Cachatra Vasco, Oliveira Maria Conceição, Lopez Oscar, Fernandez-Bolaños José G, Rauter Amélia Pilar
Centro de Química Estrutural, Institute of Molecular Sciences, Faculdade de Ciências, Universidade de Lisboa, 1749- 016 Lisboa, Portugal.
Centro de Química Estrutural, Instituto Superior Técnico, Mass Spectrometry Facility, 1049-001 Lisboa, Portugal.
Med Chem. 2023;19(3):263-275. doi: 10.2174/1871520622666220527150712.
A new family of purine nucleoside cholinesterase inhibitors was disclosed by us, with potency and selectivity over acetylcholinesterase or butyrylcholinesterase controlled by tuning structural and stereochemical features of nucleosides with perbenzylated glycosyl moieties.
Design, synthesis, and biological evaluation of new purine nucleosides were used to investigate glycon protecting group pattern required for anticholinesterase activity and selectivity.
Regioselective chemistry to introduce methyl/benzyl groups in glycon donors and Nglycosylation was used to acquire the target nucleosides. Evaluation of their biological potential and selectivity as cholinesterase inhibitors was performed.
Synthetic strategies chosen resulted in high glycon donor's overall yield and regio- and stereoselectivity was found in N-glycosylation reaction. Some of the new nucleosides are cholinesterase inhibitors and selectivity for butyrylcholinesterase was also achieved.
N-glycosylation reaction was stereoselective for the β-anomers while regioselectivity was achieved for the N isomers when glycon positions 2 and 3 were methylated. Cholinesterase inhibition was found when the 2,3-di-O-benzyl-4-O-methyl pattern is present in the sugar moiety. Amongst the new compounds, the two most promising ones showed micromolar inhibition (mixed inhibition), being one of them selective for butyrylcholinesterase inhibition.
我们公开了一类新的嘌呤核苷胆碱酯酶抑制剂，通过调整具有全苄基化糖基部分的核苷的结构和立体化学特征来控制其对乙酰胆碱酯酶或丁酰胆碱酯酶的效力和选择性。
通过设计、合成和生物学评价新的嘌呤核苷，研究抗胆碱酯酶活性和选择性所需的糖基保护基模式。
利用区域选择性化学方法在糖基供体中引入甲基/苄基，并进行N-糖基化反应以获得目标核苷。对它们作为胆碱酯酶抑制剂的生物学潜力和选择性进行了评价。
所选择的合成策略使糖基供体的总产率较高，并且在N-糖基化反应中发现了区域和立体选择性。一些新核苷是胆碱酯酶抑制剂，并且还实现了对丁酰胆碱酯酶的选择性。
当糖基位置2和3甲基化时，N-糖基化反应对β-异头物具有立体选择性，对N-异构体具有区域选择性。当糖部分存在2,3-二-O-苄基-4-O-甲基模式时，发现有胆碱酯酶抑制作用。在新化合物中，最有前景的两种化合物表现出微摩尔级抑制（混合抑制），其中一种对丁酰胆碱酯酶抑制具有选择性。
