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Published on: August 13, 2020
Choreoisosteres: Pseudoatom Variation in Macrocyclic Hinges Conserves Structure and Dynamics
Alexander J Menke1, Joseph H Reibenspies2, Casey J Patterson-Gardner1
1Department of Chemistry & Biochemistry, Texas Christian University, Fort Worth, Texas 76129, United States.
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.
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