dc.contributor.author |
Smaill, Jeffrey |
en |
dc.contributor.author |
Baker, Edward |
en |
dc.contributor.author |
Booth, RJ |
en |
dc.contributor.author |
Bridges, AJ |
en |
dc.contributor.author |
Dickson, James |
en |
dc.contributor.author |
Dobrusin, EM |
en |
dc.contributor.author |
Ivanovic, I |
en |
dc.contributor.author |
Kraker, AJ |
en |
dc.contributor.author |
Lee, Ho |
en |
dc.contributor.author |
Lunney, EA |
en |
dc.contributor.author |
Ortwine, DF |
en |
dc.contributor.author |
Palmer, Brian |
en |
dc.contributor.author |
quin, J |
en |
dc.contributor.author |
Squire, Christopher |
en |
dc.contributor.author |
Thompson, Andrew |
en |
dc.contributor.author |
Denny, William |
en |
dc.date.accessioned |
2011-11-18T01:49:13Z |
en |
dc.date.issued |
2008 |
en |
dc.identifier.citation |
European Journal of Medicinal Chemistry 43(6):1276-1296 2007 |
en |
dc.identifier.issn |
0223-5234 |
en |
dc.identifier.uri |
http://hdl.handle.net/2292/9369 |
en |
dc.description.abstract |
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 IC50 0.057 μM) 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. |
en |
dc.language |
EN |
en |
dc.publisher |
Elsevier Masson SAS |
en |
dc.relation.ispartofseries |
European Journal of Medicinal Chemistry |
en |
dc.rights |
Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. Details obtained from
http://www.sherpa.ac.uk/romeo/issn/0223-5234/ |
en |
dc.rights.uri |
https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm |
en |
dc.subject |
phenylpyrrolocarbazole |
en |
dc.subject |
Wee1 |
en |
dc.subject |
Chk1 |
en |
dc.subject |
G2/M checkpoint abrogation |
en |
dc.subject |
RADIOSENSITIZATION |
en |
dc.subject |
ABROGATION |
en |
dc.subject |
PD0166285 |
en |
dc.subject |
UCN-01 |
en |
dc.subject |
CELLS |
en |
dc.title |
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 |
en |
dc.type |
Journal Article |
en |
dc.identifier.doi |
10.1016/j.ejmech.2007.07.016 |
en |
pubs.issue |
6 |
en |
pubs.begin-page |
1276 |
en |
pubs.volume |
43 |
en |
dc.rights.holder |
Copyright: Elsevier Masson SAS |
en |
dc.identifier.pmid |
17869387 |
en |
pubs.end-page |
1296 |
en |
dc.rights.accessrights |
http://purl.org/eprint/accessRights/RestrictedAccess |
en |
pubs.subtype |
Article |
en |
pubs.elements-id |
79519 |
en |
pubs.org-id |
Medical and Health Sciences |
en |
pubs.org-id |
Medical Sciences |
en |
pubs.org-id |
Auckland Cancer Research |
en |
pubs.org-id |
Science |
en |
pubs.org-id |
Biological Sciences |
en |
pubs.org-id |
Science Research |
en |
pubs.org-id |
Maurice Wilkins Centre (2010-2014) |
en |
pubs.record-created-at-source-date |
2010-09-01 |
en |
pubs.dimensions-id |
17869387 |
en |