dc.contributor.author |
Shinde, Sujata |
en |
dc.contributor.author |
Maroz, Andrej |
en |
dc.contributor.author |
Hay, Michael |
en |
dc.contributor.author |
Patterson, Adam |
en |
dc.contributor.author |
Denny, William |
en |
dc.contributor.author |
Anderson, Robert |
en |
dc.date.accessioned |
2011-11-17T17:15:27Z |
en |
dc.date.issued |
2010-03-03 |
en |
dc.identifier.citation |
Journal of the American Chemical Society 132(8):2591-2599 03 Mar 2010 |
en |
dc.identifier.issn |
0002-7863 |
en |
dc.identifier.uri |
http://hdl.handle.net/2292/9215 |
en |
dc.description.abstract |
The mechanism by which the 1,2,4-benzotriazine 1,4-dioxide (BTO) class of bioreductive hypoxia-selective prodrugs (HSPs) form reactive radicals that kill cancer cells has been investigated by steady-state radiolysis, pulse radiolysis (PR), electron paramagnetic resonance (EPR), and density functional theory (DFT) calculations. Tirapazamine (TPZ, 3-amino BTO, 1) and a series of 3-substituted analogues, -H (2), -methyl (3), -ethyl (4), -methoxy (5), -ethoxymethoxy (6), and -phenyl (7), were reduced in aqueous solution under anaerobic steady-state radiolysis conditions, and their radicals were found to remove the substrates by short chain reactions of different lengths in the presence of formate ions. Multiple carbon-centered radical intermediates, produced upon anaerobic incubation of the compounds with cytochrome P450 reductase enriched microsomes, were trapped by N-tert-butyl-α-phenylnitrone and observed using EPR. The highly oxidizing oxymethyl radical, from compound 5, was identified, and experimental spectra obtained for compounds 1, 2, 3, and 7 were well simulated after the inclusion of aryl radicals. The identification of a range of oxidizing radicals in the metabolism of the BTO compounds gives a new insight into the mechanism by which these HSPs can cause a wide variety of damage to biological targets such as DNA. |
en |
dc.language |
EN |
en |
dc.publisher |
American Chemical Society |
en |
dc.relation.ispartofseries |
Journal of the American Chemical Society |
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/0002-7863/ |
en |
dc.rights.uri |
https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm |
en |
dc.subject |
ONE-ELECTRON REDUCTION |
en |
dc.subject |
ANTITUMOR AGENT TIRAPAZAMINE |
en |
dc.subject |
DNA-BASE DAMAGE |
en |
dc.subject |
AQUEOUS-SOLUTION |
en |
dc.subject |
1,2,4-BENZOTRIAZINE 1,4-DIOXIDES |
en |
dc.subject |
TUMOR HYPOXIA |
en |
dc.subject |
FRACTIONATED-IRRADIATION |
en |
dc.subject |
HYDROXYL RADICALS |
en |
dc.subject |
NECK-CANCER |
en |
dc.subject |
N-OXIDES |
en |
dc.title |
Characterization of Radicals Formed Following Enzymatic Reduction of 3-Substituted Analogues of the Hypoxia-Selective Cytotoxin 3-Amino-1,2,4-Benzotriazine 1,4-Dioxide (Tirapazamine) |
en |
dc.type |
Journal Article |
en |
dc.identifier.doi |
10.1021/ja908689f |
en |
pubs.issue |
8 |
en |
pubs.begin-page |
2591 |
en |
pubs.volume |
132 |
en |
dc.rights.holder |
Copyright: American Chemical Society |
en |
dc.identifier.pmid |
20141134 |
en |
pubs.end-page |
2599 |
en |
dc.rights.accessrights |
http://purl.org/eprint/accessRights/RestrictedAccess |
en |
pubs.subtype |
Article |
en |
pubs.elements-id |
118840 |
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 |
2011-11-17 |
en |
pubs.dimensions-id |
20141134 |
en |