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Journal ArticleDOI

(4-Methoxy-benzylidene)-(3-methoxy-phenyl)-amine, a Nitrogen Analog of Stilbene as a Potent Inhibitor of Melanin Production

01 Apr 2002-Chemical & Pharmaceutical Bulletin (The Pharmaceutical Society of Japan)-Vol. 50, Iss: 4, pp 450-452
TL;DR: The results suggest the possibility that (4-methoxy-benzylidene)-(3-mETHoxy-phenyl)-amine might be used as a skin whitening agent.
Abstract: The current study was carried out to investigate in vitro the effects of (4-methoxy-benzylidene)-(3-methoxyphenyl)-amine on melanin biosynthesis which is closely related to hyper-pigmentation. (4-Methoxy-benzylidene)-(3-methoxy-phenyl)-amine, a nitrogen analog of stilbene, was synthesized by a single step process. This compound inhibited the tyrosinase activity, which converts dopa to dopachrome in the biosynthetic process of melanin, and showed a UV-blocking effect at UV-B band. The compound also exhibited SOD-like activity, which is involved in the protection against auto-oxidation and inhibited melanin production in melan-a cell line. Our results suggest the possibility that (4-methoxy-benzylidene)-(3-methoxy-phenyl)-amine might be used as a skin whitening agent.

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Citations
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Journal ArticleDOI
TL;DR: An overview of agents causing hypopigmentation in human skin is presented and it is suggested that Mammalian skin or at least keratinocytes/melanocytes co-cultures should be preferred rather than pure melanocyte cultures or soluble tyrosinase.
Abstract: An overview of agents causing hypopigmentation in human skin is presented. The review is organized to put forward groups of biological and chemical agents. Their mechanisms of action cover (i) tyrosinase inhibition, maturation and enhancement of its degradation; (ii) Mitf inhibition; (iii) downregulation of MC1R activity; (iv) interference with melanosome maturation and transfer; (v) melanocyte loss, desquamation and chemical peeling. Tyrosinase inhibition is the most common approach to achieve skin hypopigmentation as this enzyme catalyses the rate-limiting step of pigmentation. Despite the large number of tyrosinase inhibitors in vitro, only a few are able to induce effects in clinical trials. The gap between in-vitro and in-vivo studies suggests that innovative strategies are needed for validating their efficacy and safety. Successful treatments need the combination of two or more agents acting on different mechanisms to achieve a synergistic effect. In addition to tyrosinase inhibition, other parameters related to cytotoxicity, solubility, cutaneous absorption, penetration and stability of the agents should be considered. The screening test system is also very important as keratinocytes play an active role in modulating melanogenesis within melanocytes. Mammalian skin or at least keratinocytes/melanocytes co-cultures should be preferred rather than pure melanocyte cultures or soluble tyrosinase.

639 citations

Journal ArticleDOI
TL;DR: In this review, tyrosinase inhibitors with natural, semi-synthetic and synthetic origins are listed up with their structures, activities and characteristics.
Abstract: Tyrosinase plays a pivotal role in the synthesis of melanin pigment synthesis on skin utilizing tyrosine as a substrate. Melanin is responsible for the protection against harmful ultraviolet irradiation, which can cause significant pathological conditions, such as skin cancers. However, it can also create esthetic problems when accumulated as hyperpigmented spots. Various skin-whitening ingredients which inhibit tyrosinase activity have been identified. Some of them, especially ones with natural product origins, possess phenolic moiety and have been employed in cosmetic products. Semi-synthetic and synthetic inhibitors have also been developed under inspiration of the natural inhibitors yet some of which have no phenolic groups. In this review, tyrosinase inhibitors with natural, semi-synthetic and synthetic origins are listed up with their structures, activities and characteristics. Further, a recent report on the adverse effect of a natural melanin synthesis inhibitor which was included in skin-whitening cosmetics is also briefly discussed.

