Abstract
The use of drug-like macrocycles is emerging as an exciting area of medicinal chemistry, with several recent examples highlighting the favorable changes in biological and physicochemical properties that macrocyclization can afford. Natural product macrocycles and their synthetic derivatives have long been clinically useful and attention is now being focused on the wider use of macrocyclic scaffolds in medicinal chemistry in the search for new drugs for increasingly challenging targets. With the increasing awareness of concepts of drug-likeness and the dangers of ‘molecular obesity’, functionalized macrocyclic scaffolds could provide a way to generate ligand-efficient molecules with enhanced properties. In this review we will separately discuss the effects of macrocyclization upon potency, selectivity and physicochemical properties, concentrating on recent case histories in oncology drug discovery. Additionally, we will highlight selected advances in the synthesis of macrocycles and provide an outlook on the future use of macrocyclic scaffolds in medicinal chemistry.
Financial & competing interests disclosure
I Collins is an employee of the Institute of Cancer Research, which has a financial interest in CHK1 inhibitors. This work was supported by Cancer Research UK [CUK] grants C309/A8274 and C19524/A10795 (studentship to J Mallinson), and by the Institute of Cancer Research. I Collins has been involved in a research collaboration on CHK1 inhibitors with Sareum Ltd. Please note that all authors who are employed by The Institute of Cancer Research are subject to a ‘Rewards to Inventors Scheme’, which may reward contributors to a programme that is subsequently licensed. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.