烟酰胺腺嘌呤二核苷酸类CD38抑制剂的合成及生物活性评价  

Synthesis and Biological Evaluation of Nicotinamide Adenine Dinucleotides Analogues as Inhibitors of CD38

作　　者：陈哲[1] KWONG Anna Ka-Yee 杨振军[1] 张亮仁[1] LEE Hon Cheung 张礼和[1] 

机构地区：[1]北京大学天然药物与仿生药物国家重点实验室,北京100191 [2]香港大学医学院生理系

出　　处：《高等学校化学学报》2012年第6期1226-1232,共7页Chemical Journal of Chinese Universities

基　　金：国家自然科学基金(批准号:90713005;20910094)资助

摘　　要：分别以1,3,5-三苯甲酰基-α-D-核糖、3,5-二苯甲酰基-2-脱氧-2,2-二氟戊呋喃糖-1-酮和D-木糖为原料,经由烟酰胺核苷及烟酰胺核苷酸中间体,合成了系列糖环经氟原子取代的烟酰胺腺嘌呤二核苷酸(NAD)类CD38抑制剂.基于对CD38的水解抑制能力的考察,评价了所合成氟代NAD类似物的活性.结果表明,糖环上氟原子取代的数目和位置对抑制剂活性的影响十分明显,烟酰胺核苷的端基构型对活性的影响较大.2个化合物均显示出非常好的CD38抑制活性,其中化合物2a的抑制活性高出阳性对照物阿糖型氟代烟酰胺腺嘌呤二核苷酸2个数量级.CD38 is the main mammalian ADP-ribosyl cyclase and a signaling enzyme responsible for catalyzing the synthesis of Ca2＋-messengers and plays a critical role in a wide range of physiological functions. It is of great interest to develop specific and generally applicable inhibitors of CD38. Fluoro-substituted nicotinamide adenine dinucleotides （NAD）, such as ara-F NMN and ara-F NAD, are catalysis-dependent inhibitors of CD38 and are often used as probes for investigating the function of CD38. For understanding the effect of fluoro-substitution on activity in more detail and discovery of active inhibitors of CD38, compounds 2a--2c were synthesized and their inhibition against the hydrolysis activities of CD38 were evaluated. The syntheses were performed by starting from the corresponding fluoro-substituted sugar, then followed by coupling with nicotinamide, regio-selective 5＇-phosphorylation and condensation with adenosine monophosphate, successively. All target compounds were purified by HPLC and characterized by NMR and HRMS. Two compounds showed strong inhibitions, especially 2＇-deoxy-2＇-fluororibonofuranosyl which gave activity with ICs0 of 0. 056 μmol/L and was two orders of magnitude higher than positive control ara-F NAD. The results also showed that the activity was greatly affected by the number and the position of fluorine atom on the sugar ring, as well as the configuration of the inhibitors. The detailed biological investigation and structure-activity relationship are underway.

关 键 词：烟酰胺腺嘌呤二核苷酸 氟代NAD类似物 CD38抑制剂 生物活性 

分 类 号：O621[理学—有机化学]