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Patrick Masson - One of the best experts on this subject based on the ideXlab platform.
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1 3 tert butylphenyl 2 2 2 trifluoroethanone as a potent transition state analogue slow binding inhibitor of human acetylcholinesterase kinetic md and qm mm studies
Biomolecules, 2020Co-Authors: Irina V Zueva, Sofya V Lushchekina, Ian R Pottie, Sultan Darvesh, Patrick MassonAbstract:Kinetic studies and molecular modeling of human acetylcholinesterase (AChE) inhibition by a fluorinated acetophenone derivative, 1-(3-tert-butylphenyl)-2,2,2-trifluoroethanone (TFK), were performed. Fast reversible inhibition of AChE by TFK is of competitive type with Ki = 5.15 nM. However, steady state of inhibition is reached slowly. Kinetic analysis showed that TFK is a slow-binding inhibitor (SBI) of type B with Ki* = 0.53 nM. Reversible binding of TFK provides a long residence time, τ = 20 min, on AChE. After binding, TFK acylates the active serine, forming an Hemiketal. Then, disruption of Hemiketal (deacylation) is slow. AChE recovers full activity in approximately 40 min. Molecular docking and MD simulations depicted the different steps. It was shown that TFK binds first to the peripheral anionic site. Then, subsequent slow induced-fit step enlarged the gorge, allowing tight adjustment into the catalytic active site. Modeling of interactions between TFK and AChE active site by QM/MM showed that the “isomerization” step of enzyme-inhibitor complex leads to a complex similar to substrate tetrahedral intermediate, a so-called “transition state analog”, followed by a labile covalent intermediate. SBIs of AChE show prolonged pharmacological efficacy. Thus, this fluoroalkylketone intended for neuroimaging, could be of interest in palliative therapy of Alzheimer’s disease and protection of central AChE against organophosphorus compounds.
Fernando Pina - One of the best experts on this subject based on the ideXlab platform.
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new procedure to calculate all equilibrium constantsin flavylium compounds application to the copigmentation of anthocyanins
ACS Omega, 2019Co-Authors: Johan Mendoza, Nuno Basílio, Victor De Freitas, Fernando PinaAbstract:A new experimental procedure to calculate all equilibrium constants of the multistate of species of anthocyanins and related compounds, including those in basic medium, is reported. The procedure is based on a series of pH jumps monitored by stopped flow from an extended pH range of solutions at pseudo-equilibrium (when there is no significant formation of trans-chalcones) or at equilibrium to pH = 1.0. The experimental procedure is described for the anthocyanin model compound 4′-hydroxyflavylium, which exhibits a peculiar behavior in moderately acidic medium, because the quinoidal base, Hemiketal, and cis-chalcone have similar mole fractions at pseudo-equilibrium, permitting good discrimination among these species. The experimental procedure can be extended to the copigmentation phenomenon and allow the calculation of the 1:1 copigmentation constants of the flavylium cation, quinoidal base, Hemiketal, and cis- and trans-chalcones (this last from the equilibrium) and their respective ionized forms. The me...
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Rationalizing the Color in Heavenly Blue Anthocyanin: A Complete Kinetic and Thermodynamic Study
2018Co-Authors: Johan Mendoza, Fernando Pina, Nuno Basílio, Tadao Kondo, Kumi YoshidaAbstract:All equilibrium and rate constants of heavenly blue anthocyanin (HBA 1) as well as the derivatives with two (HBA 2) or none (HBA 3) acylated units were determined. The three acylated units of the sugar in position 3 of the peonidin chromophore of HBA 1 are essential to confer the peculiar stability of its purple and blue colors. The sugars generate an efficient protective environment around position 2 (and 4) of the flavylium cation, through an intramolecular sandwich-type stacking that retards 35-fold the hydration reaction (kh) and increases 8.8-fold the dehydration reaction (k–h), when compared with the peonidin chromophore HBA 3. The conjugation of these two rates lowers 308-fold the hydration equilibrium constant (Kh), corresponding to a raise of the energy level of the Hemiketal by 14.2 kJ mol–1. Conversely, the pKa of the quinoidal base in HBA 1 is only slightly stabilized in comparison with that of HBA 2 and HBA 3. The energy level of Hemiketal increases with the number of acylated units, but the inversion of energies between Hemiketal and quinoidal base takes place exclusively for HBA 1 (three acylated units), permitting in moderately acidic solutions the stabilization of the purple quinoidal base. Identical inversion of energy was observed for the corresponding ionized species, allowing the stabilization of the blue ionized quinoidal base in slightly basic solutions. At pH values higher than 8, the hydroxyl groups of the hydroxycinnamic acid units start to deprotonate disrupting the intramolecular sandwich-type stacking and the more or less slow degradation of the anthocyanin is observed
