pKa Values Research Articles

How deprotonation of cohumulone and colupulone influence their UV/Vis and CD spectrum

Cohumulone and colupulone are representatives of α- and β-acids, respectively. These compounds are important antimicrobial hop (Humulus lupulus) constituents, where cohumulone is an important source of the bitter taste of beer. In this study, we examined the pH dependence of UV/Vis spectra of both compounds while CD spectra of cohumulone were also measured at various wavelengths. This facilitated the examination of the protolytic equilibrium of both compounds, where the second pKa value of cohumulone was determined for the first time. Additionally, comparing experimental spectra with spectra calculated using time-dependent density functional theory (TD-DFT) enabled the determination of the most likely deprotonation positions and corresponding species most likely present in the aqueous solution at various pH values. Last but not least, comparing calculated and experimental CD spectra of cohumulone facilitated the determination of the absolute stereoconfiguration of cohumulone.

Acidity Constants of Boronic Acids as Simply as Possible: Experimental, Correlations, and Prediction.

The wide use of boronic compounds, especially boronic acids and benzoxaboroles, in virtually all fields of chemistry is related to their specific properties. The most important of them are the ability to form cyclic esters with diols and the complexation of anions. In both cases, the equilibrium of the reaction depends mainly on the acidity of the compounds, although other factors must also be taken into account. Quantification of the acidity (pKa value) is a fundamental factor considered when designing new compounds of practical importance. The aim of the current work was to collect available values of the acidity constants of monosubstituted phenylboronic acids, critically evaluate these data, and supplement the database with data for missing compounds. Measurements were made using various methods, as a result of which a fast and reliable method for determining the pKa of boronic compounds was selected. For an extensive database of monosubstituted phenylboronic acids, their correlation with their Brønsted analogues-namely carboxylic acids-was examined. Compounds with ortho substituents do not show any correlation, which is due to the different natures of both types of acids. Nonetheless, both meta- and para-substituted compounds show excellent correlation. From a practical point of view, acidity constants are best determined from the Hammett equation. Computational approaches for determining acidity constants were also analyzed. In general, the reported calculated values are not compatible with experimental ones, providing comparable results only for selected groups of compounds.

Controlling Redox Potential of a Manganese(III)-Bis(hydroxo) Complex through Protonation and the Hydrogen-Atom Transfer Reactivity.

A series of mononuclear manganese(III)-hydroxo and -aqua complexes, [MnIII(TBDAP)(OH)2]+ (1), [MnIII(TBDAP)(OH)(OH2)]2+ (2) and [MnIII(TBDAP)(OH2)2]3+ (3), were prepared from a manganese(II) precursor and confirmed using various methods including X-ray crystallography. Thermodynamic analysis showed that protonation from hydroxo to aqua species resulted in increased redox potentials (E1/2) in the order of 1 (-0.15 V) < 2 (0.56 V) < 3 (1.11 V), while pKa values exhibited a reverse trend in the order of 3 (3.87) < 2 (11.84). Employing the Bordwell Equation, the O-H bond dissociation free energies (BDFE) of [MnII(TBDAP)(OH)(OH2)]+ and [MnII(TBDAP)(OH2)2]2+, related to the driving force of 1 and 2 in hydrogen atom transfer (HAT), were determined as 75.3 and 77.3 kcal mol-1, respectively. It was found that the thermodynamic driving force of 2 in HAT becomes greater than that of 1 as the redox potential of 2 increases through protonation from 1 to 2. Kinetic studies on electrophilic reactions using a variety of substrates revealed that 1 is only weakly reactive with O-H bonds, whereas 2 can activate aliphatic C-H bonds in addition to O-H bonds. The reaction rates increased by 1.4 × 104-fold for the O-H bonds by 2 over 1, which was explained by the difference in BDFE and the tunneling effect. Furthermore, 3, possessing the highest redox potential value, was found to undergo an aromatic C-H bond activation reaction under mild conditions. These results provide valuable insights into enhancing electrophilic reactivity by modulating the redox potential of manganese(III)-hydroxo and -aqua complexes through protonation.

