Isocyanide Multicomponent Reactions on Solid-Phase-Coupled DNA Oligonucleotides for Encoded Library Synthesis.

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Chemical Biology

Background:

• Isocyanide multicomponent reactions are vital in drug discovery.
• Their compatibility with DNA-encoded combinatorial synthesis is largely unexplored.
• DNA-encoded libraries (DELs) offer a powerful platform for hit identification.

Purpose of the Study:

• To evaluate the compatibility of key isocyanide multicomponent reactions with DNA-encoded synthesis.
• To identify potential challenges and solutions for integrating this chemistry into DEL platforms.
• To assess the chemical diversity achievable with isocyanide multicomponent reaction-based DELs.

Main Methods:

• Investigated the Ugi, Ugi-azide, and Groebke-Blackburn-Bienaymé reactions under solid-phase DNA-encoded conditions.
• Assessed DNA compatibility through monitoring depurination and reaction scope.
• Utilized a modified hexathymidine DNA sequence to mitigate DNA damage.
• Performed cheminformatic analysis of the resulting chemical space.

Main Results:

• Ugi, Ugi-azide, and Groebke-Blackburn-Bienaymé reactions demonstrated good tolerance and broad scope on solid-phase DNA.
• An oxadiazole-forming Ugi reaction variant induced DNA depurination.
• A hexathymidine DNA scaffold proved more stable for encoding this variant.
• Cheminformatic analysis confirmed the diverse chemical space accessible via these methods.

Conclusions:

• Isocyanide multicomponent reactions are largely compatible with DNA-encoded library synthesis.
• Careful selection of reaction conditions and DNA scaffolds is crucial for specific variants.
• This approach significantly expands the chemical diversity available for drug discovery efforts.