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Synthesis and Biological Evaluation of Nicotinamide Adenine Dinucleotides Analogues as Inhibitors of CD38
Chen Zhe1; Kwong Anna Ka-Yee2; Yang Zhen-Jun1; Zhang Liang-Ren1; Lee Hon Cheung2; Zhang Li-He1
关键词Nicotinamide Adenine Dinucleotides(Nad) Fluoro-substituted Nad Analogue Cd38 Inhibitor Biological Activity
刊名CHEMICAL JOURNAL OF CHINESE UNIVERSITIES-CHINESE
2012-06-10
DOI10.3969/j.issn.0251-0790.2012.06.018
33期:6页:1226-1232
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Chemistry, Multidisciplinary
研究领域[WOS]Chemistry
关键词[WOS]INOSINE MONOPHOSPHATE DEHYDROGENASE ; MEDICINAL CHEMISTRY ; RIBOSE ; FLUORINE ; NAD(+) ; CYCLIZATION ; SUBSTRATE ; DESIGN
英文摘要

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 IC50 of 0.056 mu mol/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.

语种中文
WOS记录号WOS:000305819100018
引用统计
被引频次:2[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/57080
专题北京大学药学院
作者单位1.Peking Univ, State Key Lab Nat & Biomimet Drugs, Sch Pharmaceut Sci, Beijing 100191, Peoples R China
2.Univ Hong Kong, Dept Physiol, Hong Kong, Hong Kong, Peoples R China
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Chen Zhe,Kwong Anna Ka-Yee,Yang Zhen-Jun,et al. Synthesis and Biological Evaluation of Nicotinamide Adenine Dinucleotides Analogues as Inhibitors of CD38[J]. CHEMICAL JOURNAL OF CHINESE UNIVERSITIES-CHINESE,2012,33(6):1226-1232.
APA Chen Zhe,Kwong Anna Ka-Yee,Yang Zhen-Jun,Zhang Liang-Ren,Lee Hon Cheung,&Zhang Li-He.(2012).Synthesis and Biological Evaluation of Nicotinamide Adenine Dinucleotides Analogues as Inhibitors of CD38.CHEMICAL JOURNAL OF CHINESE UNIVERSITIES-CHINESE,33(6),1226-1232.
MLA Chen Zhe,et al."Synthesis and Biological Evaluation of Nicotinamide Adenine Dinucleotides Analogues as Inhibitors of CD38".CHEMICAL JOURNAL OF CHINESE UNIVERSITIES-CHINESE 33.6(2012):1226-1232.
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