DE-NOVO DESIGN, SYNTHESIS, AND X-RAY CRYSTAL-STRUCTURES OF PYRROLINONE-BASED BETA-STRAND PEPTIDOMIMETICS

The de novo design and synthesis of a novel non-peptide scaffolding fo r beta-strand/sheet mimics are described. The scaffold consists of rep eating 3,5,5-trisubstituted pyrrolinone (enaminone) units punctuated w ith appropriate amino acid side chains. The iterative construction of the pyrrolinones exploits a highly efficient cyclization of metalloimi nes, the latter derived from C-terminal aldehydes and readily availabl e alpha-substituted alpha-amino ester building blocks. As predicted by interactive computer modeling and confirmed by X-ray crystallography, the polypyrrolinones present the side chains and carbonyl hydrogen-bo nd accepters in a solid-state conformation which mimics polypeptide be ta-sheets. Importantly, the enaminone NH protons form hydrogen bonds b oth intramolecularly, stabilizing the beta-strand conformation, and in termolecularly, promoting sheet formation. The presence or absence of the nitrogen protecting group controlled antiparallel versus parallel sheet formation.