Initiating DNA-Encoded Library Synthesis with a Hexathymidine DNA Oligonucleotide

Area of Science:

• Medicinal Chemistry
• Synthetic Chemistry
• Drug Discovery

Background:

• DNA-encoded compound libraries (DELs) are a powerful and validated technology for small molecule screening in drug discovery.
• DELs enable the rapid exploration of vast chemical spaces for identifying novel drug leads.

Purpose of the Study:

• To present a novel library synthesis strategy for DNA-encoded compounds (DELs).
• To demonstrate the utility of a chemically stable DNA anchor for DEL construction.

Main Methods:

• A synthesis strategy was developed starting with a solid-phase-bound hexathymidine DNA sequence (hexT).
• Various heterocycle conjugates were synthesized from simple precursors using metal or acid catalysis.
• The synthesized hexT conjugates were isolated, characterized, and subsequently ligated to coding DNA sequences.

Main Results:

• The developed method allows for the efficient synthesis of diverse heterocycle conjugates on a stable DNA scaffold.
• Successful isolation, characterization, and ligation of the hexT conjugates to coding DNA were achieved, demonstrating the feasibility of the strategy.

Conclusions:

• This novel synthesis strategy provides a robust platform for generating DNA-encoded compound libraries.
• The use of a stable hexT DNA anchor enhances the reliability and efficiency of DEL synthesis for drug discovery screening.