Inhibitory Effects of Esculetin on Melanin Biosynthesis

Abstract

Coumarins are widely distributed in plants and are especially abundant in the bark, leaves, and roots of Umbelliferae and Rutaceae plants. So far more than 1300 types of coumarin have been identified as natural or synthesized compounds. Coumarins have recently been reported to have interesting pharmacologic and biochemical properties such as antioxidative, 1,2) antiinflammatory, and antiallergic effects, 3,4) inhibition of platelet aggregation 5) and protein kinase, 6) induction of apoptosis, 7) and antiviral, 8) antidifferentiative, 9) and antimutagenic activity. 10)Melanin pigment is a heteropolymer of indole compounds synthesized within melanocytes in the epidermis. Inhibitory compounds on melanogenesis are useful as skin-whitening agents used in cosmetics and as treatment of hyperpigmentation. Tyrosinase is known to play a critical regulatory role in melanin biosynthesis. 11) Therefore, many tyrosinase inhibitors that suppress melanogenesis in epidermal layers have been actively studied in cosmetics and pharmaceuticals. [12][13][14][15] These observations led us to search for naturally occurring tyrosinase inhibitors.Recently, we have isolated esculetin from the seeds of Euphorbia lathyris L. as a mushroom tyrosinase inhibitory compound.16) To the best of our knowledge, this is the first report of the tyrosinase-inhibitory effects of esculetin. In this study, 18 coumarins and four cinnamic acid derivatives were examined for antityrosinase activity and study of the structure-activity relationship. We evaluated further the inhibitory effect on melanin synthesis in B16 melanoma cells and guinea pig epidermal sheets of esculetin, which showed the strongest inhibitory activity among these compounds. MATERIALS AND METHODS MaterialsCoumarin, 4-hydroxycoumarin, umbelliferone, 7-methoxycoumarin, 6-hydroxy-4-methylcoumarin, 7-hydroxy-4-methylcoumarin, esculin, esculetin, scopoletin, 7-hydroxycoumarin-4-acetic acid, and 7-hydroxycoumarin-3-carboxylic acid were purchased from Aldrich Chemical Co. (Milwaukee, WI, U.S.A.). 4-Methylesculetin, 5,7-dihydroxy-4-methylcoumarin, isoscopoletin, and fraxetin were obtained from Extrasynthese Co. (Genay, France). Daphnetin, daphnin, and daphnetin-8-glucoside were isolated from Daphne odora. The chemicals purchased were used as received.Assay of Tyrosinase-Inhibitory Activity The assay was performed as previously described.16) One milliliter of a 1.5 mM L-3,4-dihydroxyphenylalanine (DOPA) solution, 0.1 ml of dimethyl sulfoxide (DMSO) with or without sample, and 1.8 ml of 1/15 M phosphoric acid buffer solution (pH 6.8) were mixed. The mixtures were preincubated at 25°C for 10 min. Then, 0.1 ml of the aqueous solution of mushroom tyrosinase (1000 U/ml, Sigma Chemical Co., St. Louis, MO, U.S.A.) was added, and the reaction was monitored at 475 nm. A control reaction was conducted with DMSO. The percentage of inhibition of tyrosinase activity was calculated as follows: inhibition (%)ϭ(AϪB)/Aϫ100, where A represents the difference in the absorbance of the control sample between the incub...

Biotransformation of aesculin by human gut bacteria and identification of its metabolites in rat urine

“…Kaneko and colleagues [2] found that aesculetin and its 6-glycoside, aesculin, can inhibit oxidative DNA damage and formation of aberrant crypt foci and tumors. Further more, this compound shows an inhibitory effect on BOP-induced oxidative DNA damage and carcinogenesis in a hamster pancreatic tumor model [2] , as well as chemo-preventive [3] and anti-tumor activity on cancer [4] . Aesculin and aesculetin have strong antioxidative and photo-protective activities, by scavenging 1, 1-diphenyl-2-picrylhydrazyl (DPPH) radicals and superoxide anions from the xanthine/xanthine oxidase system and inhibiting oxidation of 5-(6-)-chloromethyl-2', 7'-dichlorodihydro-fluorescein diacetate [5] .…”

Design, synthesis and bioevaluation of novel umbelliferone analogues as potential mushroom tyrosinase inhibitors

“…The FT-IR spectra were recorded with Shimadzu FTIR-8400S spectrometer (Kyoto, Japan, u, cm À1 ). The 1 H NMR and 13 C NMR spectra (CDCl 3 ) and (DMSO-d 6 ) were recorded using a Bruker 400 MHz spectrometer. Chemical shifts () are reported in ppm downfield from the internal standard tetramethylsilane (TMS).…”

“…The coumarins are especially abundant in the Umbelliferae and Rutaceae families 13 and also found in higher plants where they originate from phenylpropanoid pathway 14 . Some coumarins from natural sources have also been used as therapeutic agents for humans 15 and their antibacterial, antifungal and anticancer activities make these compounds attractive for further derivatization and for screening as therapeutic agents 16 .…”

Optimization of extraction conditions for osthol, a melanogenesis inhibitor fromCnidium monnierifruits

“…In addition, plants which contain coumarins as major constituents have been used for the treatment of inflammation and other skin diseases in traditional folk medicine (Bae, 1999;Kwon et al, 2011). Recently, some natural and synthetic coumarin derivatives have been reported to inhibit melanin biosynthesis (Liu et al, 2012;Masamoto et al, 2004;Matsuda et al, 2005).…”