Interfacial chemistry on carboxylate-functionalized monolayer assemblies

Deposition of trichlorosilanes with ester groups at their remote termini provides a convenient entry to carboxylic acid-bearing siloxane-anchored self-assembled monolayers. The de-esterification of these esters has been optimized to minimize monolayer damage, and their quantitative re-esterification provides clear evidence for the stability of these systems. Both the structure of the ester-terminated monolayer and its de-esterification/esterification chemistry can be easily monitored by FTIR-ATR measurements. This spectroscopic tool, together with a liquid cell that enables IR spectra to be measured in an aqueous environment, enables a detailed structural analysis of the carboxylic acid-bearing siloxane-anchored self-assembled monolayers and an assessment of their acid/base behavior (by in situ titration). The use of D₂O instead of H₂O for the in situ titration experiments also improves the available IR window. Both monomeric and dimeric/oligomeric acid groups are seen, and the relative ease of deprotonation of these various species can be directly monitored. Monomers of alkyl carboxylic acids that are hydrogen bonded only to surrounding water molecules have a pK_a = 4.9, while the pK_a for the aggregated molecules is 9.3. Similar behavior is seen for surface-bound benzoic acids, where the two pK_a values are 4.7 and 9.0. The influence of temperature on these structures and their chemistry has been explored to a limited extent as well. When the alkylcarboxylic acid system is cooled to 10 °C, the pK_a value for the acid monomers is reduced from 4.9 to 4.5 and increases from 9.3 to 10.3 for the aggregates.     

Dissociation constants of long chain fatty acids in methanol-water and ethanol-water mixtures

The pK_a values of lauric acid, myristic acid, palmitic acid and stearic acid in methanol-water and ethanol-water mixtures of different compositions at 303 K and ionic strength, I=0.1M(KNO₃) have been determined. The pK_a values of the fatty acids have been found to increase with the alcohol content of the solvent. It has also been found that, in general, the pK_a values in the ethanolic solvent are greater than those in the methanolic solvent. In a given solvent mixture the observed pK_a value decreases in the order of stearic acid > palmitic acid > myristic acid > lauric acid. Departure from the predicted linearity of the plots of pK_a against the inverse of the dielectric constant, 1/D indicates that the electrostatic effects taken into account by the Born theory are not adequate enough to represent the total medium effects on pK_a.     

Kinetics of drug release from drug carrier of polymer/TiO2 nanotubes composite—pH dependent study

This study was to investigate the kinetics of drug release from polymer/TiO₂ nanotubes composite. Lidocaine and carprofen were selected as model drugs to represent weak base and weak acid drugs, respectively. Mathematical models used to fit the in vitro drug release experimental data indicate that at higher pH, the drug release was first order diffusion controlled. At lower pH, the release of the two drugs exhibits two staged controlled release mechanism. The first phase is due to drug diffusion and the second stage is a result of poly(lactic‐co‐glycolic acid) (PLGA) polymer degradation. The rate of drug release from polymer/TiO₂ nanotubes drug carrier was mainly controlled by three pH dependent factors: the solubility of the drug, the degree of polymer swelling/degradation, and the electrostatic force between polymer and drug. This study suggests that controlled release could be achieved for polymer/TiO₂ nanotubes drug carrier via the modulation of pK_a values of polymers and drug solubility. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 41570.     

Preclinical Characterization of Acyl Sulfonimidamides: Potential Carboxylic Acid Bioisosteres with Tunable Properties

Herein we present the preclinical characterization of novel compounds containing the linear acyl sulfonimidamide functionality. Specifically, we studied the pK_a, lipophilicity, in vitro metabolic stability, plasma protein binding, Caco‐2 permeability, and aqueous solubility for nine aryl acyl sulfonimidamides. In comparison with widely used carboxylic acid bioisosteres, the acyl sulfonimidamides were found to be less acidic and more lipophilic depending on the substitution pattern in the studied compounds. Importantly, the pK_a values (5.9–7.6) were significantly influenced by substituents on the nitrogen atom and the aryl substituents. Moreover, the acyl sulfonimidamides displayed membrane permeabilities ranging from moderate to very high, which correlated with decreased pK_a and low to negligible efflux ratios. We foresee that the chiral sulfur center and the two handles for structural diversity of linear acyl sulfonimidamides will offer new opportunities for drug design and for improving the oral bioavailability of acidic drug candidates.     

