Centro de Química e Bioquímica/Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Campo Grande, Ed. C8, Piso 5, 1749-016 Lisboa, Portugal.
Org Biomol Chem. 2014 Apr 21;12(15):2446-56. doi: 10.1039/c4ob00142g.
Alzheimer's disease (AD), the most common form of senile dementia, is characterized by high butyrylcholinesterase (BChE) levels in the brain in later AD stages, for which no treatment is available. Pursuing our studies on selective BChE inhibitors, that may contribute to understand the role of this enzyme in disease progression, we present now microwave-assisted synthesis and anticholinesterase activity of a new nucleoside series embodying 6-chloropurine or 2-acetamido-6-chloropurine linked to D-glucosyl, D-galactosyl and D-mannosyl residues. It was designed to assess the contribution of sugar stereochemistry, purine structure and linkage to the sugar for cholinesterase inhibition efficiency and selectivity. Compounds were subjected to Ellman's assay and their inhibition constants determined. The α-anomers were the most active compounds, while selectivity for BChE or acetylcholinesterase (AChE) inhibition could be tuned by the purine base, by the glycosyl moiety and by N(7)-ligation. Some of the nucleosides were far more potent than the drug galantamine, and the most promising competitive and selective BChE inhibitor, the N(7)-linked 2-acetamido-α-D-mannosylpurine, showed a Ki of 50 nM and a selectivity factor of 340 fold for BChE over AChE.
阿尔茨海默病（AD）是最常见的老年痴呆症形式，其特征是在 AD 后期大脑中丁酸酯酶（BChE）水平较高，但目前尚无治疗方法。在我们对选择性 BChE 抑制剂的研究中，我们发现这种酶可能与疾病的发展有关，因此我们提出了一种新的核苷系列，该系列包含与 D-葡萄糖基、D-半乳糖基和 D-甘露糖基相连的 6-氯嘌呤或 2-乙酰氨基-6-氯嘌呤，用于评估糖立体化学、嘌呤结构和与糖的连接对胆碱酯酶抑制效率和选择性的贡献。化合物进行了 Ellman 测定，确定了它们的抑制常数。α-异构体是最活跃的化合物，而对 BChE 或乙酰胆碱酯酶（AChE）抑制的选择性可以通过嘌呤碱基、糖基部分和 N(7)-连接来调节。一些核苷比药物加兰他敏更有效，而最有前途的竞争性和选择性 BChE 抑制剂，即 N(7)-连接的 2-乙酰氨基-α-D-甘露糖基嘌呤，对 BChE 的 Ki 值为 50 nM，对 AChE 的选择性因子为 340 倍。
