Discovery of Novel Naphthylphenylketone and Naphthylphenylamine Derivatives as Cell Division Cycle 25B (CDC25B) Phosphatase Inhibitors: Design, Synthesis, Inhibition Mechanism, and in Vitro Efficacy against Melanoma Cell Lines

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.