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.
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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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.
- 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.
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.
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.
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.
- 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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