Synthesis and Evaluation of Phosphorus Containing, Specific CDK9/CycT1 Inhibitors
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- 作者：G谩bor N茅meth ; Zolt谩n Greff ; Anna Sipos ; Zolt谩n Varga ; Rita Sz茅kely ; M贸nika Sebesty茅n ; Zsuzsa J谩szay ; Szabolcs B茅ni ; Zolt谩n Nemes ; Jean-Luc Pirat ; Jean-No毛l Volle ; David Virieux ; 脕gnes Gyuris ; Katalin Kelemenics ; 脡va 脕y ; Janos Minarovits ; Susan Szathmary ; Gy枚rgy K茅ri ; L谩szl贸 艕rfi
- 刊名：Journal of Medicinal Chemistry
- 出版年：2014
- 出版时间：May 22, 2014
- 年：2014
- 卷：57
- 期：10
- 页码：3939-3965
- 全文大小：871K
- 年卷期：v.57,no.10(May 22, 2014)
- ISSN：1520-4804
文摘
Although there is a significant effort in the design of a selective CDK9/CycT1 inhibitor, no compound has been proven to be a specific inhibitor of this kinase so far. The aim of this research was to develop novel and selective phosphorus containing CDK9/CycT1 inhibitors. Molecules bearing phosphonamidate, phosphonate, and phosphinate moieties were synthesized. Prepared compounds were evaluated in an enzymatic CDK9/CycT1 assay. The most potent molecules were tested in cell-based toxicity and HIV proliferation assays. Selectivity of shortlisted compounds against CDKs and other kinases was tested. The best compound was shown to be a highly specific, ATP-competitive inhibitor of CDK9/CycT1 with antiviral activity.