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

Abstract

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 2 O 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.

DNA Oligonucleotide−cis-Platin Binding: Ab Initio Interpretation of the Vibrational Spectra

“…The simulated changes in the IR and VCD spectra are consistent with the NMR proposition of the DNA-cis-Pt adduct geometry, except for the detailed carbonyl VCD pattern. The significant modification in the IR and VCD spectra observed experimentally 29 could be readily attributed to the complex formation. Major changes characteristic for the complexation are visible in the higher frequency region (1500-1700 cm -1 ).…”

Bioinspired interactions studied by vibrational circular dichroism

“…4). 32 Comparison of the vibrational spectra of the unmodified duplex and its cisplatin adduct reveals the conformational changes that take place upon binding. In connection with NMR and X-ray results, VCD in the nitrogen base region reveals the changes in conformation in the platinated complexes, especially in the frame of adjacent guanines during the intrastrand cisplatin interaction.…”

“…DNA-metal interactions are another group of biologically relevant interactions where VCD provided valuable information. 21,[27][28][29][30][31][32] Among the metal-DNA adducts, cisplatin-oligonucleotide is interesting, because the compound cis-diamminedichlorplatinium(II) is a member of the widely used anticancer drug family, where the interaction with DNA plays a crucial role in inducing apoptosis. VCD was shown to sensitively monitor the structural changes of d(CCTG*G*TCC)Ád(GGACCAGG) caused by cisplatin in the 1740-1500 cm 21 region and the phosphate spectral regions which are used for the oligonucleotide spectral studies (Fig.…”

“…A clear separation of signals originating from two different proteins, one labeled with 13 C, was achieved for apo-13 C-CaM and unlabeled apo-Lac. VCD was used in the spectroscopic investigation of the interaction of four terpene trilactones from Ginkgo biloba with the peptide Ab (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) that serves as a model of amyloid beta peptide (Ab). 77 Such interaction is studied because of the possible inhibition of the pathological aggregation of Ab by G. biloba, which is used in the ''treatment'' of dementia.…”

Cisplatin adducts of d(CCTCTG*G*TCTCC)·d(GGAGACCAGAGG) in aqueous solution by vibrational circular dichroism spectroscopy

“…Following our first VCD study of cis ‐DDP–DNA adducts using the octameric duplex d(CCTG‐ GTCC)·(GGACCAGG),25 we deemed it appropriate to also examine the VCD spectra of a longer oligonucleotide, specifically d(CCTCTGGTCTCC)· (GGAGACCAGAGG), crosslinked by cis ‐DDP, for which NMR9 and X‐ray13, 14 structures are also available. In this article we propose tentative assignments for VCD and absorption bands and examine the conformational changes that are taking place by comparing our results with those obtained for the same complex in solution and in the crystalline state.…”