Deliberately Losing Control of C-H Activation Processes in the Design of Small-Molecule-Fragment Arrays Targeting Peroxisomal Metabolism.

Combined photochemical arylation, "nuisance effect" (S Ar) reaction sequences have been employed in the design of small arrays for immediate deployment in medium-throughput X-ray protein-ligand structure determination. Reactions were deliberately allowed to run "out of control" in terms of selectivity; for example the ortho-arylation of 2-phenylpyridine gave five products resulting from mono- and bisarylations combined with S Ar processes. As a result, a number of crystallographic hits against NUDT7, a key peroxisomal CoA ester hydrolase, have been identified.

Matrix-assisted DOSY.

The analysis of mixtures by NMR spectroscopy is challenging. Diffusion-ordered NMR spectroscopy enables a pseudo-separation of species based on differences in their translational diffusion coefficients. Under the right circumstances, this is a powerful technique; however, when molecules diffuse at similar rates separation in the diffusion dimension can be poor.

Using Small-Molecule Probes to Investigate Aggregation of Sunset Yellow FCF: What are the Concentration Limits?

The assembly of small molecules into larger structures, often driven by noncovalent interactions such as hydrogen bonding, aromatic stacking interactions, and burial of hydrophobic surface, is of widespread interest. The interaction of small molecules with aggregates also has a large range of applications from fluorescence aggregation assays to gas storage in framework materials. Here, we utilize nuclear magnetic resonance spectroscopy to investigate the interaction of a small-molecule probe on the assembly state of sunset yellow across a wide range of relative concentrations.

Correction: Synthesis of kinase inhibitors containing a pentafluorosulfanyl moiety.

Correction for 'Synthesis of kinase inhibitors containing a pentafluorosulfanyl moiety' by Supojjanee Sansook et al., Org. Biomol.

Synthesis of kinase inhibitors containing a pentafluorosulfanyl moiety.

A series of 3-methylidene-1H-indol-2(3H)-ones substituted with a 5- or 6-pentafluorosulfanyl group has been synthesized by a Knoevenagel condensation reaction of SF-substituted oxindoles with a range of aldehydes. The resulting products were characterized by X-ray crystallography studies and were tested for biological activity versus a panel of cell lines and protein kinases. Some exhibited single digit nM activity.

A critical role for the self-assembly of Amyloid-β1-42 in neurodegeneration.

Amyloid β1-42 (Aβ1-42) plays a central role in Alzheimer's disease. The link between structure, assembly and neuronal toxicity of this peptide is of major current interest but still poorly defined. Here, we explored this relationship by rationally designing a variant form of Aβ1-42 (vAβ1-42) differing in only two amino acids.

Size-exclusion chromatographic NMR under HR-MAS.

The addition of stationary phases or sample modifiers can be used to modify the separation achievable in the diffusion domain of diffusion NMR experiments or provide information on the nature of the analyte-sample modifier interaction. Unfortunately, the addition of insoluble chromatographic stationary phases can lead to line broadening and degradation in spectral resolution, largely because of differences in magnetic susceptibility between the sample and the stationary phase. High-resolution magic angle spinning (HR-MAS) techniques can be used to remove this broadening.

A synthetic, catalytic and theoretical investigation of an unsymmetrical SCN pincer palladacycle.

The SCN ligand 2-{3-[(methylsulfanyl)methyl]phenyl}pyridine, 1, has been synthesized starting from an initial Suzuki-Miyaura (SM) coupling between 3-((hydroxymethyl)phenyl)boronic acid and 2-bromopyridine. The C-H activation of 1 with in situ formed Pd(MeCN)4(BF4)2 has been studied and leads to a mixture of palladacycles, which were characterized by X-ray crystallography. The monomeric palladacycle LPdCl 6, where L-H = 1, has been synthesized, and tested in SM couplings of aryl bromides, where it showed moderate activity.

Influence of structural isomerism and fluorine atom substitution on the self-association of naphthoic acid.

The self-association of small aromatic systems driven by π-π stacking and hydrophobic interactions is well-known. Understanding the nature of these interactions is important if they are to be used to control association. Here, we present results of an NMR study into the self-association of two isomers of naphthoic acid along with an investigation into the role of a fluorine substituent on that self-association.

Size-exclusion chromatographic NMR of polymer mixtures.

