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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
22
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pubmed:dateCreated |
2000-11-20
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pubmed:abstractText |
Flavopiridol analogues, thio- and oxoflavopiridols which contain a sulfur (16) or oxygen (18) atom linker between a chromone ring and the hydrophobic side chain, are selective cyclin-dependent kinase 1 (CDK1) inhibitors with an IC(50) of 110 and 130 nM. These analogues were prepared from key intermediate 7 by substituting the ethyl sulfoxide. Enantio pure intermediate piperidone 10 was obtained from the racemic piperidone 8 via a very efficient "dynamic kinetic resolution" in 76% yield. Hydrophobic side chains such as chlorophenyl or tert-butyl produced potent CDK1 inhibitory activity, while hydrophilic side chains such as pyrimidine or aniline caused a severe reduction in CDK inhibitory activity. These analogues are competitive inhibitors with respect to ATP, and therefore activity was dependent upon the CDK subunit without being affected by the cyclin subunit or protein substrate. Thio- and oxoflavopiridols 16 and 18 are not only selective within the CDK family but also discriminated between unrelated serine/threonine and tyrosine protein kinases. CDK1 selective thio- and oxoflavopiridol analogues inhibit the colony-forming ability of multiple human tumor cell lines and possess a unique antiproliferative profile in comparison to flavopiridol.
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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/Antineoplastic Agents,
http://linkedlifedata.com/resource/pubmed/chemical/CCNB1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/CDC2 Protein Kinase,
http://linkedlifedata.com/resource/pubmed/chemical/CDC2-CDC28 Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/CDK2 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/CDK4 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Chromones,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclin B,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclin B1,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclin D1,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclin E,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclin-Dependent Kinase 2,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclin-Dependent Kinase 4,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclin-Dependent Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Flavonoids,
http://linkedlifedata.com/resource/pubmed/chemical/Piperidines,
http://linkedlifedata.com/resource/pubmed/chemical/Protein-Serine-Threonine Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins
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pubmed:status |
MEDLINE
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pubmed:month |
Nov
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pubmed:issn |
0022-2623
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pubmed:author |
pubmed-author:CHUT MTM,
pubmed-author:ChanS SSS,
pubmed-author:HumphreysW GWG,
pubmed-author:HuntJ TJT,
pubmed-author:KellyY FYF,
pubmed-author:KimballS DSD,
pubmed-author:LeithLL,
pubmed-author:MisraR NRN,
pubmed-author:MulheronJ GJG,
pubmed-author:QianLL,
pubmed-author:SackJ SJS,
pubmed-author:TokarskiJ SJS,
pubmed-author:WautletB SBS,
pubmed-author:WebsterK RKR
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pubmed:issnType |
Print
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pubmed:day |
2
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pubmed:volume |
43
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
4126-34
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:11063609-Antineoplastic Agents,
pubmed-meshheading:11063609-Binding Sites,
pubmed-meshheading:11063609-CDC2 Protein Kinase,
pubmed-meshheading:11063609-CDC2-CDC28 Kinases,
pubmed-meshheading:11063609-Chromones,
pubmed-meshheading:11063609-Crystallography, X-Ray,
pubmed-meshheading:11063609-Cyclin B,
pubmed-meshheading:11063609-Cyclin B1,
pubmed-meshheading:11063609-Cyclin D1,
pubmed-meshheading:11063609-Cyclin E,
pubmed-meshheading:11063609-Cyclin-Dependent Kinase 2,
pubmed-meshheading:11063609-Cyclin-Dependent Kinase 4,
pubmed-meshheading:11063609-Cyclin-Dependent Kinases,
pubmed-meshheading:11063609-Enzyme Inhibitors,
pubmed-meshheading:11063609-Flavonoids,
pubmed-meshheading:11063609-Humans,
pubmed-meshheading:11063609-Models, Molecular,
pubmed-meshheading:11063609-Piperidines,
pubmed-meshheading:11063609-Protein-Serine-Threonine Kinases,
pubmed-meshheading:11063609-Proto-Oncogene Proteins,
pubmed-meshheading:11063609-Stereoisomerism,
pubmed-meshheading:11063609-Structure-Activity Relationship,
pubmed-meshheading:11063609-Tumor Cells, Cultured,
pubmed-meshheading:11063609-Tumor Stem Cell Assay
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pubmed:year |
2000
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pubmed:articleTitle |
Thio- and oxoflavopiridols, cyclin-dependent kinase 1-selective inhibitors: synthesis and biological effects.
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pubmed:affiliation |
Department of Oncology Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA. kyoung.kim@bms.com
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pubmed:publicationType |
Journal Article
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