pKa Values Research Articles

Effect of organic acid additives on sulfite oxidation in a calcium-based slurry

The forced oxidation of sulfite ions was conducted to obtain high-quality gypsum in the flue gas desulfurization system. The effects of formic, lactic, acrylic, acetic, propionic, and hexanoic acids added to calcium-based slurry on sulfite oxidation were investigated in this study. Sulfite oxidation was inhibited when the pKa value of organic acids was small or the carbon chain was long. In the identical slurry pH 6, the SO4 2- fractions of slurries with formic and lactic acids, which have the smallest pKa values, were lower than half that of the additive-free slurry. The addition of hexanoic acid with the longest carbon chain showed a similar SO4 2- fraction to that of additive-free slurry. These results indicate that the inhibitory effect on sulfite oxidation is more expressed by the acidity of organic acids. The SO4 2- fraction in the slurry affects the growth and quality of gypsum crystals. The slurry with acetic acid presented the highest SO4 2- fraction and resulted in the formation of high-quality gypsum crystals. The findings of this study can contribute to the selection of organic acid additives with high desulfurization efficiency and the production of high-quality gypsum.

What Is the Protonation State of Proteins in Crystals? Insights from Constant pH Molecular Dynamics Simulations.

X-ray crystallography is an important technique to determine the positions of atoms in a protein crystal. However, because the native environment in which proteins function, is not a crystal, but a solution, it is not a priori clear if the crystal structure represents the functional form of the protein. Because the protein structure and function often depend critically on the pH, the question arises whether proton affinities are affected by crystallization. X-ray diffraction usually does not reveal protons, which makes it difficult to experimentally measure pKa shifts in crystals. Here, we investigate whether this challenge can be addressed by performing in silico titration with constant pH molecular dynamics (MD) simulations. We compare the computed pKa values of proteins between solution and crystal environment and analyze these differences in the context of molecular interactions. For the proteins considered in this work, pKa shifts were mostly found for residues at the crystal interfaces, where the environment is more apolar in the crystal than in water. Although convergence was an obstacle, our simulations suggest that in principle it is possible to apply constant pH MD to protein crystals routinely and assess the effect of crystallization on protein function more systematically than with standard MD simulations. We also highlight technical challenges that need to be addressed to make MD simulations of crystals more reliable.

Circumventing Kinetic Barriers to Metal Hydride Formation with Metal-Ligand Cooperativity.

We report the two-electron, one-proton mechanism of cobalt hydride formation for the conversion of [CoIIICp(PPh2NBn2)(CH3CN)]2+ to [HCoIIICp(PPh2NBn2)]+. This complex catalytically converts CO2 to formate under CO2 reduction conditions, with hydride formation as a key elementary step. Through a combination of electrochemical measurements, digital simulations, theoretical calculations, and additional mechanistic and thermochemical studies, we outline the explicit role of the PPh2NBn2 ligand in the proton-coupled electron transfer (PCET) reactivity that leads to hydride formation. We reveal three unique PCET mechanisms, and we show that the amine on the PPh2NBn2 ligand serves as a kinetically accessible protonation site en route to the thermodynamically favored cobalt hydride. Cyclic voltammograms recorded with proton sources that span a wide range of pKa values show four distinct regimes where the mechanism changes as a function of acid strength, acid concentration, and timescale between electrochemical steps. Peak shift analysis was used to determine proton transfer rate constants where applicable. This work highlights the astute choices that must be made when designing catalytic systems, including the basicity and kinetic accessibility of protonation sites, acid strength, acid concentration, and timescale between electron transfer steps, to maximize catalyst stability and efficiency.

Tricyanomethane or Dicyanoketenimine-Silylation makes the Difference.