The use of chromatographic stationary phases or solvent modifiers to modulate diffusion properties in NMR experiments is now well established. Their use can be to improve resolution in the diffusion domain or to provide an insight into analyte-modifier interactions and, hence, the chromatography process. Here, we extend previous work using size-exclusion chromatographic stationary phases to the investigation of polymer mixtures.

Investigating the interaction of sunset yellow aggregates and 6-fluoro-2-naphthoic acid: increasing probe molecule complexity.

The interaction of small molecules with non-covalent assemblies is of wide interest. The use of a magnetically active reporter nucleus allows information to be obtained in the presence of spectral overlap or in cases of high dynamic range. In this paper, we explore the interaction of a larger probe molecule, 6-fluoro-2-naphthoic acid with assemblies of sunset yellow using (19)F chemical shifts and diffusion NMR methods.

NMR investigations of the interaction between the azo-dye sunset yellow and fluorophenol.

The interaction of small molecules with larger noncovalent assemblies is important across a wide range of disciplines. Here, we apply two complementary NMR spectroscopic methods to investigate the interaction of various fluorophenol isomers with sunset yellow. This latter molecule is known to form noncovalent aggregates in isotropic solution, and form liquid crystals at high concentrations.

Insights into the mechanism for gold catalysis: behaviour of gold(I) amide complexes in solution.

We report the synthesis and activity of new mononuclear and dinuclear gold amide complexes 1-7. The dinuclear complexes 6b and 7 were characterised by single crystal X-ray analysis. We also report solution NMR and freezing point depression experiments to rationalise their behaviour in solution and question the de-ligation process invoked in gold catalysis.

Chromatographic NMR with size exclusion chromatography stationary phases.

Chromatographic NMR describes the use of stationary phases or solvent additives, such as polymers, to modify the diffusion properties of analyte molecules and thereby improve the observed resolution in the diffusion domain. This paper demonstrates similar ideas using size exclusion chromatographic media and characterises the changes in the observed diffusion coefficient using a series of polymer molecular weight reference standards of known polydispersity. The results are interpreted in terms of a simple description of the size exclusion phenomena.

The open-chain triphosphanes RMe2SiCH2P(PR'2)2 (R = Me, Ph; R' = SiMe3, Cy, Ph).

The triphosphanes RMe(2)SiCH(2)P(PR'(2))(2) (R = Me, Ph; R' = SiMe(3), Cy) are synthesised in good yield via metathesis of organodichlorophosphanes and LiPR'(2), while for R' = Ph a propensity to form (Ph(2)P)(2) precludes isolation of the in situ characterised triphosphanes. Where R = Me and R' = SiMe(3) the triphosphane has also been characterised by single crystal X-ray diffraction and exhibits a single geometric conformer in the solid state, though solution-phase NMR spectra are indicative of facile conformational exchange across a wide temperature range. All of the described triphosphanes exhibit comparable behaviour, with their respective (31)P{(1)H} NMR spectra manifesting anomalous 'second-order' characteristics, which are considered using full spin-Hamiltonian simulation.

On the inversion of diffusion NMR data: Tikhonov regularization and optimal choice of the regularization parameter.

The analysis of diffusion NMR data in terms of distributions of diffusion coefficients is hampered by the ill-posed nature of the required inverse Laplace transformation. Naïve approaches such as multiexponential fitting or standard least-squares algorithms are numerically unstable and often fail. This paper updates the CONTIN approach of the application of Tikhonov regularization to stabilise this numerical inversion problem and demonstrates two methods for automatically choosing the optimal value of the regularization parameter.

The effect of Alzheimer's Aβ aggregation state on the permeation of biomimetic lipid vesicles.

Alzheimer's disease is characterized by the aggregation and deposition of the Aβ peptide. This 40 or 42 residue peptide is the product of the proteolysis of the amyloid precursor protein membrane protein and is able to assemble to form ordered, stable amyloid fibrils as well as small, soluble, and potentially cytotoxic oligomers. The toxicity of the oligomers may be associated with the ability to bind to and affect the integrity of lipid membranes.

NMR characterization of the aggregation state of the azo dye sunset yellow in the isotropic phase.

