Structure-Activity Relationships Defining the Cytotoxicity of Catechol Analogues against Human Malignant Melanoma1

The cytotoxic activities of three new synthetic catechol analogues, /H(p-hydroxyphenyl)amino|alanine (Compound 1), W-^-hydroxyphenyl)ornithine (Compound 2), and A^-i/n-hydroxyphenylJornithine (Compound 3), were determined against 10 human melanoma and 5 nonmelanoma cell lines. Activities of L-DOPA and 3,4-dihydroxybenzylamine were also measured. Dose-response curves were obtained and concentrations in w ml required to give 90% inhibition of colony forma tion (H '.„,) were calculated. Using a cutoff K «, of <2.5 as a definition of activity, Compound 2 was active in 6 of 10 melanoma and 0 of 5 nonmelanoma cell lines while both Compound 1 and L-DOPA methyl ester were active in 1 of 10 melanomas and 0 of 5 nonmelanomas. Compound 3 was inactive in all cell lines and all ICw values exceeded 100. 3,4-Dihydroxybenzylamine was active in 3 of 8 melanomas and 1 of 5 nonmelanomas. Regression analysis of ICw values for Compound 2 and tyrosinase levels in the 15 cell lines yielded a correlation coefficient of 0.93 (/' < 0.001). By contrast, a similar analysis for 3,4-dihydroxybenzylamine gave a correlation coefficient of 0.17 (P > 0.05). Spectrophotometric data indicated that Compounds 1 and 2 were oxidized by tyrosinase to quiñones. Cytotoxic activity was blocked by the tyrosinase inhibitor phenylthiocarbamide. Since the rates of activation of Com pounds 1 and 2 were identical, the higher activity of Compound 2 was probably due to its higher lipophilicity and greater intracellular accu mulation. Compounds 1 and 2 exhibited greater potency and selectivity against malignant melanoma than did the natural product L-DOPA methyl ester.