Chemical Modulation of Peptoids: Synthesis and Conformational Studies on Partially Constrained Derivatives

Abstract

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 2a,b and 3a,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 3a,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 2a and 3a. The kinetics of the cis/trans interconversion in 2a, 3a, 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.

Positional Scanning Synthesis of a Peptoid Library Yields New Inducers of Apoptosis that Target Karyopherins and Tubulin

“…Moreover, P26 was less active in BSC-1 cells (29.0 AE 0.4 mm), whereas P9 exhibited similar activities in both cell lines (IC 50 in HeLac ells 4.7 AE 0.3 mm, IC 50 in BSC-1 cells 4.7 AE 0.4 mm). Induction of apoptosis in the caspase3/7 activity was observed at 5 mm P26 ( Figure 3D).…”

“…On the basis of our previous experience, [49][50][51][52] the constriction of conformational mobility should improve activity and selectivity of these peptoid hits.…”

“…Interestingly,t he N-terminal dipeptoid P32 was inactive whereas the C-terminal dipeptoid P33 was am itotic inhibitor with as imilar IC 50 to P9 (4.4 AE 0.6 mm;F igure S23).…”

“…Structure-activity relationship (SAR) information gleaned from the library screening indicated that position R 3 wasa menable to modification, because the presenceo fa ny one of severalr esiduesa tt his position resulted in ac ytotoxic compound( Ta ble 1). Removal of aromatic rings (P20, P28)o re xchange for N-heterocycles (P24, P25)i nR 3 reduced the lipophilicity,b ut also resulted in decreased activity.B yc ombining modifications made in P20 and P25,i nactive derivative P30 was obtained.Then, to unravel the mechanism of action of P9,s uitable probesf or target identification through affinity-chromatography-based proteomics were synthesised.T ot his end, attachment of a4 ,7,10-trioxatridecanamine unit to the C-terminal end of P9 yielded P9A (Figure 2A), whichd isplayed activity similart ot hat of P9 (IC 50 for inhibition of cell viability 5.5 AE 1.1 mm,T able S8) and induced apoptosis ( Figure S9).…”

Optimizing the control of apoptosis by amide/triazole isosteric substitution in a constrained peptoid

“…A hit compound (1) was obtained [6], and structural studies of 1 showed the presence of cis/trans isomers of the tertiary amide bond exchanging at low rates ( Fig. 1) [7]. The occurrence of these cis/trans isomers has led us to freeze the cis and trans configuration by isosteric substitution using a triazole moiety [8].…”