Zwick Vincent, Simões-Pires Claudia A, Nurisso Alessandra, Petit Charlotte, Dos Santos Passos Carolina, Randazzo Giuseppe Marco, Martinet Nadine, Bertrand Philippe, Cuendet Muriel
School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Rue Michel Servet 1, CH-1211 Geneva 4, Switzerland.
School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Rue Michel Servet 1, CH-1211 Geneva 4, Switzerland; Département de Biochimie, Université de Montréal, H3C 3J7 Montréal, Québec, Canada.
Bioorg Med Chem Lett. 2016 Oct 15;26(20):4955-4959. doi: 10.1016/j.bmcl.2016.09.011. Epub 2016 Sep 7.
In recent years, the role of HDAC6 in neurodegeneration has been partially elucidated, which led some authors to propose HDAC6 inhibitors as a therapeutic strategy to treat neurodegenerative diseases. In an effort to develop a selective HDAC6 inhibitor which can cross the blood brain barrier (BBB), a modified hydroxamate derivative (compound 3) was designed and synthetized. This compound was predicted to have potential for BBB penetration based on in silico and in vitro evaluation of passive permeability. When tested for its HDAC inhibitory activity, the IC value of compound 3 towards HDAC6 was in the nM range in both enzymatic and cell-based assays. Compound 3 showed a cell-based selectivity profile close to that of tubastatin A in SH-SY5Y human neuroblastoma cells, and a good BBB permeability profile.
近年来，HDAC6在神经退行性变中的作用已得到部分阐明，这使得一些作者提出将HDAC6抑制剂作为治疗神经退行性疾病的一种治疗策略。为了开发一种能够穿过血脑屏障（BBB）的选择性HDAC6抑制剂，设计并合成了一种修饰的异羟肟酸衍生物（化合物3）。基于计算机模拟和被动通透性的体外评估，预测该化合物具有BBB穿透潜力。在测试其HDAC抑制活性时，化合物3在酶法和基于细胞的实验中对HDAC6的IC值均在纳摩尔范围内。在SH-SY5Y人神经母细胞瘤细胞中，化合物3表现出与tubastatin A相近的基于细胞的选择性特征，以及良好的BBB通透性特征。
