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Cellular effects and metabolic stability of N 1‐cyclic inosine diphosphoribose and its derivatives
Author(s) -
Kirchberger T,
Wagner G,
Xu J,
Cordiglieri C,
Wang P,
Gasser A,
Fliegert R,
Bruhn S,
Flügel A,
Lund F E,
Zhang Lh,
Potter B V L,
Guse A H
Publication year - 2006
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0706869
Subject(s) - inosine , cyclase , cd38 , nad+ kinase , chemistry , biochemistry , hypoxanthine , adenosine , second messenger system , stereochemistry , cyclic adp ribose , adenylate kinase , intracellular , biology , enzyme , microbiology and biotechnology , stem cell , cd34
Background and purpose: Recently, a number of mimics of the second messenger cyclic ADP‐ribose (cADPR) with replacement of adenosine by inosine were introduced. In addition, various alterations in the molecule ranging from substitutions at C8 of the base up to full replacement of the ribose moieties still retained biological activity. However, nothing is known about the metabolic stability and cellular effects of these novel analogues. Experimental approach: cADPR and the inosine‐based analogues were incubated with CD38, ADP‐ribosyl cyclase and NAD‐glycohydrolase and metabolism was analysed by RP‐HPLC. Furthermore, the effect of the analogues on cytokine expression and proliferation was investigated in primary T‐lymphocytes and T‐lymphoma cells. Key results: Incubation of cADPR with CD38 resulted in degradation to adenosine diphosphoribose. ADP‐ribosyl cyclase weakly catabolised cADPR whereas NAD‐glycohydrolase showed no such activity. In contrast, N 1‐cyclic inosine 5′‐diphosphoribose (N 1‐cIDPR) was not hydrolyzed by CD38. Three additional N 1‐cIDPR analogues showed a similar stability. Proliferation of Jurkat T‐lymphoma cells was inhibited by N 1‐cIDPR, N 1‐[(phosphoryl‐ O ‐ethoxy)‐methyl]‐ N 9‐[(phosphoryl‐ O ‐ethoxy)‐methyl]‐hypoxanthine‐cyclic pyrophosphate ( N 1‐cIDP‐DE) and N 1‐ethoxymethyl‐cIDPR ( N 1‐cIDPRE). In contrast, in primary T cells neither proliferation nor cytokine expression was affected by these compounds. Conclusions and Implications: The metabolic stability of N 1‐cIDPR and its analogues provides an advantage for the development of novel pharmaceutical compounds interfering with cADPR mediated Ca 2+ signalling pathways. The differential effects of N 1‐cIDPR and N 1‐cIDPRE on proliferation and cytokine expression in primary T cells versus T‐lymphoma cells may constitute a starting point for novel anti‐tumor drugs. British Journal of Pharmacology (2006) 149 , 337–344. doi: 10.1038/sj.bjp.0706869