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dc.contributor.authorDavies, Murray
dc.contributor.authorBerners-Price, Sue
dc.contributor.authorHambley, Trevor W.
dc.description.abstract1H−15N HSQC NMR spectroscopy is used to study the aquation reactions of cisplatin in 9 mM NaClO4 and 9 mM phosphate (pH 6) solutions at 298 K. For the first time in a single reaction and, therefore, under a single set of reaction conditions, the amounts of all species formed are followed and the rates of aquation, diaquation, and related anation processes are determined in both media. Binding of phosphate to aquated Pt species is observed, but the initial rate of aquation is not affected by the presence of 9 mM phosphate. The reaction between cisplatin and the 14-base-pair self-complementary oligonucleotide 5‘-d(AATTGGTACCAATT)-3‘, having a GpG intrastrand binding site, is investigated. Various kinetic models for this reaction are evaluated and the most appropriate found to be that with a reversible aquation step and a single binding site for the self-complementary duplex. The rate constant for aquation is (1.62 ± 0.02) × 10-5 s-1, with the anation rate constant fixed at 4.6 × 10-3 M-1 s-1, the value obtained from the aquation studies. The rate constants for monofunctional binding of cis-[PtCl(15NH3)2(OH2)]+ to the sequence were 0.48 ± 0.19 and 0.16 ± 0.06 M-1 s-1 for the 3‘- and 5‘-guanine bases, respectively. Closure rate constants for the monofunctional adducts are (2.55 ± 0.07) × 10-5 and (0.171 ± 0.011) × 10-5 s-1, for the 3‘- and 5‘-guanines, respectively. The presence of DNA slows the aquation of cisplatin by 30−40% compared to that observed in 9 mM NaClO4 or 9 mM phosphate, and there is some evidence that the degree of slowing is sequence dependent. The possibility that cis-[Pt(OH)(NH3)2(OH2)]+ contributes to the binding of cisplatin to DNA is investigated, and it is found that about 1% followed this route, the majority of the binding occurring via the monoaquated species cis-[PtCl(NH3)2(OH2)]+. Comparison of the rates of disappearance of cisplatin in reactions at single defined GpG, ApG, GpA, GpTpG and 1,2-interstrand GG binding sites shows that the adduct profile is determined at the level of monofunctional adduct formation.en_US
dc.publisherAmerican Chemical Societyen_US
dc.relation.ispartofjournalInorganic Chemistryen_US
dc.subject.fieldofresearchHISTORY AND ARCHAEOLOGYen_US
dc.titleSlowing of Cisplatin Aquation in the Prescence of DNA but Not in the Prescence of Phosphate:Improved Understanding of Sequence Selectivity and the roles of Monoaquated and Diaquated Species in the Binding of Cisplatin to DNAen_US
dc.typeJournal articleen_US
dc.type.descriptionC1 - Peer Reviewed (HERDC)en_US
dc.type.codeC - Journal Articlesen_US
gro.facultyGriffith Sciences, Griffith Institute for Drug Discoveryen_US
gro.hasfulltextNo Full Text

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