Synthesis and antimelanoma activity of analogues of N-acetyl-4-S-cysteaminylphenol

Anticancer Drug Des. 2000 Aug;15(4):295-302.

Abstract

N-Acetyl-4-S-cysteaminylphenol (1) has been shown by Jimbow and co-workers to possess useful antimelanoma activity. It is an analogue of a biosynthetic intermediate in the pathway to melanin and probably acts as a prodrug, being oxidized to an o-quinone which reacts with essential enzymes containing sulphydryl groups resulting in interference with cell growth and proliferation. We have synthesized a range of analogues of 1 by varying the acyl portion of the amide with the intention of increasing the lipophilicity of the compounds. A modest increase in melanoma activity against six melanoma cell lines for these analogues could be correlated with increased lipophilicity. The most active of these compounds, N-[2-[(4-hydroxyphenyl)thiol]ethyl]cyclohexanecarboxamide (9), showed promising selectivity (lack of cytotoxicity) on the non-melanotic cell line SK-Mel-24 and on an ovarian cell line. A significant improvement in antimelanoma activity was observed with a new type of analogue containing three carbon atoms between the sulphur and nitrogen. The most active of these new analogues, N-[3-[(4-hydroxyphenyl)-thiolpropyl]-1-cyclohexanecarboxamide (15), had activity comparable to cisplatin against several cell lines and low cytotoxicity towards the non-melanotic cell line.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology*
  • Cell Division / drug effects
  • Cysteamine / analogs & derivatives*
  • Cysteamine / chemical synthesis*
  • Cysteamine / pharmacology*
  • Growth Inhibitors / chemical synthesis
  • Growth Inhibitors / pharmacology
  • Humans
  • Melanoma / drug therapy*
  • Melanoma / pathology
  • Phenols / chemical synthesis*
  • Phenols / pharmacology*
  • Structure-Activity Relationship
  • Tumor Cells, Cultured / drug effects

Substances

  • Antineoplastic Agents
  • Growth Inhibitors
  • Phenols
  • Cysteamine
  • N-acetyl-4-S-cysteaminylphenol