Synthesis and Antimelanoma Activity of Reversed Amide Analogues of N-Acetyl-4-S-cysteaminylphenol

Authors: Nicoll, Kathryn¹; Robertson, Jane¹; Lant, Neil¹; Kelland, Lloyd R.²; Rogers, Paul M.³; Robins, David J.¹

Source: Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics, Volume 16, Number 2, 2006 , pp. 97-106(10)

Publisher: Cognizant Communication Corporation

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Abstract:

The melanin biosynthetic pathway from tyrosine is a potential target for combating malignant melanoma. N-Acetyl-4-S-cysteaminylphenol 1 is a previously synthesized analogue of tyrosine that probably acts by this pathway. It interferes with cell growth and proliferation via selective oxidation in melanocytes to an o-quinone that can alkylate cellular nucleophiles. We previously synthesized a range of analogues of the original lead compound 1 most of which displayed greater cytotoxicity than 1. Eighteen new analogues with the amide group reversed have now been synthesized and tested for antimelanoma activity. Most of these reverse amides showed greater cytotoxicity than N-acetyl-4-S-cysteaminylphenol towards five representative melanoma cell lines. The highest cytotoxicity was observed for the piperidine and hexamethyleneimine derivatives 7, 8, 12, 13, and 17 and the catechol 18. The most active compound, 7, had cytotoxicity comparable to cisplatin against the five melanoma cell lines. The moderate activity of 7 and 18 against SK-Mel-24 (non-tyrosinase containing) and an ovarian cell line suggests that interference with the melanin pathway may not be the only mode of action of these compounds. Assays of some of the compounds as substrates for tyrosinase showed that the catechol 18 was the best substrate and that the piperidine derivative 7 was the best substrate of the phenolic compounds synthesized.

Keywords: Antimelanoma; Cysteaminylphenol; Tyrosinase; Amide

Document Type: Research article

Affiliations: 1: WestCHEM, Department of Chemistry, University of Glasgow, Glasgow G12 8QQ, UK 2: †Cancer Research UK Centre for Cancer Therapeutics, Institute of Cancer Research, Haddow Laboratories, 15 Cotswold Road, Belmont, Sutton, Surrey SM2 5NG, UK 3: Cancer Research UK Centre for Cancer Therapeutics, Institute of Cancer Research, Haddow Laboratories, 15 Cotswold Road, Belmont, Sutton, Surrey SM2 5NG, UK

Publication date: 2006-02-01

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Formerly: Oncology Research Incorporating Anti-Cancer Drug Design
Oncology Research Featuring Preclinical and Clincal Cancer Therapeutics publishes research of the highest quality that contributes to an understanding of cancer in areas of molecular biology, cell biology, biochemistry, biophysics, genetics, biology, endocrinology, and immunology, as well as studies on the mechanism of action of carcinogens and therapeutic agents, reports dealing with cancer prevention and epidemiology, and clinical trials delineating effective new therapeutic regimens.

Synthesis and Antimelanoma Activity of Reversed Amide Analogues of N-Acetyl-4-S-cysteaminylphenol

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