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At least 1,099 records · Page 61Linked to original sources
PubMed2005

Sulfonamide drugs binding to the colchicine site of tubulin: thermodynamic analysis of the drug-tubulin interactions by isothermal titration calorimetry.

The discovery of several sulfonamide drugs paved the way toward the synthesis of 6 (N-[2-[(4-hydroxyphenyl)amino]-3-pyridinyl]-4-methoxybenzenesulfonamide, E7010) and 7 (N-(3-fluoro-4-methoxyphenyl)pentafluorobenzenesulfonamide, T138067), both of which inhibit tubulin polymerization and are under clinical development. A series of diarylsulfonamides containing an indole scaffold was also found to have antimitotic properties, but their mode of interactions with tubulin has remained unidentified so far. In this study, we demonstrate that these sulfonamide drugs bind to the colchicine site of tubulin in a reversible manner. They quenched intrinsic tryptophan fluorescence of tubulin presumably due to drug-induced conformational changes in the protein, but were unable to modulate GTPase activity of tubulin in contrast to colchicine that enhances the same enzymatic activity. Further investigation using isothermal titration calorimetry (ITC) revealed that 5 (N-(5-chloro-7-indolyl)-4-methoxybenzenesulfonamide) afforded a large positive value of heat capacity change (DeltaC(p)() = +264 cal mol(-1) K(-1)) on binding to tubulin, suggesting a substantial conformational transition in the protein along with partial enthalpy-entropy compensation. On the other hand, the 2-chloro regioisomer 2 gave a large negative value of DeltaC(p)() (-589 cal mol(-1) K(-1)) along with complete enthalpy-entropy compensation. This thermodynamic profile was thought to be attributable to a prominent contribution of van der Waals interaction and hydrogen bonding between specific groups in the drug-tubulin complex. These results indicate that a mere alteration in the position of a single substituent chlorine on the indole scaffold has a great influence on the drug-tubulin binding thermodynamics.

Antineoplastic Agents↗
PubMed2003

Synthesis of phosphoryl-tethered beta-cyclodextrins and their molecular and chiral recognition thermodynamics.

Two novel phosphoryl-bridged bis- and tris(beta-cyclodextrin)s of different tether lengths, i.e., bis[m-(N-(6-cyclodextryl)-2-aminoethylaminosulfonyl)phenyl]-m-(chlorosulfonyl)phenylphosphine oxide (5) and tris[m-(N-(6-cyclodextryl)-8-amino-3,6-diazaoctylaminosulfonyl)phenyl]phosphine oxide (6), have been synthesized by reactions of 6-oligo(ethylenediamino)-6-deoxy-beta-cyclodextrins with tris[m-(chlorosulfonyl)phenyl]phosphine oxide. The complex stability constants (K(S)), standard molar enthalpy (Delta H degrees ), and entropy changes (Delta S degrees ) were determined at 25 degrees C for the inclusion complexation of phosphoryl-modified bis- and tris-cyclodextrins (5 and 6, respectively), mono[6-O-(ethoxyhydroxyphosphoryl)]-beta-cyclodextrin (2), mono[6-O-(diethylamino-ethoxyphosphoryl)]-beta-cyclodextrin (3), and mono[6-O-(diphenoxyphosphoryl)]-beta-cyclodextrin (4) with representative alicyclic and N-Cbz-D/L-alanine guests in 0.1 M phosphate buffer solution at pH 7.2 by means of titration microcalorimetry. The thermodynamic parameters obtained indicate that the charge-dipole interaction between the phosphoryl moiety and the negatively charged guests, as well as the conformational difference of modified beta-cyclodextrins in aqueous solution, significantly contribute to the inclusion complexation and the enhanced chiral discrimination. The interactions and binding modes between the hosts and chiral guests were further studied by two-dimensional NMR spectroscopy to elucidate the influence of the structural features of hosts on their increased chiral recognition ability and to establish the correlation between the conformation of the resulting complexes and the thermodynamic parameters obtained.

