Choreoisosteres: Pseudoatom Variation in Macrocyclic Hinges Conserves Structure and Dynamics

Abstract

Differing in pseudoatom, three macrocycles with isosteric substitutions (geminal dimethyl, cyclopropyl, cyclobutyl) can be described as choreoisosteres. Under ambient conditions, they share a dynamic hinge-like motion that can be described as fully revolute in solution. The barriers to hinging, ΔG^‡, are identical within experimental error: ΔG^‡ = 14.2–15.2 kcal/mol as judged by variable-temperature ¹³C NMR spectroscopy. Consistent with conserved dynamic behavior and isosterism, other physical properties including hydrophobicity and solution/membrane diffusion constants are amenable to prediction.