Chemical and Biocatalytic Routes to Arbutin †.

Arbutin (also called ß-arbutin) is a natural product occurring in the leaves of a variety of different plants, the bearberries of the Ericaceae and Saxifragaceae families being prominent examples. It is a ß-glucoside derived from hydroquinone (HQ; 1,4-dihydroxybenzene). Arbutin has been identified in traditional Chinese folk medicines as having, inter alia, anti-microbial, anti-oxidant, and anti-inflammatory properties that useful in the treatment of different ailments including urinary diseases. Today, it is also used worldwide for the treatment of skin ailments by way of depigmenting, which means that arbutin is a component of many products in the cosmetics and healthcare industries. It is also relevant in the food industry. Hundreds of publications have appeared describing the isolation, structure determination, toxicology, synthesis, and biological properties of arbutin as well as the molecular mechanism of melanogenesis (tyrosinase inhibition). This review covers the most important aspects with special emphasis on the chemical and biocatalytic methods for the production of arbutin.

Synthesis of arbutin-gold nanoparticle complexes and their enhanced performance for whitening.

Arbutin, a natural polyphenol, possesses numerous biological activities including whitening, anti-oxidant, anti-cancer, anti-inflammatory activities, as well as strong reducing power, making it an ideal bioactive ingredient for preparing gold nanoparticles (GNPs). Previously, we developed a novel green, mild synthetic method for GNPs using glycosides such as arbutin as reducing agents and stabilizers. Herein, we optimized the synthetic method for glycoside-GNPs using arbutin, methyl ß-D-glucoside, and phenyl ß-D-glucoside and validated their whitening efficacy in vitro and in vivo. The resulting glycoside-GNPs were predominantly mono-dispersed and spherical (10.30-17.13 nm diameter). Compared with arbutin itself, arbutin-GNP complexes (GNP-A1 and GNP-P2) displayed enhanced whitening capabilities. Furthermore, GNP-P2 exhibited enhanced anti-inflammatory activity and lacked the toxicity associated with arbutin. Bioactive glycoside-GNP complexes may open new directions for cosmeceuticals, and GNP-P2 may serve as a useful whitening ingredient in future cosmeceutical applications.

Grevillosides J-Q, arbutin derivatives from the leaves of Grevillea robusta and their melanogenesis inhibitory activity.

From the 1-BuOH-soluble fraction of a MeOH extract of the leaves of Grevillea robusta, new arbutin derivatives and related compounds, named grevillosides J-Q (1-8), together with eight known compounds (9-18) were isolated. Various kind of acyl groups were attached to ß-D-glucose at the 6-position through an ester linkage. Their structures were mainly elucidated from one- and two-dimensional NMR spectroscopic data. For exploitation as skin-lightening and anti-chloasma agents, the inhibitory activities of the isolated compounds as well as ones isolated in previous experiments (19-31) toward tyrosinase and melanin-producing B16 cells were assayed. Several compounds showed promising activity.

Synthesis of acyl derivatives of salicin, salirepin, and arbutin.

The total synthesis of two natural phenolglycosides of the family Salicaceae, namely: populoside and 2-(ß-d-glucopyranosyloxy)-5-hydroxy benzyl (3-methoxy-4-hydroxy) cinnamoate and nine not found yet in plants acyl derivatives of phenoglycosides: 2-(ß-d-glucopyranosyloxy)-benzylcinnamoate, 2-(ß-d-glucopyranosyloxy)-benzyl (4-hydroxy) benzoate, 2-(ß-d-glucopyranosyloxy)-benzyl (3-methoxy-4-hydroxy) benzoate, 2-(ß-d-glucopyranosyloxy)-5-hydroxy benzyl (3,4-dihydroxy) cinnamoate, 2-(ß-d-glucopyranosyloxy)-5-hydroxy benzylcinnamoate, 2-(ß-d-glucopyranosyloxy)-5-hydroxy benzyl (4-hydroxy) benzoate, 2-(ß-d-glucopyranosyloxy)-5-hydroxy benzyl (3-methoxy-4-hydroxy) benzoate, 2-(ß-d-glucopyranosyloxy)-5-benzoyloxy benzylbenzoate and 4-(ß-d-glucopyranosyloxy)-phenylbenzoate, starting from readily available phenols and glucose was developed for the first time.

A highly regioselective route to arbutin esters by immobilized lipase from Penicillium expansum.

Immobilized lipase from Penicillium expansum, a novel and inexpensive enzyme preparation that we immobilized in our laboratory, was an excellent catalyst for highly regioselective acylation of arbutin with fatty acid vinyl esters. For the enzymatic butanoylation of arbutin, under the optimal conditions, initial reaction rate was 75.1 mM/h, and substrate conversion and regioselectivity were greater than 99%. In addition, a variety of 6'-esters of arbutin were prepared with high conversion (>99%) and excellent regioselectivity (>99%). It was found that the enzymatic reaction rate varied widely with different acyl donors, presumably owing to their different interactions with the active site of the lipase. The immobilized lipase from P. expansum displayed highest catalytic activity with medium-length straight-chain acyl donors. Acyl donors bearing a substituent or a conjugate double bond gave reduced reaction rates.

