as a tight hydrophobic cover on the catalytic center of tyrosinase.Download high-res image (100KB)Download full-size image