Imidazolium-type anion exchange membranes for improved organic acid transport and permselectivity in electrodialysis

Most commercial anion exchange membranes (AEMs) deploy quaternary ammonium moieties. Alternative cation moieties have been explored in AEMs for fuel cells, but there are no studies focused examining alternative tethered cations in AEMs for ionic separations – such as organic acid anion transport via electrodialysis. H-cell and conductivity experiments demonstrate that tethered benzyl 1-methyl imidazolium groups in polysulfone AEMs enhance lactate conductivity by 49% and improved lactate anion flux by 24x when compared to a quaternary benzyl ammonium polysulfone AEM. An electrodialysis demonstration with the imidazolium-type AEM showed a 2x improvement in lactate anion flux and 20% improvement in permselectivity when benchmarked against the quaternary ammonium AEM. Molecular dynamics and 2D NOESY NMR revealed closer binding of lactate anions to the imidazolium cations when compared to the quaternary ammonium cation. It is posited that this closer binding is responsible to greater flux values observed with imidazolium-type AEM.

Synthesis of Nucleoside-like Molecules from a Pyrolysis Product of Cellulose and Their Computational Prediction as Potential SARS-CoV-2 RNA-Dependent RNA Polymerase Inhibitors

(1R,5S)-1-Hydroxy-3,6-dioxa-bicyclo[3.2.1]octan-2-one, available by an efficient catalytic pyrolysis of cellulose, has been applied as a chiral building block in the synthesis of seven new nucleoside analogues, with structural modifications on the nucleobase moiety and on the carboxyl- derived unit. The inverted configuration by Mitsunobu reaction used in their synthesis was verified by 2D-NOESY correlations, supported by the optimized structure employing the DFT methods. An in silico screening of these compounds as inhibitors of SARS-CoV-2 RNA-dependent RNA polymerase has been carried out in comparison with both remdesivir, a mono-phosphoramidate prodrug recently approved for COVID-19 treatment, and its ribonucleoside metabolite GS-441524. Drug-likeness prediction and data by docking calculation indicated compound 6 [=(3S,5S)-methyl 5-(hydroxymethyl)-3-(6-(4-methylpiperazin-1-yl)-9H-purin-9-yl)tetrahydrofuran-3-carboxylate] as the best candidate. Furthermore, molecular dynamics simulation showed a stable interaction of structure 6 in RNA-dependent RNA polymerase (RdRp) complex and a lower average atomic fluctuation than GS-441524, suggesting a well accommodation in the RdRp binding pocket.

Trikoramides B–D, Bioactive Cyanobactins from the Marine Cyanobacterium Symploca hydnoides

Three new cyanobactins, trikoramides B (1)–D (3), have been isolated from the marine cyanobacterium, Symploca hydnoides, following a preliminary bioassay-guided isolation of the two most active polar fractions based on the brine shrimp toxicity assay. These new cyanobactins are new analogues of the previously reported cytotoxic trikoramide A (4) with differences mainly in the C-prenylated cyclotryptophan unit. Their planar structures were elucidated from their 1D and 2D NMR spectral data in combination with the HRMS/MS data. Marfey’s method, 2D NOESY NMR spectroscopic and ECD spectra analyses were used to determine the absolute stereochemistry of trikoramides B (1)–D (3). Trikoramides B (1) and D (3) exhibited cytotoxicity against MOLT-4 acute lymphoblastic leukemia cell line with IC50 values of 5.2 µM and 4.7 µM, respectively. Compounds 1 and 3 were also evaluated for their quorum-sensing inhibitory assay based on the Pseudomonas aeruginosa PAO1 lasB-gfp and rhlA-gfp bioreporter strains. Although trikoramide B (1) exhibited weak quorum-sensing inhibitory activity, the Br-containing trikoramide D (3) exhibited moderate to significant dose-dependent quorum-sensing inhibitory activities against PAO1 lasB-gpf and rhlA-gfp bioreporter strains with IC50 values of 19.6 µM and 7.3 µM, respectively.

