Pyranone, Thiopyranone, and Pyridone Inhibitors of Phosphatidylinositol 3-Kinase Related Kinases. Structure-Activity Relationships for DNA-Dependent Protein Kinase Inhibition, and Identification of th

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• 作者：Jonathan J. Hollick ; Laurent J. M. Rigoreau ; Celine Cano-Soumillac ; Xiaoling Cockcroft ; Nicola J. Curtin ; Mark Frigerio ; Bernard T. Golding ; Sophie Guiard ; Ian R. Hardcastle ; Ian Hickson ; Marc G. Humm
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：April 19, 2007
• 年：2007
• 卷：50
• 期：8
• 页码：1958 - 1972
• 全文大小：310K
• 年卷期：v.50,no.8(April 19, 2007)
• ISSN：1520-4804

文摘

Structure-activity relationships have been investigated for inhibition of DNA-dependent protein kinase(DNA-PK) and ATM kinase by a series of pyran-2-ones, pyran-4-ones, thiopyran-4-ones, and pyridin-4-ones. A wide range of IC₅₀ values were observed for pyranones and thiopyranones substituted at the 6-position,with the 3- and 5-positions proving intolerant to substitution. Related pyran-2-ones, pyran-4-ones, andthiopyran-4-ones showed similar IC₅₀ values against DNA-PK, whereas the pyridin-4-one system proved,in general, ineffective at inhibiting DNA-PK. Extended libraries exploring the 6-position of 2-morpholino-pyran-4-ones and 2-morpholino-thiopyrano-4-ones identified the first highly potent and selective ATMinhibitor 2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one (151C; ATM; IC₅₀ = 13 nM) and revealedconstrained SARs for ATM inhibition compared with DNA-PK. One of the most potent DNA-PK inhibitorsidentified, 2-(4-methoxyphenyl)-6-(morpholin-4-yl)pyran-4-one (16; DNA-PK; IC₅₀ = 220 nM) effectivelysensitized HeLa cells to the topoisomerase II inhibitor etoposide in vitro.