Tricyclic [1,2,4]triazine 1,4-dioxides as hypoxia-selective cytotoxins

Show simple item record Hay, Michael en Hicks, Kevin en Pchalek, Karin en Lee, Ho en Blaser, Adrian en Pruijn, Frederik en Anderson, Robert en Shinde, Sujata en Siim, BG en Wilson, William en Denny, William en 2011-11-18T02:17:52Z en 2012-01-30T02:20:42Z en 2008 en
dc.identifier.citation Journal of Medicinal Chemistry 51(21):6853-6865 2008 en
dc.identifier.issn 0022-2623 en
dc.identifier.uri en
dc.description.abstract A series of novel tricyclic triazine-di-N-oxides (TTOs) related to tirapazamine have been designed and prepared. A wide range of structural arrangements with cycloalkyl, oxygen-, and nitrogen-containing saturated rings fused to the triazine core, coupled with various side chains linked to either hemisphere, resulted in TTO analogues that displayed hypoxia-selective cytotoxicity in vitro. Optimal rates of hypoxic metabolism and tissue diffusion coefficients were achieved with fused cycloalkyl rings in combination with both the 3-aminoalkyl or 3-alkyl substituents linked to weakly basic soluble amines. The selection was further refined using pharmacokinetic/pharmacodynamic model predictions of the in vivo hypoxic potency (AUCreq) and selectivity (HCD) with 12 TTO analogues predicted to be active in vivo, subject to the achievement of adequate plasma pharmacokinetics. en
dc.publisher American Chemical Society en
dc.relation.ispartofseries Journal of Medicinal Chemistry en
dc.relation.replaces en
dc.relation.replaces 2292/9396 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 en
dc.rights.uri en
dc.title Tricyclic [1,2,4]triazine 1,4-dioxides as hypoxia-selective cytotoxins en
dc.type Journal Article en
dc.identifier.doi 10.1021/jm800967h en
pubs.issue 21 en
pubs.begin-page 6853 en
pubs.volume 51 en
dc.rights.holder Copyright: American Chemical Society en
dc.identifier.pmid 18847185 en
pubs.end-page 6865 en
dc.rights.accessrights en
pubs.subtype Article en
pubs.elements-id 79525 en Medical and Health Sciences en Medical Sciences en Auckland Cancer Research en Science en Science Research en Maurice Wilkins Centre (2010-2014) en Uniservices en
pubs.record-created-at-source-date 2010-09-01 en
pubs.dimensions-id 18847185 en

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