Details

Autor(en) / Beteiligte

• Vibhute, Amol M
• Konieczny, Vera
• Taylor, Colin W
• Sureshan, Kana M

Titel

Triazolophostins: a library of novel and potent agonists of IP3 receptorsElectronic supplementary information (ESI) available: Synthetic procedures and spectral data for all new compounds, crystal data for disaccharide 4 and details of the docking study. CCDC 1022279. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ob00440c

Erscheinungsjahr

2015-06

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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. IP 3 R initiate most cellular Ca 2+ signaling. AdA is the most potent agonist of IP 3 R. The structural complexity of AdA makes synthesis of its analogs cumbersome. We report an easy method for generating a library of potent triazole-based analogs of AdA, triazolophostins, which are the most potent AdA analogs devoid of a nucleobase.