Competitive reactions of interstrand and intrastrand DNA-Pt adducts: a dinuclear-platinum complex preferentially forms a 1,4-interstrand cross-link rather than a 1,2 intrastrand cross-link on binding to a GG 14-mer duplex

Berners-Price, Susan J., Davies, Murray S., Cox, John W., Thomas, Donald S., and Farrell, Nicholas (2003) Competitive reactions of interstrand and intrastrand DNA-Pt adducts: a dinuclear-platinum complex preferentially forms a 1,4-interstrand cross-link rather than a 1,2 intrastrand cross-link on binding to a GG 14-mer duplex. Chemistry, 9 (3). pp. 713-725.

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Abstract

A study of the kinetics and mechanism of the reaction between the dinuclear Pt complex [{trans-PtCl-(NH3)2}2(μ-NH2(CH2)6NH2)]2+ (1) and the 14-mer duplex 5'-d(ATACAT-G(7)G(8)TACATA)-3'-5'-d(TATG(25)-TACCATG(18)TAT)-3' is reported. [1H,15N]-HSQC NMR was used to follow the reaction at 298 K, pH 5.4. The product is primarily the 5'-5' 1,4-interstrand cross-link between G(8) and G(18) bases and exists in two conformational forms. No evidence for the possible 1,2-intrastrand G(7)G(8) adduct was seen, confirming the preferential formation of interstrand cross-links by these dinuclear complexes. An initial electrostatic association of 15N-1 with the duplex is indicated by changes in its 1H/15N chemical shifts, followed by aquation of 1 to form the monoaqua monochloro species 2, with a rate constant of 4.00′0.03 x 10-5 s-1. Monofunctional binding to the duplex occurs primarily at G(8), the 3' base of the nucleophilic GG grouping, with a rate constant of 1.5′0.7 M-1 S-1. Changes in the 1H/15N shifts indicate there is an electrostatic interaction between the unbound {PtN3Cl} group of the monofunctional adduct and the duplex. No peaks for a transient aquated monofunctional species are seen and closure of 3 to form the 1,4-G(8)G(18) interstrand cross-link (5) was treated as direct, with a rate constant of 4.47′0.06×10-5s-1. The G(8)G(18) cross-link was confirmed from analysis of the NOESY NMR spectrum of the final product. Structural perturbations for the 1,4-interstrand cross-link extend over approximately four base-pairs and are similar to those found for a 1,4-interstrand cross-link with a shorter 8-mer -GTAC- sequence. A major distortion was evident for the 5'T (T(17)) adjacent to the platinated G(18), consistent with the findings from the use of chemical probes to investigate the conformation of 1,4-interstrand cross-links.

Item ID: 4437
Item Type: Article (Research - C1)
ISSN: 1521-3765
Keywords: cancer; chemotherapy; kinetics; NMR spectroscopy; antitumor agents; DNA; kinetics; platinum
Date Deposited: 16 Jun 2009 04:19
FoR Codes: 03 CHEMICAL SCIENCES > 0302 Inorganic Chemistry > 030203 Inorganic Green Chemistry @ 100%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920102 Cancer and Related Disorders @ 51%
97 EXPANDING KNOWLEDGE > 970103 Expanding Knowledge in the Chemical Sciences @ 49%
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