31P NMR chemical shifts in hypervalent oxyphosphoranes and polymeric orthophosphates

We report the first quantum chemical investigation of the solid- and solution-state 31P NMR chemical shifts in models for phosphoryl transfer enzyme reaction intermediates and in polymeric inorganic phosphates. The 31P NMR chemical shifts of five- and six-coordinate oxyphosphoranes containing a variety of substitutions at phosphorus, as well as four-coordinate polymeric orthophosphates and four-coordinate phosphonates, are predicted with a slope of 1.00 and an R2= 0.993 (N = 34), corresponding to a 3.8 ppm (or 2.1%) error over the entire 178.3 ppm experimental chemical shift range, using Hartree-Fock methods. For the oxyphosphoranes, we used either experimental crystallographic structures or, when these were not available, fully geometry optimized molecular structures. For the four-coordinate phosphonates we used X-ray structures together with charge field perturbation, to represent lattice interactions. For the three-dimensional orthophosphates (BPO4, AlPO4, GaPO4 we again used X-ray structures, but for these inorganic systems we employed a self-consistent charge field perturbation approach on large clusters, to deduce peripheral atom charges. For pentaoxyphosphoranes, the solvent effect on 31P NMR chemical shieldings was found to be very small (<0.5 ppm). The 31P NMR chemical shielding tensors in the pentaoxyphosphoranes were in most cases found to be close to axially symmetric and were dominated by changes in the shielding tensor components in the equatorial plane (sigma22 and sigma33). The isotropic shifts were highly correlated (R2= 0.923) with phosphorus natural bonding orbital charges, with the larger charges being associated with shorter axial P-O bond lengths and, hence, more shielding. Overall, these results should facilitate the use of 31P NMR techniques in investigating the structures of more complex systems, such as phosphoryl transfer enzymes, as well as in investigating other, complex oxide structures.     

QSAR modeling of in vitro inhibition of cytochrome P450 3A4

We report the QSAR modeling of cytochrome P450 3A4 (CYP3A4) enzyme inhibition using four large data sets of in vitro data. These data sets consist of marketed drugs and drug-like compounds all tested in four assays measuring the inhibition of the metabolism of four different substrates by the CYP3A4 enzyme. The four probe substrates are benzyloxycoumarin, testosterone, benzyloxyresorufin, and midazolam. We first show that using state-of-the-art QSAR modeling approaches applied to only one of these four data sets does not lead to predictive models that would be useful for in silico filtering of chemical libraries. We then present the development and the testing of a multiple pharmacophore hypothesis (MPH) that is formulated as a conceptual extension of the traditional QSAR approach to modeling the promiscuous binding of a large variety of drugs to CYP3A4. In the simplest form, the MPH approach takes advantage of the multiple substrate data sets and identifies the binding of test compounds as either proximal or distal relative to that of a given substrate. Application of the approach to the in silico filtering of test compounds for potential inhibitors of CYP3A4 is also presented. In addition to an improvement in the QSAR modeling for the inhibition of CYP3A4, the results from this modeling approach provide structural insights into the drug-enzyme interactions. The existence of multiple inhibition data sets in the BioPrint database motivates the original development of the concept of a multiple pharmacophore hypothesis and provides a unique opportunity for formulating alternative strategies of QSAR modeling of the inhibition of the in vitro metabolism of CYP3A4.     

Novel carbazole/fluorene hybrids: host materials for blue phosphorescent OLEDs

[reaction: see text] A series of carbazole/fluorene (CBZm-Fn) hybrids were effectively synthesized through Friedel-Crafts-type substitution of the carbazole rings. These compounds were thermally and morphologically stable host materials for OLED applications. Efficient blue phosphorescent OLEDs were obtained when employing CBZ1-F2 as the host and FIrpic as the guest.     