Alanine↗
PubMed2007

Two-directional elaboration of hydroxyacetone under thermodynamically controlled conditions: allylation or 2-propynylation and aldol reaction.

Enolate generated from O-(tetrahydropyran-2-yl)hydroxyacetone under thermodynamically controlled conditions (1.3 equiv of NaH, THF, 0 degrees C to rt) was allylated at the carbon bearing the protected hydroxy group with very high regioselectively. When tert-BuOH, equivalent to the excessive portion of initially added NaH, was introduced into the mixture followed by addition of aldehyde, aldol reaction took place on the methyl group to give 1-substituted 4-hydroxy-(1E),6-heptadien-3-one in acceptable yields after acidic treatment of the mixture for dehydration and deprotection. Introducing a chiral auxiliary protecting group into hydroxyacetone led to asymmetric allylation though stereoselectivity was around 50% ee. Thus, the hidden aspect of the chemoselective nature of protected hydroxyacetone-derived enolate generated under thermodynamically controlled conditions has opened a new avenue for two-directional elaboration of hydroxyacetone that should be potentially useful in organic synthesis.

Acetone↗
PubMed2005

Calculation of thermodynamic properties of species of biochemical reactants using the inverse Legendre transform.

The determination of apparent equilibrium constants and heats of enzyme-catalyzed reactions provides a way to determine Delta(f)G degrees and Delta(f)H degrees of species of biochemical reactants. These calculations are more difficult than the calculation of transformed thermodynamic properties from species properties, and they are an application of the inverse Legendre transform. The Delta(f)G degrees values of species of a reactant can be calculated from an apparent equilibrium constant if the Delta(f)G degrees values are known for all the species of all the other reactants and the pKs of the reactant of interest are known. The Delta(f)H degrees of species of a reactant can be calculated from the heat of reaction if the Delta(f)H degrees values are known for all species of the other reactants and Delta(f)G degrees values are known for all species in the reaction. The standard enthalpies of acid dissociation of the reactant of interest are also needed. The inverse Legendre transformation is accomplished by using computer programs to set up the simultaneous equations that involve the Delta(f)H degrees of the species and solving them. Thirty two new species matrixes providing Delta(f)G degrees values and eight new species matrixes providing Delta(f)H degrees values are calculated. It is the specificity and speed of enzyme-catalyzed reactions that make it possible to determine standard thermodynamic properties of complicated species in aqueous solution that could never have been obtained classically.

Biochemical Phenomena↗
PubMed2005

The effect of water displacement on binding thermodynamics: concanavalin A.

Interactions at the binding interface of biomolecular complexes are often mediated by ordered water molecules. In this work, we considered two concanavalin A-carbohydrate complexes. In the first, a water molecule is buried at the binding interface. In the second, this water molecule is displaced by a modification of the ligand (Clarke, C.; Woods, R. J.; Gluska, J.; Cooper, A.; Nutley, M. A.; Boons, G. J. J. Am. Chem. Soc. 2001, 123, 12238-12247). We computed the contribution of this water molecule to the thermodynamic properties using statistical mechanical formulas for the energy and entropy and molecular dynamics simulations. Other contributions to the binding affinity, including desolvation, entropy of conformational restriction, and interaction between the ligand and protein, were also computed. The thermodynamic consequences of displacement of the ordered water molecule by ligand modification were in qualitative agreement with experimental data. The free energy contribution of the water molecule (-17.2 kcal/mol; -19.2 enthalpic and +2 entropic) was nearly equivalent to the additional protein-ligand interactions in trimannoside 2 (-18.9 kcal/mol). The two structural ions interact more strongly with the water than with the hydroxyl of trimannoside 2, thus favoring trimannoside 1. The contributions from desolvation and conformational entropy are much smaller but significant, compared to the binding free energy difference. The picture that emerges is that the final outcome of water displacement is sensitive to the details of the binding site and cannot be predicted by simple empirical rules.

