92267-23-7Relevant articles and documents
2′-deoxy cyclic adenosine 5′-diphosphate ribose derivatives: Importance of the 2′-hydroxyl motif for the antagonistic activity of 8-substituted cADPR derivatives
Zhang, Bo,Wagner, Gerd K.,Weber, Karin,Garnham, Clive,Morgan, Anthony J.,Galione, Antony,Guse, Andreas H.,Potter, Barry V. L.
, p. 1623 - 1636 (2008/09/20)
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.
