dc.contributor.author |
Flanagan, Jack |
en |
dc.contributor.author |
Atwell, GJ |
en |
dc.contributor.author |
Heinrich, DM |
en |
dc.contributor.author |
Brooke, DG |
en |
dc.contributor.author |
Silva, S |
en |
dc.contributor.author |
Rigoreau, LJM |
en |
dc.contributor.author |
Trivier, E |
en |
dc.contributor.author |
Turnbull, AP |
en |
dc.contributor.author |
Raynham, T |
en |
dc.contributor.author |
Jamieson, Stephen |
en |
dc.contributor.author |
Denny, William |
en |
dc.coverage.spatial |
England |
en |
dc.date.accessioned |
2017-07-12T23:25:18Z |
en |
dc.date.issued |
2014-02-01 |
en |
dc.identifier.citation |
Bioorganic and Medicinal Chemistry 22(3):967-977 01 Feb 2014 |
en |
dc.identifier.issn |
0968-0896 |
en |
dc.identifier.uri |
http://hdl.handle.net/2292/34204 |
en |
dc.description.abstract |
Inhibitors of the aldo-keto reductase enzyme AKR1C3 are of interest as potential drugs for leukemia and hormone-related cancers. A series of non-carboxylate morpholino(phenylpiperazin-1-yl)methanones were prepared by palladium-catalysed coupling of substituted phenyl or pyridyl bromides with the known morpholino(piperazin-1-yl)methanone, and shown to be potent (IC50∼100nM) and very isoform-selective inhibitors of AKR1C3. Lipophilic electron-withdrawing substituents on the phenyl ring were positive for activity, as was an H-bond acceptor on the other terminal ring, and the ketone moiety (as a urea) was essential. These structure-activity relationships are consistent with an X-ray structure of a representative compound bound in the AKR1C3 active site, which showed H-bonding between the carbonyl oxygen of the drug and Tyr55 and His117 in the 'oxyanion hole' of the enzyme, with the piperazine bridging unit providing the correct twist to allow the terminal benzene ring to occupy the lipophilic pocket and align with Phe311. |
en |
dc.language |
eng |
en |
dc.publisher |
Pergamon Press Ltd. |
en |
dc.relation.ispartofseries |
Bioorganic and 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. |
en |
dc.rights.uri |
https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm |
en |
dc.subject |
AKR |
en |
dc.subject |
Aldo–keto reductase |
en |
dc.subject |
COX |
en |
dc.subject |
Computer aided drug design |
en |
dc.subject |
Crystal structure |
en |
dc.subject |
DCM |
en |
dc.subject |
DIPEA |
en |
dc.subject |
DMSO |
en |
dc.subject |
Inhibitor |
en |
dc.subject |
Morpholylureas |
en |
dc.subject |
NADPH |
en |
dc.subject |
NSAID |
en |
dc.subject |
PBD |
en |
dc.subject |
Protein Data Bank |
en |
dc.subject |
TFA |
en |
dc.subject |
aldo–keto reductase |
en |
dc.subject |
cyclo-oxygenase |
en |
dc.subject |
dichloromethane |
en |
dc.subject |
diisopropylethylamine |
en |
dc.subject |
dimethyl sulfoxide |
en |
dc.subject |
nicotinamide adenine dinucleotide phosphate |
en |
dc.subject |
non-steroidal anti-inflammatory drugs |
en |
dc.subject |
trifluoroacetic acid |
en |
dc.subject |
3-Hydroxysteroid Dehydrogenases |
en |
dc.subject |
Catalytic Domain |
en |
dc.subject |
Chemistry Techniques, Synthetic |
en |
dc.subject |
Crystallography, X-Ray |
en |
dc.subject |
Enzyme Inhibitors |
en |
dc.subject |
Hydrogen Bonding |
en |
dc.subject |
Hydroxyprostaglandin Dehydrogenases |
en |
dc.subject |
Inhibitory Concentration 50 |
en |
dc.subject |
Models, Molecular |
en |
dc.subject |
Molecular Structure |
en |
dc.subject |
Morpholines |
en |
dc.subject |
Structure-Activity Relationship |
en |
dc.title |
Morpholylureas are a new class of potent and selective inhibitors of the type 5 17-β-hydroxysteroid dehydrogenase (AKR1C3) |
en |
dc.type |
Journal Article |
en |
dc.identifier.doi |
10.1016/j.bmc.2013.12.050 |
en |
pubs.issue |
3 |
en |
pubs.begin-page |
967 |
en |
pubs.volume |
22 |
en |
dc.rights.holder |
Copyright: Pergamon Press Ltd. |
en |
dc.identifier.pmid |
24411201 |
en |
pubs.end-page |
977 |
en |
pubs.publication-status |
Published |
en |
dc.rights.accessrights |
http://purl.org/eprint/accessRights/RestrictedAccess |
en |
pubs.subtype |
Article |
en |
pubs.elements-id |
424062 |
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 |
Pharmacology |
en |
pubs.org-id |
Science |
en |
pubs.org-id |
Science Research |
en |
pubs.org-id |
Maurice Wilkins Centre (2010-2014) |
en |
dc.identifier.eissn |
1464-3391 |
en |
dc.identifier.pii |
S0968-0896(13)01058-4 |
en |
pubs.record-created-at-source-date |
2017-07-13 |
en |
pubs.dimensions-id |
24411201 |
en |