Theoretical studies on the kinetics and mechanism of hydroxyl radical reaction with quinclorac and quinmerac herbicides in aqueous media

AbstractThe kinetic and mechanistic studies for the reaction of hydroxyl radical with two quinoline based herbicides, namely, quinclorac and quinmerac has been performed using various computational methods in aqueous media. Geometry optimizations were performed using Density Functional Theory (DFT) methods including water as the solvent. Local reactivity parameters of these herbicides towards the •OH radical are predicted using condensed Fukui function. Single point energies of various species were calculated using double hybrid method, namely, B2PLYP–D for better accuracy. The pKa values for these acid based herbicides allow them to exist in deprotonated form in aqueous condition. Hence, the calculations are also performed for the deprotonated or the anionic form apart from the neutral species. Individual rate coefficients for •OH radical addition reaction with each carbon atoms were evaluated using conventional transition state theory using one–dimensional tunneling corrections. The solvent effect on reaction is implemented through Collins–Kimball formulations. Both the approaches, namely, the Fukui index and individual rate constant determination confirms that the most reactive site for the •OH radical addition in these two herbicide is the carbon atom attached to the COOH group. The total rate constant for the •OH radical reaction with both neutral and anionic forms of these two herbicides are relatively high and equal to its diffusion‐limit value. Evaluation of the ecotoxicities of the parent herbicides and their OH adducts is estimated using the structure–activity relationship concept.

Discovery of in silico pharmacokinetic characteristics, drug-likeness, computational and experimental pKa values of selected unnatural fatty acid derivatives

The objective of this study was to synthesize a series of unnatural fatty acid derivatives, which have been identified as possessing distinctive properties and potential as new drug candidates. In light of the aforementioned considerations, it is imperative that the physicochemical profiles of these derivatives and their analogues be evaluated prior to the commencement of clinical trials, with a view to ascertaining their pharmacokinetic properties. In order to gain a deeper understanding of this phenomenon, a series of experimental and theoretical studies have been conducted. The pKaexp values of these derivatives were determined for the first time by potentiometric titration. These derivatives, and in particular compounds C-E, display satisfactory physicochemical properties and medicinal chemistry. As a consequence of the related prediction studies, it was observed that the molecules A1-B violated the Lipinski rule by only one criterion, whereas the compounds C-E did not violate it at all. With the exception of compounds A1-A3, compounds B-E exhibit good oral bioavailability. All compounds demonstrated acceptable toxicity profiles, although further in vivo and in vitro laboratory studies are recommended to provide more detailed insights. Furthermore, all molecules were identified as bioactive protease and enzyme inhibitors.

SELECTION OF SUITABLE CATALYSTS FOR PRODUCTION OF NEW NANOCOMPOSITE MATERIALS

The article is devoted to the principles of hydrolytic polycondensation of tetramethoxysilane (TMOS) in an alkaline environment. Monolithic samples of SiO2 particles and xerogels were synthesized as a result of hydrolytic polycondensation of tetramethoxysilane in alkaline medium. Amine catalysts - pyridine derivatives were used to carry out the process. As a result, samples of different sizes were synthesized depending on the concentration of substances taken as catalysts. Smaller diameter particles were obtained at lower amine concentrations and larger diameter particles at higher concentrations. As the pKa value of the catalysts used in the synthesis of xerogels increases, certain increases and decreases in the properties of the resulting particles have been observed. Thus, with an increase in the pKa value, the density and hardness of the samples decreased, the percentage of SiO2 increased, and at the same time, the gelation time in the sol-gel system decreased. Images of the synthesized particles were obtained using a scanning electron microscope (SEM). Keywords: sol-gel, hydrolysis, polycondensation, tetramethoxysilane, xerogel, pKa, catalyst, SEM.

Synthesis of 9-(substituted phenoxycarbonyl)-10-methylacridinium trifluoromethanesulfonates: Effects of the leaving group on chemiluminescent properties.