Pseudohalides such as tricyanomethanide, [C(CN)3]-, are well known in chemistry, biochemistry and industrial chemistry. The protonated species HC(CN)3, a classic hydrogen pseudohalide Brønsted acid, is a very strong acid with a pKa value of -5. However, HC(CN)3 is difficult to handle as it tends to decompose rapidly or, more precisely, to oligo- and polymerize. Therefore, silylated pseudohalide compounds with the [Me3Si]+ as the "big organometallic proton" have become interesting, exhibiting similar chemical properties but better kinetic protection. Here, the stepwise silylation of the pseudohalide anion [C(CN)3]- is reported, forming the heavier homologue of HC(CN)3, namely [Me3Si][C(CN)3], and in presence of two additional [Me3Si]+ cations even the dicationic species [(Me3Si-NC)3C]2+ as stable [B(C6F5)4]- salt. Surprisingly, in contrast to the protonated species HC(CN)3, in which the proton is bound to the central carbon atom of [C(CN)3]-, silylation of the [C(CN)3]- anion occurs at one of the three terminal nitrogen atoms, thus forming the long-sought dicyanoketenimine [Me3Si-NC-C(CN)2]. All further silylation steps take place exclusively on the terminal N atoms of the three CN groups and not on the central carbon atom, until the intriguing, highly symmetrical dication, [(Me3Si-NC)3C]2+, is finally generated. The experimental data are supported by quantum chemical calculations in terms of thermodynamics and chemical bonding.

A Novel Method for Combination of Ionic Conductivity and pH-metry Methods for the Determination of the Aqueous Solubility of a New Diisopropylammonium Hydrogenmaleate Crystalline Molecule

Dissociation constant, solubility, and thermodynamic data are very important physicochemical parameters for biological substances and their knowledge is of fundamental importance for the validation of drugs. In addition to their low cost and accessibility, Conductometric and pH-metric methods seem to be particularly suitable for the determination of these parameters given the often weak acidic or basic nature of drugs. These parameters were determined for a new synthesized diisopropylammonium hydrogenmaleate (iPr2NH2-MA) crystalline molecule. Conductometric and pH-metric methods were used for this characterization. The pH-metric method lead to pKa1 = 3.6, pKa2 = 6.7 and pKa3 = 7.5, while the conductometric method made it possible to determine two pKa values which are pKa1 = 3.5 and pKa3 = 7.8. The values of the thermodynamic parameters calculated for the enthalpy change (∆rH0) and the entropy change (∆S) of the iPr2NH2-MA acidic dissociation reaction are of the order of ∆H = 25. 36 ± 0.06 kJ.mol-1 and ∆S = 6.08 ± 0.18 kJ.mol-1.K-1. In addition, the Gibbs free energy change (ΔG) of the molecule decreased as a function of temperature. The solubility varied between 1 and 84 mg mL-1 for pH values comprised between 3.5 and 8.5 and reached its maximum Smax = 84 mg mL-1 at pH 5.6. The dissociation process was found to be is non-spontaneous, endothermic and entropically favorable. These results demonstrated on the one hand the reliability and effectiveness of the Conductometric and pH-metric methods for the characterization of molecules with acidic and/or basic sites, and on the other hand the excellent physical and chemical properties of diisopropylammonium hydrogenmaleate (iPr2NH2-MA) crystalline molecule.

Zein and 3-Aminophenyl Boronic Acid Conjugated Polyvinylpyrrolidone Polymer Blend: Electrospinning, Characterization, and Mucoadhesive Drug Delivery.

The era of mucoadhesive polymers has advanced to the next generation, focusing on targeted adhesion of chemical functional groups with mucosa. This work aims to develop boronic acid functionalized polymers, which could facilitate reversible binding with the mucin in the mucosa. Pendant groups of boronic acid were conjugated on the chains of polyvinylpyrrolidone (PVP) via C═N bonding. The evidence from FTIR spectroscopy, XPS analysis, and UV spectroscopy has been used for the confirmation of the chemical conjugation of 3-aminophenyl boronic acid (APBA) to PVP. Boronate ester formation is a pH-dependent process. High pKa values of APBA preferably cause the binding of trigonal-shaped boronic acid with sialic acid groups of mucin. Boronic acid moieties additionally benefited in mucoadhesion in comparison to PVP alone, which is a result of the formation of a five-membered boronate ester complex. The presence of boronic acid moieties enhanced the force of adhesion on porcine buccal mucosal tissue from 13.12 ± 1.52 to 19.04 ± 1.97 g force. Specific binding of the polymer to the mucosal surface caused prolonged adhesion of the polymer to the mucosal surface. A polymer blend of boronic acid functionalized PVP and zein has been explored for its potential for mucoadhesive delivery of propranolol hydrochloride.

