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dc.contributor.authorZhang, Junyongen_US
dc.contributor.authorThomas, Donald⿿S.en_US
dc.contributor.authorBerners-Price, Susan⿿J.en_US
dc.contributor.authorFarrell, Nicholasen_US
dc.date.accessioned2017-04-24T08:45:21Z
dc.date.available2017-04-24T08:45:21Z
dc.date.issued2008en_US
dc.date.modified2011-08-12T06:20:48Z
dc.identifier.issn09476539en_US
dc.identifier.doi10.1002/chem.200800408en_AU
dc.identifier.urihttp://hdl.handle.net/10072/39940
dc.description.abstractReported herein is a detailed study of the kinetics and mechanism of formation of a 1,4-GG interstrand cross-link by the dinuclear platinum anticancer compound [15N][{cis-PtCl(NH3)2}2{孎H2(CH2)6NH2}]2+ (1,1/c,c (1)). The reaction of [15N]1 with 5'-{d(ATATGTACATAT)2} (I) has been studied by [1H,15N] HSQC NMR spectroscopy in the presence of different concentrations of phosphate. In contrast with the geometric trans isomer (1,1/t,t), there was no evidence for an electrostatic preassociation of 1,1/c,c with the polyanionic DNA surface, and the pseudo-first-order rate constant for the aquation of [15N]1 was actually slightly higher (rather than lower) than that in the absence of DNA. When phosphate is absent, the overall rate of formation of the cross-link is quite similar for the two geometric isomers, occurring slightly faster for 1,1/t,t. A major difference in the DNA binding pathways is the observation of phosphate-bound intermediates only in the case of 1,1/c,c. 15 mM phosphate causes a dramatic slowing in the overall rate of formation of DNA interstrand cross-links due to both the slow formation and slow closure of the phosphate-bound monofunctional adduct. A comparison of the molecular models of the bifunctional adducts of the two isomers shows that helical distortion is minimal and globally the structures of the 1,4 interstrand cross-links are quite similar. The effect of carrier ligand was investigated by similar studies of the ethylenediamine derivative [15N]1-en. A pKa value of 5.43 was determined for the [15N]1,1/c,c-en diaquated species. The rate of reaction of [15N]1-en with duplex I is similar to that of 1,1/c,c and the overall conformation of the final adduct appears to be similar. The significance of these results to the development of "second-generation" polynuclear platinum clinical candidates based on the 1,1/c,c chelate (dach) series is discussed.en_US
dc.description.peerreviewedYesen_US
dc.description.publicationstatusYesen_AU
dc.languageEnglishen_US
dc.language.isoen_AU
dc.publisherWiley - VCHen_US
dc.publisher.placeGermanyen_US
dc.relation.ispartofstudentpublicationNen_AU
dc.relation.ispartofpagefrom6391en_US
dc.relation.ispartofpageto6405en_US
dc.relation.ispartofissue21en_US
dc.relation.ispartofjournalChemistry : a European journalen_US
dc.relation.ispartofvolume14en_US
dc.rights.retentionYen_AU
dc.subject.fieldofresearchInorganic Chemistry not elsewhere classifieden_US
dc.subject.fieldofresearchcode030299en_US
dc.titleEffects of Geometric Isomerism and Anions on the Kinetics and Mechanism of the Stepwise Formation of Long-Range DNA Interstrand Cross-Links by Dinuclear Platinum Antitumor Complexesen_US
dc.typeJournal articleen_US
dc.type.descriptionC1 - Peer Reviewed (HERDC)en_US
dc.type.codeC - Journal Articlesen_US
gro.date.issued2008
gro.hasfulltextNo Full Text


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