The high conformational flexibility of peptoids can generate problems in biomolecular selectivity as a result of undesired off-target interactions. This drawback can be counterbalanced by restricting the original flexibility to a certain extent, thus leading to new peptidomimetics. By starting from the structure of an active peptoid as an apoptosis inhibitor, we designed two families of peptidomimetics that bear either 7-substituted perhydro-1,4- diazepine-2,5-dione 2 or 3-substituted 1,4-piperazine-2,5-dione 3 moieties. We report an efficient, solid-phase-based synthesis for both peptidomimetic families 2 and 3 from a common intermediate. An NMR spectroscopic study of 2 a,b and 3 a,b showed two species in solution in different solvents that interconvert slowly on the NMR timescale. The cis/trans isomerization around the exocyclic tertiary amide bond is responsible for this conformational behavior. The cis isomers are more favored in nonpolar environments, and this preference is higher for the six-membered-ring derivative 3 a,b. We propose that the hydrogen-bonding pattern could play an important role in the cis/trans equilibrium process. These hydrogen bonds were characterized in solution, in the solid state (i.e., by using X-ray studies), and by molecular modeling of simplified systems. A comparative study of a model peptoid 10 containing the isolated tertiary amide bond under study outlined the importance of the heterocyclic moiety for the prevalence of the cis configuration in 2 a and 3 a. The kinetics of the cis/trans interconversion in 2 a, 3 a, and 10 was also studied by variable-temperature NMR spectroscopic analysis. The full line-shape analysis of the NMR spectra of 10 revealed negligible entropic contribution to the energetic barrier in this conformational process. A theoretical analysis of 10 supported the results observed by NMR spectroscopic analysis. Overall, these results are relevant for the study of the peptidomimetic/biological-target interactions. Holding in place: Conformationally constrained peptidomimetics derived from peptoids have been identified as active compounds against biological targets. A structural study of some selected peptidomimetics by using NMR spectroscopic analysis in different solvents determined the relative stability (thermodynamic) and interconversion barriers (kinetic) of the cis/trans conformers present around the exocyclic tertiary amide bond (see scheme). Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
|Chemistry - A European Journal
|Published - 4 Jul 2011
- conformation analysis
- NMR spectroscopy
- solid-phase synthesis