Insights into DNA Platination within Unusual Structural Settings

Abstract EN

2D [H1,N15] HSQC NMR spectroscopy has been used to monitor reaction and product formation between [Pt(N15H3)2I2] and nucleic acids possessing irregular topologies and containing site-specific phosphorothioate substitution in the phosphodiester backbone.

Comparison of the reaction profiles of dimer nucleic acids with and without phosphorothioate substitution is made with their short nucleic acid counterparts containing the key dimer components.

Whereas d(GpA) is relatively unreactive towards [Pt(N15H3)2I2], NMR evidence suggests that the tandem sheared mismatch duplex d(GCG3pAGC)2 reacts to form the head-to-tail interstrand G3-N7-Pt-G3-N7 cross-link.

The equivalent phosphorothioate R,S-d(GsA) reacts to form a monoiodo, monosulphur adduct, whereas the tandem sheared mismatch phosphorothioate duplex d(GCGsAG5C)2 (VIs) reacts to form the unusual intrastrand macrochelate [Pt(N15H3)2{d(VIs-G5-N7)},S]2+, in which platinum is attached at both sulphur and G5-N7.

Experimental evidence supports the formation of a stabilized mismatch duplex in which platinum is attached to two nitrogen centres in the sequence d(CGCGpTGCG) in contrast to R,S-d(CGCGsT5GCG) for which NMR evidence supports macrochelate-stabilized hairpin loop formation cross-linked at both phosphorothioate sulphur and T5-N3.