2-Aryl-1,3-thiazolodines as masked sulfhydryl agents for inhibition of melanogenesis

Napolitano, Alessandra; d’Ischia, Marco; Prota, Giuseppe; Havens, Mary; Tramposch, Kenneth M.

doi:10.1016/0304-4165(91)90151-6

Cited by 7 publications

(3 citation statements)

References 17 publications

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“…Cys is considered to be a key compound in the control of melanogenesis, as it regulates tyrosinase activity as well as the ability of L-dopaquinone to generate eumelanin or pheomelanine. 7,14) We believe that the Cys liberated by degradation of CP2Et (2a, b) or AcCP2Et (4b, d) is responsible for the melanogenesis inhibition observed. In the case of CP2Et (2a, b), it is thought that Cys released by extracellular non-enzymatic degradation is taken up into cells.…”

Section: Suppression Of Eumelanin Productionmentioning

confidence: 98%

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Synthesis, Characterization, and Evaluation of Thiazolidine Derivatives of Cysteine for Suppressing Eumelanin Production

Amino

Takino

Kaneko

et al. 2016

CHEMICAL & PHARMACEUTICAL BULLETIN

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In the pathway of melanin biosynthesis, cysteine (Cys) is utilized for the synthesis of pheomelanin. Accordingly, Cys is considered to suppress the formation of brown-black eumelanin. Although attempts have been made to utilize Cys and its derivatives as skin-whitening agents, their instability and odor hinders their application as a cosmetic agent. Herein, N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid ethyl ester (AcCP2Et) was proposed as a candidate for a stable and prolonged-release derivative of Cys to inhibit dopachrome formation after its degradation in melanocytes. It was synthesized by acetylation of 2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester (CP2Et), the condensation derivative of Cys and ethyl pyruvate. AcCP2Et suppressed melanogenesis in melanocytes in vitro, was stable in phosphate buffer at 70°C for five days, and exhibited far less odor than CP2Et. Therefore, AcCP2Et was validated to be a useful deriative of Cys for application as a skin-whitening agent. AcCP2Et comprises four stereoisomers; thus characterization of each stereoisomer was required. The stereochemistry of AcCP2Et was confirmed via a single-crystal X-ray structure analysis of N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid (AcCP) derived from AcCP2Et. In the synthesis of AcCP2Et, the acetylation of CP2Et proceeded with epimerization at C4 to give trans-isomers when excess acetyl chloride and an organic amine was used, whereas it proceeded while retaining the original (R) configuration at C4 to give the cis-and trans-isomer when an equivalent of acetyl chloride with an inorganic base was used. These results indicate that the formation of an intermolecular mixed acid anhydride is responsible for the isomerization at the C4 asymmetric center.Key words thiazolidine derivative; cysteine; suppressing eumelanin production; acetylation; stereoisomer Melanin plays an important role in determining hair, eye, and skin color. It also protects the skin from UV radiation and inhibits photocarcinogenesis. 1) However, hyperpigmentation, which is caused by melanin overproduction and accumulation, causes freckles, age spots, melisma, and melanoma. 2)Medical cosmetics that contain skin-whitening components are used for treating hyperpigmentation. The inhibitory effect of conventional pharmaceutical skin-whitening agents such as hydroquinone, arbutin, 3) and kojic acid 4) on melanogenesis is attributed to the inhibition of tyrosinase. Therefore, skin-whitening agents that have a mechanism distinct from tyrosinase inhibition should be useful.Melanin is produced in human pigment cells (melanocytes) in the skinutilizing L-tyrosine (Tyr) and L-cysteine (Cys). The melanin biosynthesis pathway comprises two main parts: the production of eumelanin and the production of pheomelanin. During eumelanogenesis, Tyr is converted to 3,4-dihydroxyphenylalanine (DOPA) by tyrosinase, which then further catalyzes the conversion of DOPA to dopaquinone. Dopaquinone is converted to 5,6-dihydroxyindole-2-carboxylic acid and 5,6-dihydroxyindole intermedi...

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Section: Suppression Of Eumelanin Productionmentioning

confidence: 98%

“…[10][11][12][13] Several 2-(substituted phenyl) thiazolidine-4-carbxylic acid derivatives have been investigated as agents for inhibition of melanogenesis or as tyrosinase inhibitors. [14][15][16] However, some of these compounds have the disadvantage of liberating toxic aldehyde upon degradation.…”

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confidence: 99%

Synthesis, Characterization, and Evaluation of Thiazolidine Derivatives of Cysteine for Suppressing Eumelanin Production

Amino

Takino

Kaneko

et al. 2016

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…Originally reported as efficient melanogenesis inhibitors in an in vitro study , 2‐aryl‐1,3‐thiazolidines obtained from aromatic aldehydes and cysteine have been recently extensively investigated for their promising antimelanogenic activity .…”

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Melanin pigmentation control by 1,3‐thiazolidines: does NO scavenging play a critical role?

Napolitano

Micillo

Monfrecola

2016

Experimental Dermatology

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Thiazolidine MHY 384 and structurally related compounds previously described may operate through multiple mechanisms that overall contribute to their remarkable potency in the control of melanin pigmentation. It is difficult at present to assess which is the most critical target of the action of these compounds i.e. the MSH- CREB-MITF signaling pathway activating tyrosinase expression, tyrosinase activity itself , the early stages of the melanogenesis pathway or also the NO induced melanogenesis via control of CREB phosphorylation or by direct scavenging, but it is possible that such a variety of mechanisms of action may represent an advantage of this class of compounds over other proposed skin depigmenting agents providing a useful strategy allowing to improve clinical efficacy, reducing the duration of therapy and the risk of adverse effects

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Toxicological Aspects of Melanin and Melanogenesis

Land¹,

Ramsden²,

Riley³

2006

The Pigmentary System

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2-Aryl-1,3-thiazolodines as masked sulfhydryl agents for inhibition of melanogenesis

Cited by 7 publications

References 17 publications

Synthesis, Characterization, and Evaluation of Thiazolidine Derivatives of Cysteine for Suppressing Eumelanin Production

Synthesis, Characterization, and Evaluation of Thiazolidine Derivatives of Cysteine for Suppressing Eumelanin Production

Melanin pigmentation control by 1,3‐thiazolidines: does NO scavenging play a critical role?

Toxicological Aspects of Melanin and Melanogenesis

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