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

Abstract

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...

Insights into self-degradation of cysteine esters and amides under physiological conditions yield new cleavable chemistry

“…S12, ESI†). It is noted that prior synthesis of 3 from the coupling of l -Cys and esterified pyruvic acid produced about a 1 : 1 diastereomer mixture, 21 which is different from this work of a diastereomeric excess.…”

“…S20 and S21, ESI†). Considering that thiazolidine derivatives are significant natural products and/or bioactive molecules, 21,22 we anticipate that this new self-degradation of Cys esters will be useful for facile preparation of all four stereoisomers of (deuterium-labeling) 2-methylthiazolidines.…”