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

Research Service, Veterans Administration Medical Center, Sepulveda, California 91343 [D. H. K.]; Division of Surgical Oncology, John Wayne Cancer Clinic, UCLA School of Medicine, Los Angeles, California 90024 [D. H. K., S. U. H-Z.]; and Developmental Therapeutics Program, National Cancer Institute, Bethesda, Maryland 20892 [R. H. S., J. S. D.]

The cytotoxic activities of three new synthetic catechol analogues, ß-[(p-hydroxyphenyl)amino]alanine (Compound 1), N^b-(p-hydroxyphenyl)ornithine (Compound 2), and N^b-(m-hydroxyphenyl)ornithine (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 µg/ml required to give 90% inhibition of colony formation (IC₉₀) were calculated. Using a cutoff IC₉₀ 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 IC₉₀ values exceeded 100. 3,4-Dihydroxybenzylamine was active in 3 of 8 melanomas and 1 of 5 nonmelanomas. Regression analysis of IC₉₀ values for Compound 2 and tyrosinase levels in the 15 cell lines yielded a correlation coefficient of 0.93 (P < 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 quinones. Cytotoxic activity was blocked by the tyrosinase inhibitor phenylthiocarbamide. Since the rates of activation of Compounds 1 and 2 were identical, the higher activity of Compound 2 was probably due to its higher lipophilicity and greater intracellular accumulation. Compounds 1 and 2 exhibited greater potency and selectivity against malignant melanoma than did the natural product L-DOPA methyl ester.

¹ This work was supported by Contract CM 57710 from the National Cancer Institute and by the Veterans Administration Medical Research Service.

² Present address: Oncotech, Inc., 1791 Kaiser Ave., Irvine, CA 92714.

Received 12/10/87. Revised 6/10/88. Accepted 6/21/88.