Widening the stimuli-responsiveness of aqueous biphasic systems by changing the ionic liquid cation basicity.

Herein we demonstrate the formation of new stimuli-responsive aqueous biphasic systems (ABS), able to respond simultaneously to temperature and pH, or just to one stimulus, therefore allowing the design of more sustainable separation processes. This dual behavior is achieved with ABS formed by mono or dicationic protic ionic liquids as phase-forming components, being defined by the ionic liquid cation chemical structure or its basicity. While ABS comprising monocationic ionic liquids only respond to the effect of temperature, systems comprising dicationic ionic liquids are simultaneously affected by both temperature and pH variations. Dicationic ionic liquids are here identified as the key to unlock a double response to stimuli, which is due to the presence of two pKa values afforded by the cation. The reported findings contribute to increase the customizability of double stimuli-responsive ABS based on ionic liquids, whose development was up to date limited to ionic liquids bearing pH-responsive anions, opening the door towards the development of more sustainable separation processes.

Computational insights into human UCP1 activators through molecular docking, MM-GBSA, and molecular dynamics simulation studies

The prevalence of obesity is rapidly increasing worldwide. Brown adipose tissue activates uncoupling protein 1 (UCP1) to generate heat through bypassing ATP synthesis, offering a potential target for obesity treatment. Targeting UCP1 activation to induce thermogenesis through small molecules presents a promising approach for obesity management. In this study, molecular docking of UCP1 activators, using 2,4-dinitrophenol (DNP) as a reference ligand (PDB ID: 8J1N, docking score: −5.343 kcal/mol), identified seven top-scoring compounds: naringin (-7.284 kcal/mol), quercetin (-6.661 kcal/mol), salsalate (-6.017 kcal/mol), rhein (-5.798 kcal/mol), mirabegron (-5.535 kcal/mol), curcumin (-5.479 kcal/mol), and formoterol (-5.451 kcal/mol). Prime MM-GBSA calculation of the top-scored molecule (i.e., naringin) in the docking study showed ΔGBind of −70.48 kcal/mol. Key interactions of these top 7 activators with UCP1 binding pocket residues Trp280, Arg276, Glu190, Arg83, and Arg91 were observed. Molecular dynamics simulations performed for 100 ns confirmed complex stability, with RMSD values below 6 Å. Additionally, most activators showed favorable intestinal absorption (>90 %) and lipophilicity (LogP 2–4), with pKa values supporting their pharmacological potential as UCP1-targeting therapeutics for obesity. These findings provide a foundation for designing potent UCP1 activators by integrating docking scores, interaction profiles, statistical profiles from MD simulations, and physicochemical assessments to develop effective anti-obesity therapies.

Direct observation of the complex S(IV) equilibria at the liquid-vapor interface

The multi-phase oxidation of S(IV) plays a crucial role in the atmosphere, leading to the formation of haze and severe pollution episodes. We here contribute to its understanding on a molecular level by reporting experimentally determined pKa values of the various S(IV) tautomers and reaction barriers for SO2 formation pathways. Complementary state-of-the-art molecular-dynamics simulations reveal a depletion of bisulfite at low pH at the liquid-vapor interface, resulting in a different tautomer ratio at the interface compared to the bulk. On a molecular-scale level, we explain this with the formation of a stable contact ion pair between sulfonate and hydronium ions, and with the higher energetic barrier for the dehydration of sulfonic acid at the liquid-vapor interface. Our findings highlight the contrasting physicochemical behavior of interfacial versus bulk environments, where the pH dependence of the tautomer ratio reported here has a significant impact on both SO2 uptake kinetics and reactions involving NOx and H2O2 at aqueous aerosol interfaces.

Determination of the pKa Value of a Brønsted Acid by 19F NMR Spectroscopy.

