利用醛-炔-胺偶联生成药物化学相关连接体

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-01-25 DOI:10.1021/acsmedchemlett.4c0053110.1021/acsmedchemlett.4c00531

Andrew McGown*, Vesna Vetma, Damien Crepin, Yan Lin, Claire Adcock, Conner Craigon, Jordan Nafie, Daniel von Emloh, Léa Sutton, Kiera Bailey, Lewis Edmunds, Manvendra Sharma, Jonathan D. Wilden, Simon J. Coles, Graham J. Tizzard, William Farnaby, Alessio Ciulli, George E. Kostakis and John Spencer*,

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Use of Aldehyde–Alkyne–Amine Couplings to Generate Medicinal Chemistry-Relevant Linkers

Copper catalyzed aldehyde–alkyne–amine (A³) couplings lead to multifunctional, racemic, propargylic amines, many on a multigram scale. As part of an industrial collaboration, a selection of linkers was purified by chiral HPLC to afford single enantiomers, the absolute configuration of which was determined by vibrational circular dichroism (vCD). To show medicinal chemistry applications, selected linkers were further derivatized into potential cellular probes and (+)-JQ1 containing PROTACs (proteolysis targeting chimeras), which degraded their target protein BRD4.

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.