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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...

The use of a proper encoding methodology is one of the most important aspects when practicing DEL technology. A "headpiece"-based double-stranded DEL encoding method is currently the most widely used for productive DEL. However, the robustness of double-stranded DEL construction conflicts with the versatility presented by singlestranded DEL applications. We here report a novel encoding method, which is based on a "reversible covalent headpiece (RCHP)". The RCHP allows reversible interconversion between double-and single-stranded DNA formats, providing an avenue to robust synthesis and allowing for the applications in distinct setups. We have validated the versatility of this encoding method with encoded self-assembled chemical library and DNA-encoded dynamic library technology. Notably, based on the RCHP-settled library construction, a unique "ternary covalent complex" mediating ligand isolation methodology against non-immobilized targets was developed.

DNA-encoded library (DEL) is an efficient high-throughput screening technology platform in drug discovery and is also gaining momentum in academic research. Today, the majority of DELs are assembled and encoded with double-stranded DNA tags (dsDELs) and has been selected against numerous biological targets; however, dsDELs are not amendable to some of the recently developed selection methods, such as the cross-linking-based selection against immobilized targets and live-cell-based selections, which require DELs encoded with single-stranded DNAs (ssDELs). Herein, we present a simple method to convert dsDELs to ssDELs using exonuclease digestion without library redesign and resynthesis. We show that dsDELs could be efficiently converted to ssDELs and used for affinity-based selections either with purified proteins or on live cells.

The functionalized 4H-pyran scaffold has aroused synthetic attention because it is widely found in many interesting pharmacologically relevant compounds. We here disclose its incorporation into DNA-encoded chemical libraries, combining this scaffold with the merits of scaffold architecture in drug design. Under the optimized DNA-compatible conditions, functionalized 4H-pyrans were efficiently formed with a broad substrate scope. Among the 4Hpyrans formed, the axial structure features rotational restriction, and the spirocyclic structure provides rigidity and three-dimensionality. These efforts open the door for the construction of DNA-encoded chemical libraries with more consideration for this structural architecture.

Annelated benzodiazepines are attractive drug-like scaffolds with a broad spectrum of biological activities. Incorporation of this heterocyclic core into DNA-encoded chemical libraries (DELs) via multicomponent assembly is highly demanded. Herein, we developed a DNA-compatible method to generate the tricyclic benzodiazepine scaffold via catalyst-free three-component condensation using a broad range of aldehyde, o-phenylenediamine, and diketone sources. With either aldehyde or o-phenylenediamine conjugated with DNA tags, functionalized 1,5-benzodiazepine scaffolds were efficiently forged, expanding the chemical space of the diazepine-centered drug-like DEL.

As a powerful platform in drug discovery, the DNA-encoded chemical library technique enables the generation of numerous chemical members with high structural diversity. Epoxides widely exist in a variety of approved drugs and clinical candidates, eliciting multiple pharmaceutical activities. Herein, we report a non-oxidative DNA-compatible synthesis of di-/trisubstituted α,β-epoxyketones by implementing aldehydes and α-chlorinated ketones as abundant building blocks. This methodology was demonstrated to cover a broad substrate scope with medium-to-excellent conversions. Further structural diversification and transformation were also successfully explored to fully leverage α,β-epoxyketone moiety.

We present the development of an efficient synthetic route to generate a DNA-compatible vinyl sulfone functional group, and the subsequent chemical transformations demonstrated the feasibility of our method in DEL construction.