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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
11
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pubmed:dateCreated |
2005-5-26
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pubmed:abstractText |
Utilizing our recently published semisynthetic approach to the (3'S)-K-252a diastereomer, we report the first synthesis of the (3'R)-10 diastereomer and a set of related epimers, with the goal of defining the stereochemical role of the 3'-sugar hydroxyl group on trkA tyrosine kinase activity and selectivity. (3'R)-10 displayed potent trkA inhibitory activity with an IC50 value of 4 nM. The corresponding deshydroxy epimer (3'S)-14 was 7-fold more potent than its 3'R counterpart (natural stereochemistry) with a trkA IC50 value of 3 nM and demonstrated >280-fold selectivity over PKC (IC50 = 850 nM). In cells, (3'S)-14 displayed potent inhibition of trkA autophosphorylation with an IC50 < 10 nM. Molecular modeling studies revealed that the 3'-OH, due to the inverted geometry, forms significant H-bonding interactions with Glu27 and Arg195, an interaction that is not attainable with the natural isomers.
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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 |
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pubmed:status |
MEDLINE
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pubmed:month |
Jun
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pubmed:issn |
0022-2623
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
2
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pubmed:volume |
48
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
3776-83
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pubmed:dateRevised |
2011-11-17
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pubmed:meshHeading |
pubmed-meshheading:15916429-Animals,
pubmed-meshheading:15916429-Carbazoles,
pubmed-meshheading:15916429-Hydrogen Bonding,
pubmed-meshheading:15916429-Hydrophobic and Hydrophilic Interactions,
pubmed-meshheading:15916429-Indole Alkaloids,
pubmed-meshheading:15916429-Mice,
pubmed-meshheading:15916429-Models, Molecular,
pubmed-meshheading:15916429-Molecular Conformation,
pubmed-meshheading:15916429-NIH 3T3 Cells,
pubmed-meshheading:15916429-Phosphorylation,
pubmed-meshheading:15916429-Protein Kinase C,
pubmed-meshheading:15916429-Receptor, trkA,
pubmed-meshheading:15916429-Stereoisomerism,
pubmed-meshheading:15916429-Structure-Activity Relationship,
pubmed-meshheading:15916429-Sugar Alcohols,
pubmed-meshheading:15916429-Thermodynamics
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pubmed:year |
2005
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pubmed:articleTitle |
Synthesis, modeling, and in vitro activity of (3'S)-epi-K-252a analogues. Elucidating the stereochemical requirements of the 3'-sugar alcohol on trkA tyrosine kinase activity.
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pubmed:affiliation |
Department of Medicinal Chemistry, Cephalon, Inc., 145 Brandywine Parkway, West Chester, Pennsylvania 19380, USA.
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pubmed:publicationType |
Journal Article
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