200 citations

Journal ArticleDOI
TL;DR: T1 isolated from Gastrodia elata is a promising candidate in developing pharmacological and cosmetic agents of great potency in skin-whitening and the molecular modeling demonstrates that the sulfur atom of T1 coordinating with the copper ions in the active site of tyrosinase is essential for mushroom tyrosine inhibition and the ability of diminishing the human melanin synthesis.
Abstract: Tyrosinase is involved in melanin biosynthesis and the abnormal accumulation of melanin pigments leading to hyperpigmentation disorders that can be treated with depigmenting agents. A natural product T1, bis(4-hydroxybenzyl)sulfide, isolated from the Chinese herbal plant, Gastrodia elata, is a strong competitive inhibitor against mushroom tyrosinase (IC50 = 0.53 μM, Ki = 58 ± 6 nM), outperforms than kojic acid. The cell viability and melanin quantification assay demonstrate that 50 μM of T1 apparently attenuates 20% melanin content of human normal melanocytes without significant cell toxicity. Moreover, the zebrafish in vivo assay reveals that T1 effectively reduces melanogenesis with no adverse side effects. The acute oral toxicity study evidently confirms that T1 molecule is free of discernable cytotoxicity in mice. Furthermore, the molecular modeling demonstrates that the sulfur atom of T1 coordinating with the copper ions in the active site of tyrosinase is essential for mushroom tyrosinase inhibition and the ability of diminishing the human melanin synthesis. These results evident that T1 isolated from Gastrodia elata is a promising candidate in developing pharmacological and cosmetic agents of great potency in skin-whitening.

130 citations

Journal ArticleDOI
TL;DR: The Cosmetic Ingredient Review (CIR) Expert Panel concluded that the 2 end points of concern, dermal sensitization and skin lightening, would not be seen at use concentrations below 1%; therefore, this ingredient is safe for use in cosmetic products up to that level.
Abstract: Kojic acid functions as an antioxidant in cosmetic products. Kojic acid was not a toxicant in acute, chronic, reproductive, and genotoxicity studies. While some animal data suggested tumor promotion and weak carcinogenicity, kojic acid is slowly absorbed into the circulation from human skin and likely would not reach the threshold at which these effects were seen. The available human sensitization data supported the safety of kojic acid at a use concentration of 2% in leave-on cosmetics. Kojic acid depigmented black guinea pig skin at a concentration of 4%, but this effect was not seen at 1%. The Cosmetic Ingredient Review (CIR) Expert Panel concluded that the 2 end points of concern, dermal sensitization and skin lightening, would not be seen at use concentrations below 1%; therefore, this ingredient is safe for use in cosmetic products up to that level.

127 citations


Cites background or methods from "(4-Methoxy-benzylidene)-(3-methoxy-..."

  • ...Kojic acid was a reference sample in a study of the tyrosinase activity of a nitrogen analog of stilbene.(7) The IC50 value of kojic acid was 275....

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  • ...The effects of acute intraperitoneal injections of kojic acid in CFLP mice were studied.(7) Preliminary findings indicated the LD50 to be between 1 and 4 g/kg body weight....

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Journal ArticleDOI
TL;DR: This review article summarizes the bioactivities, including adaptogenic, antifatigue, antidepressant, antioxidant, anti-inflammatory, antinoception, and anticancer activities, and the modulation of immune function of Rhodiola plants and its two constituents, as well as their potential to prevent cardiovascular, neuronal, liver, and skin disorders.

114 citations


Cites background from "(4-Methoxy-benzylidene)-(3-methoxy-..."

  • ...Another study reported that salidroside downregulated the phosphorylation of LPS-induced NF-kB p65 and an inhibitor of NF-kB a (IkBa) in the NF-kB signal pathway and suppressed the phosphorylation of p38, ERK, and c-jun NH(2)-terminal kinase (JNK) in MAPK signaling pathways [55,56]....

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References
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Journal ArticleDOI
TL;DR: In this article, the kinetic behavior of polyphenols common in fruits as free radical scavengers was studied using 2,2-diphenyl-1-picrylhydrazyl (DPPH).
Abstract: The kinetic behaviour of polyphenols common in fruits as free radical scavengers was studied using 2,2-diphenyl-1-picrylhydrazyl (DPPH.). After addition of different standard concentrations to DPPH. (0.025 g litre-1), the percentage of remaining DPPH. was determined at different times from the absorbances at 515 nm. The percentage remaining DPPH. against reaction time followed a multiplicative model equation: In [DPPH.REM] = b 1n t + 1n a. The slopes of these equations may be useful parameters to define the antioxidant capacity. The steeper the slope, the lower the amount of antioxidant necessary to decrease by 50% the initial DPPH. concentration (EC50). This parameter, EC50, is widely used to measure antioxidant power, but it does not takes into account the reaction time. Time needed to reach the steady state to the concentration corresponding at EC50 (T(EC50)) was calculated, and antiradical efficiency (AE) was proposed as a new parameter to characterise the antioxidant compounds where AE = 1/EC50 T(EC50). It was shown that AE is more discriminatory than EC50. AE values are more useful because they also take into account the reaction time. The results have shown that the order of the AE (x 10(-3)) in the compounds tested was: ascorbic acid (11.44) > caffeic acid (2.75) greater than or equal to gallic acid (2.62) > tannic acid (0.57) greater than or equal to DL-alpha-tocopherol (0.52) > rutin (0.21) greater than or equal to quercetin (0.19) > ferulic acid (0.12) greater than or equal to 3-tert-butyl-4-hydroxyanisole, BHA (0.10) > resveratrol (0.05).

