Development of highly potent melanogenesis inhibitor by in vitro, in vivo and computational studies (original) (raw)
Related papers
Molecules
Tyrosinase is a key enzyme target to design new chemical ligands against melanogenesis. In the current review, different chemical derivatives are explored which have been used as anti-melanogenic compounds. These are different chemical compounds naturally present in plants and semi-synthetic and synthetic compounds inspired by these natural products, such as kojic acid produced by several species of fungi; arbutin—a glycosylated hydroquinone extracted from the bearberry plant; vanillin—a phenolic aldehyde extracted from the vanilla bean, etc. After enzyme inhibition screening, various chemical compounds showed different therapeutic effects as tyrosinase inhibitors with different values of the inhibition constant and IC50. We show how appropriately designed scaffolds inspired by the structures of natural compounds are used to develop novel synthetic inhibitors. We review the results of numerous studies, which could lead to the development of effective anti-tyrosinase agents with incr...
Melanogenesis inhibition constitutes a privileged therapeutic solution to treat skin hyperpigmentation, a major dermatological concern associated with the overproduction of melanin by human tyrosinase (hsTYR). Despite the existence of many well-known TYR (tyrosinase) inhibitors commercialized in skin formulations, their hsTYR-inhibition efficacy remains poor since most of them were investigated over mushroom tyrosinase (abTYR), a model with low homology relative to hsTYR. Considering the need for new potent hsTYR inhibitors, we designed and synthesized a series of indanones starting from 4-hydroxy compound 1a, one of the two most active derivatives reported to date against the human enzyme, together with marketed thiamidol. We observed that analogues featuring 4-amino and 4-amido-2’,4’-dihydroxyindanone motifs showed two- to ten-fold increase in activity over human melanoma MNT-1 cell lysates, and a ten-fold improvement in a 4-days whole-cell experiment, compared to parent analogue ...
Natural Melanogenesis Inhibitors Acting Through the Down-Regulation of Tyrosinase Activity
Materials, 2012
Melanogenesis is a biosynthetic pathway for the formation of the pigment melanin in human skin. A key enzyme, tyrosinase, catalyzes the first and only rate-limiting steps in melanogenesis, and the down-regulation of enzyme activity is the most reported method for the inhibition of melanogenesis. Because of the cosmetically important issue of hyperpigmentation, there is a big demand for melanogenesis inhibitors. This encourages researchers to seek potent melanogenesis inhibitors for cosmetic uses. This article reviews melanogenesis inhibitors that have been recently discovered from natural sources. The reaction mechanisms of the inhibitors on tyrosinase activity are also discussed.
BioMed Research International, 2022
Tyrosinase and its related proteins are responsible for pigmentation disorders, and inhibiting tyrosinase is an established strategy to treat hyperpigmentation. The carbonyl scaffolds can be effective inhibitors of tyrosinase activity, and the fact that both benzoic and cinnamic acids are safe natural substances with such a scaffolded structure, it was speculated that hydroxyl-substituted benzoic and cinnamic acid derivatives may exhibit potent tyrosinase inhibitory activity. These moieties were incorporated into new chemotypes that displayed in vitro inhibitory effect against mushroom tyrosinase with a view to explore antimelanogenic ingredients. The most active compound, 2-((3-acetylphenyl)amino)-2-oxoethyl(E)-3-(2,4-dihydroxyphenyl)acrylate (5c), inhibited mushroom tyrosinase with an IC50 of 0.0020 ± 0.0002 μ M , while 2-((3-acetylphenyl)amino)-2-oxoethyl 2,4-dihydroxybenzoate (3c) had an IC50 of 27.35 ± 3.6 μ M in comparison to the positive control arbutin and kojic acid wit...
