Modular Solid-Phase Synthesis of Teroxazoles as a Class of a-Helix Mimetics

a-Helices are ubiquitous structural elements of proteins and are important in molecular recognition. Small molecules mimicking a-helices have proven to be valuable biophysical probes or modulators of protein-protein interactions. Here, we present modeling studies and the modular solid-phase synthesis of teroxazole derivatives as a new class of a-helix mimetics. The synthesis is compatible with a variety of functional groups and should thus be generally applicable for generating diversely substituted oligo-oxazole scaffolds. The teroxazole scaffold is predicted to be polar and to project peptidomimetic side chains at positions i, i+3, and i+6 of an a-helix, which complements projection patterns of existing helix mimetics. The scaffold retains sufficient conformational flexibility to conform to induced-fit models of protein-protein interaction inhibition.