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Synthesis and selective in vitro anti-melanoma effect of enantiomeric α-methyl- and α-ethyl-4-S-cysteaminylphenol

Yukitake, Juna; Otake, Hiromib; Inoue, Shigekia; Wakamatsu, Kazumasab; Olivares, Concepciónc; Solano, Franciscoc; Hasegawa, Katsutoshib; Ito, Shosukeb


Melanogenesis provides a unique target for the development of antitumour agents specific for malignant melanoma. Among the anti-melanoma compounds we have examined, 4-S-cysteaminylphenol (4-S-CAP), a phenolic amine, was found to have the most promising anti-melanoma effects. To further improve its efficacy as an anti-melanoma agent, we synthesized the R- and S-enantiomers (99% enantiomer excess) of α-methyl- 4-S-cysteaminylphenol (α-Me-4-S-CAP) and α-ethyl- 4-S-cysteaminylphenol (α-Et-4-S-CAP) by coupling 4-hydroxythiophenol with the oxazolines obtained from the (R)- and (S)-enantiomers of 2-amino-1-propanol and 2-amino-1-butanol, respectively. The enantiomers of α-Me-4-S-CAP and α-Et-4-S-CAP were found to be better substrates for tyrosinase than the natural substrate, l-tyrosine. In vitro experiments showed that all four enantiomers were highly cytotoxic to pigmented B16-F1 melanoma cells, the effect being 70-fold and 160-fold greater than that on non-pigmented B16-G4F melanoma cells and 3T3 fibroblasts, respectively. The cytotoxic effect against B16-F1 cells was completely inhibited by phenylthiourea, a tyrosinase inhibitor, or by N-acetyl-l-cysteine, which increases the intracellular reduced glutathione (GSH) level. 4-S-CAP and the enantiomers were taken up into B16-F1 cells at comparable rates, but showed varying rates of GSH depletion that were inversely correlated to the cytotoxicity. These results suggest that the use of enantiomers would increase the efficacy of tyrosinase-dependent cytotoxic phenols.

Departments of aClinical Immunology and bChemistry, Fujita Health University School of Health Sciences, Toyoake, Aichi 470-1192, Japan, and cDepartment of Biochemistry and Molecular Biology, School of Medicine, University of Murcia, 31000 Murcia, Spain.

Sponsorship: This study was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (13670229) and for Cancer Research (11-7) from the Ministry of Health, Labor and Welfare of Japan.

Correspondence and requests for reprints to Shosuke Ito, Fujita Health University School of Health Sciences, Toyoake, Aichi 470-1192, Japan. Tel: +81 562 93 2595; fax +81 562 93 4597; e-mail:

Received 30 April 2003 Accepted 30 June 2003

© 2003 Lippincott Williams & Wilkins, Inc.