Cisplatin-DNA Adducts by Vibrational Circular Dichroism Spectroscopy: Structure and Isomerization of d(CCTG*G*TCC)‚d(GGACCAGG) Intrastrand Cross-Linked by Cisplatin

The intrastrand cisplatin adduct of the duplex d(CCTG*G*TCC)‚d(GGACCAGG), where the asterisks denote the 1,2-intrastrand crosslink, was synthesized and studied in solution in D 2O by vibrational circular dichroism (VCD) and infrared absorption spectroscopy. Comparison of the spectra of the platinated and unmodified complexes confirmed that the entire structure is considerably distorted, as a result of the platinum coordination to the octamer duplex. The major changes in the VCD spectra were detected in the fourth base step, where the cisplatin cross-links the adjacent guanine bases G4 and G5. Platinum coordination shifts the G4-C13 and G5-C12 base pairs apart, with a concomitant disruption of the stacking between the neighboring bases T3-G4 and G5-T6. The resultant new VCD couplets were assigned to stacking interactions between A11 and A14, which implies a substantially distorted structure. Slow isomerization is indicated by diagnostic changes in VCD, converting the intrastrand adduct to other adducts. The corresponding absorption spectra remain essentially unchanged. This DNA octamer was previously studied by NMR in great detail when the isomerization was first detected after one day. Our measurements show that the conversion began soon after both strands were annealed and the first signs were detected in 2 h. This investigation again demonstrated convincingly that VCD is very sensitive to DNA structure modified by complex formation with cisplatin and may become more widely applicable for other similar applications.