title: Macrocycles in new drug discovery.
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.
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey, UK.
authors.forename: Jamie
authors.initials: J
authors.lastname: Mallinson
authors.forename: Ian
authors.initials: I
authors.lastname: Collins
mesh_terms: D001665:Binding Sites; D001688:Biological Products / Q000737:chemistry; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D006801:Humans; D047028:Macrocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
chemical_list: D001688:Biological Products; D047028:Macrocyclic Compounds; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases