He Liu, Boice Ashley, Liu Kai, Yan Xing, Jiang Yuqi, Zhang Shijun
Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA, USA.
Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA, USA.
Bioorg Med Chem Lett. 2018 Apr 1;28(6):1030-1036. doi: 10.1016/j.bmcl.2018.02.028. Epub 2018 Feb 14.
In our continuing efforts to develop bivalent compounds as potential neuroprotectants for Alzheimer's disease, a series of bivalent compounds that contain cholesterylamine and an extended spacer were synthesized and biologically characterized. Our results demonstrated that incorporation of a piperazine ring into the spacer composition significantly improved the protective potency in MC65 cell models. Our results also suggested that the optimal spacer length for such bivalent compounds ranges from 17 to 21 atoms, and further spacer extension beyond 21 atoms results no further optimization. Notably, incorporation of a piperazine ring into the spacer diminished the biometal chelating capacity for these bivalent compounds, thus suggesting structural flexibility of these compounds in interactions with metals. Collectively, the results provided valuable guidance to develop new bivalent compounds as neuroprotectants for Alzheimer's disease.
在我们持续努力开发作为阿尔茨海默病潜在神经保护剂的二价化合物的过程中，合成了一系列含有胆固醇胺和延长间隔基的二价化合物，并对其进行了生物学表征。我们的结果表明，在间隔基组成中引入哌嗪环可显著提高在MC65细胞模型中的保护效力。我们的结果还表明，此类二价化合物的最佳间隔基长度为17至21个原子，间隔基长度超过21个原子不会带来进一步优化。值得注意的是，在间隔基中引入哌嗪环降低了这些二价化合物的生物金属螯合能力，从而表明这些化合物在与金属相互作用时具有结构灵活性。总体而言，这些结果为开发新型二价化合物作为阿尔茨海默病的神经保护剂提供了有价值的指导。
