James R. Wareing

Diffusion Edited NMR: Screening Compound Mixtures by Affinity NMR to Detect Binding Ligands to Vancomycin

Affinity NMR can be used to produce an edited NMR spectrum that identifies ligands that bind to vancomycin from solution mixtures containing nonbinding molecules. The Diffusion EnCODEd Spectroscopy (DECODES) experiment performed directly on the same sample can be used to determine the structure of the binding ligands without the need for a physical separation step. The all-d amino acid tetrapeptides DDFA and DDFS, known ligands for vancomycin, were identified in the presence of eight nonbinding tetrapeptides. The bound-ligand signals in the two-dimensional DECODES spectrum are readily identified by comparison with the spectral patterns of the vancomycin cross-peaks in the 2D total correlation spectroscopy and correlation spectroscopy spectra. The screening of solution mixtures of molecules for direct detection of molecular interactions and structural identification of the interacting ligands provides a powerful new tool to complement methods, such as affinity MS, which rely on the physical separation of m...

NMR methods in combinatorial chemistry

The use of NMR spectroscopy in combinatorial chemistry has provided a versatile tool for monitoring combinatorial chemistry reactions and for assessing ligand-receptor interactions. The application of magic angle spinning NMR is widespread and has allowed structure determination to be performed on compounds attached to solid supports. A variety of two-dimensional NMR techniques have been applied to enhance the usability of the magic angle spinning NMR data. New developments for solution NMR analysis include high performance liquid chromatography, NMR, mass spectroscopy and flow NMR. NMR based methods currently being investigated may prove valuable as compound screening tools.

Palladium catalyzed double heck arylation of cyclopentene

Abstract A convenient synthesis of 1,3-diarylcyclopentenes is described via a palladium catalyzed double Heck arylation of cyclopentene with aromatic halides.

Ring-closing metathesis versus cross metathesis of resin-bound olefins

Abstract Resin-bound di-olefins were treated to metathesis conditions and both intramolecular ‘ring-closing’ metathesis (RCM) and intermolecular ‘cross’ metathesis were observed. Mono-olefin analogs produced dimers in high yield via intermolecular metathesis, despite being polymer-bound. The majority of resin-bound olefin molecules are able to come within reacting distance and 1% crosslinked polystyrene offers little or no ‘site separation’. This demonstrates a method to use olefin metathesis with the potential to prepare compound libraries on resin by dimerizing simple olefins into more complex molecules.

PhFl acetic acid: A new linker for solid phase organic synthesis

Abstract A 9-phenylfluoren-9-yl based linker for the immobilization of nitrogen and oxygen nucleophiles is described. Improved acid stability compared to the common trityl linker is demonstrated by a quantitative method for analysis of loading. This new linker is used for the synthesis of a peptide alcohol in the ‘inverse’ direction via reduction of the corresponding N linked peptide methyl ester. Several other nucleophiles are immobilized and further modified. TFA treatment releases the corresponding products in high purity.

PhFl polystyrene: A new resin for solid phase organic synthesis

Abstract A 9-phenylfluoren-9-yl polystyrene based resin is described for the attachment of nitrogen and oxygen nucleophiles. Higher acid stability compared to standard trityl resins makes this solid support an interesting alternative in solid phase organic synthesis (SPOS). Several applications are shown and the results concerning yield and crude product purity are discussed below.

Letter to the Editor: Backbone resonance assignment of the 298 amino acid catalytic domain of protein tyrosine phosphatase 1B (PTP1B)

Sebastian Meiera, Yu-Chin Lib, James Koehnb, Isidoros Vlattasc, James Wareingc, Wolfgang Jahnked, Lawrence P. Wennoglec & Stephan Grzesieka,∗ aDivision of Structural Biology and Division of Biophysical Chemistry, Biozentrum, University of Basel, 4056 Basel, Switzerland; bCore Technology Department and cNovartis Institute for Biomedical Research, Novartis Pharmaceuticals Corporation, 556 Morris Avenue, Summit, NJ 07901-1398, U.S.A.; dCore Technologies, Novartis Pharma AG, CH-4002 Basel, Switzerland

Covalent or trapped? PFG diffusion MAS NMR for combinatorial chemistry

Abstract We have demonstrated the ability to distinguish covalently bound compounds from compounds ‘trapped’ within the resin matrix in high resolution NMR spectra using PFG diffusion NMR. In addition, the signals of the solvent used to swell the resin are also eliminated from the spectrum. PFG diffusion COSY data was used to confirm the structure of the on-resin product.

Sulfonamido-aryl ethers as bradykinin B1 receptor antagonists.

The synthesis and identification of sulfonamido-aryl ethers as potent bradykinin B1 receptor antagonists from a approximately 60,000 member encoded combinatorial library are reported. Two distinct series of compounds exhibiting different structure-activity relationships were identified in a bradykinin B1 whole-cell receptor-binding assay. Specific examples exhibit K(i) values of approximately 10nM.

Farnesyl chain modification of squalene synthase inhibitor benzylfarnesylamine: Conversion to the terminal bis(trifluoromethyl) derivative

Abstract Potent squalene synthase inhibitor 1 was converted to the bis(trifluoromethyl) analog 14 in 11% overall yield for 9 steps. The amine nitrogen of 1 was protected with the 2-(trimethylsilyl)ethoxycarbonyl (TEOC) protecting group. The 10,11 olefin was selectively epoxidized, cleaved and converted to the phosphonium salt 6. The ylid from 6 underwent a Wittig condensation with hexafluoroacetone to give the TEOC containing olefin 8. Tetrabutylammonium fluoride or HF could not remove the TEOC group without isomerizing the 10,11 olefin of the farnesyl chain to the E-9,10 olefin. The bis(trifluoromethyl) olefin of 8 is very sensitive to either acidic or basic conditions. However, it was found that BF3·Et2O could remove the TEOC group without the undesired isomerization to give 14.