Institute for Pharmaceutical Chemistry, Johann Wolfgang Goethe-University, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.
Structure Genomics Consortium Buchmann Institute for Molecular Life Sciences, Johann Wolfgang Goethe-University, Max-von-Laue-Str. 15, D-60438 Frankfurt am Main, Germany.
J Med Chem. 2021 Jun 24;64(12):7991-8009. doi: 10.1021/acs.jmedchem.1c00217. Epub 2021 Jun 2.
Macrocycles are typically cyclic variants of inhibitors derived from uncyclized canonical molecules or from natural products. For medicinal chemistry, drug-like macrocycles have received increasing interest over the past few years, since it has been demonstrated that macrocyclization can favorably alter the biological and physiochemical properties as well as selectivity in comparison to the acyclic analogue. Recent drug approvals such as Lorlatinib, glecaprevir, or voxilaprevir underline the clinical relevance of drug-like macrocycles. However, the synthesis of drug-like macrocycles can be challenging, since the ring-closing reaction is generally challenging with yields depending on the size and geometry of the bridging linker. Nevertheless, macrocycles are one opportunity to expand the synthetic toolbox for medicinal chemistry to provide bioactive molecules. Therefore, we reviewed the past literature of drug-like macrocycles highlighting reactions that have been successfully used for the macrocyclization. We classified the cyclization reactions by their type, ring-size, yield, and macrocyclization efficiency index.
大环化合物通常是无环规范分子或天然产物衍生的抑制剂的环状变体。对于药物化学来说，近年来具有类药性的大环化合物受到了越来越多的关注，因为已经证明与无环类似物相比，环化可以有利地改变生物和物理化学性质以及选择性。最近的药物批准，如 Lorlatinib、glecaprevir 或 voxilaprevir，强调了具有类药性的大环化合物的临床相关性。然而，具有类药性的大环化合物的合成可能具有挑战性，因为环闭反应通常具有挑战性，收率取决于桥接连接体的大小和几何形状。尽管如此，大环化合物是扩展药物化学合成工具箱以提供生物活性分子的一种机会。因此，我们回顾了过去关于具有类药性的大环化合物的文献，强调了已成功用于大环化的反应。我们根据反应类型、环大小、产率和大环化效率指数对环化反应进行了分类。
