EGFR-targeted semiconducting polymer nanoparticles for photoacoustic imaging.

Semiconducting polymer nanoparticles (SPN), formulated from organic semiconducting polymers and lipids, show promise as exogenous contrast agents for photoacoustic imaging (PAI). To fully realise the potential of this class of nanoparticles for imaging and therapeutic applications, a broad range of active targeting strategies, where ligands specific to receptors on the target cells are displayed on the SPN surface, are urgently needed. In addition, effective strategies for quantifying the level of surface modification are also needed to support development of ligand-targeted SPN. In this paper, we have developed methods to prepare SPN bearing peptides targeted to Epidermal Growth Factor Receptors (EGFR), which are overexpressed at the surface of a wide variety of cancer cell types. In addition to fully characterising these targeted nanoparticles by standard methods (UV-visible, photoacoustic absorption, dynamic light scattering, zeta potential and SEM), we have developed a powerful new NMR method to determine the degree of conjugation and the number of targeting peptides attached to the SPN. Preliminary in vitro experiments with the colorectal cancer cell line LIM1215 indicated that the EGFR-targeting peptide conjugated SPN were either ineffective in delivering the SPN to the cells, or that the targeting peptide itself destabilised the formulation. This in reinforces the need for effective characterisation techniques to measure the surface accessibility of targeting ligands attached to nanoparticles.

Prebiotic Catalytic Peptide Ligation Yields Proteinogenic Peptides by Intramolecular Amide Catalyzed Hydrolysis Facilitating Regioselective Lysine Ligation in Neutral Water.

The prebiotic origin of catalyst-controlled peptide synthesis is fundamental to understanding the emergence of life. Building on our recent discovery that thiols catalyze the ligation of amino acids, amides, and peptides with amidonitriles in neutral water, we demonstrate the outcome of ligation depends on pH and that high pKa primary thiols are the ideal catalysts. While the most rapid thiol catalyzed peptide ligation occurs at pH 8.5-9, the most selective peptide ligation, that tolerates all proteinogenic side chains, occurs at pH 7. We have also identified the highly selective mechanism by which the intermediate peptidyl amidines undergo hydrolysis to α-peptides while demonstrating that the hydrolysis of amidines with nonproteinogenic structures, such as ß- and γ-peptides, displays poor selectivity. Notably, this discovery enables the highly α-selective protecting-group-free ligation of lysine peptides at neutral pH while leaving the functional ε-amine side chain intact.

Some Recent Advances in the Design and Use of Molecular Balances for the Experimental Quantification of Intramolecular Noncovalent Interactions of π Systems.

Herein, various molecular balances used for comparing the strengths of intramolecular noncovalent interactions are reviewed. Our overview indicates that considerable quantitative insight into the strength of noncovalent interactions can be gained through the careful design of molecular balances. Many exciting opportunities certainly exist for the design of further new balances to quantify and dissect the relative strengths of noncovalent interactions as a function of solvation and the importance of the many factors that contribute to overall molecular recognition. However, even simple model molecules can show a multiplicity of intramolecular noncovalent interactions acting in a combined fashion. It is therefore essential to undertake a detailed computational analysis to identify all possible noncovalent interactions present in a selected molecular balance prior to a quantitative experimental assessment of the strength of a particular noncovalent interaction. It is also argued that the words "torsion" and "molecular balance" seem to have become inextricably linked and, in consequence, even top pan and seesaw balances have been mistakenly referred to in these terms.

Structural and Dynamic Properties of Gallium Alkoxides.

A comparison of chlorido-gallium functionalized alkoxides as precursors for aerosol-assisted chemical vapor deposition (AACVD) was carried out. Variable-temperature (VT)-NMR studies were used to probe the fluxional behavior of these alkoxides in solution, and hence their utility as precursors. The synthesis involved the initial isolation of the dimer [GaCl(NMe2)2]2 via a salt metathesis route from GaCl3 and 2 equiv of LiNMe2. This dimer was then reacted with 4 equiv of HOCH2CH2CH2NEt2, resulting in the formation of Ga[µ-(OCH2CH2CH2NEt2)2GaCl2]3 (1). Mass spectrometry and VT-NMR confirmed the oligomeric structure of 1. Tuning of the ligand properties, namely, the chain length and substituents on N, resulted in formation of the monomers [GaCl(OR)2] (R = CH2CH2NEt2, (2); CH2CH2CH2NMe2, (3)). VT-NMR studies, supported by density functional theory calculations, confirmed that the ligands in both 2 and 3 possess a hemilabile coordination to the gallium center, owing to either a shorter carbon backbone (2) or less steric hindrance (3). Both 2 and 3 were selected for use as precursors for AACVD: deposition at 450 °C gave thin films of amorphous Ga2O3, which were subsequently annealed at 1000 °C to afford crystalline Ga2O3 material. The films were fully characterized by X-ray diffraction, X-ray photoelectron spectroscopy, scanning electron microscopy, UV-visible spectroscopy, and energy dispersive X-ray analysis.

