Late-stage functionalization (LSF) of drug molecules is an essential strategy for generating analogs of drug molecules efficiently. However, tedious procedures for determining successful reactions, the time-consuming process of condition optimization, and limitations on materials for testing have all hindered the development of LSF. Mass spectrometry (MS)-based high-throughput experimentation (HTE) is suitable for the exploration of LSF due to the ability for rapid and small-scale analysis, the intrinsically high molecular specificity of MS, and its great versatility. Among all the MS-based techniques, desorption electrospray ionization (DESI) is unique in serving not only as an analytical method but also as a synthetic tool. The contactless feature of DESI provides the capability for the direct analysis of complex and salty reaction mixtures without any sample workup, and the phenomena of reaction acceleration in microdroplets provides access to extremely fast reactions for the functionalization of drug molecules.<br/>We utilized Naloxone and PZM21 (analgesics for opioid receptors) as candidates to test LSF, with the moieties to be functionalized including the phenol group, carbonyl group, and thiophene group. Five reactions, including fluorosulfurylation, sulfur fluoride exchange (SuFEx) click chemistry, ene-type reactions, Schiff base formation, and alkenylation have been investigated. A high-throughput DESI-MS platform was implemented for the study of LSF, with key features being a throughput of about 1 sample/second, arrays of up to 6144 reaction mixtures per analysis, and sample amounts down to ca 5 ng. We demonstrate that microdroplets generated by DESI can act as micro-reactors for the synthesis of drug analogs containing functional groups such as aryl-fluorosulfates, sulfamates, and Schiff-bases without any incubation. Moreover, we showcase the screening of reaction conditions and substrate scopes without any separation of the complex reaction product mixture even though it contains salts, catalysts, and additives. Over 500 reactions were investigated and hundreds of analogs were identified. Next, we will determine structural activity relationships by high-throughput label-free DESI bioassays.

Late-stage diversification of drug molecules by high-throughput desorption electrospray ionization mass spectrometry (DESI-MS)

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