Binding Sites↗
PubMed2005

Quantum chemical semiempirical approach to the structural and thermodynamic characteristics of fluoroalkanols at the air/water interface.

In the framework of quantum chemical PM3 approximation, the geometrical structure and thermodynamic functions characteristics of the formation of monomers (n = 1-14, 34), dimers (n = 1-14, 34), and trimers and tetramers (n = 1-8) of fluoroalkanols with the composition C(n)F(2)(n+1)CH(2)CH(2)OH are calculated. It is shown that, in contrast to the fatty alcohols, which have a flat zigzag structure, the fluoroalkanol monomers are helical with an average backbone torsion angle equal to 162 degrees. For the minimum-energy structure of dimers, the self-organization of the molecules in a dimer was observed; that leads to an opposite alternation of the torsion angles corresponding to the matching atoms in the two molecules that form the dimer. This results in the fact that the most stable conformation of the dimer is the double helix. The lead (39.5 A) and diameter (7.3 A) of the double helix are determined from the calculations of C(34)F(69)CH(2)CH(2)OH dimers. Enthalpy, entropy, and Gibbs energy of the clusterization are shown to be linearly dependent on the length of the fluorinated chain. From the analysis of these thermodynamic quantities, it is concluded that dimerization of fluoroalkanols at the air/water interface takes place if the hydrocarbon link number exceeds 6, whereas for ordinary alcohols this characteristic number is 11. These calculated values agree with experimental data. The additive scheme for the evaluation of the clusterization free energies for arbitrary clusters is developed and applied to obtain the estimate of the Gibbs clusterization energy for infinitely large clusters.

Air↗
PubMed2005

Thermodynamic and structural characterization of amphiphilic melamine-type monolayers.

Monolayers of amphiphilic melamine derivatives are good candidates for the formation of supramolecular structures by hydrogen-bonding of nonsurface active species dissolved in the aqueous subphase by molecular recognition. In the present work, the thermodynamic and structural properties of the Langmuir monolayers of a homologous series of a selected amphiphilic melamine-type are characterized. Good candidates for such studies are the decyl, undecyl, and dodecyl homologues of the 2,4-di(n-alkylamino)-6-amino-1,3,5-triazine (2CnH(2n+1)-melamine) monolayers because of their two-phase coexistence region in the accessible temperature range. The characterization of the structural and phase behavior is performed by a combination of surface pressure studies with Brewster angle microscopy (BAM) imaging and Grazing incidence X-ray diffraction (GIXD) measurements. A comprehensive thermodynamic analysis provides good agreement between the experimental surface pressure - area (Pi-A) isotherms and the theoretical curves that were calculated on the basis of equations of state for a large region of monolayer stages developed by us in J. Phys. Chem. 1999, 103, 145. Theoretical curves calculated by application of equations of state only for the fluid monolayer state proposed recently by Rusanov (J. Chem Phys. 2004, 120, 10736) are in good agreement with the experiments in a limited temperature range. A rigorous equation is derived and applied to the experimental results for the calculation of the enthalpy of two-dimensional phase transition. The combination of BAM and GIXD illustrates that the microscopic long range ordering of the condensed monolayer phases is related to the lattice structure of the condensed monolayer.

Thermodynamics↗
PubMed2005

A calix(4)arene pyridine derivative and its monomeric component: structural and thermodynamic aspects of their complexation with metal cations.