Brønsted acids, such as phosphoric acids derived from chiral 1,1'-bi-2-naphthol (BINOL), are important catalysts in the formation of carbon-carbon and carbon-heteroatom bonds, for example. The catalytic activity of these Brønsted acids is strongly linked to their acidity, and as such, the evaluation of compounds to determine pKa values provides insight into their catalytic activity. Herein, a 19F{1H} NMR methodology is detailed to determine the pKa of a fluorinated binaphthyl-derived phosphinic acid, rac-1, in acetonitrile and in the presence of a fluorinated sulfonamide reference compound (2-4). The approach was tested initially using 2 and 3, with the ΔpKa (0.08) in strong agreement with previously reported values (6.6 for 2 and 6.68/6.73 for 3). Sigmoidal curves of normalised chemical shift change (Δδ) against equivalents of the base phosphazene P1-tBu added overlapped for 2 and 3, but in the case of rac-1 and either 2, 3 or 4, there was significant separation. A variety of different approaches for determining the ΔpKa were compared. Values of pKa determined when the normalised Δδ was 90% were optimal for 2 and 3, whereas a normalised Δδ of 75% was optimal for 4, resulting in the pKa of rac-1 being determined to be 8.47-8.71.

Photocleavable Protecting Groups Using a Sulfite Self‐Immolative Linker for High Uncaging Quantum Yield and Aqueous Solubility

AbstractUsing light as an external stimulus to control (bio)chemical processes offers many distinct advantages. Most importantly, it allows for spatiotemporal control simply through operating the light source. Photocleavable protecting groups (PPGs) are a cornerstone class of compounds that are used to achieve photocontrol over (bio)chemical processes. PPGs are able to release a payload of interest upon light irradiation. The successful application of PPGs hinges on their efficiency of payload release, captured in the uncaging Quantum Yield (QY). Heterolytic PPGs efficiently release low pKa payloads, but their efficiency drops significantly for payloads with higher pKa values, such as alcohols. For this reason, alcohols are usually attached to PPGs via a carbonate linker. The self‐immolative nature of the carbonate linker results in concurrent release of CO2 with the alcohol payload upon irradiation. We introduce herein novel PPGs containing sulfites as self‐immolative linkers for photocaged alcohol payloads, for which we discovered that the release of the alcohol proceeds with higher uncaging QY than an identical payload released from a carbonate‐linked PPG. Furthermore, we demonstrate that uncaging of the sulfite‐linked PPGs results in the release of SO2 and show that the sulfite linker improves water solubility as compared to the carbonate‐based systems.

Photocleavable Protecting Groups Using a Sulfite Self-Immolative Linker for High Uncaging Quantum Yield and Aqueous Solubility.

Using light as an external stimulus to control (bio)chemical processes offers many distinct advantages. Most importantly, it allows for spatiotemporal control simply through operating the light source. Photocleavable protecting groups (PPGs) are a cornerstone class of compounds that are used to achieve photocontrol over (bio)chemical processes. PPGs are able to release a payload of interest upon light irradiation. The successful application of PPGs hinges on their efficiency of payload release, captured in the uncaging Quantum Yield (QY). Heterolytic PPGs efficiently release low pKa payloads, but their efficiency drops significantly for payloads with higher pKa values, such as alcohols. For this reason, alcohols are usually attached to PPGs via a carbonate linker. The self-immolative nature of the carbonate linker results in concurrent release of CO2 with the alcohol payload upon irradiation. We introduce herein novel PPGs containing sulfites as self-immolative linkers for photocaged alcohol payloads, for which we discovered that the release of the alcohol proceeds with higher uncaging QY than an identical payload released from a carbonate-linked PPG. Furthermore, we demonstrate that uncaging of the sulfite-linked PPGs results in the release of SO2 and show that the sulfite linker improves water solubility as compared to the carbonate-based systems.

