Unusual Interstrand Pt(S,S-diaminocyclohexane)-GG Crosslink Formed by Rearrangement of a Classical Intrastrand Crosslink Within a DNA Duplex

摘要

Currently used platinum antitumor drugs, such as cisplatin (cis-[PtCl_(2)(NH_(3))_(2)]) and oxaliplatin ([Pt(oxalate)(R,R-DACH)]) (DACH velence 1,2-diaminocyclohexane), are believed to trigger apoptotic cell death by a cascade of cellular events induced by an initial reaction with DNA. This reaction yields predominantly covalent crosslinks between adjacent guanine bases, which produce a bend in the DNA double-helix. The crosslinks are generally inert and thus persistent; nevertheless some examples have been identified where an initially formed crosslink rearranges to another lesion. We report here a remarkable case of such a rearrangement where the initial duplex d(C_(1)C_(2)T_(3)T_(4)G_(5)~(*)G_(6)~(*)T_(7)C_(8)T_(9)C_(10))-d(G_(11)A_(12)G_(13)A_(14)C_(15)C_(16)A_(17)A_(18)G_(19)G_(20)) (1) (G~(*) bases cross-linked by Pt(S,S-DACH)~(2+), the enantiomer of Pt(R,R-DACH)~(2+) occurring in oxaliplatin) rearranges to the inter-strand-crosslinked species d(C_(1)C_(2)T_(3)T_(4)G_(5)G_(6)~(*)T_(7)C_(8)T_(9)C_(10))-d(G_(11)~(*)A_(12)G_(13)A_(14)C_(15)C_(16)A_(17)A_(18)G_(19)G_(20)) (2). 2 has an unprecedented structure with a head-to-tail orientation of the platinated bases G_(6)~(*) and G_(11)~(*) and a side-on interaction between G~(*)_(11) and the methyl group of T_(7). This intrastrand-to-interstrand rearrangement is a new demonstration of the kinetic instability of Pt-N bonds in strained structures.