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 H 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 , in the order of magnitude of 10 m , thermodynamically driven by both enthalpy (ΔH=-6.79 kcal mol ) and entropy (TΔS=1.21 kcal mol ). 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, k , and the second step rate constant, k , during hydrogen/deuterium exchange in D O. Meanwhile, as expected, the reactivity of C2-hydrogen was also inhibited significantly, with an upshift of 2.09 pK 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.

Cucurbit[n]uril Host‐Guest Complexes of Acids, Photoacids, and Super Photoacids

“…With thiamine, the CB[7] binds over the ethylthiazolium group, while for the phosphate esters, the CB[7] shifts to binding the pyrimidine group. A related N‐phenylacylthiazolium molecule is alagebrium ( 19 ), which has been designed for the treatment of protein glycation, implicated in diseases such as diabetes, cancer and aging related diseases . This molecule undergoes both C(2)−H/D (thiazolium) and C(α)−H/D (phenylacyl) exchanges.…”

Cucurbit[7]uril: an emerging candidate for pharmaceutical excipients

“…Upon encapsulation, the stability of the guests was enhanced, as the C(2)‐H/D exchange rate constants were found to decrease by up to 25‐fold . Recently, we observed that CB[7] stabilized alagebrium, a thiazolium derivative and an advanced glycation end‐product (AGE) breaker (to break down glycation bonds), as demonstrated by nuclear magnetic resonance experiments showing that the second‐order rate constant for H/D exchange of alagebrium in D 2 O was decreased by two orders of magnitude and induced a p K a upshift of 2.09 units for the C(2)‐hydrogen of the thiazolium ring . Meanwhile, we observed that CB[7] was able to slow down keto–enol tautomerization and stabilize the carbonyl α‐hydrogen of alagebrium, as was shown by a decrease by over one order of magnitude for both the first‐step rate constant ( K 1 , 1.85 ± 0.09 × 10 –3 to 1.55 ± 0.08 × 10 –4 s –1 ) and the second‐step rate constant ( K 2 , 7.50 ± 0.37 × 10 –4 to 9.50 ± 0.48 × 10 –5 s –1 ) of the keto–enol tautomerism …”

“…44 Meanwhile, we observed that CB [7] was able to slow down ketoenol tautomerization and stabilize the carbonyl ␣hydrogen of alagebrium, as was shown by a decrease by over one order of magnitude for both the firststep rate constant (K 1 , 1.85 ± 0.09 × 10 -3 to 1.55 ± 0.08 × 10 -4 s -1 ) and the second-step rate constant (K 2 , 7.50 ± 0.37 × 10 -4 to 9.50 ± 0.48 × 10 -5 s -1 ) of the keto-enol tautomerism. 44 We continue to expand our efforts in screening the influence of CB [7] on a variety of other drug molecules that have limited stability.…”

Alleviation of Hepatotoxicity of Arecoline (Areca Alkaloid) by a Synthetic Receptor

“…With its superior solubility, well explored biocompatibility, and higher binding affinities with N ‐containing drug molecules than cyclodextrins (CDs), CB[7] (Scheme ) has been extensively investigated for its capacity to improve the physicochemical properties as well as to modulate the biological behaviors of a variety of N ‐containing active pharmaceutical ingredients (APIs) via host‐guest encapsulation , . Recently, our research group has discovered the capability of CB[7] to improve the stability of imidazolium/thiazolium based model drug molecules through encapsulation suppressed keto‐enol tautomerism of a carbonyl α‐hydrogen, and H‐bonding induced p K a shift of the C(2)‐hydrogen . Additionally, by employing in vitro cellular models and in vivo zebrafish models, we have demonstrated that CB[7] may enhance the bio‐uptake of a hydrophobic drug, coumarin‐6, reverse the general anaesthesia induced by tricaine, and inhibit the neurotoxic effects of MPTP/MPP + .…”