The azo dye sunset yellow is known to form lyotropic liquid crystals as a function of both temperature and sample composition. Numerous studies have been performed to investigate the aggregation processes in these liquid crystals; however, less attention has been paid to the nature of the aggregates in the isotropic phase. In this study we employ diffusion nuclear magnetic resonance methods to investigate the hydrodynamic properties of sunset yellow aggregates at a range of concentrations in isotropic solution.

Topological frustration in beta alpha-repeat proteins: sequence diversity modulates the conserved folding mechanisms of alpha/beta/alpha sandwich proteins.

The thermodynamic hypothesis of Anfinsen postulates that structures and stabilities of globular proteins are determined by their amino acid sequences. Chain topology, however, is known to influence the folding reaction, in that motifs with a preponderance of local interactions typically fold more rapidly than those with a larger fraction of nonlocal interactions. Together, the topology and sequence can modulate the energy landscape and influence the rate at which the protein folds to the native conformation.

The double [3 + 2] photocycloaddition reaction.

A remarkable double [3 + 2] photocycloaddition reaction that results in the formation of fenestrane 2 from aromatic acetal 1 is reported. During the formation of 2, four carbon-carbon bonds, five new rings, and seven new stereocenters are created in a one-pot process. The reaction occurs in a sequential manner from the linear meta photocycloadduct 3, while the angular meta photocycloadduct 4 undergoes an alternative fragmentation-translocation photoreaction to afford angular tricycle 6.

Refolding of ribonuclease A monitored by real-time photo-CIDNP NMR spectroscopy.

Photo-CIDNP NMR spectroscopy is a powerful method for investigating the solvent accessibility of histidine, tyrosine and tryptophan residues in a protein. When coupled to real-time NMR, this technique allows changes in the environments of these residues to be used as a probe of protein folding. In this paper we describe experiments performed to monitor the refolding of ribonuclease A following dilution from a high concentration of chemical denaturant.

Mechanistic studies on the reductive cyclooligomerisation of CO by U(III) mixed sandwich complexes; the molecular structure of [(U(eta-C8H6{Si(i)Pr3-1,4}2)(eta-Cp*)]2(mu-eta1:eta1-C2O2).

The stoichiometric reaction of 1 equiv of CO with [(U(eta-C8H6{SiiPr3-1,4}2)(eta-Cp*)] affords the linear diuranium ynediolate complex [(U(eta-C8H6{SiiPr3-1,4}2)(eta-Cp*)]2(mu-eta1:eta1-C2O2) which does not react with further CO to give the deltate derivative [(U(eta-C8H6{SiiPr3-1,4}2)(eta-Cp*)]2(mu-eta1:eta2-C3O3). Spectroscopic and computational studies suggest a plausible mechanism for the formation of the deltate complex, in which a "zig-zag" diuranium ynediolate species is the key intermediate.

Kinetic traps in the folding of beta alpha-repeat proteins: CheY initially misfolds before accessing the native conformation.

The beta alpha-repeat class of proteins, represented by the (beta alpha)(8) barrel and the alpha/beta/alpha sandwich, are among the most common structural platforms in biology. Previous studies on the folding mechanisms of these motifs have revealed or suggested that the initial event involves the submillisecond formation of a kinetically trapped species that must at least partially unfold before productive folding to the respective native conformation can occur. To test the generality of these observations, CheY, a bacterial response regulator, was subjected to an extensive analysis of its folding reactions.

Co-acquisition of hyperpolarised 13C and 15N NMR spectra.

Recent developments in dynamic nuclear polarisation now allow significant enhancements to be generated in the cryo solid state and transferred to the liquid state for detection at high resolution. We demonstrate that the Ardenkjaer-Larsen method can be extended by taking advantage of the properties of the trityl radicals used. It is possible to hyperpolarise 13C and 15N simultaneously in the solid state, and to maintain these hyperpolarisations through rapid dissolution into the liquid state.

Applications of DNP-NMR for the measurement of heteronuclear T1 relaxation times.

Measurement of heteronuclear spin-lattice relaxation times is hampered by both low natural abundance and low detection sensitivity. Combined with typically long relaxation times, this results in extended acquisition times which often renders the experiment impractical. Recently a variant of dynamic nuclear polarisation has been demonstrated in which enhanced nuclear spin polarisation, generated in the cryo-solid state, is transferred to the liquid state for detection.