Heterocyclic alpha-helix mimetics for targeting protein-protein interactions

Abstract

The design and synthesis of alpha-helix peptidomimetics using inverse electron demand Diels-Alder reactions is described. The potency of the resulting pyridazine-based library to disrupt the Bak/Bcl-X(L) interaction was tested using an in vitro fluorescence polarization assay.

Figure 1

a) Overlay of energy minimized 4 with a generic α-helix (Minimization carried out using Macromodel (AMBER)); b) General retrosynthetic approach of the target molecule 4.

Figure 2

a) FPA for the disruption of the Bak-BH3 peptide and Bcl-X_L interaction; pale yellow bars: 10 μM of assayed compound, pale blue bars: 50 μM of assayed compound. Ctrl-1 (dark blue bar): measured polarization for Bak-BH3 and Bcl-X_L alone, Ctrl-2 (red bar): terphenyl 1 positive control, Ctrl-3 (green bar): measured polarization for Bak-BH3 peptide alone; b) Library tested in the FPA.

Scheme 1

Examples of alpha-helix mimetics: terphenyl 1, oligoamide foldamer 2, terephtalamide 3.

Scheme 2

Synthesis of N-methyl-piperazine derivative 13.

Scheme 3

Modular synthesis of the oxazole-pyridazine-piperazine scaffold 21 bearing hydrophobic substituents.

Scheme 4

Modular synthesis of the bis-oxazole scaffold.