Design, Synthesis, and Biological Evaluation of Novel Cyclic Adenosine-Inosine Monophosphate (cAIMP) Analogs That Activate Stimulator of Interferon Genes (STING).

التفاصيل البيبلوغرافية
العنوان:	Design, Synthesis, and Biological Evaluation of Novel Cyclic Adenosine-Inosine Monophosphate (cAIMP) Analogs That Activate Stimulator of Interferon Genes (STING).
المؤلفون:	Lioux T; InvivoGen , 5 Rue Jean Rodier, 31400 Toulouse, France., Mauny MA; InvivoGen , 5 Rue Jean Rodier, 31400 Toulouse, France., Lamoureux A; InvivoGen , 5 Rue Jean Rodier, 31400 Toulouse, France., Bascoul N; InvivoGen , 5 Rue Jean Rodier, 31400 Toulouse, France., Hays M; InvivoGen , 5 Rue Jean Rodier, 31400 Toulouse, France., Vernejoul F; InvivoGen , 5 Rue Jean Rodier, 31400 Toulouse, France., Baudru AS; InvivoGen , 5 Rue Jean Rodier, 31400 Toulouse, France., Boularan C; InvivoGen , 5 Rue Jean Rodier, 31400 Toulouse, France., Lopes-Vicente J; InvivoGen , 5 Rue Jean Rodier, 31400 Toulouse, France., Qushair G; InvivoGen , 5 Rue Jean Rodier, 31400 Toulouse, France., Tiraby G; InvivoGen , 5 Rue Jean Rodier, 31400 Toulouse, France.
المصدر:	Journal of medicinal chemistry [J Med Chem] 2016 Nov 23; Vol. 59 (22), pp. 10253-10267. Date of Electronic Publication: 2016 Nov 04.
نوع المنشور:	Journal Article; Research Support, Non-U.S. Gov't
اللغة:	English
بيانات الدورية:	Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE
أسماء مطبوعة:	Publication: Washington Dc : American Chemical Society Original Publication: [Easton, Pa.] : American Chemical Society, [c1963-
مواضيع طبية MeSH:	Drug Design, Adenosine/pharmacology , Cyclic IMP/pharmacology , Cytokines/metabolism , Interferon Type I/*metabolism, Adenosine/chemical synthesis ; Adenosine/chemistry ; Animals ; Cell Line ; Cyclic IMP/chemical synthesis ; Cyclic IMP/chemistry ; Dose-Response Relationship, Drug ; Humans ; Mice ; Molecular Structure ; Structure-Activity Relationship
مستخلص:	We describe novel STING-activating cyclic dinucleotides whose constituent nucleosides are adenosine and inosine and that vary by ribose substitution, internucleotide linkage position, and phosphate modification. In mammalian cells in vitro, some of these cAIMP analogs induce greater STING-dependent IRF and NF-κB pathway signaling than do the reference agonists for murine (DMXAA) or human (2',3'-cGAMP) STING. In human blood ex vivo, they induce type I interferons (IFNs) and proinflammatory cytokines: for the former, 3',3'-cAIMP (9; EC 50 of 6.4 μM) and analogs 52-56 (EC 50 of 0.4-4.7 μM), which contain one or two 2'-fluoro-2'-deoxyriboses and/or bis-phosphorothioate linkages, are more potent than 2',3'-cGAMP (EC 50 of 19.6 μM). Interestingly, 9 induces type I IFNs more strongly than do its linkage isomers 2',3'-cAIMP (10), 3',2'-cAIMP (23), and 2',2'-cAIMP (27). Lastly, some of the cAIMP analogs are more resistant than 2',3'-cGAMP to enzymatic cleavage in vitro. We hope to exploit our findings to develop STING-targeted immunotherapies.
المشرفين على المادة:	0 (Cytokines) 0 (Interferon Type I) 3545-76-4 (Cyclic IMP) K72T3FS567 (Adenosine)
تواريخ الأحداث:	Date Created: 20161027 Date Completed: 20170613 Latest Revision: 20180914
رمز التحديث:	20231215
DOI:	10.1021/acs.jmedchem.6b01300
PMID:	27783523
قاعدة البيانات:	MEDLINE

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تدمد:	1520-4804
DOI:	10.1021/acs.jmedchem.6b01300