Encapsulation of AGE-Breaker Alagebrium by Cucurbit[7]uril Improved the Stability of Both Its Carbonyl α-Hydrogen and Thiazolium C2-Hydrogen.
As determined by both1H 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 105m-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 pKaunits. 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.
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macau, P.R. China.
Shengke
S
Li
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macau, P.R. China.|Key Laboratory for Organic Electronics and Information Displays, Institute of Advanced Materials, Nanjing University of Posts & Telecommunications, 9 Wenyuan Road, Nanjing, 210046, P.R China.
Yuan-Fu
YF
Ding
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macau, P.R. China.
Hang
H
Yin
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macau, P.R. China.
Chunming
C
Wang
Aix Marseille Univ, CNRS, ICR, Marseille, France.
David
D
Bardelang
Key Laboratory for Organic Electronics and Information Displays, Institute of Advanced Materials, Nanjing University of Posts & Telecommunications, 9 Wenyuan Road, Nanjing, 210046, P.R China.
Lian-Hui
LH
Wang
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macau, P.R. China.
Ruibing
http://orcid.org/0000-0001-9489-4241
R
Wang
cucurbiturils; deuterium; host-guest systems; kinetics; tautomerism