A unified platform for nucleoside analog synthesis.

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Drug Discovery

Background:

• Nucleoside analogs (NAs) are crucial for antiviral and anticancer treatments.
• Current synthesis methods are lengthy and lack flexibility, limiting the exploration of NA chemical space.
• Developing efficient, high-throughput NA synthesis is vital for discovering new therapies.

Purpose of the Study:

• To develop a flexible and efficient platform for high-throughput synthesis of nucleoside analogs (NAs).
• To enable the production of diverse NA libraries for drug discovery.
• To identify novel NA compounds with potential therapeutic applications.

Main Methods:

• Utilized a photoredox coupling strategy for NA synthesis.
• Developed a scalable intermediate for synthesizing various NA classes, including C- and N-linked NAs.
• Applied the platform to generate a diverse library of nucleoside analogs.

Main Results:

• Successfully synthesized both C- and N-linked nucleoside analogs.
• Unified the synthesis of disparate NA classes (4'-thio, 4'-imino, ProTides) from a single intermediate.
• Identified several hit compounds with significant anti-HIV-1 activity from the synthesized library.

Conclusions:

• The reported photoredox coupling platform offers a robust and efficient method for high-throughput NA synthesis.
• This approach significantly expands the accessible chemical space of nucleoside analogs.
• The platform is expected to accelerate drug discovery efforts for antiviral and anticancer therapies.