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  • 标题:Synthesis, Characterization, and Evaluation of Thiazolidine Derivatives of Cysteine for Suppressing Eumelanin Production
  • 本地全文:下载
  • 作者:Yusuke Amino ; Yoshinobu Takino ; Megumi Kaneko
  • 期刊名称:Chemical and Pharmaceutical Bulletin
  • 印刷版ISSN:0009-2363
  • 电子版ISSN:1347-5223
  • 出版年度:2016
  • 卷号:64
  • 期号:12
  • 页码:1681-1691
  • DOI:10.1248/cpb.c16-00509
  • 语种:English
  • 出版社:The Pharmaceutical Society of Japan
  • 摘要:

    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.

  • 关键词:thiazolidine derivative;cysteine;suppressing eumelanin production;acetylation;stereoisomer
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