Cancer Research UK Cancer Therapeutics Unit, Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey, UK.
Future Med Chem. 2012 Jul;4(11):1409-38. doi: 10.4155/fmc.12.93.
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.
药物样大环的应用作为药物化学领域一个令人兴奋的方向正在兴起，最近有几个例子突出了大环化能够提供的有利的生物和物理化学性质变化。天然产物大环及其合成衍生物长期以来一直具有临床应用价值，现在人们的注意力集中在更广泛地将大环支架应用于药物化学，以寻找针对日益具有挑战性的靶标的新药。随着对药物类似物概念的认识不断提高，以及对“分子肥胖”的危险的认识不断提高，功能化的大环支架可以提供一种方法来生成具有增强性质的配体高效分子。在这篇综述中，我们将分别讨论大环化对效力、选择性和物理化学性质的影响，重点关注肿瘤药物发现中的最近的案例研究。此外，我们将突出展示大环合成方面的一些进展，并展望大环支架在药物化学中的未来应用。