Various 9-(substituted phenoxycarbonyl)-10-methylacridinium trifluoromethanesulfonates possessing electron-withdrawing substituents have been synthesized. The effect of substituents on the stability of the acridinium esters (AEs) at various temperatures in different buffers and the chemiluminescent properties have been examined. There was little correlation between the chemiluminescent properties of AEs and the pKa values of their associated phenols, but the steric effects of the ortho-substituents in the phenoxy group, as well as their electron-withdrawing natures, seem to play an important role in determining the properties. In general, when two identical substituents are present in the 2- and 6-positions, the compound is significantly more stable than when only a single substituent is present, presumably because of greater steric hindrance from the second group. The exception is the 2,6-difluorophenyl ester, which is less stable than the 2-fluorophenyl ester, presumably because the fluoro group is small. Addition of a third electron-withdrawing substituent at the 4-position, where it has no steric influence, typically increases susceptibility to decomposition. The presence of a nitro group has a significant destabilizing effect on AEs. Of the AEs studied, the 4-chlorophenyl ester showed the greatest chemiluminescent yield, while the 2-iodo-6-(trifluoromethyl)phenyl ester group showed the greatest stability in low pH buffers.

Photonic Nanochains for Continuous Glucose Monitoring in Physiological Environment.

Diabetes is a common disease that seriously endangers human health. Continuous glucose monitoring (CGM) is important for the prevention and treatment of diabetes. Glucose-sensing photonic nanochains (PNCs) have the advantages of naked-eye colorimetric readouts, short response time and noninvasive detection of diabetes, showing immense potential in CGM systems. However, the developed PNCs cannot disperse in physiological environment at the pH of 7.4 because of their poor hydrophilicity. In this study, we report a new kind of PNCs that can continuously and reversibly detect the concentration of glucose (Cg) in physiological environment at the pH of 7.4. Polyacrylic acid (PAA) added to the preparation of PNCs forms hydrogen bonds with polyvinylpyrrolidone (PVP) in Fe3O4@PVP colloidal nanoparticles and the hydrophilic monomer N-2-hydroxyethyl acrylamide (HEAAm), which increases the content of PHEAAm in the polymer shell of prepared PNCs. Moreover, 4-(2-acrylamidoethylcarbamoyl)-3-fluorophenylboronic acid (AFPBA), with a relatively low pKa value, is used as the glucose-sensing monomer to further improve the hydrophilicity and glucose-sensing performances of PNCs. The obtained Fe3O4@(PVP-PAA)@poly(AFPBA-co-HEAAm) PNCs disperse in artificial serum and change color from yellow-green to red when Cg increases from 3.9 mM to 11.4 mM, showing application potential for straightforward CGM.

An open-label phase I study to evaluate the safety, tolerability and preliminary efficacy of YY001 in patients with advanced solid tumors.

e15104 Background: Prostaglandin E2 (PGE2) receptor 4 (EP4) is the master regulator of immunosuppressive myeloid cells (IMCs), one of the major drivers of resistance to immune checkpoint blockade therapy. YY001, a novel and selective EP4 antagonist, effectively blocked the function of IMCs and enhanced cytotoxic T-cell mediated tumor elimination in preclinical studies. Here we report the preliminary data of YY001 in Chinese patients with advanced solid tumors from a phase I study approaching completion. Methods: The key eligibility criteria include: patients aged 18 to 75 years with histologically or pathologically confirmed advanced or metastatic solid tumors; refractory to or intolerant of standard treatment; at least one measurable lesion per RECIST v1.1; ECOG PS 0-1. Accelerated titration and classic 3+3 design were applied for dose escalation. The first dose was administrated once orally within 1 hour after a meal. After 3-days observation, patients took YY001 QD orally continuously in each 21-day treatment cycle. Results: 16 eligible patients were enrolled, including 100mg (n = 1)、200mg (n = 1)、300mg (n = 4)、400mg (n = 3)、500mg (n = 7), and no dose limiting toxicity (DLT) occurred. All patients have received multiple prior treatments before enrolling and the median number of prior treatment lines was five. As of the cut-off date (December 18, 2023), the median of treatment duration is 44 days and the longest is 194 days. No treatment-related adverse events (TRAEs) of ≥ Grade 3 were reported. The most common TRAEs were gastrointestinal disorders, alanine aminotransferase increased, fibrin D-dimer increased, alkaline phosphatase increased and hypoalbuminemia. No patients have DLT or AE leading death. 14 patients were evaluated and 2 patients withdrew from the study before tumor assessment. 6 of 14 patients (42.9%) achieved stable disease and 1 patient achieved Non-CR/Non-PD. The disease control rate was 46.2% (95% Cl 19.2, 74.9). The median progression-free survival and median overall survival were 2.38 (95% Cl 1.93, 4.00) and 10.12 (95% Cl 4.01, -) months, respectively. By the cut-off date, 11 patients were still alive, 1 patient was lost to follow-up and 1 patient is still under treatment. PK analysis concluded YY001 exposure increased in human plasma with increasing dose gradients from 100mg to 300mg. From 300mg to 500mg, the drug exposure in human plasma remained essentially the same, suggesting the PK value peak has been reached. The recommended phase II dose would be 300mg to 500mg. In addition, a median t1/2 of 8.7h was derived from 100mg to 500mg dose groups. Conclusions: The preliminary results suggest that YY001 had a manageable safety/tolerability profile and promising efficacy in patients with advanced solid tumors. YY001 will be combined with immune checkpoint inhibitor in a phase II study subsequently. Clinical trial information: NCT06228846 .