Heterocyclic effect boosted peroxidase-like activity of MIL(Fe) metal-organic framework for colorimetric assay and dye removal

Metal-organic frameworks (MOFs) have emerged as promising candidates for enzyme mimics due to their abundant pore structures and adjustable active sites. The catalytic activity particularly depends on the electronic character of the organic ligand. In this study, we report an iron-based MOF nanozyme FeTDC, created by replacing the 1,4-dicarboxybenzene ligand with five-membered 2,5-thiophenedicarboxylic acid (H2TDC). In comparison with the phenyl analogue, the sulfur-based heterocyclic ligand demonstrates high electron delocalization, and a low pKa value, which are beneficial for enhancing the metal/ligand interactions. Accordingly, FeTDC can facilitate the oxidation of the benzidine substrate in the presence of H2O2, thereby exhibiting remarkable peroxidase-like activity. The generation of hydroxyl radical (•OH) at the Fe active sites contributes to the catalytic process. Furthermore, the smartphone-assisted colorimetric assay of pyrophosphate was developed with high sensitivity, based on its inhibitory effect. When FeTDC was utilized for the removal of benzidine dye under high-salt condition, a 90 % of removal rate was achieved due to the synergistic effect of enzyme catalysis and physical adsorption. This work presents a novel perspective of heterocyclic effect on the design of MOF nanozymes, thereby expanding their applicability in the control of pollutants.

A proton-coupled electron transfer process from functionalized carbon dots to molecular substrates: the role of pH.

Multiple electron and proton transfers in nanomaterials pose significant demands and challenges across the various fields such as renewable energy, chemical processes, biological applications, and photophysics. In this context, pH-responsive functional group-enriched carbon dots (C-Dots) emerge as superior proton-coupled electron transfer (PCET) agents owing to the presence of multiple functional groups (-COOH, -NH2, and -OH) on the surface and redox-active sites in the core. Here, we elucidate the 2e-/2H+ transfer ability of carboxyl-enriched C-Dots (C-Dot-COOH) and amine-enriched C-Dots (C-Dot-NH2) with molecular 2e-/2H+ acceptor (benzoquinone, BQ) as a function of pKa, facilitated by the formation of new O-H bonds. The ground state and excited state pKa values of different functional groups on the surface of C-Dots are determined using steady-state absorbance and photoluminescence (PL) spectroscopy. The optical spectroscopy and electrochemical studies are employed to comprehend the influence of the surface and core of C-Dots on the proton and electron transfer processes as a function of pH. The cyclic voltammetry analysis reveals a standard Nernstian shift in E1/2 per pH unit of 30 mV, indicating that the functionalized C-Dots hold promise as candidates for the 2e-/2H+ transfer process. The calculated bond dissociation free energy (BDFE) of the electroactive O-H/N-H bonds provides a more nuanced and detailed understanding of PCET thermodynamic landscapes. These findings underscore the potential of nanoscale functionalized C-Dots for facilitating multiple PCET reactions in future energy technologies.

Sulfonamide-Sulfonimide Copolymers as Novel, Fluorine-Lean Type of Proton Exchange Membranes for Fuel Cell Application.

In this work, a novel type of fluorine-lean proton exchange membranes is presented, using sulfonamide-sulfonimide functional groups for ion conduction. These groups are constructed on a polystyrene backbone for simple and cost-efficient usage as well as rapid scalability. The polymer is further tailored by adjusting the sulfonamide functionality with various end-groups, namely pentafluorophenyl, 4-fluorophenyl, butyl and octyl groups. These groups affect the pKa, leading to pKa values of 5.7 for the pentafluorophenyl substitution and pKa 10.5 for the alkyl chain. The glass transition temperature of the sulfonamide homopolymers can be reduced from Tg=151 °C (Pentafluorophenyl) to 49 °C (Octyl), making the ionomer more flexible at room temperature. The combination of the non-swelling sulfonamide further mitigates the high water uptake of the sulfonimide while maintaining the nominal ion exchange capacity. This combination leads to extremely high proton conductivities with up to σ=283 mS cm-1 at room temperature, which is clearly outperforming Nafion and approaches values for acid doped systems. This approach can pave the way to a novel type of ion conducting class in proton exchange membrane fuel cells.

Highly Acidic Electron-Rich Brønsted Acids Accelerate Asymmetric Pictet-Spengler Reactions by Virtue of Stabilizing Cation-π Interactions.