Poly(2-oxazoline)-Based Amphiphilic Gradient Copolymers as Nanocarriers for Losartan: Insights into Drug–Polymer Interactions

The current study is focused on the development of highly stable drug nanocarriers by encapsulating losartan potassium (LSR) into an amphiphilic biocompatible poly(2-methyl-2-oxazoline)-grad-poly(2-phenyl-2-oxazoline) (PMeOxz72-grad-PPhOxz28) gradient copolymer (GC). Based on dynamic light scattering (DLS), the PMeOxz72-grad-PPhOxz28 (where the subscripts denote %wt composition of the components) GC formed micelles and aggregates of 13 nm and 96 nm in aqueous milieu. The presence of hydrophobic LSR molecules altered the structural characteristics of the GC, modulating the organization of the polymeric components and revealing the formation of hyper micellar nanostructures in addition to micelles. The 2D-NOESY experiments evidenced intermolecular interactions between the phenyl ring of LSR with the phenyl group of PPhOxz and eminent correlations between the butyl chain of LSR with the phenyl group of PPhOxz and methylene group of PMeOxz, respectively. Additionally, NMR studies as a function of temperature demonstrated that the presence of hydrophilic PMeOxz segments in the gradient core of PMeOxz72-grad-PPhOxz28 nanoassemblies induced an increased fluidity of the core matrix, especially upon heating, thus causing water penetration, resulting in increased proton mobility. Lastly, the ultrasound release profile of LSR signified that a great amount of the encapsulated LSR is tightly bound to the PMeOxz72-grad-PPhOxz28 nanoassemblies.

Nano-Assemblies from Amphiphilic PnBA-b-POEGA Copolymers as Drug Nanocarriers

The focus of this study is the development of highly stable losartan potassium (LSR) polymeric nanocarriers. Two novel amphiphilic poly(n-butyl acrylate)-block-poly(oligo(ethylene glycol) methyl ether acrylate) (PnBA-b-POEGA) copolymers with different molecular weight (Mw) of PnBA are synthesized via reversible addition fragmentation chain transfer (RAFT) polymerization, followed by the encapsulation of LSR into both PnBA-b-POEGA micelles. Based on dynamic light scattering (DLS), the PnBA30-b-POEGA70 and PnBA27-b-POEGA73 (where the subscripts denote wt.% composition of the components) copolymers formed micelles of 10 nm and 24 nm in water. The LSR-loaded PnBA-b-POEGA nanocarriers presented increased size and greater mass nanostructures compared to empty micelles, implying the successful loading of LSR into the inner hydrophobic domains. A thorough NMR (nuclear magnetic resonance) characterization of the LSR-loaded PnBA-b-POEGA nanocarriers was conducted. Strong intermolecular interactions between the biphenyl ring and the butyl chain of LSR with the methylene signals of PnBA were evidenced by 2D-NOESY experiments. The highest hydrophobicity of the PnBA27-b-POEGA73 micelles contributed to an efficient encapsulation of LSR into the micelles exhibiting a greater value of %EE compared to PnBA30-b-POEGA70 + 50% LSR nanocarriers. Ultrasound release profiles of LSR signified that a great amount of the encapsulated LSR is strongly attached to both PnBA30-b-POEGA70 and PnBA27-b-POEGA73 micelles.

Spontaneous and frequent conformational dynamics induced by A…A mismatch in d(CAA)·d(TAG) duplex

Base pair mismatches in DNA can erroneously be incorporated during replication, recombination, etc. Here, the influence of A…A mismatch in the context of 5′CAA·5′TAG sequence is explored using molecular dynamics (MD) simulation, umbrella sampling MD, circular dichroism (CD), microscale thermophoresis (MST) and NMR techniques. MD simulations reveal that the A…A mismatch experiences several transient events such as base flipping, base extrusion, etc. facilitating B–Z junction formation. A…A mismatch may assume such conformational transitions to circumvent the effect of nonisostericity with the flanking canonical base pairs so as to get accommodated in the DNA. CD and 1D proton NMR experiments further reveal that the extent of B–Z junction increases when the number of A…A mismatch in d(CAA)·d(T(A/T)G) increases (1–5). CD titration studies of d(CAA)·d(TAG)n=5 with the hZαADAR1 show the passive binding between the two, wherein, the binding of protein commences with B–Z junction recognition. Umbrella sampling simulation indicates that the mismatch samples anti…+ syn/+ syn…anti, anti…anti & + syn…+ syn glycosyl conformations. The concomitant spontaneous transitions are: a variety of hydrogen bonding patterns, stacking and minor or major groove extrahelical movements (with and without the engagement of hydrogen bonds) involving the mismatch adenines. These transitions frequently happen in anti…anti conformational region compared with the other three regions as revealed from the lifetime of these states. Further, 2D-NOESY experiments indicate that the number of cross-peaks diminishes with the increasing number of A…A mismatches implicating its dynamic nature. The spontaneous extrahelical movement seen in A…A mismatch may be a key pre-trapping event in the mismatch repair due to the accessibility of the base(s) to the sophisticated mismatch repair machinery.