Dihalohydration of Alkynols: A Versatile Approach to Diverse Halogenated Molecules.

In this paper we outline how dihalohydration reactions of propargylic alcohols can be used to access a wide variety of useful halogenated building blocks. A novel procedure for dibromohydration of alkynes has been developed, and a selection of dichloro and dibromo diols and cyclic ethers were synthesized. The dihalohydration of homo-propargylic alcohols provides a useful route to 3-halofurans, which were shown to readily undergo cycloaddition reactions under mild conditions. Finally, a novel ring expansion of propargylic alcohols containing a cyclopropylalkyne provides access to halogenated alkenylcyclobutanes.

Tin chemical shift anisotropy in tin dioxide: On ambiguity of CSA asymmetry derived from MAS spectra.

Two different axial symmetries of the 119Sn chemical shift anisotropy (CSA) in tin dioxide with the asymmetry parameter (η) of 0 and 0.27 were reported previously based on the analysis of MAS NMR spectra. By analyzing the static powder pattern, we show that the 119Sn CSA is axially symmetric. A nearly axial symmetry and the principal axis system of the 119Sn chemical shift tensor in SnO2 were deduced from periodic scalar-relativistic density functional theory (DFT) calculations of NMR parameters. The implications of fast small-angle motions on CSA parameters were also considered, which could potentially lead to a CSA symmetry in disagreement with a crystal symmetry. Our analysis of experimental spectra using spectral simulations and iterative fittings showed that MAS spectra recorded at relatively high frequencies do not show sufficiently distinct features in order to distinguish CSAs with η ≈ 0 and η ≈ 0.4. The example of SnO2 shows that both the MAS lineshape and spinning sideband analyses may overestimate the η value by as much as ∼0.3 and ∼0.4, respectively. The results confirm that a static powder pattern must be analysed in order to improve the accuracy of the CSA asymmetry measurements. The measurements on SnO2 nanoparticles showed that the asymmetry parameter of the 119Sn CSA increases for nm-sized particles with a larger surface area compared to µm-sized particles. The increase of the η value for tin atoms near the surface in SnO2 was also confirmed by DFT calculations.

Noncovalent Interactions of π Systems with Sulfur: The Atomic Chameleon of Molecular Recognition.

The relative strength of noncovalent interactions between a thioether sulfur atom and various π systems in designed top pan molecular balances was determined by NMR spectroscopy. Compared to its oxygen counterpart, the sulfur atom displays a remarkable ability to interact with almost equal facility over the entire range of π systems studied, with the simple alkene emerging as the most powerful partner. With the exception of the O⋅⋅⋅heteroarene interaction, all noncovalent interactions of sulfur with π systems are favoured over oxygen.

Microfibrous Solid Dispersions of Poorly Water-Soluble Drugs Produced via Centrifugal Spinning: Unexpected Dissolution Behavior on Recrystallization.

Temperature-controlled, solvent-free centrifugal spinning may be used as a means of rapid production of amorphous solid dispersions in the form of drug-loaded sucrose microfibers. However, due to the high content of amorphous sucrose in the formulations, such microfibers may be highly hygroscopic and unstable on storage. In this study, we explore both the effects of water uptake of the microfibers and the consequences of deliberate recrystallization for the associated dissolution profiles. The stability of sucrose microfibers loaded with three selected BCS class II model drugs (itraconazole (ITZ), olanzapine (OLZ), and piroxicam (PRX)) was investigated under four different relative humidity conditions (11, 33, 53, and 75% RH) at 25 °C for 8 months, particularly focusing on the effect of the highest level of moisture (75% RH) on the morphology, size, drug distribution, physical state, and dissolution performance of microfibers. While all samples were stable at 11% RH, at 33% RH the ITZ-sucrose system showed greater resistance against devitrification compared to the OLZ- and PRX-sucrose systems. For all three samples, the freshly prepared microfibers showed enhanced dissolution and supersaturation compared to the drug alone and physical mixes; surprisingly, the dissolution advantage was largely maintained or even enhanced (in the case of ITZ) following the moisture-induced recrystallization under 75% RH. Therefore, this study suggests that the moisture-induced recrystallization process may result in considerable dissolution enhancement compared to the drug alone, while overcoming the physical stability risks associated with the amorphous state.

The structure of tagetitoxin.