Comparison of Classical and Green RPLC Methods in the Determination of pKa Values of Some Piperazine Group Antihistamines.

In this study, protonation constant values and liquid chromatographic behaviors of hydrophobic cyclizine, chlorcyclizine, hydroxyzine, cinnarizine, cetirizine, meclizine, and buclizine in some water-organic solvent binary mixtures were examined for the first time using classical and green reverse phase liquid chromatography methods. In the isocratic study, the relationship of the retention time and mobile phase pH in water-organic solvent binary mixtures containing acetonitrile (45, 50, 55, 60, 65%, v/v), methanol (60, 65, 70, 75%, v/v) and ethanol (45, 50, 55, 56, 59, 60, 62, 65%, v/v) were determined at 37 °C. In the study, XBridge C18 and Gemini NX C18 columns suitable for the chemical properties of basic compounds were used. The obtained liquid chromatographic data were analyzed using the linear solvation energy relationship methodology and the SOLVER program. The aqueous protonation constant values of the investigated compounds were calculated using the linear relationship between the protonation constant data calculated in studied binary mixtures and some macroscopic constant values of the solvents used. The greenness of methods developed using three different solvents was evaluated with the Analytical Greenness Metric Approach, the Green Analytical Procedures Index, and the Green Solvent Selection Tool approaches.

Antiaromaticity of Cycloheptatrienyl Anions: Structure, Acidity, and Magnetic Properties.

Investigations of the nature and degree of antiaromaticity of cycloheptatrienyl anion derivatives using both experimental and computational tools are presented. The ground state of cycloheptatrienyl anion in the gas phase is triplet, planar and Baird-aromatic. In DMSO, it assumes a singlet distorted allylic form with a paratropic ring current. The other derivatives in both phases assume either allylic or diallylic conformations depending on the substituent pattern. A combination of experimental and computational methods was used to determine the pKa values of 16 derivatives in DMSO, which ranged from 36 to -10.7. We revealed that the stronger stabilization of the anionic system, which correlates with acidity, does not necessarily imply a lower degree of antiaromaticity in terms of magnetic properties. Conversely, the substitution pattern first affects the geometry of the ring through the bulkiness of the substituents and their better conjugation with a more distorted system. Consequently, the distortion reduces the cyclic conjugation in the π-system and thereby decreases the paratropic current in a magnetic field, which manifests itself as a decrease in the NICS. The triplet-state geometries and magnetic properties are nearly independent on the substitution pattern, which is typical for simple aromatic systems.

Comparative study of iontophoresis-assisted transdermal delivery of bupivacaine and lidocaine as anesthetic drugs.

