Reagent-Based Scaffold Diversity for DNA-Encoded Library Design: Solid Phase Synthesis of DNA-Tagged sp³-Rich...

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Biotechnology

Background:

• Synthesizing diverse, three-dimensional molecular scaffolds is crucial for drug discovery.
• Traditional methods for creating sp3-rich heterocycles often require harsh conditions incompatible with DNA-encoded libraries.
• Developing new synthetic strategies that are compatible with DNA-templated synthesis is essential for expanding chemical space.

Purpose of the Study:

• To develop a robust method for synthesizing sp3-rich heterocycles compatible with DNA-encoded libraries.
• To demonstrate the utility of controlled pore glass solid support-connected DNA oligonucleotide-aldehyde conjugates in library synthesis.
• To enable the generation of diverse scaffolds for further chemical modification and library expansion.

Main Methods:

• Utilized controlled pore glass solid support-connected DNA oligonucleotide-aldehyde conjugates.
• Employed SnAP reagents for condensation and cyclization reactions.
• Incorporated a Boc-protecting group for purification and facile removal.
• Assessed the stability of the DNA barcode under acidic deprotection conditions.

Main Results:

• Successfully synthesized various sp3-rich heterocycles.
• Demonstrated that the Boc-group facilitates product purification.
• Confirmed that acidic deprotection conditions are tolerated by the chemically stabilized DNA barcode.
• Established reagent-based scaffold diversity for subsequent library synthesis.

Conclusions:

• The developed method provides a versatile platform for DNA-encoded library synthesis of sp3-rich heterocycles.
• This approach overcomes the limitations of strictly dry reaction conditions in DNA-encoded library formats.
• The methodology allows for the generation of diverse scaffolds with handles for further functionalization, expanding possibilities for drug discovery.