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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
18
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pubmed:dateCreated |
2003-8-27
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pubmed:abstractText |
6-aryl-2-morpholin-4-yl-4H-pyran-4-ones and 6-aryl-2-morpholin-4-yl-4H-thiopyran-4-ones were synthesised and evaluated as potential inhibitors of the DNA repair enzyme DNA-dependent protein kinase (DNA-PK). Several compounds in each series exhibited superior activity to the chromenone LY294002, and were of comparable potency to the benzochromenone NU7026 (IC(50)=0.23 microM). Importantly, members of both structural classes were found to be selective inhibitors of DNA-PK over related phosphatidylinositol 3-kinase-related kinase (PIKK) family members. A multiple-parallel synthesis approach, employing Suzuki cross-coupling methodology, was utilised to prepare libraries of thiopyran-4-ones with a range of aromatic groups at the 3'- and 4'-positions on the thiopyran-4-one 6-aryl ring. Screening of the libraries resulted in the identification of 6-aryl-2-morpholin-4-yl-4H-thiopyran-4-ones bearing naphthyl or benzo[b]thienyl substituents at the 4'-position, as potent DNA-PK inhibitors with IC(50) values in the 0.2-0.4 microM range.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/2-(4-morpholinyl)-8-phenyl-4H-1-benz...,
http://linkedlifedata.com/resource/pubmed/chemical/Antineoplastic Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Chromones,
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Activated Protein Kinase,
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Morpholines,
http://linkedlifedata.com/resource/pubmed/chemical/Nuclear Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/PRKDC protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Protein-Serine-Threonine Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Pyrones
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pubmed:status |
MEDLINE
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pubmed:month |
Sep
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pubmed:issn |
0960-894X
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
15
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pubmed:volume |
13
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
3083-6
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:12941339-Animals,
pubmed-meshheading:12941339-Antineoplastic Agents,
pubmed-meshheading:12941339-Chromones,
pubmed-meshheading:12941339-DNA-Activated Protein Kinase,
pubmed-meshheading:12941339-DNA-Binding Proteins,
pubmed-meshheading:12941339-Enzyme Inhibitors,
pubmed-meshheading:12941339-Humans,
pubmed-meshheading:12941339-Inhibitory Concentration 50,
pubmed-meshheading:12941339-Morpholines,
pubmed-meshheading:12941339-Nuclear Proteins,
pubmed-meshheading:12941339-Protein-Serine-Threonine Kinases,
pubmed-meshheading:12941339-Pyrones,
pubmed-meshheading:12941339-Structure-Activity Relationship
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pubmed:year |
2003
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pubmed:articleTitle |
2,6-disubstituted pyran-4-one and thiopyran-4-one inhibitors of DNA-Dependent protein kinase (DNA-PK).
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pubmed:affiliation |
Northern Institute for Cancer Research, School of Natural Sciences-Chemistry, Bedson Building, University of Newcastle, Newcastle Upon Tyne NE1 7RU, UK.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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