Nature Reviews Chemistry ( IF 38.1 ) Pub Date : 2024-07-09 , DOI: 10.1038/s41570-024-00623-0
Jet Tsien 1 , Chao Hu 1 , Rohan R Merchant 2 , Tian Qin 1
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Benzenes, the most ubiquitous structural moiety in marketed small-molecule drugs, are frequently associated with poor ‘drug-like’ properties, including metabolic instability, and poor aqueous solubility. In an effort to overcome these limitations, recent developments in medicinal chemistry have demonstrated the improved physicochemical profiles of C(sp3)-rich bioisosteric scaffolds relative to arenes. In the past two decades, we have witnessed an exponential increase in synthetic methods for accessing saturated bioisosteres of monosubstituted and para-substituted benzenes. However, until recent discoveries, analogous three-dimensional ortho-substituted and meta-substituted biososteres have remained underexplored, owing to their ring strain and increased s-character hybridization. This Review summarizes the emerging synthetic methodologies to access such saturated motifs and their impact on the application of bioisosteres for ortho-substituted, meta-substituted and multi-substituted benzene rings. It concludes with a perspective on the development of next-generation bioisosteres, including those within novel chemical space.
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用于苯的三维饱和富含 C(sp3) 的生物等排体
苯并烯是市售小分子药物中最普遍的结构部分,通常与较差的“类药物”特性有关,包括代谢不稳定性和较差的水溶性。为了克服这些限制,药物化学的最新发展表明,相对于芳烃,富含 C(sp3) 的生物等排支架的物理化学特征有所改善。在过去的二十年里,我们目睹了获得单取代和对位取代苯的饱和生物等排体的合成方法呈指数级增长。然而,直到最近的发现,由于它们的环应变和增加的 s 性杂交,类似的三维邻位取代和元取代生物底体仍未得到充分探索。本文总结了获得这种饱和基序的新兴合成方法及其对邻位取代、间位取代和多取代苯环的生物等排体应用的影响。最后,它对下一代生物等排体的发展提出了看法,包括那些在新型化学空间中的生物等排体。