Screening of an Epigenetic Drug Library Identifies 4-((hydroxyamino)carbonyl)-N-(2-hydroxyethyl)-N-Phenyl-Benzeneacetamide that Reduces Melanin Synthesis by Inhibiting Tyrosinase Activity Independently of Epigenetic Mechanisms

Song, Hyunjoo; Hwang, Yun Jeong; Ha, Jae Won; Boo, Yong Chool

doi:10.3390/ijms21134589

Cited by 8 publications

(5 citation statements)

References 61 publications

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“…Tyrosinase (EC 1.14.18.1) is the central rate-limiting enzyme in the melanogenesis pathway, as it catalyzes the hydroxylation of l -Tyrosine to l -3,4-dihydroxyphenylalanine ( l -DOPA) as well its subsequent oxidation to Dopachrome [ 12 , 13 ]. As tyrosinase is a metalloenzyme with two copper ions; chelators that can sequester copper have also shown promise as a target for pigmentation disorders [ 14 , 15 , 16 ]. The intracellular transport of tyrosinase is regulated by copper uptake and the N-glycosylation process [ 17 ]; the role of the enzyme α-glucosidase has been implicated in this glycosylation process in previous reports [ 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

CMT-308, a Nonantimicrobial Chemically-Modified Tetracycline, Exhibits Anti-Melanogenic Activity by Suppression of Melanosome Export

Goenka

Simon

2020

Biomedicines

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CMT-308 is a nonantimicrobial chemically-modified tetracycline (CMT), which we have previously shown exhibits antifungal activity and pleiotropic anti-inflammatory activities, including inhibition of the enzymatic activity of matrix metalloproteinases (MMPs). Based on its chemical structure, we hypothesized that CMT-308 could inhibit melanogenesis and might be a candidate for the treatment of skin hyperpigmentation disorders which occur due to unregulated melanin biosynthesis and/or transport. CMT-308 was first studied for any effects on activity of the enzyme tyrosinase in vitro using a purified preparation of mushroom tyrosinase; the mode of inhibition of the soluble fungal enzyme was evaluated by Lineweaver-Burk and Dixon plots as well as by non-linear least squares fitting. Next, the effects of CMT-308 were tested in mammalian cell cultures using B16F10 mouse melanoma cells and further validated in darkly-pigmented human melanocytes (HEMn-DP). Our results showed that micromolar concentrations of CMT-308 inhibited mushroom tyrosinase enzyme activity, using the first two substrates in the melanogenesis pathway (l-tyrosine and l-3,4-dihydroxyphenylalanine (l-DOPA)); CMT-308 inhibited mushroom tyrosinase primarily via a mixed mode of inhibition, with the major contribution from a competitive mode. In B16F10 cell cultures, CMT-308 (10 µM) significantly diminished total melanin levels with a selective reduction of extracellular melanin levels, under both basal and hormone-stimulated conditions without any cytotoxicity over a duration of 72 h. Studies of potential mechanisms of inhibition of melanogenesis in B16F10 cells showed that, in mammalian cells, CMT-308 did not inhibit intracellular tyrosinase activity or the activity of α-glucosidase, an enzyme that regulates maturation of tyrosinase. However, CMT-308 suppressed MITF protein expression in B16F10 cells and showed copper chelating activity and antioxidant activity in a cell-free system. The significantly lower extracellular melanin levels obtained at 10 µM indicate that CMT-308’s anti-melanogenic action may be attributed to a selective inhibition of melanosome export with the perinuclear aggregation of melanosomes, rather than a direct effect on the tyrosinase-catalyzed steps in melanin biosynthesis. These results were validated in HEMn-DP cells where CMT-308 suppressed dendricity in a fully reversible manner without affecting intracellular melanin synthesis. Furthermore, the capacity of CMT-308 to inhibit melanosome export was retained in cocultures of HEMn-DP and HaCaT. In summary, our results offer promise for therapeutic strategies to combat the effects of hyperpigmentation by use of CMT-308 at low micromolar concentrations.

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Section: Introductionmentioning

confidence: 99%

CMT-308, a Nonantimicrobial Chemically-Modified Tetracycline, Exhibits Anti-Melanogenic Activity by Suppression of Melanosome Export

Goenka

Simon

2020

Biomedicines

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“…Therefore, we examined the direct inhibitory effect of Hir on tyrosinase activity using a cell-free mushroom tyrosinase system. Kojic acid (KA) was used as a positive control to directly inhibit tyrosinase activity [ 33 ]. As shown in Figure 4 a, Hir had an inhibitory effect on the oxidation activity of mushroom tyrosinase in a dose-dependent manner.…”

Section: Resultsmentioning

confidence: 99%

Hirsutanone Isolated from the Bark of Alnus japonica Attenuates Melanogenesis via Dual Inhibition of Tyrosinase Activity and Expression of Melanogenic Proteins