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effect of β cyclodextrin on the multistate species distribution of 3 methoxy 4 7 dihydroxyflavylium discrimination of the two Hemiketal enantiomers
Journal of Agricultural and Food Chemistry, 2017Co-Authors: Sandra Gago, Nuno Basílio, Alexandre Quintas, Fernando PinaAbstract:The effect of β-cyclodextrin on the mole fraction distribution of the multistate species of the anthocyanin model compound, 3-methoxy-4′,7-dihydroxyflavylium, was studied by NMR, stopped flow, circular dichroism, and UV–visible absorption spectroscopy. The formation of inclusion complexes with Hemiketal and trans-chalcone, possessing transition dipole moments in a parallel orientation to the cyclodextrin n-fold axis, was unequivocally proved by means of the positive-induced circular dichroism signal. The discrimination of the two Hemiketal enantiomers was achieved by the splitting of 1H NMR peaks in the presence β-cyclodextrin. The spectroscopic data shows that the β-cyclodextrin has only moderate enantioselectivity, slightly favoring one of the optical isomers. The observed binding affinity of β-cyclodextrin for the 3-methoxy-4′,7-dihydroxyflavylium multistate species increases in the order flavylium cation < quinoidal base < Hemiketal < trans-chalcone < cis-chalcone. As a result of this selectivity and ...
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flavylium based dual photochromism addressing cis trans isomerization and ring opening closure by different light inputs
Chemical Communications, 2015Co-Authors: Sandra Gago, Artur J Moro, Nuno Basílio, Fernando PinaAbstract:The multistate system of 4′,7-dihydroxy-3-methoxyflavylium is constituted by a multiequilibrium involving trans-chalcone, cis-chalcone, Hemiketal, flavylium cation and quinoidal base. This system possesses two independently addressable inter-connected photochromic systems based on the cis–trans isomerization and ring opening-closure of the Hemiketal.
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photochromism of flavylium systems an overview of a versatile multistate system
Dyes and Pigments, 2012Co-Authors: Fernando Pina, Vesselin Petrov, Cesar A T LaiaAbstract:Abstract Flavylium is the basic structure of anthocyanins, an important family of natural dyes responsible for the color in many flowers and fruits. While anthocyanins in vitro are involved in a pH dependent equilibrium between a flavylium cation (acidic species) and a Hemiketal (as major basic species), some synthetic flavylium compounds present the trans -chalcone as the major basic species. In this case irradiation of the trans -chalcone leads to appearance of colored products, either a flavylium cation and/or a quinoidal base, via cis -chalcone and Hemiketal. Taking profit from the complexity of the network it is possible to design photochromic systems, exhibiting a thermal back reaction, or models for optical memories, when the back reaction is prevented. The flavylium photochromism was also observed in ionic liquids, gels, micelles and reversed micelles opening up possible applications. In this work an overview of the photochromism of synthetic flavylium compounds is presented, from the first observations of the light effect to recent developments.
Pei Nian Liu - One of the best experts on this subject based on the ideXlab platform.
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cascade reaction of alkynols and 7 oxabenzonorbornadienes involving transient Hemiketal group directed c h activation and synergistic rhiii sciii catalysis
Organic Letters, 2016Co-Authors: Liang Liang Jiang, Shuang Chen, Zheng Lu Huang, Li Dang, Pei Nian LiuAbstract:As the first cascade C–H activation directed by a transient group, reaction of alkynols and 7-oxabenzonorbornadienes has been achieved via synergistic rhodium and scandium catalysis to afford spirocyclic dihydrobenzo[a]fluorenefurans. This transformation proceeds by a transient Hemiketal group directed C–H activation, dehydrative naphthylation, and intramolecular Prins-type cyclization. Mechanistic studies and density functional theory calculations indicate that the rate-determining step is C–H bond cleavage and both the transient Hemiketal group and synergistic RhIII/ScIII catalysis play key roles.
