Biomedical subjects
Publications and source records attributed to Christopher J Urch.
A supramolecular approach has been used to investigate the free energies of intermolecular aromatic stacking interactions. Chemical double mutant cycles have been used to measure the effect of a range of substituents on face-to-face stacking interactions with phenyl and pentafluorophenyl rings. Electrostatic effects dominate the trends in interaction energy.
Chemical double mutant cycles have been used to quantify the interactions of halogens with the faces of aromatic rings in chloroform. The halogens are forced over the face of an aromatic ring by an array of hydrogen-bonding interactions that lock the complexes in a single, well-defined conformation. These interactions can also be engineered into the crystal structures of simpler model compounds, but experiments in solution show that the halogen-aromatic interactions observed in the solid state are all unfavourable, regardless of whether the aromatic rings contain electron-withdrawing or electron-donating substituents. The halogen-aromatic interactions are repulsive by 1-3 kJ mol(-1). The interactions with fluorine are slightly less favourable than with chlorine and bromine.
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Thirty five oxapenem analogues substituted with a range of tertiary groups at C-2 have been synthesised and evaluated as broad-spectrum beta-lactamase inhibitors. All analogues enhanced the activity of ceftazidime against bacterial isolates producing Class A and Class C beta-lactamases. Compounds with cyclic substituents at C-1' (attached to C-6) were associated with enhanced antibacterial activity against Staphylococcus aureus. (R) Stereochemistry at C-1' led to synergistic activity against beta-lactamase negative enterococci. (S) Stereochemistry at C-1' was associated with enhanced inhibition of Class A beta-lactamases and lack of synergistic activity against enterococci. AM-113 was unstable in serum and not detectable following subcutaneous or oral dosing in mice. AM-112 and AM-115 achieved good serum levels following subcutaneous dosing. AM-114 exhibited 30% bioavailability following oral dosing. AM-112 [(1'R,5R,6R)-2-(4-ammonio-1,1-dimethylbutyl)-6-(1'-hydroxyethyl)oxapenem-3-carboxylate] achieved the greatest protection of ceftazidime against Gram-negatives producing Class A or C beta-lactamases.
The ability to selectively conjugate carbohydrate molecules to a protein is a key step in the preparation of conjugate vaccines, while facile methods for linking carbohydrates to polymers or solid surfaces to produce diagnostic probes and functional microarrays are also sought. Here, we describe a simple, single-step method of producing glycosylhydrazides from unprotected sugars, which were then linked in a controlled manner to a desired carrier, through an appropriate linker. The method was chemoselective and did not require coupling reagents, and the native pyranose form of the reducing end residue was retained. Initially, mono- and disaccharide hydrazides were produced from the corresponding reducing sugars and linked to BSA through a bifunctional linker. Final exemplification of the procedure was demonstrated by the preparation of a LewisY tetrasaccharide protein conjugate, which was recognized by a LewisY monoclonal antibody indicating the preservation of the natural conformation of the tetrasaccharide in the final construct. It is envisaged that this method will have general applicability to a variety of functionally diverse reducing sugars and provide a route to highly defined glycoconjugates, without the need for elaborate synthetic strategies.