Synthesis and Evaluation of the Anticancer and Trypanocidal Activities of Boronic Tyrphostins

Molecules containing an (cyanovinyl)arene moiety are known as tyrphostins because of their ability to inhibit proteins from the tyrosine kinase family, an interesting target for the development of anticancer and trypanocidal drugs. In the present work, (E)‐(cyanovinyl)benzeneboronic acids were synthesized by Knoevenagel condensations without the use of any catalysts in water through a simple protocol that completely avoided the use of organic solvents in the synthesis and workup process. The in vitro anticancer and trypanocidal activities of the synthesized boronic acids were also evaluated, and it was discovered that the introduction of the boronic acid functionality improved the activity of the boronic tyrphostins. In silico target fishing with the use of a chemogenomic approach suggested that tyrosine‐phosphorylation‐regulated kinase 1a (DYRK1A) was a potential target for some of the designed compounds.     

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

The supramolecular chemistry of host-guest complexes of cucurbit[n]urils (CB[n]) with acidic guests in the ground (HG⁺) and excited states (HG⁺*) are reviewed. The effects of CB[n] complexation on the guests’ pK_a and/or pK_a* values are related to relative binding constants and host-guest structures of the acid form of the guest and its conjugate base. Included are carbon acids, guests of biological and medicinal interest, dyes and related polyaromatic guests, and other organic and organometallic guests. The applications of the pK_a shifts to the solubility, stability, and bioavailabilty of drug molecules, the stability and enhanced spectral properties of dyes, and in pH-induced self-sorting, micelle formation, host-guest shuttling, and controlled guest release, are discussed.     

A DNA‐Encoded Library of Chemical Compounds Based on Common Scaffolding Structures Reveals the Impact of Ligand Geometry on Protein Recognition

A DNA‐encoded chemical library (DECL) with 1.2 million compounds was synthesized by combinatorial reaction of seven central scaffolds with two sets of 343×492 building blocks. Library screening by affinity capture revealed that for some target proteins, the chemical nature of building blocks dominated the selection results, whereas for other proteins, the central scaffold also crucially contributed to ligand affinity. Molecules based on a 3,5‐bis(aminomethyl)benzoic acid core structure were found to bind human serum albumin with a K_d value of 6 nm , while compounds with the same substituents on an equidistant but flexible l ‐lysine scaffold showed 140‐fold lower affinity. A 18 nm tankyrase‐1 binder featured l ‐lysine as linking moiety, while molecules based on d ‐Lysine or (2S,4S)‐amino‐l ‐proline showed no detectable binding to the target. This work suggests that central scaffolds which predispose the orientation of chemical building blocks toward the protein target may enhance the screening productivity of encoded libraries.     

Context-Dependence of the Reactivity of Cysteine and Lysine Residues

The S-alkylation of Cys residues with a maleimide and the N^ϵ-acylation of Lys residues with an N-hydroxysuccinimide (NHS) ester are common methods for bioconjugation. Using Cys and Lys derivatives as proxies, we assessed differences in reactivity depending on the position of Cys or Lys in a protein sequence. We find that Cys position is exploitable to improve site-selectivity in maleimide-based modifications. Reactivity decreases substantially in the order N-terminal>in-chain>C-terminal Cys due to modulation of sulfhydryl pK_a by the α-ammonium and carboxylate groups at the termini. A lower pK_a value yields a larger fraction thiolate, which promotes selectivity while somewhat decreasing thiolate nucleophilicity in accord with =0.41. Lowering pH and salt concentration enhances selectivity still further. In contrast, differences in the reactivity of Lys towards an NHS ester were modest due to an appreciable decrease in amino group nucleophilicity with a lower pK_a of its conjugate acid. Hence, site-selective Lys modification protocols will require electrophiles other than NHS esters.     

