Agents with potential specificity against melanotic melanoma.

Agents were designed to exploit the high tyrosinase activity in melanotic melanoma relative to normal tissues. If specific tyrosinase activation of these agents occurred, the production of toxic metabolites in the melanoma cells would produce selective cell kill. Synthesis and antitumor activities of three new amino acids, 1a [beta-[(p-hydroxyphenyl)amino]alanine hydrochloride], 1b [N delta-(p-hydroxyphenyl)ornithine hydrochloride], and 1c [N delta-(m-hydroxyphenyl)ornithine dihydrochloride], were described. Compounds 1a and 1b were approximately 2-fold more active against the B-16 melanotic melanoma than the amelanotic melanoma cell line in vitro. Compound 1b was approximately 2-fold more potent than compound 1a against either cll line and was 8-fold more potent than L-glutamic acid gamma-(4-hydroxyanilide), a natural product isolated from mushroom. No significant growth inhibitory activity was found for the m-hydroxy analogue 1c at 100 micrometers, the highest concentration tested. Similarly, compound 1b exhibited better activity against P-388 (ED50 = 9.5 x 10(-6) M) than 1a (ED50 = 3.2 x 10(-5) M) and was about 30-fold more potent than 1c. Against human epidermoid carcinoma of the nasopharynx (KB), these agents showed modest inhibitory activity with ED50 values in the range of 1.2 to 3 x 10(-4) M. No in vivo activity against P-388 and B-16 at doses up to 150-200 mg/kg was observed. The biological results suggest that a nonspecific oxidation rather than a specific tyrosinase activation is involved in the biological action of these new compounds.