dc.contributor.author |
Tercel, Moana |
en |
dc.contributor.author |
Atwell, Graham |
en |
dc.contributor.author |
Yang, S |
en |
dc.contributor.author |
Stevenson, Ralph |
en |
dc.contributor.author |
Botting, KJ |
en |
dc.contributor.author |
Boyd, Maruta |
en |
dc.contributor.author |
Smith, E |
en |
dc.contributor.author |
Anderson, Robert |
en |
dc.contributor.author |
Denny, William |
en |
dc.contributor.author |
Wilson, William |
en |
dc.contributor.author |
Pruijn, Frederik |
en |
dc.date.accessioned |
2011-11-17T17:21:52Z |
en |
dc.date.accessioned |
2012-03-01T22:00:09Z |
en |
dc.date.issued |
2009 |
en |
dc.identifier.citation |
Journal of Medicinal Chemistry 52(22):7258-7272 2009 |
en |
dc.identifier.issn |
0022-2623 |
en |
dc.identifier.uri |
http://hdl.handle.net/2292/12530 |
en |
dc.description.abstract |
Nitrochloromethylbenzindolines (nitroCBIs) are a new class of hypoxia-activated prodrugs for antitumor therapy. The recently reported prototypes undergo hypoxia-selective metabolism to form potent DNA minor groove alkylating agents and are selectively toxic to some but not all hypoxic tumor cell lines. Here we report a series of 31 analogues that bear an extra electron-withdrawing substituent that serves to raise the one-electron reduction potential of the nitroCBI. We identify a subset of compounds, those with a basic side chain and sulfonamide or carboxamide substituent, that have consistently high hypoxic selectivity. The best of these, with a 7-sulfonamide substituent, displays hypoxic cytotoxicity ratios of 275 and 330 in Skov3 and HT29 human tumor cell lines, respectively. This compound (28) is efficiently and selectively metabolized to the corresponding aminoCBI, is selectively cytotoxic under hypoxia in all 11 cell lines examined, and demonstrates activity against hypoxic tumor cells in a human tumor xenograft in vivo. |
en |
dc.publisher |
American Chemical Society |
en |
dc.relation.ispartofseries |
Journal of Medicinal Chemistry |
en |
dc.relation.replaces |
http://hdl.handle.net/2292/9244 |
en |
dc.relation.replaces |
2292/9244 |
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.title |
Hypoxia-Activated Prodrugs: Substituent Effects on the Properties of Nitro seco-1,2,9,9a-Tetrahydrocyclopropa[c]benz[e]indol-4-one (nitroCBI) Prodrugs of DNA Minor Groove Alkylating Agents |
en |
dc.type |
Journal Article |
en |
dc.identifier.doi |
10.1021/jm901202b |
en |
pubs.issue |
22 |
en |
pubs.begin-page |
7258 |
en |
pubs.volume |
52 |
en |
dc.rights.holder |
Copyright: American Chemical Society |
en |
dc.identifier.pmid |
19877646 |
en |
pubs.end-page |
7272 |
en |
dc.rights.accessrights |
http://purl.org/eprint/accessRights/RestrictedAccess |
en |
pubs.subtype |
Article |
en |
pubs.elements-id |
118319 |
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 |
2010-09-01 |
en |
pubs.dimensions-id |
19877646 |
en |