Synthesis and antimelanoma activity of analogues of N-acetyl-4-S-cysteaminylphenol.
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.
Lant
N J
NJ
Department of Chemistry, University of Glasgow, UK.
McKeown
P
P
Kelland
L R
LR
Rogers
P M
PM
Robins
D J
DJ
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D003543:Cysteamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology*; D006131:Growth Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D010636:Phenols / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D006131:Growth Inhibitors; D010636:Phenols; D003543:Cysteamine; C066420:N-acetyl-4-S-cysteaminylphenol