The potential of macrocyclic peptides as therapeutics has garnered much attention over the last several years. Unlike their linear counterparts, macrocycles have higher resistance to enzymatic degradation and often display improved bioavailability. However, macrocycles are typically not lipophilic enough for cellular membrane penetration, which prevents them from interacting with intracellular targets. Methods to increase cellular permeability have involved the incorporation of bicyclic scaffolds, d-amino acids and N-methylation of amides. These modifications exert their effect through conformational control of macrocycles and have been well studied in the literature. In contrast, the structural consequences of heterocycle incorporation into macrocyclic rings has not been as exhaustively investigated. In this mini-review we discuss key examples in which heterocycles influence the conformational stability and other properties of macrocycles.

在过去的几年中，大环肽作为治疗剂的潜力备受关注。与它们的线性对应物不同，大环化合物对酶促降解具有更高的抵抗力，并且通常显示出更高的生物利用度。但是，大环化合物通常不具有亲脂性，无法穿透细胞膜，从而阻止了它们与细胞内靶标的相互作用。增加细胞通透性的方法涉及掺入双环支架，d-氨基酸和酰胺的N-甲基化。这些修饰通过大环的构象控制发挥其作用，并且已经在文献中进行了充分的研究。相反，尚未将杂环掺入大环中的结构后果进行详尽的研究。在这个小型审查中，我们讨论了杂环影响大环构象稳定性和其他性质的关键例子。