The incorporation of the isoindole core into the DNA-encoded chemical library is highly desirable for the great potential pharmacological characters exampled by molecules like lenalidomide. Herein, we reported a DNA-compatible protocol for the OPA-mediated transformation of amines into drug-like moieties represented by isoindolinone and thio-2-isoindole, respectively. The high conversion and wide substrate-scope property of our protocol render its feasibility in the manipulation of terminal amines on oligonucleotide conjugates, including "cap-and-catch" purification, sequential synthesis during DEL construction, and on-DNA macrocyclization.

DNA-Compatible ortho-Phthalaldehyde (OPA)-Mediated 2-Substituted Isoindole Core Formation and Applications.

Sulfur/selenium-containing electron-rich arenes (ERAs) exist in a wide range of both approved and investigational drugs with diverse pharmacological activities. These unique chemical structures and bioactive properties, if combined with the emerging DNA-encoded chemical library (DEL) technique, would facilitate drug and chemical probe discovery. However, it remains challenging, as there is no general DNA-compatible synthetic methodology available for the formation of C–S and C–Se bonds in aqueous solution. Herein, an in-solution direct oxidative coupling procedure that could efficiently integrate sulfur/selenium into the ERA under mild conditions is presented. This method features simple DNA-conjugated electron-rich arenes with a broad substrate scope and a transition-metal free process. Furthermore, this synthetic methodology, examined by a scale-up reaction test and late-stage precise modification in a mock peptide-like DEL synthesis, will enable its utility for the synthesis of sulfur/selenium-containing DNA-encoded libraries and the discovery of bioactive agents.

/pdf/in-solution-direct-oxidative-coupling-for-the-integration-of-2w0j9216.pdf

In-solution direct oxidative coupling for the integration of sulfur/selenium into DNA-encoded chemical libraries

Visible Light-Promoted Divergent Benzoheterocyclization from Aldehydes for DNA-Encoded Chemical Libraries.

Abstract Tumor necrosis factor α (TNF‐α) inhibitors have shown great success in the treatment of autoimmune diseases. However, to date, approved drugs targeting TNF‐α are restricted to biological macromolecules, largely due to the difficulties in using small molecules for pharmaceutical intervention of protein–protein interactions. Herein the power of a natural product‐enriched DNA‐encoded library (nDEL) is exploited to identify small molecules that interfere with the protein–protein interaction between TNF‐α and the cognate receptor. Initially, to select molecules capable of binding to TNF‐α , “late‐stage” DNA modification method is applied to construct an nDEL library consisted of 400 sterically diverse natural products and pharmaceutically active chemicals. Several natural products, including kaempferol, identified not only show direct interaction with TNF‐α, but also lead to the blockage of TNF‐α/TNFR1 interaction. Significantly, kaempferol attenuates the TNF‐α signaling in cells and reduces the 12‐O‐tetradecanoylphorbol‐13‐acetateinduced ear inflammation in mice. Structure‐activity‐relationship analyses demonstrate the importance of substitution groups at C‐3, C‐7, and C‐4' of kaempferol. The nDEL hit, kaempferol, represents a novel chemical scaffold capable of specifically recognizing TNF‐α and blocking its signal transduction, a promising starting point for the development of a small molecule TNF‐α inhibitor for use in the clinical setting.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/advs.202201258

Haimei Wei

Papers

Sequential DNA-Encoded Building Block Fusion for the Construction of Polysubstituted Pyrazoline Core Libraries.