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学科主题: 药学
题名:
Synthesis and biological evaluation of novel membrane-permeant cyclic ADP-ribose mimics: N-1-[(5 ′′-O-phosphorylethoxy)methyl]-5 ′-O-phosphorylinosine 5 ′,5 ′′-cyclicpyrophosphate (cIDPRE) and 8-substituted derivatives
作者: Gu, XF; Yang, Z; Zhang, L; Kunerth, S; Fliegert, R; Weber, K; Guse, AH; Zhang, L
刊名: JOURNAL OF MEDICINAL CHEMISTRY
发表日期: 2004-11-04
DOI: 10.1021/jm040092t
卷: 47, 期:23, 页:5674-5682
收录类别: SCI ; IC
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Chemistry, Medicinal
研究领域[WOS]: Pharmacology & Pharmacy
关键词[WOS]: INDUCED CA2+ RELEASE ; ADENOSINE-DIPHOSPHORIBOSE CADPR ; T-LYMPHOCYTES ; CARBOCYCLIC-RIBOSE ; DIPHOSPHATE-RIBOSE ; CALCIUM-RELEASE ; CELL-LINES ; RECEPTORS ; ANALOG ; POTENT
英文摘要:

N-1- [(5"-O-Phosphorylethoxy)methyl] -5′-O-phosphorylinosine 5′,5"-cyclicpyrophosphate (cIDPRE 2a) and the 8-substituted derivatives 8-bromo-, 8-azido-, 8-amino-, and 8-Cl-cIDPRE (2b-e) were synthesized from N1- [(5"-acetoxyethoxy)methyl] -2′,3′-O-isopropylideneinosine (5) in good yields. The pharmacological activities of cIDPRE and the 8-substituted derivatives (2a-e) were analyzed in intact and permeabilized. human Jurkat T-lymphocytes. The results indicate that cIDPRE permeates the plasma membrane, releases Ca2+ from an intracellular, cADPR-sensitive Ca2+ store, and subsequently initiates Ca2+ release-activated Ca2+ entry. The Ca2+-releasing activity of cIDPRE was confirmed directly in permeabilized. cells. Using time-resolved confocal Ca2+ imaging at the single cell level, the development of global Ca2+ signals starting from local small Ca2+ signals evoked by cIDPRE was observed. 8-N-3-cIDPRE 2c and 8-NH2-cIDPRE 2d were similarly effective in their agonistic activity as compared to cIDPRE 2a, showing almost indistinguishable concentration-response curves for 2a, 2c, and 2d and very similar kinetics of Ca2+ signaling. In contrast, the halogenated derivatives 8-Br- and 8-Cl-cIDPRE (2b and 2e) did not significantly elevate [Ca2+](i). Therefore, cIDPRE 2a, 8-N-3-cIDPRE 2c, and 8-NH2-cIDPRE 2d are novel membrane permeant cADPR mimic and may provide important novel tools to study cADPR-mediated Ca2+ signaling in intact cells.

语种: 英语
WOS记录号: WOS:000224841600013
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/64407
Appears in Collections:北京大学药学院_期刊论文

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作者单位: 1.Peking Univ, Sch Pharmaceut Sci, Natl Lab Nat & Biomimet Drugs, Beijing 100083, Peoples R China
2.Univ Hamburg, Hosp Eppendorf, Ctr Med Expt, Inst Biochem & Mol Biol 1, D-20246 Hamburg, Germany

Recommended Citation:
Gu, XF,Yang, Z,Zhang, L,et al. Synthesis and biological evaluation of novel membrane-permeant cyclic ADP-ribose mimics: N-1-[(5 ′′-O-phosphorylethoxy)methyl]-5 ′-O-phosphorylinosine 5 ′,5 ′′-cyclicpyrophosphate (cIDPRE) and 8-substituted derivatives[J]. JOURNAL OF MEDICINAL CHEMISTRY,2004,47(23):5674-5682.
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