A Diketone Linchpin Strategy for On-DNA Macrocyclization and Late-Stage Diversification

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Chemical Biology

Background:

• DNA-encoded libraries (DELs) are powerful tools for drug discovery.
• Macrocyclic peptides offer unique therapeutic potential but are challenging to synthesize and diversify.
• Developing efficient methods for constructing diverse macrocyclic peptide DNA-encoded libraries (MPDELs) is crucial.

Purpose of the Study:

• To develop a DNA-compatible linchpin strategy for constructing and diversifying macrocyclic peptide DNA-encoded libraries.
• To introduce a versatile 1,3-diketone linchpin for efficient macrocyclization and late-stage functionalization.
• To demonstrate the platform's compatibility with DNA-encoded library synthesis and its potential for expanding chemical space.

Main Methods:

• Treatment of DNA-conjugated linear peptides with 1,5-dichloropentane-2,4-dione (DPD) for macrocyclization.
• DNA-compatible late-stage diversification reactions.
• Scale-up tests, cross-substrate scope studies, and enzymatic ligation experiments.

Main Results:

• Highly efficient macrocyclization using the DPD linchpin strategy.
• Successful synthesis of four classes of heterocycle-embedded DNA-conjugated macrocycles (pyrazoles, azolopyrimidines, 2-aminonicotinamides, 2-hydroxynicotinonitriles).
• Broad substrate scope and high conversion rates achieved in diversification reactions.

Conclusions:

• The developed linchpin strategy is DNA-compatible and efficient for MPDEL construction.
• The platform enables versatile late-stage diversification, significantly expanding accessible chemical space.
• This approach provides a robust method for generating diverse macrocyclic peptide libraries for drug discovery.