氟代烟酰胺核苷磷酸酯的一釜合成  

One-pot synthesis of fluoro-substituted nicotinamide nucleoside phosphates

作　　者：陈哲[1] 杨振军[1] 张亮仁[1] 张礼和[1] 

机构地区：[1]北京大学药学院天然药物与仿生药物国家重点实验室,北京100191

出　　处：《中国药物化学杂志》2012年第2期104-112,共9页Chinese Journal of Medicinal Chemistry

基　　金：国家自然科学基金项目(90713005,209100,9481172917)

摘　　要：目的改进氟代烟酰胺核苷单磷酸酯(1a,ara-F NMN)的合成方法并合成一系列新的氟代烟酰胺核苷磷酸酯。方法以氟代糖3为原料,经溴代、去保护和单磷酸化反应得到ara-F NMN。以烟酰胺核苷6为关键中间体,经磷酸化和酯化反应的一釜合成,得到系列氟代烟酰胺核苷磷酸二酯、磷酸三酯和硫代磷酸二酯。结果与结论优化了合成方法并对新化合物的结构进行了确证。Fluoro-substituted nucleotides（1a,1b） are potent CD38 inhibitors.However,they display poor permeability and less resistant to hydrolysis.It is of great interest to develop specific and generally applicable inhibitors of CD38 with membrane permeability,as well as improved anti-hydrolysis ability.In this study,a new class of fluoro-substituted nicotinamide nucleoside phosphates（1c,2）,including phosphodiesters,thiophosphodiesters and phosphotriesters,has been synthesized from nicotinamide nucleoside 6 by a one-pot reaction of phosphorylation and esterification.All target compounds were characterized by NMR and HRMS.The synthesis of ara-F NMN（1a） has also been improved,in which the synthesis was performed by starting from the corresponding fluoro-substituted sugar 3,then followed by bromination with HBr,coupling with nicotinamide,deprotection with K2CO3/MeOH and monophosphorylation with POCl3,successively.The detailed biological investigation and structure-activity relationship of these novel NAD analogues are underway.

关 键 词：化学合成 氟代NAD类似物 烟酰胺核苷磷酸酯 一釜合成 

分 类 号：R914[医药卫生—药物化学]