A Bridging Strategy for On-DNA Dithiocarbamate Library Synthesis

Area of Science:

• Medicinal Chemistry
• Chemical Biology
• Synthetic Organic Chemistry

Background:

• Dithiocarbamates (DTCs) are vital scaffolds in medicinal chemistry, frequently found in therapeutic agents.
• Current DNA-encoded library (DEL) technologies face challenges in synthesizing DTCs due to a lack of robust on-DNA methods.

Purpose of the Study:

• To establish a general and efficient procedure for on-DNA dithiocarbamate formation.
• To enable the construction of DELs incorporating DTCs for accelerated drug discovery.

Main Methods:

• Development of a novel carbon disulfide (CS₂) bridging strategy for on-DNA DTC synthesis.
• Coupling of diverse aliphatic secondary amines and alkyl halides under mild, DNA-compatible conditions.

Main Results:

• Achieved high conversion rates and excellent DNA compatibility for the on-DNA DTC formation.
• Successfully constructed a prototype DNA-encoded library featuring the newly synthesized DTCs.
• Demonstrated the method's ability to link various amines and alkyl halides efficiently.

Conclusions:

• The developed CS₂ bridging strategy overcomes limitations in on-DNA DTC synthesis.
• This method significantly expands the accessible chemical space for DELs.
• Facilitates rapid discovery of novel dithiocarbamate-based therapeutics.