Encapsulation of AGE-Breaker Alagebrium by Cucurbit[7]uril Improved the Stability of Both Its Carbonyl α-Hydrogen and Thiazolium C2-Hydrogen

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• 作者：Shengke Li ; Yuan-Fu Ding ; Hang Yin ; Prof. Chunming Wang ; Dr. David Bardelang ; Prof. Lian-Hui Wang and Prof. Ruibing Wang
• 刊名：Chemistry – An Asian Journal
• 出版年：2016
• 出版时间：November 7, 2016
• 年：2016
• 卷：11
• 期：21
• 页码：3126-3133
• 全文大小：1344K
• ISSN：1861-471X

文摘

As determined by both ¹H NMR and UV/Vis spectroscopic titration, ESI-MS, isothermal titration calorimetry, and DFT molecular modeling, advanced glycation end products (AGE) breaker alagebrium (ALA) formed 1:1 guest–host inclusion complexes with cucurbit[7]uril (CB[7]), with a binding affinity, K_a, in the order of magnitude of 10⁵ lass="smallCaps">m⁻¹, thermodynamically driven by both enthalpy (ΔH=−6.79 kcal mol⁻¹) and entropy (TΔS=1.21 kcal mol⁻¹). For the first time, a dramatic inhibition of keto–enol tautomerism of the carbonyl α-hydrogen of ALA has been observed, as evidenced by over an order of magnitude decrease of both the first step rate constant, k₁, and the second step rate constant, k₂, during hydrogen/deuterium exchange in D₂O. Meanwhile, as expected, the reactivity of C2-hydrogen was also inhibited significantly, with an upshift of 2.09 pK_a units. This discovery will not only provide an emerging host molecule to modulate keto–enol tautomerism, but also potentially lead to a novel supramolecular formulation of AGE-breaker ALA for improved stability and therapeutic efficacy.