Postoperative pain management is an important aspect of the overall surgical care process. Effective pain management not only provides patient comfort but also promotes faster recovery and reduces the risk of complications. Bupivacaine (BUP) and Lidocaine (LID) transdermal drug deliveries via thermoplastic polyurethane matrix (TPU) and iontophoresis technique are proposed here as alternative routes for postoperative pain instead of the injection route. Under applied electric field, the amounts of BUP and LID released were 95% and 97% from the loaded amounts, which were higher than the passive patch of 40%. The time to equilibrium of BUP turned out to be faster than the time to equilibrium of LID by approximately 1.5 times. This was due to 2 factors namely the drug molecular weight and the drug pKa value; they play an important role in the selection of a suitable drug for fast-acting or long-acting for the postoperative patients. By using this transdermal patch via iontophoresis system, BUP was deemed as the suitable drug for fast-acting due to the shorter time to equilibrium, whereas LID was the suitable drug for long-acting. The in-vitro drug release - permeation study through a porcine skin indicated the efficiency and potential of the system with the amounts of drug permeated up to 76% for BUP and 81% for LID. The TPU transdermal system was demonstrated here as potential to deliver BUP and LID for postoperative patients.

The electronic, structural and nonlinear optical properties of licochalcone L in the aqueous solution and gaseous phase: A DFT study

In the present article, various conformers of licochalcone L, a chalcone derivative extracted from the G. inflata root, have been analyzed in the aqueous solution and gaseous phase using calculation based on density functional theory (DFT). Nonlinear optical parameters such as dipole moment (μ), mean polarizability (α), polarizability anisotropy (Δα) and the first order hyperpolarizability (β) have been estimated to examine the NLO properties of the title molecule. These parameters were found to be significantly higher than those of standard molecules, indicating the potential NLO applications of licochalcone L. The analysis of natural bond orbitals (NBO) has been carried out to characterize various intramolecular interactions. The nucleus-independent chemical shift (NICS) technique has been used to investigate the aromaticity. Further, the pKa values have been computed for each hydroxyl group, revealing that the neutral form predominates at physiological pH, while the monoanionic form becomes predominant at pH greater than 9. The impact of solvation on the molecular electrostatic potentials and frontier molecular orbitals has been investigated for the neutral as well as monoanionic form of licochalcone L. A variety of global chemical reactivity descriptors have been calculated to highlight the structure-activity relationship.

2‐ and 3‐Fluorocyclobutane Building Blocks for Organic and Medicinal Chemistry

Multigram synthesis of 3‐fluorinated cyclobutane building blocks has been disclosed. The proposed synthetic schemes were based on the nucleophilic fluorination and eventually led to 3‐fluorocyclocutanecarboxylic acid as a key target compound and intermediate. Further functional group transformations provided monofluorinated cyclobutane‐derived alcohols, amines, bromides, thiols, sulfonyl chlorides, etc. Furthermore, the synthesis of diastereopure cis‐ and trans‐isomeric 2‐ and 3‐fluorocyclobutane­carboxylic acids and amines was also performed. In both cases, diastereomer separation was used to obtain pure stereoisomers. The effect of the fluorine position and relative spatial orientation on the physicochemical properties of the corresponding monoflurinated derivatives was studied by measurements of pKa and logP values.

Thermodynamics of Proton-Coupled Electron Transfer at Tricopper μ-Oxo/Hydroxo/Aqua Complexes.

Multicopper oxidases (MCOs) utilize a tricopper active site to reduce dioxygen to water through 4H+ 4e- proton-coupled electron transfer (PCET). Understanding the thermodynamics of PCET at a tricopper cluster is essential for elucidating how MCOs harness the oxidative power of O2 while mitigating oxidative damage. In this study, we determined the O-H bond dissociation free energies (BDFEs) and pKa values of a series of tricopper hydroxo and tricopper aqua complexes as synthetic models of the tricopper site in MCOs. Tricopper intermediates on the path of alternating electron and proton transfer (ET-PT-ET-PT-ET) have modest BDFE(O-H) values in the range of 53.0-57.1 kcal/mol. In contrast, those not on the path of ET-PT-ET-PT-ET display much higher (78.1 kcal/mol) or lower (44.7 kcal/mol) BDFE(O-H) values. Additionally, the pKa of bridging OH and OH2 motifs increase by 8-16 pKa units per oxidation state. The same oxidation state changes have a lesser impact on the pKa of N-H motif in the secondary coordination sphere, with an increase of ca. 5 pKa units per oxidation state. The steeper pKa increase of the tricopper center promotes proton transfer from the secondary coordination sphere. Overall, our study shed light on the PCET pathway least prone to decomposition, elucidating why tricopper centers are an optimal choice for promoting efficient oxygen reduction reaction.

