dc.contributor.author |
Denny, William |
en |
dc.contributor.author |
Atwell, Graham |
en |
dc.contributor.author |
Roberts, PB |
en |
dc.contributor.author |
Anderson, Robert |
en |
dc.contributor.author |
Boyd, Maruta |
en |
dc.contributor.author |
Lock, CJL |
en |
dc.contributor.author |
Wilson, William |
en |
dc.coverage.spatial |
UNITED STATES |
en |
dc.date.accessioned |
2012-03-21T00:17:28Z |
en |
dc.date.issued |
1992 |
en |
dc.identifier.citation |
Journal of Medicinal Chemistry 35(26):4832-4841 1992 |
en |
dc.identifier.issn |
0022-2623 |
en |
dc.identifier.uri |
http://hdl.handle.net/2292/14783 |
en |
dc.description.abstract |
A series of isomeric 4- [ [3-(dimethylamino)propyll amino] nitroquinolines has been synthesized and evaluated as hypoxia-selective cytotoxins and as radiosensitizers of hypoxic cells. The compounds showed widely-differing hypersensitivity factors (ratios of cytotoxicity against wild- type and repair-deficient mammalian cells). Many compounds showed oxygen-sensitive bioreduction resulting in DNA alkylation, while others show oxygen-insensitive modes of action. Of the nitro isomers studied, the 5-nitro showed the greatest hypoxic selectivity. A series of ring-substituted analogues were then prepared, in an effort to lower its reduction potential of -286 mV. Structure- activity studies showed that the effects of substitution on reduction potential were complex, being mediated by electronic and steric effects on the nitro group, as well as by effects on quinoline pKa. Two compounds of lower reduction potential, the 3- and 8-methyl analogues, showed improved selectivity (47- and 60-fold in a clonogenic assay). These two compounds also showed the highest "in vitro therapeutic indices" of the series as hypoxic cell radiosensitizers. Despite these favorable in vitro properties, neither compound had activity against hypoxic cells in SCCVII tumors when adminisierid a t 60% of the MTD. |
en |
dc.language |
eng |
en |
dc.publisher |
American Chemical Society |
en |
dc.relation.ispartofseries |
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/0022-2623/ |
en |
dc.rights.uri |
https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm |
en |
dc.subject |
Animals |
en |
dc.subject |
Antineoplastic Agents |
en |
dc.subject |
Cell Hypoxia |
en |
dc.subject |
Mice |
en |
dc.subject |
Mice, Inbred C3H |
en |
dc.subject |
Nitroquinolines |
en |
dc.subject |
Structure-Activity Relationship |
en |
dc.subject |
Tumor Cells, Cultured |
en |
dc.title |
Hypoxia-selective antitumor agents. 6. 4-(Alkylamino)nitroquinolines: A new class of hypoxia-selective cytotoxins |
en |
dc.type |
Journal Article |
en |
dc.identifier.doi |
10.1021/jm00104a008 |
en |
pubs.issue |
26 |
en |
pubs.begin-page |
4832 |
en |
pubs.volume |
35 |
en |
dc.rights.holder |
Copyright: American Chemical Society |
en |
dc.identifier.pmid |
1479583 |
en |
pubs.end-page |
4841 |
en |
dc.rights.accessrights |
http://purl.org/eprint/accessRights/RestrictedAccess |
en |
pubs.subtype |
Article |
en |
pubs.elements-id |
131286 |
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 |
Science Research |
en |
pubs.org-id |
Maurice Wilkins Centre (2010-2014) |
en |
pubs.record-created-at-source-date |
2012-08-06 |
en |
pubs.dimensions-id |
1479583 |
en |