Integrated microfluidic devices with enhanced separation performance: application to phosphoproteome analyses of differentiated cell model systems

This work reports on the application of a microfluidic device integrating nanoscale LC to nanoelectrospray MS (nano-LC-chip-MS) for the analysis of complex protein digests. Peak profile analyses of more than 700 peptide ions, reproducibly detected across replicate nano-LC-chip-MS runs (n = 5), indicated that the system provided RSD values of 0.24% on retention time, +/- 30 ppm on m/z measurement and +/- 30% variation on intensity over three orders of magnitude. RP adsorbant media with different alkyl chains and particle size packed in both trapping and separation channels were investigated to improve the chromatographic performance of this system. A two-fold improvement in chromatographic peak capacity was achieved using microfluidic devices comprising a 5 mircrom C3 trap with 2.5 microm C18 trap separation channel compared to the traditional 5 microm C18 stationary phase. Enhanced sample selectivity for the identification of phosphopeptides was obtained by combining immobilized metal affinity media prior to peptide separation on the RP microfluidic device. This system was evaluated in the context of differential phosphoproteome analyses to identify changes in signaling events and protein expression of human monocytes following the administration of phorbol ester.     

Early excited state dynamics of 6-styryl-substituted pyrylium salts exhibiting dual fluorescence

A series of 6-styryl-2,4-diphenylpyrylium salts exhibiting dual fluorescence has been investigated by fluorescence up-conversion in conjunction with quantum chemical calculations. The short-wavelength emission is due to an excited state localized on the pyrylium fragment and the long-wavelength emission arises from a charge-transfer state delocalized over the whole molecule. The two fluorescing states do not exhibit a precursor-successor relationship. The rise time of the short-wavelength fluorescence is smaller than 200 fs, and that of the long-wavelength emission depends on the electron-donating property of the styryl group substituent. The rise is almost prompt with the weaker donors but is slower, wavelength and viscosity dependent with the strongest electron-donating group. A model involving a S(2)/S(1) conical intersection is proposed to account for these observations.     

Detection of chemical warfare simulants by phosphorylation of a coumarin oximate

The detection of chemical warfare simulants is attained by the PET mechanism that gives an "off-on" fluorescent response with a half-life of approximately 50 ms upon phosphorylation of a reactive oximate functionality; the X-ray crystal structure of the oximate was also obtained and is discussed.     

Fluorescence quenching immunoassay performed in an ionic liquid

We describe the first example of immunoanalysis performed within an ionic liquid with minimal deleterious effect; our results bode well for the development of second-generation biosensors, particularly in applications involving poorly water soluble analytes including pesticides, phospholipids, and illicit drugs.     

Characterisation of the thermally accessible spin triplet state in dimers of the 7pi ClCNSSS+* in the solid state

[ClCNSSS]2(2+) is the first example of a thiazyl radical dimer where population of a thermally excited spin triplet state has been detected, as is proved by VT-powder and single-crystal EPR spectroscopy.     

Complexes of iron and cobalt with new tripodal amido-polyphosphine hybrid ligands

Divalent complexes of iron and cobalt with new, monoanionic tripodal amido-polyphosphine ligands have been thoroughly characterized, and XRD analysis reveals geometries that are distinct for this class of ligand.     

The difluorotoluene debate--a decade later

2,4-Difluorotoluene is unusual among hydrofluorocarbons because it is shaped like the DNA base thymine. It was first synthesised as a nucleotide analogue and incorporated into DNA a decade ago. Although it is a nonpolar molecule, it was found to be replicated by DNA polymerase enzymes as if it were thymine. We concluded that replication of DNA base pairs can occur without Watson-Crick hydrogen bonds, and hypothesised that steric effects, rather than these hydrogen bonds, were the main arbiters of DNA replication fidelity. A debate was initiated then, with claims by some that the molecule is polar and forms hydrogen bonds with adenine, thus supporting the hydrogen bonding theory of DNA replication. Here we discuss the evolution of this debate, and reflect on the relevant data that have since come from hundreds of papers and dozens of laboratories. Although discussion on this topic continues, the steric hypothesis for DNA replication is now widely accepted among biochemists, and the changing paradigm has been reflected in textbooks.