dc.contributor.author | Zhang, Junyong | |
dc.contributor.author | Thomas, Donald S | |
dc.contributor.author | Berners-Price, Susan J | |
dc.contributor.author | Farrell, Nicholas | |
dc.date.accessioned | 2018-02-13T03:41:48Z | |
dc.date.available | 2018-02-13T03:41:48Z | |
dc.date.issued | 2008 | |
dc.date.modified | 2011-08-12T06:20:48Z | |
dc.identifier.issn | 0947-6539 | |
dc.identifier.doi | 10.1002/chem.200800408 | |
dc.identifier.uri | http://hdl.handle.net/10072/39940 | |
dc.description.abstract | Reported 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{μ-NH2(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. | |
dc.description.peerreviewed | Yes | |
dc.description.publicationstatus | Yes | |
dc.language | English | |
dc.language.iso | eng | |
dc.publisher | Wiley - VCH | |
dc.publisher.place | Germany | |
dc.relation.ispartofstudentpublication | N | |
dc.relation.ispartofpagefrom | 6391 | |
dc.relation.ispartofpageto | 6405 | |
dc.relation.ispartofissue | 21 | |
dc.relation.ispartofjournal | Chemistry : a European journal | |
dc.relation.ispartofvolume | 14 | |
dc.relation.uri | http://purl.org/au-research/grants/ARC/DP0662817 | |
dc.relation.grantID | DP0662817 | |
dc.relation.funders | ARC | |
dc.rights.retention | Y | |
dc.subject.fieldofresearch | Chemical sciences | |
dc.subject.fieldofresearch | Inorganic chemistry not elsewhere classified | |
dc.subject.fieldofresearchcode | 34 | |
dc.subject.fieldofresearchcode | 340299 | |
dc.title | Effects 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 Complexes | |
dc.type | Journal article | |
dc.type.description | C1 - Articles | |
dc.type.code | C - Journal Articles | |
gro.date.issued | 2008 | |
gro.hasfulltext | No Full Text | |
gro.griffith.author | Berners-Price, Sue J. | |