1,812 citations

Journal ArticleDOI
TL;DR: The nitrite method was found to be the best for this SOD assay kit and modified to give better sensitivity and minimize interference by coexisting protein, a factor which has been previously ignored.

870 citations

Journal ArticleDOI
TL;DR: An immortal line of pigmented melanocytes, “melan‐a”, has been derived from normal epidermal melanoblasts from embryos of inbred C57BL mice, providing an excellent parallel non‐tumorigenic line for studies of the cellular and molecular basis of melanoma malignancy.
Abstract: An immortal line of pigmented melanocytes, "melan-a", has been derived from normal epidermal melanoblasts from embryos of inbred C57BL mice. The conditions favouring proliferation of these cells largely resemble those for normal, non-established mouse melanoblasts and melanocytes, and include a low extracellular pH and the presence of a tumour promoter, tetradecanoyl phorbol acetate (TPA) or teleocidin. Melan-a cells have the diploid chromosome number and do not form tumours in syngeneic or nude mice. They are therefore the first known line of non-tumorigenic mouse melanocytes, although an aneuploid melanocyte line of untested tumorigenicity has been reported (Sato et al., 1985). Melan-a cells are syngeneic with the B16 melanoma and its sublines, and provide an excellent parallel non-tumorigenic line for studies of the cellular and molecular basis of melanoma malignancy.

437 citations

Journal ArticleDOI
TL;DR: Investigation of inhibitory effects of glabridin on melanogenesis and inflammation using cultured B16 murine melanoma cells and guinea pig skins concluded that two hydroxyl groups of gl abridin are important for the inhibition of melanin synthesis and that thehydroxyl group at the 4' position of this compound is more closely related to melan in synthesis.
Abstract: Glabridin is the main ingredient in hydrophobic fraction of licorice extract affecting on skins. In this study, we investigated inhibitory effects of glabridin on melanogenesis and inflammation using cultured B16 murine melanoma cells and guinea pig skins. The results indicated that glabridin inhibits tyrosinase activity of these cells at concentrations of 0.1 to 1.0 microg/ml and had no detectable effect on their DNA synthesis. Combined analysis of SDS-polyacrylamide gel electrophoresis and DOPA staining on the large granule fraction of these cells disclosed that glabridin decreased specifically the activities of T1 and T3 tyrosinase isozymes. It was also shown that UVB-induced pigmentation and erythema in the skins of guinea pigs were inhibited by topical applications of 0.5% glabridin. Anti-inflammatory effects of glabridin in vitro were also shown by its inhibition of superoxide anion productions and cyclooxygenase activities. These data indicated that glabridin is a unique compound possessing more than one function; not only the inhibition of melanogenesis but also the inhibition of inflammation in the skins. By replacing each of hydroxyl groups of glabridin with others, it was revealed that the inhibitory effect of 2'-O-ethyl glabridin was significantly stronger than that of 4'-O-ethyl-glabridin on melanin synthesis in cultured B16 cells at the concentration of 1.0 mg/ml. With replacement of both of two hydroxyl groups, the inhibitory effect was totally lost. Based on these data, we concluded that two hydroxyl groups of glabridin are important for the inhibition of melanin synthesis and that the hydroxyl group at the 4' position of this compound is more closely related to melanin synthesis.

332 citations

Journal ArticleDOI
TL;DR: The properties of MG in vitro, including pigmentation inhibition in melanocytes, tyrosinase inhibition and selectivity, reduced cytotoxicity relative to HQ, and lack of mutagenic potential in mammalian cells, establish MG as a superior candidate skin-lightening agent.

313 citations

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Our results suggest the possibility that (4-methoxy-benzylidene)-(3-methoxy-phenyl)-amine might be used as a skin whitening agent.