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

Abstract

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, Ka, in the order of magnitude of 105 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 pKa 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. Show more