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Cascade Reaction of Alkynols and 7‑Oxabenzonorbornadienes Involving Transient Hemiketal Group Directed C–H Activation and Synergistic RhIII/ScIII Catalysis
2016Co-Authors: Liang Liang Jiang, Shuang Chen, Li Dang, Zheng Lu Huang, Pei Nian LiuAbstract:As the first cascade C–H activation directed by a transient group, reaction of alkynols and 7-oxabenzonorbornadienes has been achieved via synergistic rhodium and scandium catalysis to afford spirocyclic dihydrobenzo[a]fluorenefurans. This transformation proceeds by a transient Hemiketal group directed C–H activation, dehydrative naphthylation, and intramolecular Prins-type cyclization. Mechanistic studies and density functional theory calculations indicate that the rate-determining step is C–H bond cleavage and both the transient Hemiketal group and synergistic RhIII/ScIII catalysis play key roles
Irina V Zueva - One of the best experts on this subject based on the ideXlab platform.
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1 3 tert butylphenyl 2 2 2 trifluoroethanone as a potent transition state analogue slow binding inhibitor of human acetylcholinesterase kinetic md and qm mm studies
Biomolecules, 2020Co-Authors: Irina V Zueva, Sofya V Lushchekina, Ian R Pottie, Sultan Darvesh, Patrick MassonAbstract:Kinetic studies and molecular modeling of human acetylcholinesterase (AChE) inhibition by a fluorinated acetophenone derivative, 1-(3-tert-butylphenyl)-2,2,2-trifluoroethanone (TFK), were performed. Fast reversible inhibition of AChE by TFK is of competitive type with Ki = 5.15 nM. However, steady state of inhibition is reached slowly. Kinetic analysis showed that TFK is a slow-binding inhibitor (SBI) of type B with Ki* = 0.53 nM. Reversible binding of TFK provides a long residence time, τ = 20 min, on AChE. After binding, TFK acylates the active serine, forming an Hemiketal. Then, disruption of Hemiketal (deacylation) is slow. AChE recovers full activity in approximately 40 min. Molecular docking and MD simulations depicted the different steps. It was shown that TFK binds first to the peripheral anionic site. Then, subsequent slow induced-fit step enlarged the gorge, allowing tight adjustment into the catalytic active site. Modeling of interactions between TFK and AChE active site by QM/MM showed that the “isomerization” step of enzyme-inhibitor complex leads to a complex similar to substrate tetrahedral intermediate, a so-called “transition state analog”, followed by a labile covalent intermediate. SBIs of AChE show prolonged pharmacological efficacy. Thus, this fluoroalkylketone intended for neuroimaging, could be of interest in palliative therapy of Alzheimer’s disease and protection of central AChE against organophosphorus compounds.
Liang Liang Jiang - One of the best experts on this subject based on the ideXlab platform.
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cascade reaction of alkynols and 7 oxabenzonorbornadienes involving transient Hemiketal group directed c h activation and synergistic rhiii sciii catalysis
Organic Letters, 2016Co-Authors: Liang Liang Jiang, Shuang Chen, Zheng Lu Huang, Li Dang, Pei Nian LiuAbstract:As the first cascade C–H activation directed by a transient group, reaction of alkynols and 7-oxabenzonorbornadienes has been achieved via synergistic rhodium and scandium catalysis to afford spirocyclic dihydrobenzo[a]fluorenefurans. This transformation proceeds by a transient Hemiketal group directed C–H activation, dehydrative naphthylation, and intramolecular Prins-type cyclization. Mechanistic studies and density functional theory calculations indicate that the rate-determining step is C–H bond cleavage and both the transient Hemiketal group and synergistic RhIII/ScIII catalysis play key roles.
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Cascade Reaction of Alkynols and 7‑Oxabenzonorbornadienes Involving Transient Hemiketal Group Directed C–H Activation and Synergistic RhIII/ScIII Catalysis
2016Co-Authors: Liang Liang Jiang, Shuang Chen, Li Dang, Zheng Lu Huang, Pei Nian LiuAbstract:As the first cascade C–H activation directed by a transient group, reaction of alkynols and 7-oxabenzonorbornadienes has been achieved via synergistic rhodium and scandium catalysis to afford spirocyclic dihydrobenzo[a]fluorenefurans. This transformation proceeds by a transient Hemiketal group directed C–H activation, dehydrative naphthylation, and intramolecular Prins-type cyclization. Mechanistic studies and density functional theory calculations indicate that the rate-determining step is C–H bond cleavage and both the transient Hemiketal group and synergistic RhIII/ScIII catalysis play key roles