THE PREORGANIZATION OF ALPHA-HELIX MIMETICS AROUND A CHIRAL AXIS: TOWARD SELECTIVE INHIBITORS OF PROTEIN-PROTEIN INTERACTIONS
Arianna Ayonon, Mari Gabra, Jeffrey Gustafson.
San Diego State University, San Diego, CA.
Atropisomerism is a stereochemical phenomenon that arises from differential substitution around a single bond. As this axis is rotatable, atropisomers can exist as either stable isolable species or rapidly interconverting mixtures. The stereochemical stability of a chiral axis is primarily determined by the size of the substituent adjacent (ortho) to the axis. Rapidly interconverting atropisomerism is common throughout biologically active scaffolds; however, while only one atropisomer possesses the desired activities, the other displays no activity or even off-target effects. Our goal is to investigate the effects of atropisomer conformation on the selectivity of α-helix mimetics. Control of atropisomer conformation via the synthesis of sterochemically stable terephthalamide analogs will lead to improved target selectivities. Results have shown these analogs to have unexpectedly high stereochemical stabilities compared to literature compounds with similar substitutions adjacent to the axis. Further investigation showed analogs with significantly decreased steric bulk, exchanging chlorine for bromine, were also surprisingly stable. Characterization of these α-helix mimetics is accomplished through 1H nuclear magnetic resonance (1H NMR) and chiral high performance liquid chromatography (HPLC). Current synthesis of further point-mutant analogs is underway to explore the nonobvious factors that are affecting this unexpected stereochemical stability.