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首页> 外文期刊>Anti-Cancer Drug Design >Synthesis and anti-melanoma activity of analogues of N-acetyl-4-S-cysteaminylphenol substituted with two methyl groups alpha to the nitrogen.
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Synthesis and anti-melanoma activity of analogues of N-acetyl-4-S-cysteaminylphenol substituted with two methyl groups alpha to the nitrogen.

机译：氮上两个甲基取代的N-乙酰基-4-S-半胱氨酰苯酚类似物的合成和抗黑色素瘤活性。

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摘要

N-Acetyl-4-S-cysteaminylphenol 1 is an analogue of a biosynthetic intermediate in the pathway to melanin. It is probably oxidized to an o-quinone which can alkylate cellular nucleophiles resulting in interference with cell growth and proliferation. It is reported to have useful anti-melanoma activity. We previously synthesized a range of analogues of 1 by varying the acyl portion of the amide. A modest increase in melanoma activity against six melanoma cell lines for these analogues could be correlated with increased lipophilicity. Thirteen new analogues of 1 containing two methyl groups at the alpha-position of the amino component and various acyl groups have now been prepared and assessed for anti-melanoma activity against six human melanoma cell lines. Most of the new compounds displayed greater cytotoxicity than the lead compound 1. The highest cytotoxicity against the cell lines was observed for the cyclohexylacetamide 11 followed by the cyclohexylcarboxamide 10 and the 2,2-dimethylpropanamide 6. The IC50 values of the most cytotoxic compound 11 against the cell lines were comparable with those of cisplatin. Small variations in the acyl components of these analogues, such as reducing the ring size, lengthening the carbon chain and reducing the amount of chain branching, resulted in a considerable loss of cytotoxicity. The moderate activity of 6, 10 and 11 against SK-Mel-24 cells (non-tyrosinase containing) and an ovarian cell line suggests that interference with the melanin pathway may not be their only mode of action.
机译：N-乙酰基-4-S-半胱氨酰苯酚1是黑色素途径中生物合成中间体的类似物。它可能被氧化为邻醌，可以烷基化细胞亲核试剂，从而干扰细胞生长和增殖。据报道具有有用的抗黑素瘤活性。我们以前通过改变酰胺的​​酰基部分合成了一系列1的类似物。对于这些类似物，针对六种黑色素瘤细胞系的黑色素瘤活性的适度增加可能与亲脂性增加有关。现在已经制备了13个新的1的类似物，其中1个在氨基成分的α位置含有两个甲基和各种酰基，并评估了其对六种人类黑素瘤细胞系的抗黑素瘤活性。大多数新化合物显示出比先导化合物1更大的细胞毒性。环己基乙酰胺11对细胞系的细胞毒性最高，其次是环己基羧酰胺10和2,2-二甲基丙酰胺6。最具细胞毒性的化合物11的IC50值对抗细胞系的作用与顺铂相当。这些类似物的酰基组分的微小变化，例如减小环的大小，延长碳链和减少链支化的量，导致细胞毒性的显着损失。 6、10和11对SK-Mel-24细胞（不含酪氨酸酶）和卵巢细胞的中等活性表明，干扰黑色素途径可能不是其唯一的作用方式。

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