1-(2,4-Dihydroxyphenyl)-3-(2,4-dimethoxy-3-methylphenyl)propane, a Novel Tyrosinase Inhibitor with Strong Depigmenting Effects

Abstract

Abnormal pigmentation is related to a variety of cosmetic and clinical conditions including melasma, lentigo, age spots, inflammatory hypermelanosis and trauma-induced hyperpigmentation.1) A number of studies have been devoted to producing safe and efficient depigmenting agents. However, many popular depigmenting compounds either lack potency or produce undesirable side effects.Skin color depends on the type and quantity of melanin, a natural pigment produced by melanocytes. The major ratelimiting step in melanin biosynthesis involves the enzyme tyrosinase [EC 1.14.18.1]. Mutations that eliminate activity of the tyrosinase gene result in albinism.2) Tyrosinase, a coppercontaining binuclear enzyme catalyzes three steps of melanin biosynthesis: the hydroxylation of tyrosine to 3,4-dihydroxyphenylalanine (DOPA), oxidation of DOPA to DOPAquinone, and oxidation of 5,6-dihydroxyindole to indolequinone. Because of its key role in melanogenesis, tyrosinase is an attractive target in the search for various kinds of depigmenting agents. [3][4][5][6] This study is a report of the discovery and characterization of a novel tyrosinase inhibitor: 1-(2,4-dihydroxyphenyl)-3-(2,4-dimethoxy-3-methylphenyl)propane (coded as UP302), isolated from a medicinal plant. UP302 inhibited tyrosinase with nanomolar potency and exhibited strong skin-whitening effects. ResultsIdentification of UP302 A screening of 1144 plant extracts identified 20 extracts that inhibited DOPA oxidase activity of mushroom tyrosinase. Three compounds were isolated and identified from two different families of plants, Moraceae and Liliacea (Fig. 1). All three compounds shared a common diarylpropane structure, revealing the existence of a new class of tyrosinase inhibitors. Compound 3, isolated from Dianella ensifolia (Liliacea) exhibited the highest potency with IC 50 value equal to 0.24 mM. This compound, 1-(2,4-dihydroxyphenyl)-3-(2,4-dimethoxy-3-methylphenyl) propane (CAS# 869743-37-3) was coded as UP302, reflecting the molecular mass of this agent (302 Da).Enzyme Kinetics Studies As UP302 is not a very abundant compound in nature (0.01-0.05% of plant dry weight), an organic synthesis procedure was developed to produce enough of this compound for further studies. Figure 2 demonstrates that synthetic UP302 is equally capable of inhibiting mushroom tyrosinase as its plant-derived counterpart. Therefore, all the following studies were performed 1292 Vol. 56, No. 9 A series of diarylpropane compounds was isolated by screening a plant extract library for inhibitors of mushroom tyrosinase. The most potent compound, 1-(2,4-dihydroxyphenyl)-3-(2,4-dimethoxy-3-methylphenyl)propane (UP302: CAS# 869743-37-3), was found in the medicinal plant Dianella ensifolia. Synthetic and plantderived versions of UP302 inhibited mushroom tyrosinase with similar potencies. UP302 inhibited mushroom tyrosinase with K i ‫3.0؍‬ m mM, in a competitive and reversible fashion. UP302 was 22 times more potent than Kojic acid in inhibiting murine tyrosinase, with IC 50 values of 12 and 273 m m...

1-(2,4-Dihydroxyphenyl)-3-(2,4-dimethoxy-3-methylpheny)propane inhibits melanin synthesis by dual mechanisms

“…In this study, we found that DP which was reported by Nesterov et al as a tyrosinase inhibitor [20] reduced melanin content in NHEM (Fig. 1) and in a reconstructed human skin model (Fig.…”

“…Recently, Nesterov et al, characterized a novel tyrosinase inhibitor: 1-(2,4-dihydroxyphenyl)-3-(2,4-dimethoxy-3-methylpheny) propane (DP) [20]. They isolated DP from a methanol extract of medicinal plant Dianella ensifolia and was subsequently synthesized and assigned the INCI name Dimethoxytolyl Propylresorcinol.…”

The Combination of a Retinoid, a Phenolic Agent and an Antioxidant Improves Tolerance while Retaining an Optimal Depigmenting Action in Reconstructed Epidermis

“…MelanoDerm™ (MatTek Corporation, Ashland, Mass., USA), a viable reconstructed 3-dimensional epidermis containing normal human melanocytes and keratinocytes [13], was used and processed for pigmentation assessments according to the manufacturer's instructions as previously described [11]. Briefly, epidermal equivalents with an air-liquid interface were treated once every other day over 2 weeks with 50 mg of oil-in-water cream containing the active compounds at the mentioned concentrations.…”

The Potential Depigmenting Activity of Retinaldehyde

“…MelanoDerm™ (MatTek Corporation, Ashland, Mass., USA), a viable reconstructed 3-dimensional epidermis containing normal human melanocytes and keratinocytes [16], was used and processed for pigmentation assessments according to the manufacturer's instructions as previously described [15]. Briefly, epidermal equivalents with air-liquid interface were treated once every other day during 2 weeks with 50 mg of oil-in-water cream containing RAL 0.05% (1.8 m M ); the cream was applied using a small spatula rinsed with ethanol just before use.…”