Chemical Probes to Study ADP-Ribosylation: Synthesis and Biochemical Evaluation of Inhibitors of the Human ADP-Ribosyltransferase ARTD3/PARP3

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• 作者：Anders E. G. Lindgren ; Tobias Karlberg ; Torun Ekblad ; Sara Spjut ; Ann-Gerd Thorsell ; C. David Andersson ; Ton Tong Nhan ; Victor Hellsten ; Johan Weigelt ; Anna Linusson ; Herwig Sch眉ler ; Mikael Elofsson
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：December 12, 2013
• 年：2013
• 卷：56
• 期：23
• 页码：9556-9568
• 全文大小：927K
• 年卷期：v.56,no.23(December 12, 2013)
• ISSN：1520-4804

文摘

The racemic 3-(4-oxo-3,4-dihydroquinazolin-2-yl)-N-[1-(pyridin-2-yl)ethyl]propanamide, 1, has previously been identified as a potent but unselective inhibitor of diphtheria toxin-like ADP-ribosyltransferase 3 (ARTD3). Herein we describe synthesis and evaluation of 55 compounds in this class. It was found that the stereochemistry is of great importance for both selectivity and potency and that substituents on the phenyl ring resulted in poor solubility. Certain variations at the meso position were tolerated and caused a large shift in the binding pose. Changes to the ethylene linker that connects the quinazolinone to the amide were also investigated but proved detrimental to binding. By combination of synthetic organic chemistry and structure-based design, two selective inhibitors of ARTD3 were discovered.