Article: Synthesis and biological evaluation of nicotinamide adenine dinucleotides analogues as inhibitors of CD38

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TitleSynthesis and biological evaluation of nicotinamide adenine dinucleotides analogues as inhibitors of CD38
AuthorsChen, Z2
Kwong, AKY1
Yang, ZJ2
Zhang, LR2
Lee, HC1
Zhang, LH2
KeywordsBiological Activity
Cd38 Inhibitor
Fluoro-Substituted Nad Analogue
Nicotinamide Adenine Dinucleotides(Nad)
Issue Date2012
PublisherJilin Daxue. The Journal's web site is located at http://www.cjcu.jlu.edu.cn/
CitationGaodeng Xuexiao Huaxue Xuebao/Chemical Journal Of Chinese Universities, 2012, v. 33 n. 6, p. 1226-1232 [How to Cite?]
DOI: http://dx.doi.org/10.3969/j.issn.0251-0790.2012.06.018
AbstractCD38 is the main mammalian ADP-ribosyl cyclase and a signaling enzyme responsible for catalyzing the synthesis of Ca 2+-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 nicotina-mide 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 nicoti-namide, 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 IC 50 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.
ISSN0251-0790
2011 Impact Factor: 0.619
2011 SCImago Journal Rankings: 0.039
DOIhttp://dx.doi.org/10.3969/j.issn.0251-0790.2012.06.018
ReferencesReferences in Scopus
DC Field
Value
dc.contributor.authorChen, Z
dc.contributor.authorKwong, AKY
dc.contributor.authorYang, ZJ
dc.contributor.authorZhang, LR
dc.contributor.authorLee, HC
dc.contributor.authorZhang, LH
dc.date.accessioned2012-10-30T06:17:10Z
dc.date.available2012-10-30T06:17:10Z
dc.date.issued2012
dc.description.abstractCD38 is the main mammalian ADP-ribosyl cyclase and a signaling enzyme responsible for catalyzing the synthesis of Ca 2+-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 nicotina-mide 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 nicoti-namide, 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 IC 50 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.
dc.description.natureLink_to_subscribed_fulltext
dc.identifier.citationGaodeng Xuexiao Huaxue Xuebao/Chemical Journal Of Chinese Universities, 2012, v. 33 n. 6, p. 1226-1232 [How to Cite?]
DOI: http://dx.doi.org/10.3969/j.issn.0251-0790.2012.06.018
dc.identifier.doihttp://dx.doi.org/10.3969/j.issn.0251-0790.2012.06.018
dc.identifier.epage1232
dc.identifier.issn0251-0790
2011 Impact Factor: 0.619
2011 SCImago Journal Rankings: 0.039
dc.identifier.issue6
dc.identifier.scopuseid_2-s2.0-84864385576
dc.identifier.spage1226
dc.identifier.urihttp://hdl.handle.net/10722/171795
dc.identifier.volume33
dc.languageeng
dc.publisherJilin Daxue. The Journal's web site is located at http://www.cjcu.jlu.edu.cn/
dc.publisher.placeChina
dc.relation.ispartofGaodeng Xuexiao Huaxue Xuebao/Chemical Journal of Chinese Universities
dc.relation.referencesReferences in Scopus
dc.subjectBiological Activity
dc.subjectCd38 Inhibitor
dc.subjectFluoro-Substituted Nad Analogue
dc.subjectNicotinamide Adenine Dinucleotides(Nad)
dc.titleSynthesis and biological evaluation of nicotinamide adenine dinucleotides analogues as inhibitors of CD38
dc.typeArticle
Author Affiliations
  1. The University of Hong Kong
  2. Peking University