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

Abstract

Passive membrane permeability is a fundamental challenge in the development of bioactive macrocycles. To achieve this objective, chemists have resorted to various strategies, the most common of which is deployment of N‐methylated amino acids and/or D‐amino acids. Here we investigate the effect of heterocyclic grafts on the passive membrane permeability of macrocycles and report the structural consequences of iterative amino acid replacement by azole rings. Through stepwise substitution of amino acid residues for heterocycles, we show that lipophilicity and PAMPA permeability of a macrocycle can be vastly improved. Overall, changes in permeability do not scale linearly as more heterocycles are incorporated, underscoring the subtleties of conformation‐property relationships in this class of molecule. NMR analysis and molecular dynamics simulations provide insights into the structural consequences of the added heterocycles and these frameworks can now be applied as macrocyclic scaffolds for drug discovery.

Potent De Novo Macrocyclic Peptides That Inhibit O‐GlcNAc Transferase through an Allosteric Mechanism

“…While the current generation of macrocycles are not active within cells, enhancing the permeability of such compounds is a topic of intense current interest. Accordingly, we anticipate that application of emerging strategies, including promising new experimental [50,51] and computational methods, [52] to these series of macrocyclic OGT inhibitors will be a productive future line of research that will ultimately deliver selective cell-active allosteric OGT inhibitors. Finally, the ability to append a biotin affinity tag to these OGT-targeted macro-cycles, without perturbing the high affinity of these compounds, enables the efficient isolation of OGT samples through a simple one-step affinity purification.…”

Synthetic Tools that Enable Synthesis and Understanding of Bioactive Macrocycles

“…Together with George Saunders, we have implemented a property-driven path towards privileged macrocyclic scaffolds that should facilitate rational design strategies in macrocycle-driven drug discovery. 29 Because unusual conformations can be stabilized in constrained environments, we now wonder if conformation/activity studies can be performed on large rings akin to how structure/activity relationships are being done in drug discovery programs. This exciting possibility suggests new avenues for the discovery of bioactive molecules.…”

Single Atom Ring Contraction of Peptide Macrocycles Using Cornforth Rearrangement

“…[14] We also demonstrated that 1,3,4-oxadiazole-based systems can stabilize intramolecular hydrogen-bond networks and help to impose conformationally rigid turn motifs in cyclic peptides (Figure 1A). [15][16][17] In addition to their utility in pre-organizing conformations, heterocyclic motifs possess reactivity that can be exploited in peptide macrocycles. For example, the aziridine functionality embedded within peptide backbones can lead to effective and site-specific late-stage ring expansion (Figure 1B).…”

“…We also demonstrated that 1,3,4‐oxadiazole‐based systems can stabilize intramolecular hydrogen‐bond networks and help to impose conformationally rigid turn motifs in cyclic peptides (Figure 1A). [15–17] …”