High-throughput microdroplet-based synthesis using automated array-to-array transfer.

Area of Science:

• Chemical synthesis and drug discovery
• Analytical chemistry and instrumentation

Background:

• Automated synthesis and high-throughput screening are crucial for accelerating drug discovery.
• Current methods require integration of synthesis and screening technologies.

Purpose of the Study:

• To develop an automated high-throughput picomole scale synthesis system.
• To integrate synthesis and screening using a single technology.

Main Methods:

• Utilized desorption electrospray ionization (DESI) for microdroplet formation and transfer.
• Employed a two-dimensional reactant array for automated synthesis.
• Facilitated on-the-fly chemical transformations during droplet flight.

Main Results:

• Generated 172 analogs with a 64% success rate using multiple reaction types.
• Achieved synthesis throughput of approximately 45 seconds per reaction.
• Produced sufficient product amounts (low ng to low μg) for bioactivity screening.
• Validated quantitative performance using liquid chromatography-mass spectrometry (LC/MS).

Conclusions:

• The developed system consolidates key early drug discovery steps.
• It bridges high-throughput DESI for reaction screening and label-free bioassays.
• This technology enables efficient analog generation and screening for drug discovery.