Based on detailed analysis of newly acquired NMR data, we show that the previously revised structure of tagetitoxin is incorrect. A new structure of tagetitoxin is proposed which is consistent with the NMR and MS data.

Synthesis of substituted benzooxaborinin-1-ols via palladium-catalysed cyclisation of alkenyl- and alkynyl-boronic acids.

Two new palladium-catalysed reactions have been developed for the synthesis of stable 4-substituted benzooxaborinin-1-ols. A palladium-catalysed cyclisation of ortho-alkenylbenzene boronic acids can be used to access 4-chlorobenzooxaborinin-1-ols via a Wacker-type oxidation and chlorination. Alternatively, ortho-alkynylbenzene boronic acids undergo a palladium-catalysed oxyallylation reaction to provide 4-allylbenzooxaborinin-1-ols.

Synthesis of novel and potent vorapaxar analogues.

Vorapaxar is a first-in-class PAR-1 antagonistic drug based on the ent-himbacine scaffold. Detailed in this article are enantioselective and racemic routes to various novel vorapaxar analogues. Biological testing revealed these compounds to have moderate to excellent potencies against PAR-1 with the most potent analogue demonstrating an IC50 of 27 nM.

Intramolecular Acylal Cyclisation (IAC) as an Efficient Synthetic Strategy towards the Total Synthesis of Erythrina Alkaloid Derivatives.

Compounds that comprise the erythrina alkaloid class of natural products are based on a tetracyclic spiroamine framework and exhibit a range of biological activities on the central nervous system. Herein, we report a new and efficient total synthesis of this multiple-ring system based on an intramolecular acylal cyclisation (IAC) approach. Using this methodology, the tetracyclic core was rapidly assembled over a two-step domino process catalysed by a Lewis acid. The effect of heteroatoms, substituents and ring size on the IAC has also been investigated, and the broad application of this procedure is demonstrated by the synthesis of a library of derivatives in good yields with excellent regioselectivity.

Photolysis of phenylalanine in the presence of oxidized carbon nanotubes.

Photolyses at 254 nm of phenylalanine (Phe) in aqueous solutions, were carried out in the presence of oxidized carbon nanotubes modified by the reaction with SO2 (mNTO). Kinetics of the photolyses were followed by UV spectrophotometry at 220 nm, and the products were characterized by HPLC, XPS, and (13)C-SSNMR. The ratio of the initial rates of photolysis in the presence and absence of mNTO, k*/ko*, showed a systematic decrease. The photolytic decay of Phe occurs with minor formation of tyrosine. The mass of nanotubes produced an exponential attenuation of the photolytic decomposition of Phe. Total carbon analyses (TCA) showed no inorganic carbon formation after the photolyses. The first-order rate constant of photofunctionalization of mNTO by the insertion of phenylalanine onto the nanotube matrix was calculated from TCA to be kin = 30.1 min(-1). Comparison of the XPS spectra of the mNTO before and after the photolysis, using the atom inventory technique, suggests the insertion of Phe along with the extrusion of a sulfide radical anion ((•)S(-)) which undergo subsequent oxidation to SO4(2-). The obtained results show the effects of mNTO on the photolysis of Phe and provide a new method of photofunctionalization of carbon materials, modified by the intermediates of the reduction of SO2, with an organic moiety.

A lactate-derived chiral aldehyde for determining the enantiopurity of enantioenriched primary amines.

In this paper we describe the use of a chiral aldehyde derived from lactate esters for determining the enantiopurity of primary amines, via the formation of diastereomeric imines. The method was shown to be suitable for reproducibly determining the enantiopurity of a diverse set of chiral amines. Both enantiomers of the aldehyde can be prepared in two steps from commercially available materials.

Is there an intramolecular hydrogen bond in 2-halophenols? A theoretical and spectroscopic investigation.

The Abraham solute hydrogen bond acidity parameter A can be derived both from physical methods, A(Gen) and NMR experiments, A(NMR) and results for a large number of hydroxylic solutes show that the two methods agreed very well. However for halophenols the values of A(NMR) were not consistent with the A(Gen) values. The values of A(NMR) suggest that there is no intra-molecular hydrogen bonding in any of the 2-halophenols. In contrast the values of A(Gen) indicate that there is no intra-molecular hydrogen bonding in 2-fluorophenol, but weak intra-molecular hydrogen bonding in 2-chloro, 2-bromo, and 2-iodo-phenol. In view of this uncertainty in the presence or absence of intra-molecular H-bonds in the 2-halophenols, a detailed investigation of the methods used in the literature is presented together with a novel NMR method to determine the ratio of cis and trans forms in these compounds. The experimental data is complemented by a detailed theoretical analysis of the structures and bonding in these molecules to assess the presence or absence of an intra-molecular H-bond. We conclude that there is weak hydrogen bonding in 2-chloro, 2-bromo and 2-iodophenol but very little in 2-fluorophenol.

