Abstract
The interactions of DNA with oxaliplatin (Pt(R,R-DACH)) or its enantiomer (Pt(S,S-DACH)) were investigated using magnetic tweezers and atomic force microscope. In the process of DNA condensation induced by Pt-DACH, only diadducts and micro-loops are formed at low Pt-DACH concentrations, while at high Pt-DACH concentrations, besides the diadducts and micro-loops, long-range cross-links are also formed. The diadduct formation rate of Pt(R,R-DACH) is higher than that of Pt(S,S-DACH). However, the proportions of micro-loops and long-range cross-links for Pt(S,S-DACH) are higher than those for Pt(R,R-DACH). We propose a model to explain these differences between the effect of Pt(R,R-DACH) and that of Pt(S,S-DACH) on DNA condensation. The study has strong implications for the understanding of the effect of chirality on the interaction between Pt-DACH and DNA and the kinetics of DNA condensation induced by platinum complexes.
Highlights
The clinical success of cisplatin as an anticancer drug has resulted in the synthesis of new platinum complexes as potential drug candidates
DNA condensation induced by RR or SS of different concentrations was studied by using both magnetic tweezers and atomic force microscopy (AFM)
When DNA molecules are incubated with Pt-DACH of low concentrations, from the magnetic tweezers experiments we find that the curves of DNA extension versus time can be fitted well by a double-exponential decay model, which are assumed to correspond to two concurrent pseudo-first order reactions
Summary
The clinical success of cisplatin as an anticancer drug has resulted in the synthesis of new platinum complexes as potential drug candidates. Among these complexes, oxaliplatin has shown a broad antitumor activity [1,2,3,4] and a lack of cross-resistance with cisplatin [3,5,6]. Positively charged aquated platinum complexes approach DNA quickly with electrostatic attraction and preferentially coordinate to the N7 atom of guanine residues to form monoadducts.
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