Lutz S. Richter

A TFA-cleavable linkage for solid-phase synthesis of hydroxamic acids

Abstract A novel linkage for the solid-phase synthesis of hydroxamic acids is described. The linkage is stable to all reagents commonly used in Fmoc peptide synthsis. Cleavage is induced by treatment with trifluoroacetic acid, providing hydroxamic acids in high purity and good yields.

SYNTHESIS OF PEPTIDE NUCLEIC ACIDS (PNA) BY SUBMONOMER SOLID-PHASE SYNTHESIS

Abstract A simple, versatile method for the synthesis of Peptide Nucleic Acids (PNA) from readily available building blocks has been developed. The approach is based on submonomer solid phase synthesis and allows for the structural variation of both the backbone and the nucleobase sidechain. The efficiency of the method was demonstrated by the synthesis of PNA oligomers in high purity and good yields.

Nmr Structural Characterization of Oligo-N-Substituted Glycine Lead Compounds from a Combinatorial Library

Synthesis and screening of combinatorial librariesfor pharmaceutical lead discovery is a rapidlyexpanding field. Oligo-N-substituted glycines (NSGs)were one of the earliest sources of moleculardiversity in combinatorial libraries. In one of thefirst demonstrations of the power of combinatorialchemistry, two NSG trimers, CHIR-2279 and CHIR-4531,were identified as nM ligands for two 7-transmembraneG-protein-coupled receptors. The NMR characterizationof these two lead compounds was undertaken to verifycovalent connectivity and to determine solutionconformations, if any. The sequential chemical shiftassignments were performed using a new strategy forassigning 1H and 13C resonances of NSGs. The conformational preferences were then determined inboth an aqueous co-solvent system and an organicsolvent to probe the effects of hydrophobic collapse. NSGs are expected to be more flexible than peptidesdue to the tertiary amide, with both cis andtrans amide bond conformations being accessible. Solution NMR studies indicate that although CHIR-2279and CHIR-4531 have identical backbones and termini,and very similar side chains, they do not display thesame solution conformational characteristics.