Integrating a quinone substructure into histone deacetylase inhibitors to cope with Alzheimer's disease and cancer

将醌亚结构整合到组蛋白去乙酰化酶抑制剂中以应对阿尔茨海默病和癌症

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作者:Melissa Guardigni, Giulia Greco, Eleonora Poeta, Alan Santini, Elisa Tassinari, Christian Bergamini, Chiara Zalambani, Angela De Simone, Vincenza Andrisano, Elisa Uliassi, Barbara Monti, Maria Laura Bolognesi, Carmela Fimognari, Andrea Milelli

Abstract

Alzheimer's disease (AD) and cancer are among the most devastating diseases of the 21st century. Although the clinical manifestations are different and the cellular mechanisms underlying the pathologies are opposite, there are different classes of molecules that are effective in both diseases, such as quinone-based compounds and histone deacetylase inhibitors (HDACIs). Herein, we investigate the biological effects of a series of compounds built to exploit the beneficial effects of quinones and histone deacetylase inhibition (compounds 1-8). Among the different compounds, compound 6 turned out to be a potent cytotoxic agent in SH-SY5Y cancer cell line, with a half maximal inhibitory concentration (IC50) value lower than vorinostat and a pro-apoptotic activity. On the other hand, compound 8 was nontoxic up to the concentration of 100 μM and was highly effective in stimulating the proliferation of neural precursor cells (NPCs), as well as inducing differentiation into neurons, at low micromolar concentrations. In particular, it was able to induce NPC differentiation solely towards a neuronal-specific phenotype, without affecting glial cells commitment.

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