Macrocycles: lessons from the distant past, recent developments, and future directions

Abstract

A noticeable increase in molecular complexity of drug targets has created an unmet need in the therapeutic agents that are larger than traditional small molecules. Macrocycles, which are cyclic compounds comprising 12 atoms or more, are now recognized as molecules that "are up to the task" to interrogate extended protein interfaces. However, because macrocycles (particularly the ones based on peptides) are equipped with large polar surface areas, achieving cellular permeability and bioavailability is anything but straightforward. While one might consider this to be the Achilles' heel of this class of compounds, the synthetic community continues to develop creative approaches toward the synthesis of macrocycles and their site-selective modification. This perspective provides an overview of both mechanistic and structural issues that bear on macrocycles as a unique class of molecules. The reader is offered a historical foray into some of the classic studies that have resulted in the current renaissance of macrocycles. In addition, an attempt is made to overview the more recent developments that give hope that macrocycles might indeed turn into a useful therapeutic modality.

Fig. 1. Representative macrocycles. (A): [18]-Crown-6; (B): octreotide; and (C): erythromycin.

Fig. 2. Peptidases prefer extended conformations: a substrate-derived aminomethylene inhibitor (A) and its complex with the Rous sarcoma virus (RSV) protease S9 (B) (pdb id: 1a94).

Fig. 3. Cyclosporine A: membrane conformation (A) and conformation during target engagement (B, pdb id: 2z6w).

Fig. 4. Zwitterionic control over conformation of linear peptide precursors. (A): Zwitterion-driven formation of circular conformations in solution; (B): zwitterionic control of multicomponent peptide cyclization; and (C): zwitterion-driven formation of cyclic polymers.

Fig. 5. Seebach's C-selective alkylation of cyclic peptides.

Fig. 6. (A): Cyclol-driven formation of the GFP chromophore; and (B): transannular collapse in cyclic peptides.

Fig. 7. (A): Transannular attack during palau'amine synthesis; (B): asymmetric control over transannular Diels–Alder cycloaddition; and (C): transannular collapse driven by olefin isomerization-conjugate addition.

Fig. 8. (A): Romidepsin – disulfide-containing natural product; and (B): θ-defensin and its network of disulfide bonds (shown in yellow).

Fig. 9. (A): Stapled peptide synthesis; (B and C): two views of the stapled peptide bound to MDM2 (side chains are omitted for clarity, pdb id: 3v3b).

Fig. 10. (A): Site-selective epimerization of a cyclic peptide; (B): ring contraction strategy for macrocycle synthesis; and (C): integrative approach to macrocycles.

Fig. 11. (A): Integration of tris(bromomethyl)xylene into the phage display workflow; and (B): a pose of a crystallographically characterized xylene-constrained inhibitor of human urokinase-type plasminogen activator (pdb id: 3qn7).

Fig. 12. (A): A hypothetical potential energy diagram linking two macrocycle conformations; and (B): co-crystallization with macrocycles may require energy to overcome the conformational barrier between different states (pdb id: 3aob).

Fig. 13. (A): Constrained small molecules do not always result in more favorable entropy of binding; and (B): macrocycles can show unfavorable binding entropy compared to linear controls.

Fig. 14. From measurement to computation: assessing the properties of macrocycles.

Fig. 15. (A): Control over macrocycle conformation using fluorination; and (B): periodicity of β-sheet formation in cyclic peptides.

Fig. 16. (A): Light-induced control of gramicidin S; and (B): inducing conformational changes in cyclosporine A.

Fig. 17. Kinetic control over cis- and trans- like transition states in macrocycles (amino acid side chains are omitted for clarity).

Fig. 18. Formation of nanotubes from cyclic peptides (alternating stereochemistry not included for clarity).

Fig. 19. Selected crystal structures of macrocycles and their targets. (A): An RGD-based macrocycle complexed with the extracellular segment of integrin α₅β₃ (pdb id: ; 1lfg); (B): microcystin – a covalent phosphatase inhibitor (pdb id: ; 1fjm); and (C): Anacor's boron-containing macrocyclic HCV inhibitor (pdb id: ; 2xni).

Fig. 20. Subtle structure/properties effects in macrocycles. (A): Excessive N-methylation can be a detriment to cellular permeability; and (B): a dramatic effect of serine for threonine substitution on intrinsic clearance in rat liver microsome.

Fig. 21. Macrocycles complexed with transporters. (A): P-gp complexed with a selenium-containing cyclic peptide (pdb id: 3g61); and (B): multidrug and toxic compound extrusion transporter complexed with a cyclic peptide (pdb id:; 3vvr).

Fig. 22. Peptide macrocycles and the challenge of conformational control in all areas of accessible space.