CDC25 phosphatases play a critical role in the regulation of the cell cycle and thus represent attractive cancer therapeutic targets. We previously discovered the 4-(2-carboxybenzoyl)phthalic acid (NSC28620) as a new CDC25 inhibitor endowed with promising anticancer activity in breast, prostate, and leukemia cells. Herein, we report a structure-based optimization of NSC28620, leading to the identification of a series of novel naphthylphenylketone and naphthylphenylamine derivatives as CDC25B inhibitors. Compounds 7j, 7i, 6e, 7f, and 3 showed higher inhibitory activity than the initial lead, with Ki values in the low micromolar range. Kinetic analysis, intrinsic fluorescence studies, and induced fit docking simulations provided a mechanistic understanding of the activity of these derivatives. All compounds were tested in the highly aggressive human melanoma cell lines A2058 and A375. Compound 4a potently inhibited cell proliferation and colony formation, causing an increase of the G2/M phase and a reduction of the G0/G1 phase of the cell cycle in both cell lines.

中文翻译：

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发现新型萘基苯酮和萘基苯胺衍生物作为细胞分裂周期25B（CDC25B）磷酸酶抑制剂：设计，合成，抑制机理和针对黑素瘤细胞系的体外功效。

CDC25磷酸酶在细胞周期的调节中起关键作用，因此代表了有吸引力的癌症治疗靶标。我们先前发现了4-（2-羧基苯甲酰基）邻苯二甲酸（NSC28620）作为一种新型CDC25抑制剂，在乳腺癌，前列腺癌和白血病细胞中具有有希望的抗癌活性。在这里，我们报告了NSC28620的基于结构的优化，从而导致鉴定出一系列新型的萘基苯基酮和萘基苯基胺衍生物作为CDC25B抑制剂。化合物7j，7i，6e，7f和3显示出比初始铅更高的抑制活性，Ki值在低微摩尔范围内。动力学分析，内在荧光研究和诱导拟合对接模拟提供了对这些衍生物活性的机械理解。所有化合物均在高度侵袭性的人类黑素瘤细胞系A2058和A375中进行了测试。化合物4a有效抑制细胞增殖和集落形成，导致两种细胞系中细胞周期的G2 / M期增加和G0 / G1期减少。