Mendel-Brno 2000

category image Volume: 17
Issue Number 6, Part 2
June 2000

Solution Studies of cis-[Pt(NH3)2Cl2] Adducts of d(CCTG*G*TCC) .d(GGACCAGG) by Vibrational Circular Dichroism Spectroscopy

cis-Diamminedichloroplatinum(II), known as cisplatin, is a widely used anticancer drug that binds to and crosslinks DNA forming various adducts. The major DNA adduct of this drug results from coordination of two adjacent guanine bases to platinum to form the 1,2-intrastrand crosslink cis-[Pt(NH3)2{d(GpG)-N7(1),-N7(2)}]. While its therapeutic effects have been well established, its mechanism of action is still under intense study. The understanding of this mechanism may in turn help to rationalize the syntheses of new platinum drugs, which will be more effective and less toxic than cisplatin.

In the present study, a relatively new spectroscopic technique, namely Vibrational Circular Dichroism (VCD) spectroscopy, was employed to characterize the influence of cisplatin coordination on the conformation of a model octameric DNA duplex. As has been amply demonstrated by others and in our laboratory, VCD can deliver enhanced sensitivity compared to conventional absorption spectroscopy to conformational changes in DNA structure and especially to those resulting from changing stacking interactions.

The duplex d(CCTG*G*TCC).d(GGACCAGG), where G*G* denotes the platinum coordination site, was studied by VCD in D2O solution. The VCD features were correlated with the structure of this octamer, which was previously elucidated by NMR spectroscopy.1 The data confirmed that this adduct is metastable even at 2'C, and that a slow isomerization starts approximately after 3 hours converting it into other adducts.1


1 D. Yang, S.S.G.E. van Boom, J. Reedijk, J.H. van Boom and A.H.-J. Wang, Biochemistry 34, 12912-12921 (1995).

D.Tsankov1,3, B. Kalisch2, J.H. van de Sande2 and H. Wieser1

1Department of Chemistry, Faculty of Science,
University of Calgary, Calgary, AB, T2N 1N4, Canada.
2Department of Biochemistry and Molecular Biology,
Faculty of Medicine, University of Calgary, Calgary, AB, T2N 1N4, Canada.
3Institute of Organic Chemistry,
Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria.