Antimelanoma Effect of 4-S-Cysteaminylcatechol, an Activated Form of 4-S-Cysteaminylphenol

Rational chemotherapy of malignant melanoma could be developed by taking advantage of the presence of melanogenic enzymes in melanoma cells. 4- S -Cysteaminylphenol (4- S -CAP) has been evaluated for melanocytotoxicity and antimelanoma effect. Although 4- S -CAP is selectively toxic to pigmented melanoma cells, it is not potent enough when applied as a single agent. To increase the efficacy of 4- S -CAP, we synthesized 4- S -cysteaminylcatechol (4- S -CAC), an activated form of 4- S -CAP, and compared its biochemical properties and antimelanoma effects with those of the isomers 3- S -cysteaminylcatechol (3- S -CAC) and 2- S -cysteaminyl-hydroquinone (2- S -CAH). 4- S -CAC was found to be a better substrate for melanoma tyrosinase than was l-3,4-dihydroxyphenylalanine, the natural catecholic substrate. 3- S -CAC was a poor substrate, whereas 2- S -CAH was not a substrate. 4- S -CAC was the most cytotoxic to three lines of melanoma cells in vitro , followed by 2- S -CAH and 3- S -CAC. When applied i.p. for 9 days at a dose of 100 mg/kg, 4- S -CAC·HCl, increased by 46–52% the life span of C57BL/6 mice inoculated i.p. with B16 melanoma; this effect was comparable to that of a 50 mg/kg dose of 5-(3,3-dimethyltriazenyl)-1 H -imidazole-4-carboxamide. 3- S -CAC was marginally effective, whereas 2- S -CAH was toxic to the host. This systemic toxicity of 2- S -CAH reflected its susceptibility to autoxidation. Growth of B16 melanoma cells inoculated s.c. was significantly inhibited by i.p. administration of 4- S -CAC·HCl (200 mg/kg) for 5 days ( P < 0.05). These results suggest that 4- S -CAC is a potent antimelanoma agent, the effect of which is mostly mediated through tyrosinase oxidation.