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

Abstract

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 alpha-methyl- 4-S-cysteaminylphenol (alpha-Me-4-S-CAP) and alpha-ethyl- 4-S-cysteaminylphenol (alpha-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 alpha-Me-4-S-CAP and alpha-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.

• Authors: Jun Yukitake, Hiromi Otake, Shigeki Inoue, Kazumasa Wakamatsu, Concepción Olivares, Francisco Solano, Katsutoshi Hasegawa, Shosuke Ito
• Journal: Melanoma research (Melanoma Res) Vol. 13 Issue 6 Pg. 603-9 (Dec 2003) ISSN: 0960-8931 [Print] England
• PMID: 14646624 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Phenols
• methyl-4-S-cysteaminylphenol
• Tyrosine
• Cysteamine
• Monophenol Monooxygenase
• Glutathione
• 4-S-cysteaminylphenol
• Acetylcysteine

Topics

• 3T3 Cells
• Acetylcysteine (metabolism)
• Animals
• Antineoplastic Agents (chemical synthesis, therapeutic use)
• Cell Line, Tumor
• Cysteamine (analogs & derivatives, therapeutic use)
• Glutathione (metabolism)
• Inhibitory Concentration 50
• Kinetics
• Magnetic Resonance Spectroscopy
• Melanoma (drug therapy)
• Melanoma, Experimental
• Mice
• Models, Chemical
• Monophenol Monooxygenase (antagonists & inhibitors, metabolism)
• Phenols (chemistry)
• Stereoisomerism
• Time Factors
• Tyrosine (metabolism)