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rdf:type |
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lifeskim:mentions |
umls-concept:C0031727,
umls-concept:C0038477,
umls-concept:C0220781,
umls-concept:C0243071,
umls-concept:C0243077,
umls-concept:C1004514,
umls-concept:C1155874,
umls-concept:C1332753,
umls-concept:C1421500,
umls-concept:C1883254,
umls-concept:C2304069
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pubmed:issue |
6
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pubmed:dateCreated |
2008-6-2
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pubmed:abstractText |
A series of N-6 substituted 9-hydroxy-4-phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones were prepared from N-substituted (5-methoxyphenyl)ethenylindoles. The target compounds were tested for their ability to inhibit the G2/M cell cycle checkpoint kinases, Wee1 and Chk1. Analogues with neutral or cationic N-6 side chains were potent dual inhibitors. Acidic side chains provided potent (average IC(50) 0.057 microM) and selective (average ratio 223-fold) Wee1 inhibition. Co-crystal structures of inhibitors bound to Wee1 show that the pyrrolo[3,4-c]carbazole scaffold binds in the ATP-binding site, with N-6 substituents involved in H-bonding to conserved water molecules. HT-29 cells treated with doxorubicin and then target compounds demonstrate an active Cdc2/cyclin B complex, inhibition of the doxorubicin-induced phosphorylation of tyrosine 15 of Cdc2 and abrogation of the G2 checkpoint.
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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 |
0223-5234
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pubmed:author |
pubmed-author:BakerEdward NEN,
pubmed-author:BoothR JohnRJ,
pubmed-author:BridgesAlexander JAJ,
pubmed-author:DennyWilliam AWA,
pubmed-author:DicksonJames MJM,
pubmed-author:DobrusinEllen MEM,
pubmed-author:IvanovicIvanI,
pubmed-author:KrakerAlan JAJ,
pubmed-author:LeeHo HHH,
pubmed-author:LunneyElizabeth AEA,
pubmed-author:OrtwineDaniel FDF,
pubmed-author:PalmerBrian DBD,
pubmed-author:QuinJohnJ3rd,
pubmed-author:SmaillJeff BJB,
pubmed-author:SquireChristopher JCJ,
pubmed-author:ThompsonAndrew MAM
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pubmed:issnType |
Print
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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 |
1276-96
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:17869387-Carbazoles,
pubmed-meshheading:17869387-Cell Cycle Proteins,
pubmed-meshheading:17869387-HT29 Cells,
pubmed-meshheading:17869387-Humans,
pubmed-meshheading:17869387-Magnetic Resonance Spectroscopy,
pubmed-meshheading:17869387-Models, Molecular,
pubmed-meshheading:17869387-Nuclear Proteins,
pubmed-meshheading:17869387-Protein Kinase Inhibitors,
pubmed-meshheading:17869387-Protein-Tyrosine Kinases,
pubmed-meshheading:17869387-Structure-Activity Relationship
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pubmed:year |
2008
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pubmed:articleTitle |
Synthesis and structure-activity relationships of N-6 substituted analogues of 9-hydroxy-4-phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones as inhibitors of Wee1 and Chk1 checkpoint kinases.
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pubmed:affiliation |
Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1020, New Zealand. j.smaill@auckland.ac.nz
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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