Factors Affecting Formation and Structure of DNA Intrastrand Cross-Links by Dinuclear Platinum Complexes
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Dinuclear platinum complexes are currently undergoing pre-clinical evaluation. The development of this series has been driven by the hypothesis that a different spectrum of antitumor activity in comparison to that of cisplatin (cis-[PtCl2(NH3)2], cis-DDP) will be achieved by altering the mode of DNA binding relative to that of cisplatin and its analogues. Dinuclear platinum complexes form a unique array of DNA adducts including (Pt, Pt) interstrand and (Pt, Pt) intrastrand cross-links. A (Pt, Pt) intrastrand adduct between two adjacent guanines is the structural analog of the major adduct formed by cis-DDP2. This cis-DDP-d(GpG) adduct produces a rigid, directed bend 30-35° into the major groove of DNA, confirmed by both X- ray and NMR structural determinations on oligonucleotide fragments containing site-specific adducts3, 4. This bend is recognised by damage recognition proteins containing the HMG-binding domain5. In contrast, the global structural distortions of DNA induced by the dinuclear platinum complexes are recognized only weakly by HMG-domain proteins.6 This contribution summarises our results on the structural reasons for these differences, as exemplified by comparative studies on DNA-DNA intrastrand adducts between adjacent guanines.
KeywordsPlatinum Complex Major Groove Steric Hinderance Dinuclear Platinum Adjacent Guanine
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