Macrocycles: lessons from the distant past, recent developments, and future directions

TLDR

The growing complexity of drug targets has created a need for larger therapeutic agents, and macrocycles—cyclic compounds of 12 or more atoms—are increasingly viewed as capable of engaging extended protein interfaces, though their large polar surface areas pose challenges to cellular permeability and bioavailability that chemists are actively addressing. This perspective reviews the mechanistic and structural issues relevant to macrocycles as a distinct class of molecules and surveys recent advances that suggest they could become viable therapeutics. The authors trace the historical development of macrocycles, highlighting classic studies that have sparked the current renaissance, and discuss recent synthetic strategies and site‑selective modifications that improve their drug‑like properties.

Abstract

A noticeable increase in molecular complexity of drug targets has created an unmet need in the therapeutic agents that are larger than traditional small molecules. Macrocycles, which are cyclic compounds comprising 12 atoms or more, are now recognized as molecules that "are up to the task" to interrogate extended protein interfaces. However, because macrocycles (particularly the ones based on peptides) are equipped with large polar surface areas, achieving cellular permeability and bioavailability is anything but straightforward. While one might consider this to be the Achilles' heel of this class of compounds, the synthetic community continues to develop creative approaches toward the synthesis of macrocycles and their site-selective modification. This perspective provides an overview of both mechanistic and structural issues that bear on macrocycles as a unique class of molecules. The reader is offered a historical foray into some of the classic studies that have resulted in the current renaissance of macrocycles. In addition, an attempt is made to overview the more recent developments that give hope that macrocycles might indeed turn into a useful therapeutic modality.