A new synthesis of alpha-arbutin via Lewis acid catalyzed selective glycosylation of tetra-O-benzyl-alpha-D-glucopyranosyl trichloroacetimidate with hydroquinone.

alpha-Arbutin has huge application potentials in the cosmetic industry, as its inhibitory effect on human tyrosinase is stronger than that of its naturally occurring anomer arbutin (4-hydroxyphenyl beta-D-glucopyranoside). Enzymatic synthesis was preferred for alpha-arbutin previously, and now a new chemical synthesis is reported. The reaction of tetra-O-benzyl-alpha-D-glucopyranosyl trichloroacetimidate, as glycosyl donor, with hydroquinone was initiated by catalytic amounts of trimethylsilyl trifluoromethanesulfonate (TMSOTf), resulting in 4-hydroxyphenyl 2,3,4,6-tetra-O-benzyl-alpha-D-glucopyranoside with high stereoselectivity and yield, and then to alpha-arbutin quantitatively after deprotection.

Synthesis of arbutin by two-step reaction from glucose.

Arbutin was synthesized from glucose by two-step reaction below: (a) 2,3,4,6-tetra-O-acetyl-alpha-D-glucosyl chloride or bromide was prepared by glucose and acetyl halide (chloride or bromide). (b) 2,3,4,6-tetra-O-acetyl-alpha-D-glucosyl halide (Cl, Br) reacted with hydroquinone, methanol as solvent at pH=9.5-10.0.

Syntheses of arbutin-alpha-glycosides and a comparison of their inhibitory effects with those of alpha-arbutin and arbutin on human tyrosinase.

The effects of 4-hydroxyphenyl alpha-glucopyranoside (alpha-arbutin) and 4-hydroxyphenyl beta-glucopyranoside (arbutin) on the activity of tyrosinase from human malignant melanoma cells were examined. The inhibitory effect of alpha-arbutin on human tyrosinase was stronger than that of arbutin. The K(i) value for alpha-arbutin was calculated to be 1/20 that for arbutin. We then synthesized arbutin-alpha-glycosides by the transglycosylation reaction of cyclomaltodextrin glucanotransferase using arbutin and starch, respectively, as acceptor and donor molecules. The structural analyses using 13C- and 1H-NMR proved that the transglycosylated products were 4-hydroxyphenyl beta-maltoside (beta-Ab-alpha-G1) and 4-hydroxyphenyl beta-maltotrioside (beta-Ab-alpha-G2). These arbutin-alpha-glycosides exhibited competitive type inhibition on human tyrosinase, and their K(i) values were calculated to be 0.7 mM and 0.9 mM, respectively. These arbutin-alpha-glycosides possessed stronger inhibitory activity than arbutin, but less activity than alpha-arbutin. These results suggested that the alpha-glucosidic linkage of hydroquinone-glycosides plays an important role in the inhibitory effect on human tyrosinase.

Lipase-catalyzed synthesis of arbutin cinnamate in an organic solvent and application of transesterification to stabilize plant pigments.

Arbutin cinnamate was synthesized from arbutin (4-hydroxyphenyl beta-D-glucopyranoside) and vinyl cinnamate by regioselective transesterification with a bacterial lipase in acetonitrile. The product was identified by NMR and FAB-MS analyses. These spectra showed that one ester bond was formed between the primary alcohol moiety of the D-glucose of arbutin and the carboxyl residue of cinnamic acid. Furthermore, plant pigments such as isoquercitrin (quercetin 3-O-beta-D-glucopyranoside) and callistephin (pelargonidin 3-O-beta-D-glucopyranoside) were also converted to their corresponding cinnamate esters in the same manner.

The alpha-D-glucosyl C-2 hydroxyl is required for binding to the H(+)-sucrose transporter in phloem.

The specificity of uptake of sucrose into isolated phloem tissue from Apium graveolens has been investigated using a number of analogues of sucrose. The presence of a single saturable transport system for sucrose was confirmed using the double isotope method of Inui and Christensen (J. Gen. Physiol. 50 (1966) 203-224). 4-Hydroxyphenyl beta-D-fructofuranoside showed no inhibition of sucrose uptake, whereas 4-hydroxyphenyl alpha-D-glucopyranoside showed competitive inhibition with a Ki of 6.7 mM. 4-Methoxyphenyl alpha-D-glucopyranoside also inhibited sucrose uptake competitively (Ki = 6.0 mM). This compound was also synthesised radioactively labelled with 14C and its uptake into phloem tissue was conclusively demonstrated to occur by active transport on the same carrier as sucrose. Contrastingly, 4-methoxyphenyl alpha-D-2-deoxyglucopyranoside displayed non-competitive inhibition of sucrose influx (Ki = 2.5 mM) and uptake of the 14C-labelled compound was insensitive to FCCP, PCMBS and sucrose. We conclude that the hydroxyl group at the C-2 position on the glucopyranosyl moiety is essential for binding to the sucrose carrier in this tissue.