Diversity-Oriented Synthesis of Novel Trihalomethyl-Containing Spirochromeno[3,4-a](thia)pyrrolizidines and Spirochromeno-[3,4-a]indolizidines by One-Pot, Three-Component [3+2]-Cyclo­addition Reaction

Regio- and stereoselective methods for the synthesis of 6′-trifluoro(trichloro)methyl substituted spiro[acenaphthylene-1,11′-chromeno[3,4-a](thia)pyrrolizidin]-2-ones and spiro[acenaphthylene-1,12′-chromeno[3,4-a]indolizidin]-2-ones have been developed based on the three-component reaction of 3-nitro-2-trifluoro(trichloro)methyl-2H-chromenes with azomethine ylides generated in situ from acenaphthenequinone and cyclic α-amino acids. The cycloaddition proceeds under mild conditions in ethanol or DMSO, and only endo-isomers of the products with cis-arrangement of nitro and trifluoromethyl groups are formed. The relative configuration of cycloadducts is reliably confirmed by X-ray diffraction analysis and by 2D NOESY spectroscopy.

Experimental Characterization of the Association of Nine Novel Cyclodextrin Derivatives with Two Guest Compounds

We investigate the binding of native β-cyclodextrin (β-CD) and eight novel β-CD derivatives with two different guest compounds, using isothermal calorimetry (ITC) and 2D NOESY NMR. In all cases, the stoichiometry is 1:1 and binding is exothermic. Overall, modifications at the 3’ position of β-CD, which is at the secondary face, weaken binding by several kJ/mol relative to native β-CD, while modifications at the 6’ position (primary face) maintain or somewhat reduce the binding affinity. The variations in binding enthalpy are larger than the variations in binding free energy, so entropy-enthalpy compensation is observed. Characterization of the bound conformations with NOESY NMR shows that the polar groups of the guests may be situated at either face, depending on the host molecule, and, in some cases, both orientations are populated. The present results were used in the SAMPL7 blinded prediction challenge whose results are detailed in the same special issue of JCAMD.

Experimental Characterization of the Association of Nine Novel Cyclodextrin Derivatives with Two Guest Compounds

We investigate the binding of native β-cyclodextrin (β-CD) and eight novel β-CD derivatives with two different guest compounds, using isothermal calorimetry (ITC) and 2D NOESY NMR. In all cases, the stoichiometry is 1:1 and binding is exothermic. Overall, modifications at the 3’ position of β-CD, which is at the secondary face, weaken binding by several kJ/mol relative to native β-CD, while modifications at the 6’ position (primary face) maintain or somewhat reduce the binding affinity. The variations in binding enthalpy are larger than the variations in binding free energy, so entropy-enthalpy compensation is observed. Characterization of the bound conformations with NOESY NMR shows that the polar groups of the guests may be situated at either face, depending on the host molecule, and, in some cases, both orientations are populated. The present results were used in the SAMPL7 blinded prediction challenge whose results are detailed in the same special issue of JCAMD.

Hydrogen Bonding in a l-Glutamine-Based Polyamidoamino Acid and its pH-Dependent Self-Ordered Coil Conformation

This paper reports on synthesis, acid–base properties, and self-structuring in water of a chiral polyamidoamino acid, M-l-Gln, obtained from the polyaddition of N,N′-methylenebisacrylamide with l-glutamine, with the potential of establishing hydrogen bonds through its prim-amide pendants. The M-l-Gln showed pH-responsive circular dichroism spectra, revealing ordered conformations. Structuring was nearly insensitive to ionic strength but sensitive to denaturing agents. The NMR diffusion studies were consistent with a population of unimolecular nanoparticles thus excluding aggregation. The M-l-Gln had the highest molecular weight and hydrodynamic radius among all polyamidoamino acids described. Possibly, transient hydrogen bonds between l-glutamine molecules and M-l-Gln growing chains facilitated the polyaddition reaction. Theoretical modeling showed that M-l-Gln assumed pH-dependent self-ordered coil conformations with main chain transoid arrangements reminiscent of the protein hairpin motif owing to intramolecular dipole moments and hydrogen bonds. The latter were most numerous at the isoelectric point (pH 4.5), where they mainly involved even topologically distant main chain amide N–H and side chain amide C=O brought to proximity by structuring. Hydrogen bonds at pH 4.5 were also suggested by variable temperature NMR. The 2D NOESY experiments at pH 4.5 confirmed the formation of compact structures through the analysis of the main chain/side chain hydrogen contacts, in line with MD simulations.