Atropisomerism in medicinal chemistry: challenges and opportunities
Atropisomerism in medicinal chemistry: challenges and opportunities
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DOI：
10.4155/fmc-2017-0152
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发表时间：
2018-02-01
影响因子：
4.2
通讯作者：
Gustafson, Jeffrey L.
中科院分区：
文献类型：
--
作者：
Toenjes, Sean T.;Gustafson, Jeffrey L.
阻转异构现象是一种在药物化学中普遍存在的轴向手性的动态类型。存在稳定的阻转异构的美国FDA批准的药物和实验化合物的几个实例，并且在每种情况下，这些化合物的阻转异构体具有显著不同的生物活性。快速相互转化的阻转异构现象甚至更普遍，并且虽然此类化合物通常被认为是非手性的，但它们以阻转选择性方式结合其蛋白质靶标，其中不相关的阻转异构体对所需活性贡献很小。最近已经证明，可以通过合成阻转异构体稳定且纯的类似物来调节互变阻转异构体的各种性质。在此，我们讨论药物发现中的阻转异构现象的例子以及未来的挑战和机遇。
Atropisomerism is a dynamic type of axial chirality that is ubiquitous in medicinal chemistry. There are several examples of stable atropisomeric US FDA-approved drugs and experimental compounds, and in each case the atropisomers of these compounds possess drastically different biological activities. Rapidly interconverting atropisomerism is even more prevalent, and while such compounds are typically considered achiral, they bind their protein targets in an atroposelective fashion, with the nonrelevant atropisomer contributing little to the desired activities. It has been recently demonstrated that various properties of an interconverting atropisomer can be modulated through the synthesis of atropisomer stable and pure analogs. Herein we discuss examples of atropisomerism in drug discovery as well as challenges and opportunities moving forward.