Polyelectrolyte effect and conformational transition in a restricted polyacid structure

In a polyacid consisting of polyacrylic acid attached to a polyamide matrix, marked effects in equilibrium acid–base characteristics are observed, attributable to a hindered polyelectrolyte structure. In the presence of neutral electrolyte, the very high values found for pK_a drop sharply. A break in the Henderson-Hasselbalch curve indicates a conformational transition at α = 0.55 which is deferred to 0.95 by the presence of neutral electrolyte.     

Measurement of the overall volumetric oxygen transfer coefficient in alkane‐aqueous dispersions

BACKGROUND: A reliable procedure for the determination of the volumetric oxygen transfer coefficient (K_La) in hydrocarbon–aqueous dispersions is critical to the assessment of oxygen transfer in hydrocarbon‐based bioprocesses. The pressure step procedure (PSP) and gassing out procedure (GOP) for K_La determination were evaluated in n‐C_10–13 alkane–aqueous dispersions over agitation rates (600 to 1200 rpm) and alkane concentrations (up to 20%) typical of hydrocarbon‐based bioprocesses. RESULTS: K_La from the procedures diverged progressively as agitation increased, with K_La underprediction attenuated at high alkane. At 1200 rpm and 5% alkane, K_La from the GOP was underpredicted by 49%. Compared with K_La from the PSP, K_La from the PSP without nitrogen transport was the same, but K_La from the PSP without response lag (PSP‐lag) was underpredicted by approximately 50% at 1200 rpm. Moreover, K_La from the PSP‐lag was lower than K_La from the GOP, except at 1200 rpm and alkane concentration up to 5%. CONCLUSION: The PSP was superior to the GOP in alkane–aqueous dispersions, particularly at extreme agitation and low alkane concentrations. This was attributable to the probe response lag and the non‐uniformity of gas composition inherent in the GOP and independent of the rate of coincident nitrogen transport. Copyright © 2009 Society of Chemical Industry     

Glass transitions of organic compounds. III. Cellulose substrate technique and aliphatic alcohols

The cellulose blotter/torsion pendulum technique used for the determination of relaxations that occur in low molecular weight compounds, oligomeric materials, and amorphous polymers is discussed. The glass transition temperature of a number of aliphatic alcohols and hydrocarbons have been determined and correlated with a method proposed by Gorskii in 1934. The glass transition temperature and molecular weight of these compounds follow the relationship T_g = BM^a rather than T_g = T_g(∞) - K/M. Although differences exist between the primary, secondary, and tertiary alcohols, they appear to follow a similar general pattern. In contrast, the hydrocarbons investigated have markedly different behavior.     

Mass transfer in external-loop airlift bioreactors using static mixers

The influence of static mixers on the overall gas-liquid volumetric mass transfer coefficient (K_La_L) was examined in an external-loop type airlift bioreactor (approximately 15 L volume, 1.8 m static liquid height, A_r/A_d = 0.444). The study was conducted with aqueous salt solution (0.15 kmol ? m^?3 NaCl) and with pseudoplastic solutions of carboxymethyl cellulose (0.2 ? 0.6 wt./vol. % (g/100 mL) CMC). Over a broad range of power law parameters K (10^?3 ? 10 Pa ? sⁿ) and n (0.5 ? 1.0), the presence of static mixers in the riser was found to enhance the K_La_L relative to mixer-free mode of operation. The extent of increase in K_La_L depended on the fluid “thickness”, K: the higher the K, the greater the K_La_L intensification due to static mixers. For otherwise identical conditions, the presence of static mixers improved K_La_L by 30-500%, depending on the fluid. The boost in K_La_L was associated with increased gas holdup and gas-liquid interfacial area, which arose due to bubble breakup accomplished by the static mixing elements. Potential advantages of static mixers in upgrading the performance of oxygen-limited fermentations were pointed out.     

