High-Throughput Drug Derivatization and Bioassay by Desorption Electrospray Ionization Mass Spectrometry

Area of Science:

• Medicinal Chemistry
• Analytical Chemistry
• Drug Discovery

Background:

• Drug discovery relies on efficient synthesis and bioactivity testing.
• High-throughput (HT) methods are crucial for accelerating this process.
• Late-stage functionalization (LSF) allows for rapid diversification of drug candidates.

Purpose of the Study:

• To demonstrate the applicability of HT desorption electrospray ionization mass spectrometry (DESI MS) for LSF of drugs.
• To rapidly generate and characterize a modified opioid library.
• To integrate LSF with HT bioassays on a single platform for expedited drug discovery.

Main Methods:

• Utilized an automated HT-DESI MS platform for drug modification.
• Employed aza-Michael addition and sulfur (VI) fluoride exchange reactions for LSF.
• Performed MS analysis for reaction product characterization at >1 reaction per second.
• Conducted HT label-free bioassays on crude reaction mixtures using DESI-MS.

Main Results:

• Successfully demonstrated LSF of nor-opioid scaffolds using HT-DESI MS.
• Generated and characterized a diverse library of functionalized opioid analogs.
• Achieved rapid synthesis and analysis, with reactions occurring during droplet flight.
• Integrated LSF and bioassays, enabling direct structure-activity relationship evaluation.

Conclusions:

• The automated HT-DESI MS platform accelerates the creation of diverse drug libraries through LSF.
• Combining accelerated LSF with direct bioassays on the same platform significantly expedites early drug discovery.
• This integrated approach facilitates rapid structure-activity relationship evaluation for novel drug development.