氟代烟酰胺核苷磷酸酯的一釜合成.docVIP

  氟代烟酰胺核苷磷酸酯的一釜合成# 陈哲，杨振军，张亮仁，张礼和** （北京大学 药学院 天然药物及仿生药物国家重点实验室） 5 10 15 20 25 30 35 40 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。 关键词：药物化学；化学合成；氟代 NAD 类似物；烟酰胺核苷磷酸酯；一釜合成 中图分类号：R914 One-pot synthesis of fluoro-substituted nicotinamide CHEN Zhe, YANG Zhenjun, ZHANG Liangren, ZHANG Lihe (State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China) Abstract: Fluoro-substituted nucleotides are potent CD 38 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, 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 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. Key words: chemical synthesis; fluoro-substituted NAD analogue; nicotinamide nucleoside phosphate; one-pot synthesis 0 引言 烟酰胺腺嘌呤二核苷酸（NAD）及其类似物具有广泛的药理和生物活性，在治疗药物 的发现过程中起着非常重要的作用。如噻唑-4-甲酰胺腺嘌呤二核苷酸、苯甲酰胺腺嘌呤二 核苷酸和麦考酚酸腺嘌呤二核苷酸等是有效的黄嘌呤单核苷酸脱氢酶抑制剂[1-3]；烟酰胺次 黄嘌呤二核苷酸和烟酰胺鸟嘌呤二核苷酸是有效的ADP-核糖基环化酶抑制剂[4]；烟酰胺核 苷磷酸二酯能促进微生物细胞的生长[5]。其他类似物，如2?-氟代烟酰胺核苷酸（1a, 1b, 图1） 及其衍生物对CD38的水解活性具有较强的抑制作用，是研究CD38生物功能的重要工具药物 [6-