Molecular Environment Modulates CO2 Liberation from Carboxy-Biotin.

Carboxy-biotin serves as a coenzyme in certain carboxylases, exhibiting the remarkable capability to transfer a carboxy group to specific substrates. This process is made possible by the presence of biotin, a unique molecule that consists of a sulfur-containing tetrahydrothiophene ring fused to a ureido group. It is covalently attached to the enzyme via a flexible linker, allowing for its functionality. Biotin-dependent carboxylases consist of two distinct domains. The first domain (BC) facilitates biotin carboxylation by utilizing ATP, while the second domain (CT) transfers CO2 to the substrate. The process of ATP-dependent carboxylation using bicarbonate in the biotin carboxylase domain (BC) is well-known. However, the precise mechanism by which CO2 is released in the carboxyltransferase domain (CT) is still not fully understood. We employed advanced computational chemistry methods to investigate the decarboxylation process of carboxy-biotin in various molecular environments and different protonation states. Regardless of the polarity of the molecular surroundings, decarboxylation only occurs spontaneously in the protonated form. To determine the protonation state of biotin in different environments, we established an accurate computational chemistry method for calculating the pKa value of carboxy-biotin, reaching sub-kcal/mol accuracy. Based on our findings, nonpolar environments, such as the active site of the carboxyltransferase domain, have the ability to cause the spontaneous release of CO2 from carboxy-biotin. The CO2 release takes place spontaneously from protonated carboxy-biotin, promoting the carboxylation of substrates.

Biological and equilibrium studies of Co(II), Cu(II), Zn(II), and Cd(II) complexes of 1‐formyl‐3‐semicarbazide: Docking studies

1‐Formyl‐3‐semicarbazide (FSC, HL) and its metal complexes with Co(II), Cu(II), Zn(II), and Cd(II) ions have been synthesized and characterized by elemental analysis, liquid chromatography‐mass spectrometry (LC–MS), infrared (IR), electronic, nuclear magnetic resonance (NMR) and electron spin resonance (ESR) spectroscopy, thermogravimetric analysis (TGA), magnetic susceptibility, and conductivity measurements. The chelates are non‐electrolytic in nature with distorted octahedral geometry. The kinetic and thermodynamic properties were calculated using the Coats–Redfern relation results in positive enthalpy change values and negative entropy change values. The equilibrium studies of FSC with Co(II), Zn(II), and Cd(II) ion have been carried out by potentiometric pH titrations in 70% v/v DMF‐water medium at 303 K and 0.1 M (KNO3) ionic strength. The study revealed that FSC is monobasic acid with pKa value of 8.84. The stability constants suggested the formation of 1:1 Co(II)‐FSC complex, and Zn(II)‐FSC and Cd(II)‐FSC systems revealed the formation of both 1:1 and 1:2 complexes in the solution. DNA binding studies for the metal chelates have been carried out using electronic absorption spectra, fluorescence emission spectra, and viscosity measurements revealing groove binding for Co(II), and Zn(II) complexes, and intercalation mode of binding for Cu(II)‐FSC complex with CT‐DNA. The Kb values from absorption studies are Co(II)‐FSC = 0.9990 × 102, Cu(II)‐FSC = 2.433 × 104, and Zn(II)‐FSC = 8.277 × 102 M−1, and the KSV values from the competitive fluorescence emission studies are Co(II)‐FSC = 0.19212 and Cu(II)‐FSC = 0.11482 M−1. Molecular docking carried out for both ligand and its Co(II) and Zn(II) complexes also revealed groove mode of binding, and Cu(II) complex showed intercalative mode of binding. The inhibition constants for HL, Co(II), Cu(II), and Zn(II) are 1460, 0.478, 0.122, and 0.194 μM, respectively. The antimicrobial activity has been studied using agar disk diffusion method against Escherichia coli and Bacillus subtilis. FSC has been found to be more active against gram +ve and gram –ve bacteria than its metal chelates.

