Driggers Edward M, Hale Stephen P, Lee Jinbo, Terrett Nicholas K
Ensemble Discovery, 99 Erie Street, Cambridge, Massachusetts 02139, USA.
Nat Rev Drug Discov. 2008 Jul;7(7):608-24. doi: 10.1038/nrd2590.
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.
大环天然产物已经进化以履行多种生化功能，并且它们深刻的药理特性促使其发展成为药物。大环在构象预组织的环状结构中提供了多样的官能团和立体化学复杂性。这可以导致对蛋白质靶点具有高亲和力和选择性，同时保持足够的生物利用度以到达细胞内位置。尽管具有这些宝贵特性，并且有超过100种源自天然产物的上市大环药物已被证明取得成功，但在药物发现领域，这一结构类别仍未得到充分探索。部分原因是对合成难度和非药物样性质的担忧。本综述描述了越来越多支持大环疗法的数据，并表明由于合成药物化学的最新进展，这类化合物在性质上可以完全类似药物且易于制备。