Uto

Tung

Shoyama

2022

Plants

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Hirsutanone (Hir) and oregonin (Ore) are diarylheptanoids isolated from the bark of Alnus japonica. In this study, we investigated the anti-melanogenic activity of Hir and Ore in B16-F1 murine melanoma and normal human epidermal melanocytes (HEMn-DP) and elucidated the mechanisms of action. In B16-F1 cells, Hir and Ore suppressed melanin synthesis induced by α-melanocyte-stimulating hormone (α-MSH) without cytotoxicity. The inhibitory effect of Hir on melanin synthesis was much stronger than that of Ore. In addition, Hir reduced melanin content in HEMn-DP cells. As tyrosinase is a key enzyme in melanin synthesis, the effect of Hir on tyrosinase activity was assessed. The results demonstrated that Hir partially decreased tyrosinase activity and intracellular tyrosinase activity. Moreover, Hir suppressed the protein expression of melanogenic enzymes, including tyrosinase, tyrosinase-related protein (TRP)-1, and TRP-2, leading to reduced melanin biosynthesis. Hir also led to the suppression of cAMP response element-binding protein (CREB) phosphorylation and microphthalmia-associated transcription factor (MITF) expression, which control the expression of melanogenic enzymes. These results suggest that Hir suppressed melanin synthesis by dual inhibition of tyrosinase activity and the CREB/MITF pathway leading to the expression of melanogenic enzymes and may be a potent cosmetic and therapeutic agent for hyperpigmentation disorders.

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“…FSHHLG-NH 2, RFWG-NH 2 , RLWG-NH 2 , FRWG-NH 2, RFW-NH 2 , RFG-NH 2 , RLG-NH 2 , RLW-NH 2 , WG-NH 2 , and G-NH 2 display very potent antimelanogenic activities in cells compared to arbutin [ 124 , 125 ]. Furthermore, there are lots of non-peptidic molecules, of which antimelanogenic effects were verified in cells [ 15 , 32 , 82 , 136 , 137 , 138 ] or in vivo [ 139 , 140 , 141 , 142 ]. Therefore, further studies are needed to examine the clinical utility of various peptidic molecules versus non-peptidic molecules for the treatment of skin pigmentary disorders.…”

Section: Discussionmentioning

confidence: 99%

Up- or Downregulation of Melanin Synthesis Using Amino Acids, Peptides, and Their Analogs

Boo

2020

Biomedicines

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Harmonious synthesis and distribution of melanin in the skin contribute to the expression of beauty and the maintenance of health. When skin pigmentary disorders occur because of internal or external factors or, when there is a need to artificially increase or reduce the pigmentation level of the skin for aesthetic or therapeutic purposes, various pharmacological therapies are applied but the results are not always satisfactory. Studies have been conducted to improve the efficacy and safety of these treatment strategies. In this review, we present the latest studies regarding peptides and related compounds that may be useful in artificially increasing or reducing skin melanin levels. Certain analogs of α-melanocyte stimulating hormone (MSH) and oligopeptides with the sequences derived from the hormone were shown to promote melanin synthesis in cells and in vivo models. Various amino acids, peptides, their analogs, and their hybrid compounds with other chemical moieties were shown to inhibit tyrosinase (TYR) catalytic activity or downregulate TYR gene expression. Certain peptides were shown to inhibit melanosome biogenesis or induce autophagy, leading to decreased pigmentation. In vivo and clinical evidence are available for some compounds, including [Nle4-D-Phe7]-α-MSH, glutathione disulfide, and glycinamide hydrochloride. For many other compounds, additional studies are required to verify their efficacy and safety in vivo and in clinical trials. The accumulating information regarding pro- and antimelanogenic activity of peptides and related compounds will lead to the development of novel drugs for the treatment of skin pigmentary disorders.

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Screening of an Epigenetic Drug Library Identifies 4-((hydroxyamino)carbonyl)-N-(2-hydroxyethyl)-N-Phenyl-Benzeneacetamide that Reduces Melanin Synthesis by Inhibiting Tyrosinase Activity Independently of Epigenetic Mechanisms

Cited by 8 publications

References 61 publications

CMT-308, a Nonantimicrobial Chemically-Modified Tetracycline, Exhibits Anti-Melanogenic Activity by Suppression of Melanosome Export

CMT-308, a Nonantimicrobial Chemically-Modified Tetracycline, Exhibits Anti-Melanogenic Activity by Suppression of Melanosome Export

Hirsutanone Isolated from the Bark of Alnus japonica Attenuates Melanogenesis via Dual Inhibition of Tyrosinase Activity and Expression of Melanogenic Proteins

Up- or Downregulation of Melanin Synthesis Using Amino Acids, Peptides, and Their Analogs

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