The interaction of a calix(4)arene derivative, namely 5,11,17,23-tetra-tert-butyl-25,26,27,28-tetra[2-(4-pyridyl)methoxy]calix(4)arene, 1a, and its monomeric component, p-tert-butylphenoxy-4-pyridine, 1b, with metal cations has been investigated in acetonitrile and methanol. (1)H NMR measurements carried out in CD(3)CN show the primary role played by the pyridyl nitrogens in their complexation with metal cations. Conductance measurements demonstrated that for all cations (except mercury) the composition of the metal ion complexes of 1a is 1:1 (ligand:metal cation). However, 1a hosts two mercury cations per unit of ligand. For the monomer 1b, complexes of 2:1 (ligand:metal cation) stoichiometries are formed with the exception of Pb(2+) (1:1 composition). The thermodynamics of complexation of these systems are reported in acetonitrile. Data in methanol are limited to stability constant values for mercury(II) and these ligands. This paper demonstrates for the first time that thermodynamic data for the complexation of the monomeric component of the ligand and metal cations contribute significantly to the interpretation of systems involving cation-calixarene interactions in solution.

Calixarenes↗
PubMed2005

Thermodynamic properties underlying the alpha-helix-to-beta-sheet transition, aggregation, and amyloidogenesis of polylysine as probed by calorimetry, densimetry, and ultrasound velocimetry.

In this work, we performed a detailed thermodynamic study of an aggregation-prone polypeptide, polylysine, to gain a deeper insight into the scenario of physicochemical events during its unfolding, aggregation, and amyloidogenesis. The precise and simultaneous determination of the partial molar volume, the heat capacity, and the coefficients of thermal expansion, as well as adiabatic and isothermal compressibility of the protein upon unfolding and aggregation, yields a thermodynamic picture of the aggregation process highlighting the importance of volume fluctuations during unfolding and amyloidogenesis of proteins.

Amyloid beta-Peptides↗
PubMed2005

Thermodynamics of self-assembling of hydrophobically modified cationic polysaccharides and their mixtures with oppositely charged surfactants in aqueous solution.

Microcalorimetric techniques, combined with turbidity measurements, were used to study the thermodynamics of self-assembling of hydrophobically modified cationic polysaccharides and their mixtures with oppositely charged surfactants in aqueous solution. The studied polyelectrolytes were a series of polymers based on dextran having pendant N-(2-hydroxypropyl)-N,N-dimethyl-N-alkylammonium chloride groups randomly distributed along the polymer backbone. The parameters for their micellization process are evaluated from the results of the observed dilution enthalpy curves and compared with those of the related cationic surfactants (DTAC and CTAC). The microcalorimetric results for the mixed systems (polyelectrolytes with oppositely charged surfactants) are used along with turbidity measurements to characterize systematically the thermodynamics of their interaction. The phase behavior is described and the interaction enthalpies are derived from the differences between the observed enthalpy curves with and without polyelectrolyte. Therefore, we discuss in detail the effect of changing the alkyl chain length of polyelectrolyte pendant groups, the molecular weight of the dextran backbone, and the temperature of the measurements on the interactions between polyelectrolyte and surfactant.

Cations↗
PubMed2006

Thermodynamics of hydrogen bonding in hydrophilic and hydrophobic media.

The thermodynamics of hydrogen bond breaking and formation was studied in solutions of alcohol (methanol, ethanol, 1-propanol) molecules. An extensive series of over 400 molecular dynamics simulations with an aggregate length of over 900 ns was analyzed using an analysis technique in which hydrogen bond (HB) breaking is interpreted as an Eyring process, for which the Gibbs energy of activation DeltaG can be determined from the HB lifetime. By performing simulations at different temperatures, we were able to determine the enthalpy of activation DeltaH and the entropy of activation TDeltaS for this process from the Van't Hoff relation. The equilibrium thermodynamics was determined separately, based on the number of donor hydrogens that are involved in hydrogen bonds. Results (DeltaH) are compared to experimental data from Raman spectroscopy and found to be in good agreement for pure water and methanol. The DeltaG as well as the DeltaG are smooth functions of the composition of the mixtures. The main result of the calculations is that DeltaG is essentially independent of the environment (around 5 kJ/mol), suggesting that buried hydrogen bonds (e.g., in proteins) do not contribute significantly to protein stability. Enthalpically HB formation is a downhill process in all substances; however, for the alcohols there is an entropic barrier of 6-7 kJ/mol, at 298.15 K, which cannot be detected in pure water.

