Late-stage modification of bioactive compounds:Improving druggability through efficient molecular editing  

作　　者：Tongyu Huo Xinyi Zhao Zengrui Cheng Jialiang Wei Minghui Zhu Xiaodong Dou Ning Jiao 

机构地区：[1]State Key Laboratory of Natural and Biomimetic Drugs,School of Pharmaceutical Sciences,Peking University,Beijing 100191,China [2]Changping Laboratory,Beijing 102206,China [3]Shanghai Key Laboratory of Green Chemistry and Chemical Processes,East China Normal University,Shanghai 200062,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第3期1030-1076,共47页药学学报（英文版）

基　　金：Financial support from the National Key R&D Program of China(No.2021YFA1501700);the National Natural Science Foundation of China(Nos.22293014,22131002,22161142019,81821004);the Ministry of Science and Technology of China Changping Laboratory,Peking University Special Fund for COVID-19;the New Cornerstone Science Foundation through the XPLORER PRIZE。

摘　　要：Synthetic chemistry plays an indispensable role in drug discovery,contributing to hit compounds identification,lead compounds optimization,candidate drugs preparation,and so on.As Nobel Prize laureate James Black emphasized,“the most fruitful basis for the discovery of a new drug is to start with an old drug”1.Late-stage modification or functionalization of drugs,natural products and bioactive compounds have garnered significant interest due to its ability to introduce diverse elements into bioactive compounds promptly.Such modifications alter the chemical space and physiochemical properties of these compounds,ultimately influencing their potency and druggability.To enrich a toolbox of chemical modification methods for drug discovery,this review focuses on the incorporation of halogen,oxygen,and nitrogen—the ubiquitous elements in pharmacophore components of the marketed drugs—through late-stage modification in recent two decades,and discusses the state and challenges faced in these fields.We also emphasize that increasing cooperation between chemists and pharmacists may be conducive to the rapid discovery of new activities of the functionalized molecules.Ultimately,we hope this review would serve as a valuable resource,facilitating the application of late-stage modification in the construction of novel molecules and inspiring innovative concepts for designing and building new drugs.

关 键 词：Late-stage modification Drug space HALOGENATION OXYGENATION NITROGENATION Synthetic chemistry 

分 类 号：R914.5[医药卫生—药物化学]