Synthesis and antimelanoma activity of reversed amide analogues of N-acetyl-4-S-cysteaminylphenol.
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 oquinone 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.
Nicoll
Kathryn
K
WestCHEM, Department of Chemistry, University of Glasgow, Glasgow G12 8QQ, UK.
Robertson
Jane
J
Lant
Neil
N
Kelland
Lloyd R
LR
Rogers
Paul M
PM
Robins
David J
DJ
D000577:Amides / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003543:Cysteamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology*; D015394:Molecular Structure; D010636:Phenols / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity*; D013329:Structure-Activity Relationship
D000577:Amides; D000970:Antineoplastic Agents; D010636:Phenols; D003543:Cysteamine; C066420:N-acetyl-4-S-cysteaminylphenol