Competitive formation of both long-range 5′-5′ and short-range antiparallel 3′-3′ DNA interstrand cross-links by a trinuclear platinum complex on binding to a 10-mer duplex

• Published in: Dalton transactions : an international journal of inorganic chemistry 2013-03, Vol.42 (9), p.3181-3187
• Main Authors: Ruhayel, Rasha A, Berners-Price, Susan J, Farrell, Nicholas P
• Format: Article
• Language: English
• Subjects: Base Sequence; Binding, Competitive; DNA - chemistry; DNA - genetics; DNA - metabolism; Oligodeoxyribonucleotides - chemistry; Oligodeoxyribonucleotides - genetics; Oligodeoxyribonucleotides - metabolism; Organoplatinum Compounds - metabolism; Organoplatinum Compounds - pharmacology
• ISSN: 1477-9226; 1477-9234
• DOI: 10.1039/c2dt32079g

2D [ 1 H, 15 N] HSQC NMR spectroscopy has been used to monitor the reaction of fully 15 N-labelled [{ trans -PtCl(NH 3 ) 2 } 2 (μ- trans -Pt(NH 3 ) 2 {NH 2 (CH 2 ) 6 NH 2 } 2 )] 4+ (Triplatin, BBR3464 or 1,0,1/ t,t,t ( 15 N- 1 )) with the self-complementary 10-mer DNA duplex 5′-{d(ACGTATACGT) 2 } (duplex I ) at pH 5.4 and 298 K. Initial electrostatic interactions were observed in the minor groove of the duplex, followed directly by aquation to form the monoaqua monochloro species. There was evidence for two discrete monofunctional adducts, through covalent binding at the guanine N7 sites, and one had distinctly different 1 H/ 15 N chemical shifts to those observed previously in analogous reactions. Bifunctional adduct formation followed by binding at a second guanine N7 site with evidence for both the 3′-3′ 1,2-GG and 5′-5′ 1,6-GG interstrand cross-links in a ratio of 2 : 1. The results show that cross-link preference is kinetically controlled and will depend critically on the reaction conditions, explaining why in a previous reaction of 1 with duplex I the major adduct isolated by HPLC had two simultaneous 3′-3′ 1,2-interstrand cross-links. The trinuclear platinum drug BB3464 forms both 3′-3′ 1,2-GG and 5′-5′ 1,6-GG interstrand cross-links on binding to a 10-mer duplex.