SYNTHESIS AND ANTITUMOR EFFECT OF THE MELANOGENESIS-BASED ANTIMELANOMA AGENT N-PROPIONYL-4-S-CYSTEAMINYLPHENOL

Chemotherapy of malignant melanoma is still a great challenge, as no e ffective drugs are available. The development of melanogenesis-based d rugs is a promising area of research because melanogenesis is a unique biochemical pathway operating only in melanoma cells (and their norma l counterparts) so that the tumour can be targeted. We have been using cysteinylphenol, a sulphur containing analogue of tyrosine, and deriv atives for that purpose. N-Acetyl-4-S-cysteaminylphenol was found to h ave the best antimelanoma effect in cell culture systems and in mice b earing B16 melanoma rumours. It also caused depigmentation of the skin , suggesting the possibility of use as a hypopigmenting agent. To impr ove the efficiency of the drug, we thought of replacing the acetyl gro up in N-acetyl-4-S-cysteaminylphenol with a propionyl group in the hop e that increased hydrophobicity would increase the cellular uptake of the drug. N-Propionyl-4-S-cysteaminylphenol was synthesized by condens ing 4-hydroxythiophenol with 2-ethyl-2-oxazoline. The drug showed both cytostatic and cytocidal effects in a human melanotic melanoma cell l ine. The drug was found to be a good depigmenting agent for the black hair follicles of C57 black mice when given s.c. for 14 days. A 10-day treatment with N-propionyl-4-S-cysteaininylphenol at 300 mg/kg body w eight reduced the growth rate of B16 melanoma s.c. rumours in mice by 36%. The propionyl derivative was found to increase the life span of m ice bearing melanoma more effectively than did the acetyl derivative. BIOCHEM PHARMACOL 55;12:2023-2029, 1998. (C) 1998 Elsevier Science Inc .