Octafluorocyclopentene engages linear, unprotected peptides in relative-rate-controlled polysubstitution cascades. In one flask at ambient temperature, the reactions generate stable, fluoro-crowned macrobicyclic structures that display dual-loop surfaces. A subset of these molecules was found to have unusually high membrane permeability, as measured by PAMPA. Structures with a bridging imidazole unit were overrepresented in this group. To probe this finding, a larger set of compounds was synthesized wherein peripheral functionality and the bridging residue were incrementally varied. Crystallographic data, NMR studies, and MD simulations indicate the imidazole-bridged structures adopt conformations stabilized by internal H-bonding. The heterocycle further serves to occlude cavity water and allows macrobicycles harboring polar residues, such as serine and aspartate, to retain passive permeability. Calculations reveal a quantity termed 'desolvation cost efficiency' that is predictive of PAMPA performance. This parameter may be leveraged for the de novo design of polar peptidomimetics that can enter cells passively.
Cooper et al. (Wed,) studied this question.