Resorcinol alkyl glucosides as potent tyrosinase inhibitors.

Resorcinol alkyl glucosides 7-12 were developed as novel tyrosinase inhibitors based on the structure of rhododendrin. These were synthesized from 2,4-dibenzyloxybenzaldehyde using either the Wittig or the Horner-Wadsworth-Emmons reaction with Koenigs-Knorr glycosylation as key steps. The tyrosinase inhibitory activity of 7-12 increased with the length of the alkyl spacer between resorcinol and glucose. The 50% inhibitory concentration (IC50) of tetradecyl derivative 12 was 0.39 µM, making it the most potent of the compounds synthesized. The IC50 of 8 (3.62 µM) with a propyl spacer was ca 10 times that of 7 (35.9 µM) with an ethyl spacer. This significant activity difference suggests that an interaction between resorcinol alkyl glucoside and tyrosinase may increase remarkably if the length of the alkyl spacer exceeds C3.

Chemical synthesis and tyrosinase-inhibitory activity of isotachioside and its related glycosides.

Isotachioside (1) and its related natural product 2 are isolated from Isotachis japonica and Protea neriifolia, respectively, and are categorized as analogs of arbutin (3), a tyrosinase inhibitor for practical use. Both of the natural products and several derivatives such as glucoside 4, xyloside 5, cellobioside 6, and maltoside 7 were synthesized via Schmidt glycosylation as a key step, and their tyrosinase inhibitory activity was evaluated. The half maximal inhibitory concentration (IC50) of 1-3 could not be determined even when the concentration was increased to 1000 µM. Contrastingly, glycosides 4-7, missing methyl and benzoyl groups, acted as tyrosinase inhibitors with IC50s of 417 µM, 852 µM, 623 µM, and 657 µM, respectively. Among these novel inhibitors, derivative 4 was the most potent, indicating that the structural combination of resorcinol and glucose was significant for inducing the inhibitory effect.

Chemical synthesis, redox transformation, and identification of sonnerphenolic C, an antioxidant in Acer nikoense.

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.

Rhododendrol glycosides as stereospecific tyrosinase inhibitors.

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.

Synthesis of dihydroresveratrol glycosides and evaluation of their activity against melanogenesis in B16F0 melanoma cells.

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.

Chemical synthesis and tyrosinase inhibitory activity of rhododendrol glycosides.

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.