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

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.

SB1518, a novel macrocyclic pyrimidine-based JAK2 inhibitor for the treatment of myeloid and lymphoid malignancies

“…Recent advances in synthetic medicinal chemistry are beginning to change this scenario. 4 Herein, we report for the first time the structure and the pharmacological profile of SB1518, a novel low-molecularweight macrocycle with potent inhibitory activities against JAK2 and FLT3. SB1518 exhibits favorable pharmaceutical properties and shows efficacy in cellular and animal models of hematological malignancies as well as primary cells derived from patients with myeloproliferative disease.…”

“…4 As such, macrocyclic organic compounds in general constitute a structural class that possesses immense potential for pharmacological applications, but their utility has not been fully exploited because of the synthetic challenges and concerns over apparent lack of 'druglikeness'. Recent advances in synthetic medicinal chemistry are beginning to change this scenario.…”

Macrocycles by the trillions

“…2 One challenge has been generating sufficiently large and diverse libraries of synthetic macrocycles to identify drug leads. To overcome this hurdle, a team led by Hiroaki Suga has now merged two technologiesone developed by Suga in 2008 to incorporate non-natural amino acids into large libraries of peptide macrocycles 3 and the other developed independently in 1997 by Jack Szostak and Hiroshi Yanagawa for displaying natural peptide and protein libraries on mRNA.…”

Stereospecific ring expansion from orthocyclophanes with central chirality to metacyclophanes with planar chirality

“…Such an intriguing chiral metacyclophane unit is found in various natural products like galeon and vancomycin 27 . Chiral metacyclophanes also constitute a key structural component of some pharmaceuticals 28,29 and supramolecular host materials that accept small molecules [30][31][32] . Consequently, the development of methods to stereoselectively construct chiral metacyclophane skeletons has been of growing interest [33][34][35][36][37][38] .…”