Correction: Is there an intramolecular hydrogen bond in 2-halophenols? A theoretical and spectroscopic investigation.

Correction for 'Is there an intramolecular hydrogen bond in 2-halophenols? A theoretical and spectroscopic investigation' by Michael H. Abraham et al., Phys. Chem. Chem. Phys., 2015, DOI: 10.1039/c5cp04061b.

Noncovalent Lone Pair⋠⋠⋠(No-π!)-Heteroarene Interactions: The Janus-Faced Hydroxy Group.

A comparative study using NMR spectroscopy and designed top-pan molecular balances demonstrates that the noncovalent interaction of a hydroxy group with π-deficient pyrazine and quinoxaline units involves a lone pair-heteroarene interaction which is much stronger and solvent independent when measured relative to the classical π-facial hydrogen bond to a benzene ring. Alkyl fluorides also prefer the heteroarene rings over the benzene ring. The attractive interaction between a quinoxaline and a terminal alkyne is also stronger than the intramolecular hydrogen bond to an arene.

Surfing π†clouds for noncovalent interactions: arenes versus alkenes.

A comparative study of molecular balances by NMR spectroscopy indicates that noncovalent functional-group interactions with an arene dominate over those with an alkene, and that a π-facial intramolecular hydrogen bond from a hydroxy group to an arene is favored by approximately 1.2 kJ mol(-1). The strongest interaction observed in this study was with the cyano group. Analysis of the series of groups CH2CH3, CH=CH2, C≡CH, and C≡N shows a correlation between conformational free-energy differences and the calculated charge on the C(α) atom of these substituents, which is indicative of the electrostatic nature of their π interactions. Changes in the free-energy differences of conformers show a linear dependence on the solvent hydrogen bond acceptor parameter ß.

Motional timescale predictions by molecular dynamics simulations: case study using proline and hydroxyproline sidechain dynamics.

We propose a new approach for force field optimizations which aims at reproducing dynamics characteristics using biomolecular MD simulations, in addition to improved prediction of motionally averaged structural properties available from experiment. As the source of experimental data for dynamics fittings, we use (13) C NMR spin-lattice relaxation times T1 of backbone and sidechain carbons, which allow to determine correlation times of both overall molecular and intramolecular motions. For structural fittings, we use motionally averaged experimental values of NMR J couplings. The proline residue and its derivative 4-hydroxyproline with relatively simple cyclic structure and sidechain dynamics were chosen for the assessment of the new approach in this work. Initially, grid search and simplexed MD simulations identified large number of parameter sets which fit equally well experimental J couplings. Using the Arrhenius-type relationship between the force constant and the correlation time, the available MD data for a series of parameter sets were analyzed to predict the value of the force constant that best reproduces experimental timescale of the sidechain dynamics. Verification of the new force-field (termed as AMBER99SB-ILDNP) against NMR J couplings and correlation times showed consistent and significant improvements compared to the original force field in reproducing both structural and dynamics properties. The results suggest that matching experimental timescales of motions together with motionally averaged characteristics is the valid approach for force field parameter optimization. Such a comprehensive approach is not restricted to cyclic residues and can be extended to other amino acid residues, as well as to the backbone.

Water scaffolding in collagen: Implications on protein dynamics as revealed by solid-state NMR.

Solid-state NMR studies of collagen samples of various origins confirm that the amplitude of collagen backbone and sidechain motions increases significantly on increasing the water content. This conclusion is supported by the changes observed in three different NMR observables: (i) the linewidth dependence on the 1H decoupling frequency; (ii) 13C CSA changes for the peptide carbonyl groups, and (iii) dephasing rates of 1H-13C dipolar couplings. In particular, a nearly threefold increase in motional amplitudes of the backbone librations about C-Cα or N-Cα bonds was found on increasing the added water content up to 47 wt%D2 O. On the basis of the frequencies of NMR observables involved, the timescale of the protein motions dependent on the added water content is estimated to be of the order of microseconds. This estimate agrees with that from wideline T2(1)H NMR measurements. Also, our wideline 1H NMR measurements revealed that the timescale of the microsecond motions in proteins reduces significantly on increasing the added water content, i.e., an ∼15-fold increase in protein motional frequencies is observed on increasing the added water content to 45 wt% D2 O. The observed changes in collagen dynamics is attributed to the increase in water translational diffusion on increasing the amount of added water, which leads to more frequent "bound water/free water" exchange on the protein surface, accompanied by the breakage and formation of new hydrogen bonds with polar functionalities of protein.