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

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.

Organic Synthesis through Radical Innovation:Frustrated Radical Pairs

Frustrated Lewis Pairs(FLPs)represent a unique class of interactions in Lewis acid-base chemistry,driven by spatial hindrance or incongruent orbital energy levels that hinder the formation of effective coordination bonds.FLPs have received significant attention for their application in activating small molecules and facilitating organic synthesis reactions.Recent developments have led to the emergence of Frustrated Radical Pairs(FRPs)as an extension of the radical family.FRPs are formed from FLPs through Single Electron Transfer(SET)and exhibit the ability to activate a variety of chemical bonds.While research on FLPs is well-established,investigations into FRPs in organic reactions remain limited.This review highlights the current state of FRPs in organic synthesis,delves into mechanistic insights,explores their potential,and underscores the challenges in this emerging field.

Nitrogenation of Amides via C–C and C–N Bond Cleavage

Amides are among the fundamental chemicals in organic chemistry.Compared to other carbonyl functional groups,the transformation of amide is relatively difficult and remains a challenge.The traditional deconstruction transformations of amides to other functional products are usually limited to twisted or electronically activated amides.Herein,we describe a direct nitrogenation approach to convert amides into nitriles.This chemistry provides a novel amide transformation pathway via both C–C and C–N bond cleavage.Interestingly,the simple,readily available,and inexpensive inorganic salt NaNO2 is successfully employed as a nitrogen source in this organic N-incorporation process.Applications of this study are demonstrated through the latestage modification of drug and natural product derivatives.