DNA-Compatible Synthesis of α,β-Epoxyketones for DNA-Encoded Chemical Libraries

Abstract

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.

Simple and Practical DNA Quantification Method for DNA-Encoded Library Synthesis

“…Nevertheless, DNA is vulnerable and susceptible to damage under a variety of chemical reaction conditions . Thus, there is an imperative necessity to develop a method that is simple, rapid, practicable, and accurate for monitoring the DNA’s viability during chemical conversion. − Consequently, this should not only facilitate the application of known DNA-compatible reactions to a wide variety of substrates but would also guide the exploration of new on-DNA chemistry. − As part of our efforts to develop novel DNA-compatible reactions and their subsequent implementation in routine DEL synthesis, we recognized DNA damage as a critical and imperative matter to address. Our efforts have resulted in the development of an LC-MS-based method meeting these requirements.…”

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

“…DNA-encoded chemical library (DEL) has been proved to be a powerful tool in hit discovery and widely accepted in both the pharmaceutical industry and academia during recent years. , In a DEL, each synthetic chemotype (chemical compound) is covalently tethered with an identical encoding genotype (DNA tag), and the spatial encoding in traditional high throughput screening is replaced with DNA encoding, therefore allowing the biologically active ligand discovery process at a relatively low cost. − The high level of productivity of DEL in hit discovery has been confirmed by preclinical and clinical drug candidates ranging from kinase inhibitors to epigenetic modulators. − The success of DELs heavily relies on the collection of compounds with drug-like properties. ,− Therefore, the development of DNA-compatible synthetic methods to expand the chemical composition of DEL is highly desired. − Critically, several methodologies have been developed recently to generate drug-like moieties with the encoded DNA tag. − While medicinal chemistry research has continuously witnessed drug-like moieties demonstrating fascinating pharmacological activities, there are still limitations in the expansion of DNA-compatible reactions in pursuit of drug-like moieties …”

DNA-Compatible Diversification of Indole π-Activated Alcohols via a Direct Dehydrative Coupling Strategy

“…DNA-encoded chemical libraries (DELs) technology combines the power of combinatorial synthetic chemistry with effective DNA barcoding methodology to offer a collection of millions of encoded chemical members . This technology has emerged as a valuable platform for drug discovery and has been widely adopted by academia and the pharmaceutical industry …”