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2'-deoxy cyclic adenosine 5'-diphosphate ribose derivatives: importance of the 2'-hydroxyl motif for the antagonistic activity of 8-substituted cADPR derivatives.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2008 Mar 27; Vol. 51 (6), pp. 1623-36. Date of Electronic Publication: 2008 Feb 28. - Publication Year :
- 2008
-
Abstract
- The structural features needed for antagonism at the cyclic ADP-ribose (cADPR) receptor are unclear. Chemoenzymatic syntheses of novel 8-substituted 2'-deoxy-cADPR analogues, including 8-bromo-2'-deoxy-cADPR 7, 8-amino-2'-deoxy-cADPR 8, 8- O-methyl-2'-deoxy-cADPR 9, 8-phenyl-2'-deoxy-cADPR 10 and its ribose counterpart 8-phenyl-cADPR 5 are reported, including improved syntheses of established antagonists 8-amino-cADPR 2 and 8-bromo-cADPR 3. Aplysia californica ADP-ribosyl cyclase tolerates even the bulky 8-phenyl-nicotinamide adenine 5'-dinucleotide as a substrate. Structure-activity relationships of 8-substituted cADPR analogues in both Jurkat T-lymphocytes and sea urchin egg homogenate (SUH) were investigated. 2'-OH Deletion decreased antagonistic activity (at least for the 8-amino series), showing it to be an important motif. Some 8-substituted 2'-deoxy analogues showed agonist activity at higher concentrations, among which 8-bromo-2'-deoxy-cADPR 7 was, unexpectedly, a weak but almost full agonist in SUH and was membrane-permeant in whole eggs. Classical antagonists 2 and 3 also showed previously unobserved agonist activity at higher concentrations in both systems. The 2'-OH group, without effect on the Ca (2+)-mobilizing ability of cADPR itself, is an important motif for the antagonistic activities of 8-substituted cADPR analogues.
- Subjects :
- Animals
Aplysia
Cyclic ADP-Ribose chemistry
Humans
Jurkat Cells
Lytechinus
Molecular Conformation
Ovum metabolism
Stereoisomerism
Structure-Activity Relationship
T-Lymphocytes metabolism
ADP-ribosyl Cyclase drug effects
Calcium metabolism
Cyclic ADP-Ribose analogs & derivatives
Cyclic ADP-Ribose pharmacology
Ovum drug effects
T-Lymphocytes drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 0022-2623
- Volume :
- 51
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 18303825
- Full Text :
- https://doi.org/10.1021/jm7010386