Organic & Biomolecular Chemistry
It is shown that a triazole ring can replace adenine without compromising the potency of AdA and provide facile routes to novel AdA analogs.
Abstract
IP 3 receptors are channels that mediate the release of Ca 2+ from the intracellular stores of cells stimulated by hormones or neurotransmitters. Adenophostin A (AdA) is the most potent agonist of IP 3 receptors, with the β -anomeric adenine contributing to the increased potency. The potency of AdA and its stability towards the enzymes that degrade IP 3 have aroused interest in AdA analogs for biological studies. The complex structure of AdA poses problems that have necessitated optimization of synthetic conditions for each analog. Such lengthy one-at-a-time syntheses limit access to AdA analogs. We have addressed this problem by synthesizing a library of triazole-based AdA analogs, triazolophostins, by employing click chemistry. An advanced intermediate having all the necessary phosphates and a β -azide at the anomeric position was reacted with various alkynes under Cu( I ) catalysis to yield triazoles, which upon deprotection gave triazolophostins. All eleven triazolophostins synthesized are more potent than IP 3 and some are equipotent with AdA in functional analyses of IP 3 receptors. We show that a triazole ring can replace adenine without compromising the potency of AdA and provide facile routes to novel AdA analogs. ( 31 P coupled, ipso carbons of POCH 2 Ph); 31 P NMR (202.4 MHz, CDCl − 1.49, − 1.920, − 2.092; 19 F NMR (470.68 MHz, CDCl 113.585; Anal. for C 82 H 81 FN 3 O 18 P 3 C, 65.29; H, 5.41; N, 2.79. Found: C, 64.98; H, 5.11; N, 2.93.