1-Propanol↗
PubMed2006

Open-system nonequilibrium steady state: statistical thermodynamics, fluctuations, and chemical oscillations.

Gibbsian equilibrium statistical thermodynamics is the theoretical foundation for isothermal, closed chemical, and biochemical reaction systems. This theory, however, is not applicable to most biochemical reactions in living cells, which exhibit a range of interesting phenomena such as free energy transduction, temporal and spatial complexity, and kinetic proofreading. In this article, a nonequilibrium statistical thermodynamic theory based on stochastic kinetics is introduced, mainly through a series of examples: single-molecule enzyme kinetics, nonlinear chemical oscillation, molecular motor, biochemical switch, and specificity amplification. The case studies illustrate an emerging theory for the isothermal nonequilibrium steady state of open systems.

Enzymes↗
PubMed2006

The rectified second law of thermodynamics.

Equilibrium thermodynamics is combined with Jarzynski's irreversible work theorem to quantify the excess entropy produced by irreversible processes. The resulting rectified form of the second law parallels the first law, in the sense that it facilitates the experimental measurement of excess entropy changes resulting from irreversible work and heat exchanges, just as the first law quantifies energy changes produced by either reversible or irreversible work and heat exchanges. The general form of the rectified second law is further applied to a broad class of quasi-static irreverisble (QSI) processes, for which all of the thermodynamic functions of both the system and surroundings remain continuously well-defined, thus facilitating excess entropy measurements by integrating exact differential functions along QSI paths. The results are illustrated by calculating the mechanical and thermal excess entropy produced by the irreversible unfolding of an RNA molecule.

Algorithms↗
PubMed1998

Thermodynamic analysis of moisture sorption isotherms.

This article illustrates how thermodynamic functions can be calculated from moisture sorption isotherms for water-solid systems. The materials evaluated include the drugs albuterol sulfate and indomethacin, the carbohydrates sucrose, raffinose, and trehalose, and the polymers poly(vinyl pyrrolidone) and microcrystalline cellulose. The results demonstrated that significant positive and negative deviations from ideality occurred for water and solid components, respectively, producing higher free energy materials than for the ideal mixtures. The calculations quantitatively discriminated major differences in thermodynamic activity and free energy for all of the solid phases studied, arising from the uniqueness in chemical interactions. This approach to analyzing moisture sorption data is invaluable in advancing our understanding of the physical chemistry of water-solid systems.

Adsorption↗
PubMed1999

Characterization of racemic species of chiral drugs using thermal analysis, thermodynamic calculation, and structural studies.

The identification of the racemic species, as a racemic compound, a racemic conglomerate, or a racemic solid solution (pseudoracemate), is crucial for rationalizing the potential for resolution of racemates by crystallization. The melting points and enthalpies of fusion of a number of chiral drugs and their salts were measured by differential scanning calorimetry. Based on a thermodynamic cycle involving the solid and liquid phases of the enantiomers and racemic species, the enthalpy, entropy and Gibbs free energy of the racemic species were derived from the thermal data. The Gibbs free energy of formation, is always negative for a racemic compound, if it can exist, and the contribution from the entropy of mixing in the liquid state to the free energy of formation is the driving force for the process. For a racemic conglomerate, the entropy of mixing in the liquid state is close to the ideal value of R ln 2 (1.38 cal.mol-1. K-1). Pseudoracemates behave differently from the other two types of racemic species. When the melting points of the racemic species is about 30 K below that of the homochiral species, is approximately zero, indicating that the racemic compound and racemic conglomerate possess similar relative stabilities. The powder X-ray diffraction patterns and 13C solid-state nuclear magnetic resonance spectra are valuable for revealing structural differences between a racemic compound and a racemic conglomerate. Thermodynamic prediction, thermal analysis, and structural study are in excellent agreement for identifying the nature of the racemic species.

