Synthesis and antimelanoma activity of sterically congested tertiary amide analogues of N-acetyl-4-S-cysteaminylphenol.
Interference with the biosynthetic pathway to melanin may be a useful means for developing new chemotherapeutic drugs to combat malignant melanoma. N-Acetyl-4-S-cysteaminylphenol (1) is an analogue of tyrosine that is involved in the pathway to melanin. It is probably oxidized selectively in melanocytes to an o-quinone that can alkylate thiol groups on important cellular enzymes, resulting in interference with cell growth and proliferation. We previously synthesized a range of more lipophilic analogues of 1 by independently varying the acyl portion and introducing substitution alpha to the nitrogen. Most of the new compounds displayed greater cytotoxicity than the original lead compound 1. We also made a series of tertiary amides that again showed higher cytotoxicity than 1. In this work three new acetamides and two new cyclohexanecarboxamides containing 4-S-cysteaminylphenol were prepared incorporating both substitution alpha to the nitrogen and different substituents on the nitrogen of the amide in each compound to increase lipophilicity and to reduce further the possibility of hydrolysis of the amides. Most of the new tertiary amides showed greater cytotoxicity towards five representative melanoma cell lines than the parent secondary amide. The highest cytotoxicity against these five cell lines with IC50 values of 1-15 nicroM, comparable to cisplatin, was observed for N-[2[(4-hydroxyphenyl)thio]-1,1-dimethylethyl]-N-methylcyclohexanecarboxamide (8c). The IC50 values of 14.5 and 5.4 microM for this compound against SK-Mel-24 (not containing tyrosinase) and an ovarian cell line, respectively, suggest that interference with the melanin pathway may not be the only mode of action of this new compound. The cyclohexanecarboxamides were better substrates for mushroom tyrosinase (EC 1.14.18.1) than the acetamides.
Ferguson
Jillian
J
Department of Chemistry, University of Glasgow, Glasgow G12 8QQ, UK.
Rogers
Paul M
PM
Kelland
Lloyd R
LR
Robins
David J
DJ
D000363:Agaricales / Q000201:enzymology; D000577:Amides / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003543:Cysteamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020128:Inhibitory Concentration 50; D008543:Melanins / Q000737:chemistry; D008545:Melanoma / Q000188:drug therapy*; D008956:Models, Chemical; D014442:Monophenol Monooxygenase / Q000737:chemistry / Q000378:metabolism; D009584:Nitrogen / Q000737:chemistry; D010100:Oxygen / Q000378:metabolism; D010636:Phenols / Q000138:chemical synthesis* / Q000494:pharmacology*; D013237:Stereoisomerism; D013440:Sulfides / Q000737:chemistry; D013997:Time Factors; D014466:Ultraviolet Rays
D000577:Amides; D000970:Antineoplastic Agents; D008543:Melanins; D010636:Phenols; D013440:Sulfides; D003543:Cysteamine; C066420:N-acetyl-4-S-cysteaminylphenol; D014442:Monophenol Monooxygenase; D009584:Nitrogen; D010100:Oxygen