Two-Dimensional Barriers for Probing Conformational Shifts in Macrocycles

Abstract

We describe the development and use of composite two-dimensional barriers in macrocyclic backbones. These tunable constructs derive their mode of action from heterocyclic rearrangements. The Boulton-Katritzky reaction has been identified as a particularly versatile means to effect a composite barrier, allowing the examination of the influence of heterocycle translocation on conformation. Kinetic studies using 1H NMR have revealed that the in-plane atom movement is fast in 17, 18, 19-membered rings but slows down in 16-membered rings. The analysis by NMR and MD simulation experiments is consistent with the maintenance of rare cis-amide motifs during conformational interconversion. Taken together, our investigation demonstrates that heterocyclic rearrangement reactions can be used to control macrocyclic backbones and provides fundamental insights that may be applicable to the development of a wide range of other conformational control elements.

Well-Tempered Metadynamics Simulations Predict the Structural and Dynamic Properties of a Chiral 24-Atom Macrocycle in Solution

“…Current interest in macrocycles derives in great part from their potential application in medicine. − Unlike small-molecule drugs that traditionally bind to well-defined active or allosteric sites, macrocycles can also access an alternate therapeutic paradigm by targeting protein–protein interfaces which are often disordered . Recognition of conformationally fluid regions on proteins can occur if a macrocycle adopts an extended conformation to display the requisite array of functional groups necessary for productive binding.…”

Property‐Driven Development of Passively Permeable Macrocyclic Scaffolds Using Heterocycles**

“…Similarly, a thiazole ring within the macrocyclic natural product Sanguinamide A stabilises two β‐turns yet the homodetic control containing Ala in its place exhibits conformational flexibility [43, 44] . These findings, amongst others, highlight the ability of heterocycles to promote structural organisation within cyclic peptides (Figure 1B) [34, 45–47] . In the case of Sanguinamide A, the homodetic control shows similar permeability to the natural product.…”

Property‐Driven Development of Passively Permeable Macrocyclic Scaffolds Using Heterocycles**

“…[43,44] These findings, amongst others, highlight the ability of heterocycles to promote structural organisation within cyclic peptides (Figure 1B). [34,[45][46][47] In the case of Sanguinamide A, the homodetic control shows similar permeability to the natural product. Furthermore, the macrocyclic natural product Patellamide C contains several heterocyclic linkages and displays excellent permeability.…”