High‐Throughput Optimization of Photochemical Reactions using Segmented‐Flow Nanoelectrospray‐Ionization Mass Spectrometry

• Published in: Angewandte Chemie Vol. 135; no. 28
• Main Authors: Sun, Alexandra C., Steyer, Daniel J., Robinson, Richard I., Ginsburg‐Moraff, Carol, Plummer, Scott, Gao, Jinhai, Tucker, Joseph W., Alpers, Dirk, Stephenson, Corey R. J., Kennedy, Robert T.
• Format: Journal Article
• Language: English
• Published: Weinheim Wiley Subscription Services, Inc 10-07-2023
• Subjects: Catalysis; Chemistry; Continuous Flow; Drug discovery; High-Throughput Experimentation; Ionization; Mass Spectrometry; Mass spectroscopy; Microfluidics; Optimization; Pharmacokinetics; Photocatalysis; Photochemical reactions; Photochemicals; Photoredox catalysis
• ISSN: 0044-8249; 1521-3757
• DOI: 10.1002/ange.202301664

Within the realm of drug discovery, high‐throughput experimentation techniques enable the rapid optimization of reactions and expedited generation of drug compound libraries for biological and pharmacokinetic evaluation. Herein we report the development of a segmented flow mass spectrometry‐based platform to enable the rapid exploration of photoredox reactions for early‐stage drug discovery. Specifically, microwell plate‐based photochemical reaction screens were reformatted to segmented flow format to enable delivery to nanoelectrospray ionization‐mass spectrometry analysis. This approach was demonstrated for the late‐stage modification of complex drug scaffolds, as well as the subsequent structure–activity relationship evaluation of synthesized analogs. This technology is anticipated to expand the robust capabilities of photoredox catalysis in drug discovery by enabling high‐throughput library diversification.
Segmented‐flow mass spectrometry was used to enable the rapid screening of nanomole‐scale photoredox reactions for drug discovery. Nanoelectrospray‐ionization mass spectrometry analysis was carried out at throughputs as high as 2.9 samples/s, allowing for the late‐stage modification of complex drug scaffolds as well as the subsequent structure–activity relationship (SAR) evaluation of prepared analogues.