Determination of the acid–base characteristics of lignocellulosic surfaces by inverse gas chromatography

The surface acid–base characteristics of samples of cellulose, pine wood, and kenaf powder were determined by inverse gas chromatography (IGC). The test substrates were packed in a deactivated glass column and the IGC probes were injected at infinite dilution. The surface acid–base parameters were expressed in terms of the acceptor K_A and donor K_D parameters, analogous to the Gutmann acceptor and donor numbers derived from the Lewis concept of acids and bases. The K_A and K_D values were calculated from the experimental values of the enthalpy of desorption, corresponding to the specific acid–base interactions, and literature values of the acceptor and donor numbers for the acid–base probes, chloroform, carbon tetrachloride, ethyl acetate, and diethyl ether. Values of K_A and K_D suggest that the surfaces of cellulose, pine wood, and kenaf powder that have been washed by extraction with toluene/ethanol (2 : 1, v/v) are amphoteric, with a relatively greater capacity to accept electrons. The effect of the washing procedure on the dispersive component of the surface energy of the pine wood and kenaf powder was also determined. It was observed that the values for the washed substrates were relatively greater than those of the nonwashed counterparts. © 1997 John Wiley & Sons, Inc. J Appl Polym Sci 65:1013–1020, 1997     

Surface reactivity of fuel shales from the Baltic basin

The distribution and content of acid–base centers at the surface of fuel shales and shale ash are determined. The results indicate that they may be used as fillers in polymer composites, filter materials, and sorbents. The surface of fuel shales is characterized by the presence of centers with pK_a = +1.5, pK_a = +3.5, pK_a = +6.4, pK_a = +9.5, and pK_a = +14. At the surface of shale ash, we find centers with pK_a = +1.5, pK_a = +4.1, pK_a = +6.4, pK_a = +9.5, and pK_a = +14.2. The presence of acidic and basic Bronsted centers indicates sorptional activity with respect to organic pollutants (petroleum and its products, for example) and ionic heavy metals.     

Stabilizing p-Dithiobenzyl Urethane Linkers without Rate-Limiting Self-Immolation for Traceless Drug Release

Exploiting the redox sensitivity of disulfide bonds is a prevalent strategy in targeted prodrug designs. In contrast to aliphatic disulfides, p-thiobenzyl-based disulfides have rarely been used for prodrug designs, given their intrinsic instability caused by the low pK_a of aromatic thiols. Here, we examined the interplay between steric hindrance and the low-pK_a effect on thiol–disulfide exchange reactions and uncovered a new thiol–disulfide exchange process for the self-immolation of p-thiobenzyl-based disulfides. We observed a central leaving group shifting effect in the α,α-dimethyl-substituted p-dithiobenzyl urethane linkers (DMTB linkers), which leads to increased disulfide stability by more than two orders of magnitude, an extent that is significantly greater than that observed with typical aliphatic disulfides. In particular, the DMTB linkers display not only high stability, but also rapid self-immolation kinetics due to the low pK_a of the aromatic thiol, which can be used as a general and robust linkage between targeting reagents and cytotoxic drugs for targeted prodrug designs. The unique and promising stability characteristics of the present DMTB linker will likely inspire the development of novel targeted prodrugs to achieve traceless release of drugs into cells.     

