High‐Throughput Diversification of Complex Bioactive Molecules by Accelerated Synthesis in Microdroplets

Late‐stage diversification of drug molecules is an important strategy in drug discovery that can be facilitated by reaction screening using high‐throughput experimentation. Here we present a rapid method for functionalizing bioactive molecules based on accelerated reactions in microdroplets. Reactio...

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Bibliographic Details
Published in:Angewandte Chemie International Edition 2023-05, Vol.62 (22), p.e202300956-n/a
Main Authors: Huang, Kai‐Hung, Morato, Nicolás M., Feng, Yunfei, Cooks, R. Graham
Format: Article
Language:English
Subjects:
Biological activity
Chemical synthesis
Chemistry, Pharmaceutical
Drug Discovery
Fluorides
Ionization
Late-Stage Synthesis
Mass Spectrometry
Mass spectroscopy
Naloxone
Opioids
Screening
Spectrometry, Mass, Electrospray Ionization - methods
Sufex Click Chemistry
Sulfur
Sulfur fluorides
Tandem Mass Spectrometry
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Summary:Late‐stage diversification of drug molecules is an important strategy in drug discovery that can be facilitated by reaction screening using high‐throughput experimentation. Here we present a rapid method for functionalizing bioactive molecules based on accelerated reactions in microdroplets. Reaction mixtures are nebulized at throughputs better than 1 reaction/second and the accelerated reactions occurring in the microdroplets are followed by desorption electrospray ionization mass spectrometry (DESI‐MS). Because the accelerated reactions occur on the millisecond timescale, they allow an overall screening throughput of 1 Hz working at the low nanogram scale. Using this approach, an opioid agonist (PZM21) and an antagonist (naloxone) were diversified using three reactions important in medicinal chemistry: sulfur fluoride exchange (SuFEx) click reactions, imine formation reactions, and ene‐type click reactions. Some 269 functionalized analogs of naloxone and PZM21 were generated and characterized by tandem mass spectrometry (MS/MS) after screening over 500 reactions. High‐throughput late‐stage functionalization of complex molecules was achieved using an automated platform based on desorption‐electrospray‐ionization mass spectrometry. Accelerated reactions in microdroplets enable the ultrafast synthesis of diversified drug molecules. Over 250 analogues of bioactive compounds were generated and characterized using nanogram amounts of material in less than 1 second per reaction.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.202300956