Calorimetry, Differential Scanning↗
PubMed2004

Thermodynamics of temperature-sensitive polyether-modified poly(acrylic acid) microgels.

The temperature-induced structural changes and thermodynamics of ionic microgels based on poly(acrylic acid) (PAA) networks bonded with poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide) (PEO-PPO-PEO) (Pluronic) copolymers have been studied by small-angle neutron scattering (SANS), ultra-small-angle neutron scattering (USANS), differential scanning calorimetry (DSC), and equilibrium swelling techniques. Aggregation within microgels based on PAA and either the hydrophobic Pluronic L92 (average composition, EO8PO52EO8; PPO content, 80%) or the hydrophilic Pluronic F127 (average composition, EO99PO67EO99; PPO content, 30%) was studied and compared to that in the solutions of the parent Pluronic. The neutron scattering results indicate the formation of micelle-like aggregates within the F127-based microgel particles, while the L92-based microgels formed fractal structures of dense nanoparticles. The microgels exhibit thermodynamically favorable volume phase transitions within certain temperature ranges due to reversible aggregation of the PPO chains, which occurs because of hydrophobic associations. The values of the apparent standard enthalpy of aggregation in the microgel suspensions indicate aggregation of hydrophobic clusters that are more hydrophobic than the un-cross-linked PPO chains in the Pluronic. Differences in the PPO content in Pluronics L92 and F127 result in a higher hydrophobicity of the resulting L92-PAA-EGDMAmicrogels and a larger presence of hydrophobic, densely cross-linked clusters that aggregate into supramolecular structures rather than micelle-like aggregates such as those formed in the F127-PAA-EGDMA microgels.

Acrylic Resins↗
PubMed2005

Electrochemical investigation of redox thermodynamics of immobilized myoglobin: ionic and ligation effects.

In this study, we investigated redox thermodynamics of myoglobin as well as the ionic (phosphate ions) and ligation (imidazole) effects via a dynamic electrochemical approach. We employed a previously established system that features nonmediated, direct electrochemistry of myoglobin and myoglobin in an immobilized state (i.e., diffusionless electrochemistry). Thermodynamics parameters were obtained by measuring redox potential (E degrees ') of myoglobin at varied temperature (T), in the presence and in the absence of specific ions or axial ligands. As a step further, we evaluated contributions from allosteric effect and axial iron ligation by partitioning E degrees ' changes into entropic and enthalpic terms. Compensation phenomena between the entropic and enthalpic changes were observed in all these cases. On the basis of these studies, we also correlated these phenomena to possible structural variations.

Allosteric Regulation↗
PubMed2006

Synthesis and thermodynamic studies of oligodeoxyribonucleotides containing tandem lesions of thymidine glycol and 8-oxo-2'-deoxyguanosine.

Thymidine glycol (Tg), which is also known as 5,6-dihydroxy-5,6-dihydrothymidine, and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) are two major types of DNA damage products induced by reactive oxygen species (ROS). Here, we report the synthesis of oligodeoxyribonucleotides (ODNs) containing both Tg and 8-oxodG. The dual incorporation of the two single-base lesions was achieved by using a phosphoramidite building block of 8-oxodG with ultramild base protecting group and a building block of Tg whose nucleobase hydroxyl groups were protected with acetyl functionality. The availability of ODNs carrying neighboring 8-oxodG and Tg provided authentic substrates for assessing the formation and examining the replication and repair of this kind of tandem lesions. In addition, thermodynamic parameters derived from melting temperature data revealed that tandem lesions destabilized the double helix to a greater extent than either of the two single-base lesions alone. The thermodynamic results could offer a basis for understanding the repair of the tandem base lesions.

8-Hydroxy-2'-Deoxyguanosine↗