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dc.contributor.authorShalders, RL
dc.contributor.authorBlanch, G
dc.contributor.authorBrown, CL
dc.contributor.authorYoung, DJ
dc.contributor.authorPrakash, AS
dc.date.accessioned2019-05-10T00:59:07Z
dc.date.available2019-05-10T00:59:07Z
dc.date.issued1999
dc.identifier.issn0009-2797
dc.identifier.doi10.1016/S0009-2797(98)00102-1
dc.identifier.urihttp://hdl.handle.net/10072/120921
dc.description.abstractWe have recently synthesised a series of compounds based on the simplest functional unit of CC-1065 containing a para substituted phenethyl halide moiety. These compounds alkylate N3 of adenines in a similar fashion to CC-1065, as well as N7 of guanines to a limited extent [9]. In this work we compared the para amino substituted derivative (2) with the published hydroxyl compound (1) in terms of stability, DNA reactivity and pH dependence using gel electrophoresis techniques. The results show that 2 has a shorter lifetime and is at least 2.5 times more reactive with DNA than 1. It is completely hydrolysed between 30 and 60 min in buffer and its reaction with DNA is complete within 5 min. In contrast, only a fraction of 1 is hydrolysed after 60 min and retains reactivity towards DNA even after 3 h. The reactivities of both 1 and 2 with DNA are pH dependent and reaction rates rapidly decrease in the range pH 5.8–8.8. Preliminary molecular modelling studies suggest that the p-amino group on 2 enables the drug to bind to the AT-rich minor groove more effectively, thus stabilising the orientation of the substrate in the groove such that the reactive cyclopropyl ring is located close to the nucleophilic centre N3 of adenine. A possible mechanism of action of these drugs is presented based on these findings.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherElsevier Science
dc.publisher.placeIreland
dc.relation.ispartofpagefrom83
dc.relation.ispartofpageto94
dc.relation.ispartofjournalChemico-Biological Interactions
dc.relation.ispartofvolume117
dc.subject.fieldofresearchBiochemistry and cell biology
dc.subject.fieldofresearchcode3101
dc.titleStability and DNA alkylation rates of the simplest functional analogues of CC-1065, para-hydroxy and para-amino phenethyl bromides
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
gro.facultyGriffith Sciences, Griffith Institute for Drug Discovery
gro.hasfulltextNo Full Text
gro.griffith.authorBrown, Chris L.
gro.griffith.authorYoung, David
gro.griffith.authorBlanch, Gregory
gro.griffith.authorShalders, Robyn


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