dc.contributor.author |
Hay, Michael |
en |
dc.contributor.author |
Pchalek, Karin |
en |
dc.contributor.author |
Pruijn, Frederik |
en |
dc.contributor.author |
Hicks, Kevin |
en |
dc.contributor.author |
Siim, Bronwyn |
en |
dc.contributor.author |
Anderson, Robert |
en |
dc.contributor.author |
Shinde, Sujata |
en |
dc.contributor.author |
Phillips, Victoria |
en |
dc.contributor.author |
Denny, William |
en |
dc.contributor.author |
Wilson, William |
en |
dc.date.accessioned |
2011-11-17T17:22:04Z |
en |
dc.date.issued |
2007 |
en |
dc.identifier.citation |
Journal of Medicinal Chemistry 50(26):6654-6664 2007 |
en |
dc.identifier.issn |
0022-2623 |
en |
dc.identifier.uri |
http://hdl.handle.net/2292/9245 |
en |
dc.description.abstract |
Tirapazamine (TPZ) and related 1,2,4-benzotriazine 1,4 dioxides (BTOs) are selectively toxic under hypoxia, but their ability to kill hypoxic cells in tumors is generally limited by their poor extravascular transport. Here we show that removing hydrogen bond donors by replacing the 3-NH2 group of TPZ with simple alkyl groups increased their tissue diffusion coefficients as measured in multicellular layer cultures. This advantage was largely retained using solubilizing 3-alkylaminoalkyl substituents provided these were sufficiently lipophilic at pH 7.4. The high reduction potentials of such compounds resulted in rates of metabolism too high for optimal penetration into hypoxic tissue, but electron-donating 6- and 7-substituents moderated metabolism. Pharmacokinetic/pharmacodynamic model-guided screening was used to select BTOs with optimal extravascular transport and hypoxic cytotoxicity properties for evaluation against HT29 human tumor xenografts in combination with radiation. This identified four novel 3-alkyl BTOs providing greater clonogenic killing of hypoxic cells than TPZ at equivalent host toxicity, with the 6-morpholinopropyloxyBTO 22 being 3-fold more active. |
en |
dc.language |
EN |
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 |
MULTICELLULAR LAYER CULTURES |
en |
dc.subject |
PREDICTS RADIATION RESPONSE |
en |
dc.subject |
PHASE-II TRIAL |
en |
dc.subject |
CANCER-THERAPY |
en |
dc.subject |
TUMOR HYPOXIA |
en |
dc.subject |
BIOREDUCTIVE DRUGS |
en |
dc.subject |
ANTICANCER DRUG |
en |
dc.subject |
SOLID TUMORS |
en |
dc.subject |
NECK-CANCER |
en |
dc.subject |
DNA-DAMAGE |
en |
dc.title |
Hypoxia-Selective 3-Alkyl 1,2,4-Benzotriazine 1,4-Dioxides: The Influence of Hydrogen Bond Donors on Extravascular Transport and Antitumor Activity |
en |
dc.type |
Journal Article |
en |
dc.identifier.doi |
10.1021/jm701037w |
en |
pubs.issue |
26 |
en |
pubs.begin-page |
6654 |
en |
pubs.volume |
50 |
en |
dc.rights.holder |
Copyright: AMER CHEMICAL SOC |
en |
dc.identifier.pmid |
18052317 |
en |
pubs.end-page |
6664 |
en |
dc.rights.accessrights |
http://purl.org/eprint/accessRights/RestrictedAccess |
en |
pubs.subtype |
Article |
en |
pubs.elements-id |
75524 |
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 |
Pathology |
en |
pubs.org-id |
Science |
en |
pubs.org-id |
Science Research |
en |
pubs.org-id |
Maurice Wilkins Centre (2010-2014) |
en |
pubs.org-id |
Uniservices |
en |
pubs.record-created-at-source-date |
2010-09-01 |
en |
pubs.dimensions-id |
18052317 |
en |