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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. 相似文献
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Actinic keratoses (AKs) represent the second most common reason to visit a dermatologist in the United States and their therapy has become a major portion of most dermatologists' practice. An ever-increasing array of therapeutic options exist for the therapy of actinic keratoses, offering physicians and patients a greater number of choices than ever before. Patient expectations and needs seem to be changing at the same time, thus effecting therapeutic decision-making. While destructive therapies with resultant wounds, time for wound healing, and possible hypopigmentation or scarring were acceptable in the past, many patients from the baby-boom generation are now developing AKs and have little tolerance for any time for wound healing or any cosmetic changes. This paper will raise some fundamental questions regarding AKs and their management. 相似文献