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The exploration of macrocycles for drug discovery — an underexploited structural class

Key Points

  • Macrocyclic natural products have evolved to fulfil numerous biochemical functions, and their pharmacological properties have led to their development as drugs.

  • The current set of more than 100 marketed macrocycle drugs are almost exclusively derived from natural products, and yet this structural class has been poorly explored within drug discovery.

  • A macrocycle provides diverse functionality and stereochemical complexity in a conformationally pre-organized ring structure, which can result in high affinity and selectivity for protein targets, while preserving sufficient bioavailability to reach intracellular locations.

  • Macrocycles have demonstrated repeated success when addressing targets that have proved to be highly challenging for standard small-molecule drug discovery, especially in modulating macromolecular processes such as protein–protein interactions.

  • Macrocyclic drugs often function in a manner that is qualitatively distinct from small molecules. They can be productively considered as among the smallest examples of biomolecules that exhibit functional sub-domains.

  • Readily accessible synthetic macrocycles can provide attractive ligands for disease-significant targets, and such compounds can provide high levels of target affinity and selectivity, as well as presenting drug-like bioavailability and stability.

Abstract

Macrocyclic natural products have evolved to fulfil numerous biochemical functions, and their profound pharmacological properties have led to their development as drugs. A macrocycle provides diverse functionality and stereochemical complexity in a conformationally pre-organized ring structure. This can result in high affinity and selectivity for protein targets, while preserving sufficient bioavailability to reach intracellular locations. Despite these valuable characteristics, and the proven success of more than 100 marketed macrocycle drugs derived from natural products, this structural class has been poorly explored within drug discovery. This is in part due to concerns about synthetic intractability and non-drug-like properties. This Review describes the growing body of data in favour of macrocyclic therapeutics, and demonstrates that this class of compounds can be both fully drug-like in its properties and readily prepared owing to recent advances in synthetic medicinal chemistry.

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Figure 1: Improving target affinity through macrocyclization: part 1.
Figure 2: Improving target affinity through macrocyclization: part 2.
Figure 3: Improving target selectivity through macrocyclization: part 1.
Figure 4: Improving target selectivity through macrocyclization: part 2.
Figure 5: Improving physicochemical properties through macrocyclization.
Figure 6: Improving pharmacokinetic properties through macrocyclization: part 1.
Figure 7: Improving pharmacokinetic properties through macrocyclization: part 2.
Figure 8: Examples of improved methods for synthesizing macrocycle libraries.

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Acknowledgements

We are grateful to C. Wilson for generating the protein structure figures. We are also grateful to D. Livingston for assistance in compiling a list of marketed naturally occurring macrocycles, and to him, M. Taylor and L. Reid for useful feedback on content and style.

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Correspondence to Nicholas K. Terrett.

Supplementary information

Supplementary information S1 (box)

Cyclic peptides in nature and their conformations. (PDF 154 kb)

Supplementary information S2 (box)

Examples of improved methods for macrocycle synthesis. (PDF 258 kb)

Supplementary information S3 (box)

Non-covalent assemblies of macrocycles. (PDF 182 kb)

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Glossary

Natural product

A chemical compound or substance produced by a living organism, and thus found in nature.

Rule of 5

A series of guidelines initially proposed by Lipinski. The molecular mass, lipophilicity and hydrogen-bonding groups collectively determine whether a chemical compound with a certain pharmacological or biological activity has properties that would make it a likely orally active drug.

Bioavailability

One of the principal pharmacokinetic properties of drugs, this is the proportion of an administered dose of drug that reaches the systemic circulation unchanged and is thus available to provide a pharmacological effect.

FKBP12

Also known as FKBPA1, FKBP12 is a human protein that binds the immunosuppressant molecule tacrolimus, which is used in treating patients after organ transplant and patients suffering from autoimmune disorders.

mTOR

The mammalian target of rapamycin, which is analogous to the Saccharomyces cerevisiae proteins TOR1 and TOR2. The mTOR pathway is currently under investigation for its role in the control of the cell cycle and in human cancer.

FRAP

FKBP12-rapamycin-associated protein.

Olefin metathesis

An organic chemical reaction catalysed by metals such as nickel, tungsten, ruthenium and molybdenum. It involves redistribution of double bonds resulting in new chemical compounds, or a new ring if the reaction occurs intramolecularly.

Metal-templated chelation

The use of a metal ion to hold a linear precursor to a macrocycle in an energetically favourable conformation, resulting in higher yields or faster reaction rates.

Staudinger ligation

A reaction between an azide and a phosphine in aqueous media that results in the production of an amide linkage.

Wittig double-bond formation reaction

A reaction of a phosphorous ylid with an aldehyde to generate an alkene.

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Driggers, E., Hale, S., Lee, J. et al. The exploration of macrocycles for drug discovery — an underexploited structural class. Nat Rev Drug Discov 7, 608–624 (2008). https://doi.org/10.1038/nrd2590

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