High-Throughput Diversification of Complex Bioactive Molecules by Accelerated Synthesis in Microdroplets.
High-Throughput Diversification of Complex Bioactive Molecules by Accelerated Synthesis in Microdroplets.
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通过微滴加速合成实现复杂生物活性分子的高通量多样化。
DOI：
10.1002/anie.202300956
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Cooks,RGraham
中科院分区：
文献类型：
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作者：
Huang,Kai-Hung;Morato,NicolásM;Feng,Yunfei;Cooks,RGraham
药物分子的后期多样化是药物发现的重要策略，可以通过使用高通量实验的反应筛选来促进。在这里，我们提出了一种基于微滴加速反应的生物活性分子功能化的快速方法。反应混合物以优于1个反应/秒的速度雾化，微滴中发生的加速反应随后用解吸电喷雾电离质谱法（DESI‐MS）进行。由于加速反应发生在毫秒级时间尺度上，因此它们允许在低纳克尺度下工作的总筛选吞吐量为1hz。使用这种方法，阿片激动剂（PZM21）和拮抗剂（纳洛酮）通过药物化学中重要的三种反应进行多样化：氟化硫交换（SuFEx）点击反应、亚胺生成反应和烯型点击反应。在筛选了500多个反应后，合成了269个功能化的纳洛酮和PZM21类似物，并用串联质谱（MS/MS）对其进行了表征。
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.