Vibhute Amol M, Pushpanandan Poornenth, Varghese Maria, Koniecnzy Vera, Taylor Colin W, Sureshan Kana M
School of Chemistry , Indian Institute of Science Education and Research Thiruvananthapuram , Kerala 695016 , India . Email:
Department of Pharmacology , University of Cambridge , Tennis Court Road , Cambridge , CB2 1PD , UK.
RSC Adv. 2016 Nov 3;6(89):86346-86351. doi: 10.1039/c6ra19413c. Epub 2016 Sep 5.
Inositol 1,4,5-trisphosphate receptors (IPRs) are tetrameric intracellular channels through which many extracellular stimuli initiate the Ca signals that regulate diverse cellular responses. There is considerable interest in developing novel ligands of IPR. Adenophostin A (AdA) is a potent agonist of IPR and since some dimeric analogs of IPR ligands are more potent than the corresponding monomer; we considered whether dimeric AdA analogs might provide agonists with increased potency. We previously synthesized traizolophostin, in which a simple triazole replaced the adenine of AdA, and showed it to be equipotent to AdA. Here, we used click chemistry to synthesize four homodimeric analogs of triazolophostin, connected by oligoethylene glycol chains of different lengths. We evaluated the potency of these analogs to release Ca through type 1 IPR and established that the newly synthesized dimers are equipotent to AdA and triazolophostin.
肌醇 1,4,5 - 三磷酸受体（IPRs）是四聚体细胞内通道，许多细胞外刺激通过该通道引发钙信号，从而调节多种细胞反应。开发新型 IPR 配体引起了人们的极大兴趣。腺嘌呤磷酯素 A（AdA）是 IPR 的一种强效激动剂，由于 IPR 配体的一些二聚体类似物比相应的单体更有效；我们考虑二聚体 AdA 类似物是否可能提供效力更高的激动剂。我们之前合成了三唑磷酯素，其中一个简单的三唑取代了 AdA 的腺嘌呤，并表明它与 AdA 效力相当。在此，我们使用点击化学合成了四种三唑磷酯素的同二聚体类似物，它们由不同长度的寡聚乙二醇链连接。我们评估了这些类似物通过 1 型 IPR 释放钙的效力，并确定新合成的二聚体与 AdA 和三唑磷酯素效力相当。
