Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg, 9, rue Edward Steichen, L-2540 Luxembourg, Luxembourg.
Department of Pharmacotherapy and Pharmaceutics, Faculté de Pharmacie, Université Libre de Bruxelles, Boulevard du Triomphe, 1050 Brussels, Belgium.
Molecules. 2018 Feb 5;23(2):333. doi: 10.3390/molecules23020333.
NAD⁺-dependent histone deacetylases (sirtuins) are implicated in cellular processes such as proliferation, DNA repair, and apoptosis by regulating gene expression and the functions of numerous proteins. Due to their key role in cells, the discovery of small molecule sirtuin modulators has been of significant interest for diverse therapeutic applications. In particular, it has been shown that inhibition of sirtuin 1 and 2 activities is beneficial for cancer treatment. Here, we demonstrate that the fungal metabolite eurochevalierine from the fungus inhibits sirtuin 1 and 2 activities (IC about 10 µM) without affecting sirtuin 3 activity. The binding modes of the eurochevalierine for sirtuin 1 and 2 have been identified through computational docking analyses. Accordingly, this sequiterpene alkaloid induces histone H4 and α-tubulin acetylation in various cancer cell models in which it induces strong cytostatic effects without affecting significantly the viability of healthy PBMCs. Importantly, eurochevalierine targets preferentially cancer cell proliferation (selectivity factor ≫ 7), as normal human primary CD34⁺ stem/progenitor cells were less affected by the treatment. Finally, eurochevalierine displays suitable drug-likeness parameters and therefore represent a promising scaffold for lead molecule optimization to study the mechanism and biological roles of sirtuins and potentially a basis for development into therapeutics.
NAD⁺依赖性组蛋白去乙酰化酶（sirtuins）通过调节基因表达和许多蛋白质的功能，参与细胞增殖、DNA 修复和细胞凋亡等细胞过程。由于它们在细胞中的关键作用，小分子 sirtuin 调节剂的发现对于各种治疗应用具有重要意义。特别是，已经表明抑制 sirtuin 1 和 2 的活性有益于癌症治疗。在这里，我们证明真菌代谢产物 eurochevalierine 抑制 sirtuin 1 和 2 的活性（IC 约为 10µM），而不影响 sirtuin 3 的活性。通过计算对接分析确定了 eurochevalierine 与 sirtuin 1 和 2 的结合模式。因此，这种倍半萜生物碱在各种癌细胞模型中诱导组蛋白 H4 和α-微管蛋白乙酰化，在不显著影响健康 PBMC 活力的情况下诱导强烈的细胞抑制作用。重要的是，eurochevalierine 优先靶向癌细胞增殖（选择性因子 ≫ 7），因为正常人类原代 CD34⁺干细胞/祖细胞受治疗的影响较小。最后，eurochevalierine 具有合适的类药性参数，因此代表了优化先导分子的有前途的支架，以研究 sirtuins 的机制和生物学作用，并可能为开发成为治疗剂奠定基础。
