A General Set of DNA-Compatible Reactions for Preparing DNA-Tagged Multisubstituted Pyrroles

Abstract

DNA-encoded library (DEL) technology provided a powerful screening platform for identifying potential bioactive small molecules with high affinity to biologically interesting targets. Essential to a successful DEL campaign are the drug-like small molecular moieties of DNA-encoded libraries with expanded chemical space. Our laboratory has been working on developing and producing novel DNA-encoded libraries that complement current reported DELs. Herein, we demonstrated a general set of DNA-compatible reactions that enable the preparation of pyrrole-based DNA-encoded libraries in which the DNA tags are linked to the N position of the pyrrole central core. Further diversification could be rapidly incorporated into the pyrrole scaffold by robust iodination and Suzuki coupling reactions.

Mask and Release Strategy‐Enabled Diversity‐Oriented Synthesis for DNA‐Encoded Library

“…Rapid advancements in DEL chemistry, [32][33][34] mainly including the building block (BB) connection reactions such as diazo-transfer, [35] amide formation, [36] diarylether synthesis, [37] various cross-coupling reaction, [38][39][40][41][42][43][44][45] C-H activation and functionalization, [46][47][48][49] photopromoted reaction, [50][51][52] sulfur-fluoride exchange (SuFEx) click chemistry, [53] bioinspired click selenylation, [54][55][56] and the progresses of on-DNA privileged heterocycles synthesis have further driven its rapid evolution and applications in basic research and drug discovery. [47,48,65,[57][58][59][60][61][62][63][64] However, at present, it is well recognized that the diversity of DEL is more dependent on the availability of the core skeletons than the commercially available common BBs. [27] Generally, a conventional DEL is synthesized by an interactive encoding and chemical connection of commercially available building blocks (BBs) on a starting DNA-encoded core skeletons containing two or three functionalities, which was usually synthesized by time-consuming and laborious off-DNA synthesis (Figure 1a).…”

“…Rapid advancements in DEL chemistry, [ 32–34 ] mainly including the building block (BB) connection reactions such as diazo‐transfer, [ 35 ] amide formation, [ 36 ] diarylether synthesis, [ 37 ] various cross‐coupling reaction, [ 38–45 ] C‐H activation and functionalization, [ 46–49 ] photo‐promoted reaction, [ 50–52 ] sulfur–fluoride exchange (SuFEx) click chemistry, [ 53 ] bioinspired click selenylation, [ 54–56 ] and the progresses of on‐DNA privileged heterocycles synthesis have further driven its rapid evolution and applications in basic research and drug discovery. [ 47,48,65,57–64 ] However, at present, it is well recognized that the diversity of DEL is more dependent on the availability of the core skeletons than the commercially available common BBs. [ 27 ]…”

Enolate–Azide [3 + 2]-Cycloaddition Reaction Suitable for DNA-Encoded Library Synthesis

“…Actually, the idiosyncratic properties of DNA and the properties of combinatorial synthesis have excluded many conventional organic reactions that have been widely used in modern synthetic medicinal chemistry from the DEL chemistry toolbox. Fortunately, researchers worldwide have dedicated themselves to developing a set of DNA-compatible chemical reactions, for instance, diazo-transfer, diarylether synthesis, amide formation, hydrogenation, cross-coupling reaction, − ring-closing metathesis, C–H activation and functionalization, − photopromoted reaction, sulfur-fluoride exchange (SuFEx) click chemistry, bioinspired click selenylation, , cycloaddition reaction, and the on-DNA synthesis of privileged heterocycles such as isocoumarin, azoles, benzimidazole, pyrazoline, pyrrole, and others. ,− Even so, continuously expanding the toolbox of DNA-compatible chemical reactions that can fulfill the stringent criteria of high fidelity, good conversions, chemoselectivity, predictability, and broad substrate scope is still the pillar to promote the future development of DEL technology.…”