Diastereofacial solid phase synthesis and self-promoted cleavage of a [2.2.1] bicyclic diversity scaffold

[reaction: see text]. We have previously described a diastereofacially selective 1,3-dipolar cycloaddition reaction of isomünchnones with vinyl ethers. While adapting this methodology for solid phase synthesis, we discovered a chemoselective and self-promoted linker aminolysis that provides liberated product in high purity, at a significantly enhanced rate. Herein we describe the implementation of a chiral auxiliary as a solid-phase linker, the detailed investigation of its unique aminolysis, and the utility of this cleavage within a chemical diversity format.     

Photodynamic actinometry using microspheres: concept, development and responsivity

Photodynamic therapy (PDT) relies on three main ingredients, oxygen, light and photoactivating compounds, although the PDT response is definitively contingent on the site and level of reactive oxygen species (ROS) generation. This study describes the development of a novel, fluorescent-based actinometer microsphere system as a means of discerning spatially resolved dosimetry of total fluence and ROS production. Providing a high resolution, localized, in situ measurement of fluence and ROS generation is critical for developing in vivo PDT protocols. Alginate-poly-L-lysine-alginate microspheres were produced using ionotropic gelation of sodium alginate droplets, ranging from 80 to 200 microm in diameter, incorporating two dyes, ADS680WS (ADS) and Rhodophyta-phycoerythrin (RPE), attached to the spheres' inside and outside layers, respectively. To test the responsivity and dynamic range of RPE for ROS detection, the production of ROS was initiated either chemically using increasing concentrations of potassium perchromate or photochemically using aluminum tetrasulphonated phthalocyanine. The generation of singlet oxygen was confirmed by phosphorescence at 1270 nm. The resulting photodegradation and decrease in fluorescence of RPE was found to correlate with increased perchromate or PDT treatment fluence, respectively. This effect was independent of pH (6.5-8) and could be inhibited using sodium azide. RPE was not susceptible to photobleaching with light alone (670 nm; 150 Jcm(-2)). ADS, which absorbs light between 600 and 750 nm, showed a direct correlation between radiant exposure (670 nm; 0-100 Jcm(-2)) and diminished fluorescence. Photobleaching was independent of irradiance (10-40 mW cm(-2)). We propose that actinometer microspheres may provide a means for obtaining high spatial resolution information regarding delivered PDT dose within model systems during investigational PDT development and dosimetric information for clinical extracorporeal PDT as in the case of ex vivo bone marrow purging.     

Spin coupling in distorted high-valent Fe(IV)-porphyrin radical complexes

In order to study structural influences on the interaction of Fe(IV) (S=1) and porphyrin cation radical (S=1/2) in high-valent iron porphyrin complexes of the type ¦X-(TMP)Fe=O¦⁺(Cl^–), X=I, Br₂, Br₄ were generated by mCPBA oxidation of corresponding Fe(III) porphyrins. The halogen substitution at the peripheral positions of the porphyrin leads to distortion of the planar porphyrin ring of ¦(TMP)Fe=O¦⁺. The new species have beeen investigated by temperature-dependent EPR and field-dependent Mössbauer spectroscopy; for the evaluation of spectra, we adopted the spin-Hamiltonian formalism including exchange interaction explicitly. As in ¦(TMP)Fe=O¦⁺, strong ferromagnetic spin coupling was observed with|J₀|D=0.9–1 and a zero-field spltting ofD32 cm^–1. For consistent parametrization of EPR and Mössbauer results, anisotropic coupling had to be introduced. Compared to ¦(TMP)Fe=O¦⁺ [1], analysis of the spectroscopic data shows that zero-field splitting and spin coupling is only slightly affected by the halogen distortion of the porphyrin structure.     

Simultaneously quantifying parent drugs and screening for metabolites in plasma pharmacokinetic samples using selected reaction monitoring information-dependent acquisition on a QTrap instrument

Bioanalytical support of plasma pharmacokinetic (PK) studies for drug discovery programs primarily involves the quantitative analysis of dosed compounds using liquid chromatography/atmospheric pressure ionization tandem mass spectrometry (LC/MS/MS) operated in selected reaction monitoring (SRM) mode. However, there is a growing need for information on the metabolism of new chemical entities (NCEs), in addition to the time-concentration profiles from these studies. In this paper, we present a novel approach to not only quantify parent drugs with SRM, but also simultaneously screen for metabolites using a hybrid triple quadrupole/linear ion trap (QqQ(LIT)) instrument. This was achieved by incorporating both the conventional SRM-only acquisition of parent compounds and the SRM-triggered information-dependent acquisition (IDA) of potential metabolites within the same scan cycle during the same LC/MS/MS run. Two test compounds were used to demonstrate the applicability of this approach. Plasma samples from PK studies were processed by simple protein precipitation and the supernatant was diluted with water before injection. The fast scanning capability of the linear ion trap allowed for the information-dependent acquisition of metabolite MS/MS spectra (<1 s/scan), in addition to the collection of adequate data points for SRM-only channels. The MS/MS spectra obtained from potential metabolites in post-dose samples correlated well with the spectra of the parent compounds studied, therefore providing additional confirmatory structure information without the need for repetitive analyses. Relative quantitative time-concentration profiles of identified metabolites were also obtained. Furthermore, this articulated SRM+SRM-IDA approach generated equivalent quantitative results for parent compounds to those obtained by conventional SRM-only analysis. This approach has been successfully used to support discovery PK screening programs.     

Unrestricted perfect pairing: the simplest wave-function-based model chemistry beyond mean field

The perfect pairing (PP) approximation from generalized valence bond theory is formulated in an unrestricted fashion for both closed- and open-shell systems using a coupled cluster ansatz. In the model chemistry proposed here, active electron pairs are correlated, but the unpaired or radical electrons remain uncorrelated, leading to a linear number of decoupled cluster amplitudes which can be solved for analytically. The alpha and beta spatial orbitals are variationally optimized independently. This minimal treatment of electron-electron correlation noticeably improves upon symmetry-breaking problems and other pathologies in Hartree-Fock (HF) theory and may be computed using the resolution of the identity approximation at only a factor of several times more effort than HF itself. PP also generally predicts improved molecular structures over HF. This compact, correlated wave function potentially provides a useful starting point for dynamical correlation corrections.