Electron-rich heteroaromatic imidodiphosphorimidates (IDPis) catalyze the asymmetric Pictet-Spengler reaction of N-carbamoyl-β-arylethylamines with high stereochemical precision. This particular class of catalysts furthermore provides a vital rate enhancement compared to related Brønsted acids. Here we present experimental studies on the underlying reaction kinetics that shed light on the specific origins of rate acceleration. Analysis of Hammett plots, kinetic isotope effects, reaction orders, Eyring plots, and isotopic scrambling experiments, allowed us to gather insights into the molecular interactions between the chiral Brønsted acid and catalytically formed intermediates. Based on rigorously determined pKa values as well as the experimental evidence, we propose that attractive intermolecular forces offered by electron-rich π-surfaces of the chiral counteranion enthalpically stabilize cationic intermediates and transition states by way of cation-π interactions. This view is furthermore supported by in-depth density functional theory calculations. Our deepened understanding of the reaction mechanism allowed us to develop a method for accessing 1-aryltetrahydroisoquinolines from aromatic dimethyl acetals, a substrate class that was thus far inaccessible via catalytic asymmetric Pictet-Spengler reactions.

Synthesis of Azabicyclic Isosteres of Piperazine 2S-Carboxylic Acid.

Methods have been developed for the stereocontrolled synthesis of bicyclic diaza [3.3.0] octane carboxylic acids as possible isosteres of piperazine 2S-carboxylic acid. In the first approach, l-pyroglutamic acid was functionalized adopting new as well as documented reaction sequences via Michael and aza-Michael reactions, leading to two of the four intended isosteres. An alternative shorter route relying on enolate chemistry starting with N-Pf 4-keto l-proline methyl ester led to two other isosteres. Calculated pKa values and density functional theory (DFT) calculations have provided some insights into the relative basicities of the nitrogen atoms in these diaza [3.3.0] octane carboxylic acids in relation to piperazine 2S-carboxylic acid.

Development of Donor-acceptor-type Molecules and Their Application as Analytical Reagents

π-Extended donor-acceptor (D-A)-type molecules, which bear both electron-donor and electron-acceptor substituents on the backbone, exhibit unique optical properties, such as bathochromic shifts in absorption and emission, large Stokes shifts, solvatochromic behavior, and fluorescence quenching in polar solvents. These unique properties are attributed to intramolecular charge transfer (ICT) or twisted intramolecular charge transfer (TICT) in the ground and excited states. This review article introduces three types of D-A-type molecules that are used as detection reagents for (1) methanol, (2) amino acids during solid-phase peptide synthesis (SPPS), and (3) amines present in the biological environment. For methanol detection, D-A-type fluorophores with basic guanidine moieties were developed to differentiate between methanol (MeOH) and ethanol (EtOH) based on the small difference in their pKa values (ΔpKa=0.4). Selective protonation of the guanidine moiety in methanol disrupts the D-A structure, allowing emission in the resultant polar environment. Similarly, an acid-base reaction between the hydrogen chloride (HCl) salts of the D-A-type molecules and amines is applied to detect amines during SPPS. In this method, a colorless solution of an HCl salt of the D-A-type molecule is deprotonated by amines, forming a yellow solution. This is the first reported quantitative and non-destructive colorimetric method for detecting amines. Finally, a turn-on-type amine-labeling reagent was developed for the nucleophilic aromatic substitution (SNAr) reaction. This new reagent enables protein staining of living cells with a large Stokes shift and without solvent-polarity-dependent fluorescence quenching.