Mass transfer and deodorization efficiency in a countercurrent spray tower for low superficial gas velocities

The aim of this study was to characterize mass transfer and deodorization efficiency in a countercurrent spray tower for low superficial gas velocities. The influence of operating parameters (U_G = 0.005 to 0.025 m s^?1, U_L = 6.1 × 10^?5 to 2.4 × 10^?4 m s^?1) on the liquid retention (ε_L), the drop diameter (d_g), the interfacial area (a) and the overall liquid and gas phase mass transfer coefficients (K_La, K_Ga) were estimated. The spray efficiency of some malodorous compounds was also estimated. A negative influence of the superficial gas velocity was demonstrated, during the spraying of water or chemical neutralizing scrubbing solutions. There was also an increase with the liquid flow rate. Abatements obtained were very good with respect to ammonia (>90%), and acceptable for the other compounds.     

Modelling Oxygen Transfer and Aerobic Growth in Shake Flasks and Well‐Mixed Bioreactors

Oxygen transfer is an important aspect of aerobic metabolism. In this work, microbial growth on glucose (fast metabolism) and phenol (slow metabolism) have been studied using Pseudomonas putida in shake flasks and a mixed bioreactor considering both substrate and oxygen depletion. Under typical operating conditions, the highest mass transfer coefficient (K_La) for the aerated well‐mixed bioreactor was found to be 50.8 h^?1, while the maximum non‐aerated shake flask K_La was 21.1 h^?1. The presence of media and/or dead cells did not have significant effect on measured values of K_La. A new equation for prediction of K_La in shake flasks with an absolute average deviation of 11.1% is introduced, and a combined model for oxygen mass transfer and microbial growth is shown to fit experimental data during growth on glucose and phenol in both shake flasks and the mixed bioreactor with an absolute average deviation of 19.3%.     

An Inexpensive and Efficient Copper Catalyst for N‐Arylation of Amines,Amides and Nitrogen‐Containing Heterocycles

An inexpensive and efficient catalyst system has been developed for the N‐arylation of nitrogen‐containing compounds including a variety of amines, amides, indole and imidazole. This simple protocol uses CuI as the catalyst, commercial available pipecolinic acid as the new ligand, K₂CO₃ as the base and DMF as the solvent.     

Chemoenzymatic Synthesis of GDP‐L‐Fucose Derivatives as Potent and Selective α‐1,3‐Fucosyltransferase Inhibitors

Fucosyltransferases (FucTs) usually catalyze the final step of glycosylation and are critical to many biological processes. High levels of specific FucT activities are often associated with various cancers. Here we report the development of a chemoenzymatic method for synthesizing a library of guanosine diphosphate β‐L ‐fucose (GDP‐Fuc) derivatives, followed by in situ screening for inhibitory activity against bacterial and human α‐1,3‐FucTs. Several compounds incorporating appropriate hydrophobic moieties were identified from the initial screening. These were individually synthesized, purified and characterized in detail for their inhibition kinetics. Compound 5 had a K_i of 29 nM for human FucT‐VI, and is 269 and 11 times more selective than for Helicobacter pylori FucT (K_i=7.8 μM) and for human FucT‐V (K_i=0.31 μM).     

Discovery of an Allosteric Ligand Binding Site in SMYD3 Lysine Methyltransferase

SMYD3 is a multifunctional epigenetic enzyme with lysine methyltransferase activity and various interaction partners. It is implicated in the pathophysiology of cancers but with an unclear mechanism. To discover tool compounds for clarifying its biochemistry and potential as a therapeutic target, a set of drug-like compounds was screened in a biosensor-based competition assay. Diperodon was identified as an allosteric ligand; its R and S enantiomers were isolated, and their affinities to SMYD3 were determined (K_D=42 and 84 μM, respectively). Co-crystallization revealed that both enantiomers bind to a previously unidentified allosteric site in the C-terminal protein binding domain, consistent with its weak inhibitory effect. No competition between diperodon and HSP90 (a known SMYD3 interaction partner) was observed although SMYD3–HSP90 binding was confirmed (K_D=13 μM). Diperodon clearly represents a novel starting point for the design of tool compounds interacting with a druggable allosteric site, suitable for the exploration of noncatalytic SMYD3 functions and therapeutics with new mechanisms of action.