Green DES based microextraction method for monitoring brilliant black BN (E151) in diverse food matrices

A green deep eutectic solvent (DES) based microextraction method was established for separation and spectrophotometric determination of E151 in food matrices. DES composed of tetra pentyl ammonium bromide and 1-octanol (1:5) was used. Important analytical microextraction parameters including pH, volume of DES and time of vortex mixing were optimized using Box-Behnken design of Response Surface Methodology. The other variables including composition ratio of DES and sample volume were optimized by one variable at a time optimization process. The method exhibited linear behaviour for E151 having concentration range between 132–12000 µg/L with 30 preconcentration factor. The relative standard deviation, detection limit and quantitation limit were determined to be 5 %, 40 and 132 µg/L, respectively. The scores of analytical greenness and applicability for the method were determined to be 0.69 and 62.5, respectively. pK values of E151 were determined. Extraction mechanisms of E151 were elucidated. The method was applied to foodstuffs and water samples to determine their E151 contents by analyte addition recovery tests with recovery values ranging between 94–103 %.

Energetics of the H-Bond Network in Exiguobacterium sibiricum Rhodopsin.

Exiguobacterium sibiricum rhodopsin (ESR) functions as a light-driven proton pump utilizing Lys96 for proton uptake and maintaining its activity over a wide pH range. Using a combination of methodologies including the linear Poisson-Boltzmann equation and a quantum mechanical/molecular mechanical approach with a polarizable continuum model, we explore the microscopic mechanisms underlying its pumping activity. Lys96, the primary proton uptake site, remains deprotonated owing to the loss of solvation in the ESR protein environment. Asp85, serving as a proton acceptor group for Lys96, does not form a low-barrier H-bond with His57. Instead, deprotonated Asp85 forms a salt-bridge with protonated His57, and the proton is predominantly located at the His57 moiety. Glu214, the only acidic residue at the end of the H-bond network exhibits a pKa value of ∼6, slightly elevated due to solvation loss. It seems likely that the H-bond network [Asp85···His57···H2O···Glu214] serves as a proton-conducting pathway toward the protein bulk surface.

Assessment of the antinociceptive, respiratory-depressant, and reinforcing effects of the low pKa fluorinated fentanyl analogs, FF3 and NFEPP

RationaleRecent studies report that fentanyl analogs with relatively low pKa values produce antinociception in rodents without other mu opioid-typical side effects due to the restriction of their activity to injured tissue with relatively low pH values. However, it is unclear if and to what degree these compounds may produce mu opioid-typical side effects (respiratory depression, reinforcing effects) at doses higher than those required to produce antinociception. ObjectivesThe present study compared the inflammatory antinociceptive, respiratory-depressant, and reinforcing effects of fentanyl and two analogs of intermediate (FF3) and low (NFEPP) pKa values in terms of potency and efficacy in male and female Sprague-Dawley rats. MethodsNociception was produced by administration of Complete Freund's Adjuvant into the hind paw of subjects, and antinociception was measured using an electronic Von Frey test. Respiratory depression was measured using whole-body plethysmography. Reinforcing effects were measured in self-administration using a progressive-ratio schedule of reinforcement. The dose ranges tested for each drug encompassed no effect to maximal effects. ResultsAll compounds produced full effects in all measures but varied in potency. FF3 and fentanyl were equipotent in antinociception and self-administration, but FF3 was less potent than fentanyl in respiratory depression. NFEPP was less potent than fentanyl in every measure. The magnitude of potency difference between antinociception and other effects was greater for FF3 than for NFEPP or fentanyl, indicating that FF3 had the widest margin of safety when relating antinociception to respiratory-depressant and reinforcing effects. ConclusionsLow pKa fentanyl analogs possess potential as safer analgesics, but determining the optimal degree of difference for pKa relative to fentanyl will require further study due to some differences between the current results and findings from prior work with these analogs.