Structure-activity relationships defining the cytotoxicity of catechol analogues against human malignant melanoma.

Abstract

The cytotoxic activities of three new synthetic catechol analogues, beta-[(p-hydroxyphenyl)amino]alanine (Compound 1), N delta-(p-hydroxyphenyl)ornithine (Compound 2), and N delta-(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 micrograms/ml required to give 90% inhibition of colony formation (IC90) were calculated. Using a cutoff IC90 of less than 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 less than 0.001). By contrast, a similar analysis for 3,4-dihydroxybenzylamine gave a correlation coefficient of 0.17 (P greater than 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.

• Authors: D H Kern, R H Shoemaker, S U Hildebrand-Zanki, J S Driscoll
• Journal: Cancer research (Cancer Res) Vol. 48 Issue 18 Pg. 5178-82 (Sep 15 1988) ISSN: 0008-5472 [Print] United States
• PMID: 3136917 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Catechols
• Phenylthiourea
• Monophenol Monooxygenase

Topics

• Antineoplastic Agents (therapeutic use)
• Catechols (therapeutic use)
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• Enzyme Activation
• Humans
• Melanoma (drug therapy)
• Monophenol Monooxygenase (metabolism)
• Phenylthiourea (pharmacology)
• Structure-Activity Relationship
• Tumor Stem Cell Assay