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

Abstract

Adapting high-throughput (HT) synthetic methods to the modification of drugs and to testing of their bioactivity should expedite drug discovery. Here, we demonstrate the applicability of HT desorption electrospray ionization mass spectrometry (DESI MS) to achieve late-stage functionalization (LSF) and so to rapidly generate a modified opioid library. Specifically, aza-Michael addition and sulfur (VI) fluoride exchange (SuFEx) reactions were used for functionalization. The modified drugs are both synthesized and characterized using an automated HT-DESI MS platform, with the reaction occurring during the droplet flight. Analysis by MS characterizes reaction products at a throughput of ˃ 1 reaction per second. With this platform, multiple nor-opioid scaffolds and functionalization reagents were screened and a selection of the hits obtained was subjected to HT label-free bioassays using the same DESI-MS platform. This combination of accelerated LSF reactions to rapidly create a diverse library of functionalized drugs with direct bioassays of the crude reaction mixtures for SAR evaluation, both using the same platform, is anticipated to help expedite the early drug discovery process.