Novel isosorbide-based substrates for human butyrylcholinesterase

Gilmer, John F.; Lally, Maeve N.; Gardiner, P.; Dillon, Gerald Patrick; Gaynor, Joanne M.; Reidy, Sean

doi:10.1016/j.cbi.2005.10.095

Cited by 9 publications

(9 citation statements)

References 3 publications

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“…Isosorbide-2,5-diesters are in general rapidly and exclusively hydrolyzed at the 2-ester . The rate of hydrolysis of the isosorbide-2-benzoate ester increases 20-fold across the series −5-OH, −5-nitrate, −5-benzoate with an accompanying depression of K M values, indicating that the rate enhancement is substrate affinity driven . We also reported recently on isosorbide-2-carbamate esters as low nM and selective inhibitors of BuChE over AChE (6 × 10 4 ) .…”

Section: Chemistrysupporting

confidence: 53%

“…35 The rate of hydrolysis of the isosorbide-2-benzoate ester increases 20fold across the series -5-OH, -5-nitrate, -5-benzoate with an accompanying depression of K M values, indicating that the rate enhancement is substrate affinity driven. 30 We also reported recently on isosorbide-2-carbamate esters as low nM and selective inhibitors of BuChE over AChE (6 Â 10 4 ). 31 These compounds were characterized as time-dependent pseudosubstrate competitive inhibitors.…”

Section: Chemistrymentioning

confidence: 78%

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Isosorbide-Based Aspirin Prodrugs: Integration of Nitric Oxide Releasing Groups

et al. 2009

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Aspirin prodrugs and related nitric oxide releasing compounds hold significant therapeutic promise, but they are hard to design because aspirin esterification renders its acetate group very susceptible to plasma esterase mediated hydrolysis. Isosorbide-2-aspirinate-5-salicylate is a true aspirin prodrug in human blood because it can be effectively hydrolyzed to aspirin upon interaction with plasma BuChE. We show that the identity of the remote 5-ester dictates whether aspirin is among the products of plasma-mediated hydrolysis. By observing the requirements for aspirin release from an initial panel of isosorbide-based esters, we were able to introduce nitroxymethyl groups at the 5-position while maintaining ability to release aspirin. Several of these compounds are potent inhibitors of platelet aggregation. The design of these compounds will allow better exploration of cross-talk between COX inhibition and nitric oxide release and potentially lead to the development of selective COX-1 acetylating drugs without gastric toxicity.

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Section: Chemistrysupporting

confidence: 53%

Section: Chemistrymentioning

confidence: 78%

Isosorbide-Based Aspirin Prodrugs: Integration of Nitric Oxide Releasing Groups

et al. 2009

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“…1) are hydrolysed extremely rapidly by BuChE [1]. Here we report the results of studies on the interactions of these isosorbide esters with AChE, which show that these compounds are actually reversible inhibitors of AChE, as opposed to substrates for the enzyme as was the case in BuChE.…”

Section: Introductionmentioning

confidence: 81%

Novel isosorbide di-ester compounds as inhibitors of acetylcholinesterase

Carolan

Gaynor

Dillon

et al. 2008

Chemico-Biological Interactions

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We report herein that a variety of isosorbide di-esters, previously reported to be novel substrates for butyrylcholinesterase (BuChE, EC 3.1.1.8), are in fact inhibitors of the homologous enzyme acetylcholinesterase (AChE), with IC 50 values in the micromolar range. In vitro studies show that they are mixed inhibitors of the enzyme, and thus the ternary enzymeinhibitor-substrate complex can form in acetylcholinesterase. This is rationalised by molecular modelling which shows that the compounds bind in the mid-gorge area. In this position, simultaneous substrate binding might be possible, but the hydrolysis of this substrate is prevented. The di-esters dock within the butyrylcholinesterase gorge in a very different manner, with the ester sidechain at the 5-position occupying the acyl pocket at residues Leu286 and Val288, and the 2-ester binding to Trp82. The carbonyl group of the 2-ester is susceptible to nucleophilic attack by Ser198 of the catalytic triad. The larger residues of the acyl pocket in acetylcholinesterase prevent binding in this manner. The results complement each other and explain the differing behaviours of the esters in the cholinesterase enzymes. These findings may prove very significant for future work.

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“…It is made up of two cis -fused tetrahydrofuran rings, which are nearly planar, and contains two hydroxyls at positions 2 and 5, as shown in Figure 1 [ 20 , 21 ]. Isosorbide has found potential applications in the biomedical field, including aspirin prodrugs [ 22 , 23 ], substrates for human butyrylcholinesterase [ 24 ], tissue engineering scaffolds [ 25 , 26 ], and dental restorative materials [ 27 , 28 , 29 , 30 ].…”

Section: Introductionmentioning

confidence: 99%

Hydrophobically Modified Isosorbide Dimethacrylates as a Bisphenol-A (BPA)-Free Dental Filling Material

et al. 2021

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A series of bio-based hydrophobically modified isosorbide dimethacrylates, with para-, meta-, and ortho- benzoate aromatic spacers (ISBGBMA), are synthesized, characterized, and evaluated as potential dental restorative resins. The new monomers, isosorbide 2,5-bis(4-glyceryloxybenzoate) dimethacrylate (ISB4GBMA), isosorbide 2,5-bis(3-glyceryloxybenzoate) dimethacrylate (ISB3GBMA), and isosorbide 2,5-bis(2-glyceryloxybenzoate) dimethacrylate (ISB2GBMA), are mixed with triethylene glycol dimethacrylate (TEGDMA) and photopolymerized. The resulting polymers are evaluated for the degree of monomeric conversion, polymerization shrinkage, water sorption, glass transition temperature, and flexural strength. Isosorbide glycerolate dimethacrylate (ISDGMA) is synthesized, and Bisphenol A glycerolate dimethacrylate (BisGMA) is prepared, and both are evaluated as a reference. Poly(ISBGBMA/TEGDMA) series shows lower water sorption (39–44 µg/mm3) over Poly(ISDGMA/TEGDMA) (73 µg/mm3) but higher than Poly(BisGMA/TEGDMA) (26 µg/mm3). Flexural strength is higher for Poly(ISBGBMA/TEGDMA) series (37–45 MPa) over Poly(ISDGMA/TEGDMA) (10 MPa) and less than Poly(BisGMA/TEGDMA) (53 MPa) after immersion in phosphate-buffered saline (DPBS) for 24 h. Poly(ISB2GBMA/TEGDMA) has the highest glass transition temperature at 85 °C, and its monomeric mixture has the lowest viscosity at 0.62 Pa·s, among the (ISBGBMA/TEGDMA) polymers and monomer mixtures. Collectively, this data suggests that the ortho ISBGBMA monomer is a potential bio-based, BPA-free replacement for BisGMA, and could be the focus for future study.

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Novel isosorbide-based substrates for human butyrylcholinesterase

Cited by 9 publications

References 3 publications

Isosorbide-Based Aspirin Prodrugs: Integration of Nitric Oxide Releasing Groups

Isosorbide-Based Aspirin Prodrugs: Integration of Nitric Oxide Releasing Groups

Novel isosorbide di-ester compounds as inhibitors of acetylcholinesterase

Hydrophobically Modified Isosorbide Dimethacrylates as a Bisphenol-A (BPA)-Free Dental Filling Material

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