Biochimica et Biophysica Acta (BBA) - General Subjects, 2012
Background: Tyrosinase inhibitors have become increasingly important because of their ability to inhibit the synthesis of the pigment melanin. A search for new agents with strong tyrosinase activity led to the synthesis of the tyrosinase inhibitor (E)-3-(2,4-dihydroxybenzylidene)pyrrolidine-2,5-dione (3-DBP). Methods: The inhibitory effect of 3-DBP on tyrosinase activity and melanin production was examined in murine melanoma B16F10 cells. Additional experiments were performed using HRM2 hairless mice to demonstrate the effects of 3-DBP in vivo. Results: The novel compound, 3-DBP, showed an inhibitory effect against mushroom tyrosinase (IC 50 =0.53 μM), which indicated that it was more potent than the well-known tyrosinase inhibitor kojic acid (IC 50 =8.2 μM). When tested in B16F10 melanoma cells treated with α-melanocyte stimulating hormone (α-MSH), 3-DBP also inhibited murine tyrosinase activity, which in turn induced a decrease in melanin production in these cells. The anti-melanogenic effect of 3-DBP was further verified in HRM2 hairless mice. The skin-whitening index (L value) of HRM2 hairless mice treated with 3-DBP before irradiation with UVB was greater than that of UVB-irradiated mice that were not treated with 3-DBP. General significance: The newly synthesized 3-DBP has a potent inhibitory effect on tyrosinase. In addition to an in vitro investigation of the effects of 3-DBP on tyrosinase, in vivo studies using an HRM2 hairless mouse model demonstrated the anti-melanogenic potency of 3-DBP. Our newly synthesized 3-DBP showed efficient tyrosinase inhibitory effect in vivo and in vitro. Our finding suggests that 3-DBP can be an effective skin-whitening agent.
Analogues of N-hydroxycinnamoylphenalkylamides as inhibitors of human melanocyte-tyrosinase
Bioorganic & medicinal …, 2006
Melanin play a major role in human skin protection and their biosynthesis is vital. Due to their color, they contribute to the skin pigmentation. Tyrosinase is a key enzyme involved in the first stage of melanin synthesis, catalyzing the transformation of tyrosine to L L-dopaquinone. The aim of the present study was to study molecules able to inhibit melanin synthesis through inhibition of tyrosinase and their potential use in treating pigmentation-related disorders. We targeted amides obtained from coupling p-hydroxycinnamic acid derivatives with phenylalkylamines. The biological activity was evaluated on human melanocytes by an assay which measures tyrosine-catalyzed L L-Dopa oxidation. The most active amides were: trans-N-caffeoyltyramine, N-dihydrocaffeoyltyramine, and trans-N-dihydro-p-hydroxycinnamoyltyramine which induce complete inhibition at 0.1 mM. At the latter concentration, kojic acid, which was used as the reference inhibitor, was inactive.
An Updated Organic Classification of Tyrosinase Inhibitors on Melanin Biosynthesis
Current Organic Chemistry, 2015
Tyrosinase (EC 1.14.18.1) is known to be the rate-limiting enzyme responsible for catalyzing the first two steps in the synthesis of melanin pigments that determine the coloring of hair, skin and eyes. Tyrosinase catalyzes two-sequence distinct bio-reactions in pigment productions: L-tyrosine to L-dopa (hydroxylation); and L-dopa to dopaquinone (oxidation). The inhibition of tyrosinase has been established as one of the major strategies to regulate the production of melanin and the inhibitors are used to treat hyper-pigmentation and other unwanted effects from melanogenesis. There are now a variety of medicaments inhibiting melanin synthesis to treat excess melanin production or hyper-pigmentation of human skin, including the usage of natural plant extracts or chemically synthesized compounds. Recently, due to an increasing emphasis on healthy concepts, attention has been drawn to the usage of naturally produced crude materials and drugs in cosmetics and pharmaceutical applications. In this review, we demonstrate melanogenic inhibitory factors such as flavonoids, stilbenes, simple phenolics, furans, triterpenes, alkaloids, and other synthetic compounds. The structure-activity relationships are classified in terms of their inhibition of tyrosinase functions and copper chelating activity.