Synthesis of cysteinylphenol, cysteaminylphenol, and related compounds, and in vivo evaluation of antimelanoma effect

Abstract

Phenolic and catecholic compounds were synthesized, by combination with cysteine or cysteamine through thioether bond, and their antimelanoma and melanocytotoxic effects were evaluated. Among nine compounds tested, 4-S-cysteaminylphenol (CAP) resulted in an increase in the life span (% ILS) of melanoma-bearing mice and in the growth inhibition (% GI) of melanoma tissue. 4-S-Cysteinylphenol (CP) and its methyl ester form also showed some increase in % GI. The 2-S-isomers of CP and CAP and diphenolic derivatives of CP did not show any significant antimelanoma effect. In addition, the s.c. injection of 4-S-CAP and 4-S-CP, in particular 4-S-CAP, caused the depigmentation of black hair which was manifested by loss of functioning melanocytes, as seen under light microscopy. The 4-S-CAP appears to provide a basis for development of a new class of antimelanoma and melanocytotoxic agents that are more stable than catecholic compounds, which have been most widely utilized as a source of rational chemotherapy for malignant melanoma.

The in vivo antimelanoma effect of 4‐S‐cysteaminylphenol and its N‐acetyl derivative

“…The methods for synthesis of 4-S-CP and 4-S-CAP were described in our previous report (Miura et al, 1987). NAc-4-S-CAP was also prepared by the method of Padgette et al (1984).…”

“…The details of tumor preparation and growth characteristics were reported in our previous study (Miura et al, 1987). Briefly, excised tumors were homogenized in normal saline.…”

“…We hypothesized that this effect would possibly be enhanced by creating cysteinyl homologues of tyrosine, i.e., cysteinylphenol (CP) and its decarboxylation product, cysteaminylphenol (CAP). Sulphur would increase the affinity of tyrosine to tyrosinase and lipophilicity to the plasma membrane, and therefore increase its potential incorporation into melanin pigments and melanocytes Miura et al, 1987). It was expected that these phenolic compounds would be much more stable than catecholic compounds, which have been utilized as rational anti-melanoma agents in many previous studies, e .…”

The killing effect of 4-S-cysteaminylphenol, a newly synthesised melanin precursor, on B16 melanoma cell lines

“…Pursuing our quest further, in this report, we have evaluated the killing effects of 4-S-CAP on B16 melanoma cell lines possessing different melanin-producing activities, and have authors (Dr S. Ito), and the details of this chemical synthesis have been reported previously (Miura et al, 1987). The drug solution was freshly prepared in a Ham's F-10 medium (Gibco, Grand Island, NY) just before use at the beginning of each experiment.…”

“…Therefore, in a search for more effective melanocytotoxic agents, we have synthesised various phenolic compounds as substrates for tyrosinase, and have demonstrated that, among these synthetic compounds, 4-S-cysteaminylphenol (4-S-CAP) possesses the most significant effect in inhibiting the growth of melanomas in experimental mice (Miura et al, 1987). Pursuing our quest further, in this report, we have evaluated the killing effects of 4-S-CAP on B16 melanoma cell lines possessing different melanin-producing activities, and have authors (Dr S. Ito), and the details of this chemical synthesis have been reported previously (Miura et al, 1987).…”