Abstract
2D HSQC NMR spectroscopy has been used to monitor reaction and product formation between 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 , 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 , 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.
Highlights
The concept of targeted approaches to cancer chemotherapy is increasingly delivering candidate innovations with real potential for application in the clinic [1,2,3]
The outcome of monitoring the reaction of each isolated dimer subunit by 2D [1H, 15N] HSQC NMR spectroscopy is shown summarized as a single reaction snapshot in each case (Figure 1)
The work presented in this paper extends the understanding of the manner by which platinum(II) molecules interact with standard phosphodiester and modified phosphorothioate nucleic acids by exploring their reaction with [Pt(15NH3)2I2]
Summary
The concept of targeted approaches to cancer chemotherapy is increasingly delivering candidate innovations with real potential for application in the clinic [1,2,3]. Distress to patients caused through the toxic side-effects brought about by systemic delivery of active drugs could be reduced or perhaps eliminated in instances where a cancer is localized, and an inactive prodrug could be delivered and activated solely at the target site, either through reduction within the cell [4] or by means of some external stimulation mechanism [5, 6]. The aim of such localization together with the specific targeting of genes associated with cell immortalization is of real value in the development of new candidate targeting drugs. Such an approach would enable gene targeting with localized therapy, provided the initial drug delivery could be prosecuted with the drug in a dormant, inactive (i.e., prodrug) state as proposed with activation taking place by means of an external inducing agent [15,16,17]
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