Halogenated monopyridinium oximes are less effective in reactivation of phosphylated cholinesterases than bisquaternary oximes

Mono-quaternary pyridinium oximes derived from K-oximes K027, K048 and K203 were designed, synthesized and evaluated for the reactivation of organophosphate-inhibited cholinesterases. The incorporation of the halogen atoms to the structure decreased the pKa value of the oxime group resulting in an increased formation of oximate necessary for reactivation. The stability and pKa values were found to be similar to analogous bis-quaternary compounds. Some mono-quaternary oximes resulted as relatively strong inhibitors of human acetylcholinesterase. Nevertheless, the reactivation ability of mono-quaternary oximes for organophosphate-inhibited cholinesterases was lower compared to their bis-quaternary analogues. These results were further confirmed by the determination of reactivation kinetics, when in some cases novel compounds showed improvement reactivation compared to the tested standards, but no improvement to bis-quaternary K-oximes. A computational study investigated reactivation process for K027, and its two analogues for VX-inhibited AChE. This study revealed slight differences between reactivation of mono-quaternary and bis-quaternary oximes.Abbreviations: 2-PAM, pralidoxime; AChE, acetylcholinesterase; ACN, acetonitrile; ATCI, acetylcholine iodide; BChE, butyrylcholinesterase; BTCI, butyrylcholine iodide; Bu3SnSnBu3, bis(tributyltin) Et2O, diethyl ether; ChEs, cholinesterases; CNS, central nervous system; DAD, diode array detector; DIBAL-H, diisobutylaluminium hydride; DMF, dimethylformamide; DMSO, dimethyl sulfoxide; DTNB, 5,5́-dithiobis-2-nitrobenzoic acid; Et3N, triethylamine; EtOAc, ethyl acetate; EWG, electron withdrawing group; HI-6, asoxime; hrAChE, human recombinant acetylcholinesterase; hrBChE, human recombinant butyrylcholinesterase; hrChEs, human recombinant cholinesterases; HPLC, high-performance liquid chromatography; HRMS, high-resolution mass spectrometry; KD, dissociation constant; kr, first-order reactivation rate constant; kr2, second-order reactivation rate constant; LüH-6, obidoxime; MeOH, methanol; MM, molecular mechanics; MMC-4, methoxime; m.p., melting point; NCIs, non-covalent interactions; NEDPA, 4-nitrophenyl ethyl dimethylphosphoramidate; NEMP, 4-nitrophenyl ethyl methylphosphonate; NIMP, isopropyl methylphosphonate; NMR, nuclear magnetic resonance spectroscopy; OPs, organophosphates; PBS, phosphate-buffered saline; Pd(dppf)Cl2.CH2Cl2, [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) in complex with dichloromethane; pKa, negative decimal logarithm of the dissociation constant; POX, paraoxon; PPh3, triphenylphosphine; QM, quantum mechanics r.t., room temperature; SN2, bimolecular nucleophilic substitution; SNAc, nucleophilic acyl substitution; THF, tetrahydrofuran; TMC-4, trimedoxime; TNB, 5-thio-2-nitrobenzoic acid; UHPLC, ultra high-performance liquid chromatography; UV, ultraviolet; UV–VIS, ultraviolet–visible.

Combinatorial Synthesis of Alkyl Chain-Capped Poly(β-Amino Ester)s for Effective siRNA Delivery.

Poly (β-amino ester) (PBAE) is a class of biodegradable polymers containing ester bonds in their main chain, extensively investigated as cationic polymer carriers for siRNA. Most current PBAE carriers rely on termination with hydrophilic or charged amines. In this study, a polymer platform consisting of 168 PBAE polymers with hydrophobic alkyl chain terminals is constructed through sequential aza-Michael addition. A large number of effective carriers are identified through in vitro screening of the PBAE platform for siLuc delivery to HeLa-Luc cells. Specifically, PA8-C6 and PA8-C8 achieve remarkable gene knockdown efficacies of up to 80% with low cytotoxicity. Certain materials from the PA2 and PA5 series demonstrate potent siRNA delivery capabilities associated with elevated cytotoxicity. The pKa value of PBAE is predominantly determined by the hydrophilic amine side chains rather than the end-capping groups. A pKa range of ≈6.2-6.5 may contribute to the excellent delivery capability for PA8 series carriers. The co-formulation of PBAE carriers with helper lipids leads to the reduced size and surface charges of the polyplex NPs with siRNA, consequently decreasing the cytotoxicity and enhancing siRNA delivery efficacy. These findings hold significant implications for the development of novel degradable polymer carriers for siRNA delivery.