Theoretical Study of Cisplatin Binding to DNA:  The Importance of Initial Complex Stabilization

Raber, Johan; Zhu, Chen; Eriksson, Leif A.

doi:10.1021/jp050057d

Cited by 106 publications

(105 citation statements)

References 53 publications

(85 reference statements)

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“…[26] In recent years, theoretical approaches have increasingly added insight into cisplatins chemistry, including its electronic structure, [27,28] hydrolysis, [27,[29][30][31] structural properties of DNA base-cisplatin complexes [27,32,33] and effect on DNA base pairing. [34][35][36] For instance, Eriksson et al [37] studied the attack of activated cisplatin on DNA and showed that guanine gives a lower barrier than adenine for both mono-and bifunctional complexes. Leszczynski et al [32] showed that the expected G-Pt-G structure is indeed the most stable, along with A-Pt-G.…”

Section: Cis-diamminodichloroplatinum(ii) (Cis-[ptcl 2 a C H T U N G mentioning

confidence: 99%

A QM/MM Study of Cisplatin–DNA Oligonucleotides: From Simple Models to Realistic Systems

Robertazzi

Platts

2006

Chemistry A European J

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QM/MM calculations were employed to investigate the role of hydrogen bonding and pi stacking in several single- and double-stranded cisplatin-DNA structures. Computed geometrical parameters reproduce experimental structures of cisplatin and its complex with guanine-phosphate-guanine. Following QM/MM optimisation, single-point DFT calculations allowed estimation of intermolecular forces through atoms in molecules (AIM) analysis. Binding energies of platinated single-strand DNA qualitatively agree with myriad experimental and theoretical studies showing that complexes of guanine are stronger than those of adenine. The topology of all studied complexes confirms that platination strongly affects the stability of both single- and double-stranded DNAs: Pt-N-H...X (X = N or O) interactions are ubiquitous in these complexes and account for over 70 % of all H-bonding interactions. The pi stacking is greatly reduced by both mono- and bifunctional complexation: the former causes a loss of about 3-4 kcal mol(-1), whereas the latter leads to more drastic disruption. The effect of platination on Watson-Crick GC is similar to that found in previous studies: major redistribution of energy occurs, but the overall stability is barely affected. The BH&H/AMBER/AIM approach was also used to study platination of a double-stranded DNA octamer d(CCTG*G*TCC)d(GGACCAGG), for which an experimental structure is available. Comparison between theory and experiment is satisfactory, and also reproduces previous DFT-based studies of analogous structures. The effect of platination is similar to that seen in model systems, although the effect on GC pairing was more pronounced. These calculations also reveal weaker, secondary interactions of the form Pt...O and Pt...N, detected in several single- and double-stranded DNA.

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Section: Cis-diamminodichloroplatinum(ii) (Cis-[ptcl 2 a C H T U N G mentioning

confidence: 99%

A QM/MM Study of Cisplatin–DNA Oligonucleotides: From Simple Models to Realistic Systems

Robertazzi

Platts

2006

Chemistry A European J

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“…To clarify the preference of cisplatin for guanine over adenine, Baik et al [45] carried out DFT studies on the first substitution of cisplatin binding to purine bases. However, Raber et al [46] suggested that the preference of cisplatin toward guanine is governed by the thermodynamic stability of reactant complex (RC) formation in combination with higher activation energy for the adenine substitution. Furthermore, Deubel [47] probed kinetic factors governing the competition between nitrogen and sulfur ligands in cisplatin binding.…”

Section: Introductionmentioning

confidence: 99%

A DFT study of a novel oxime anticancer trans platinum complex: Monofunctional and bifunctional binding to purine bases

Xu¹,

Zhou²

2011

Int J of Quantum Chemistry

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ABSTRACT:The first and second substitution reactions binding of the anticancer drug trans-[Pt((CH 3 ) 2 C¼ ¼NOH)((CH 3 ) 2 CHNH 2 )Cl 2 ] to purine bases were studied computationally using a combination of density functional theory and isoelectric focusing polarized continuum model approach. Our calculations demonstrate that the trans monoaqua and diaqua reactant complexes (RCs) can generate either trans-or cismonoadducts via identical or very similar trans trigonal-bipyramidal transition-state structures. Furthermore, these monoadducts can subsequently close by coordination to the adjacent purine bases to form 1,2-intrastrand Pt-DNA adducts and eventually distort DNA in the same way as cisplatin. Thus, it is likely that the transplatin analogues have the same mechanism of anticancer activity as cisplatin. For the first substitutions, the activation free energies of monoaqua complexes are always lower than that of diaqua complexes. The lowest activation energy for monoaqua substitutions is 16.2 kcal/mol for guanine and 16.5 kcal/mol for adenine, whereas the lowest activation energy for diaqua substitutions is 17.1 kcal/mol for guanine and 25.9 kcal/ mol for adenine. For the second substitutions, the lowest activation energy from transmonoadduct to trans-diadduct is 19.1 kcal/mol for GG adduct and 20.7 kcal/mol for GA adduct, whereas the lowest activation energy from cis-monoadduct to cis-diadduct is 18.9 kcal/mol for GG adduct and 18.5 kcal/mol for GA adduct. In addition, the first and second substitutions prefer guanine over adenine, which is explained by the remarkable larger complexation energy for the initial RC in combination with lower activation energy for the guanine substitution. Overall, the hydrogen-bonds play an important role in stabilizing these species of the first and second substitutions.

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“…The reason for this behavior is the formation of interstrand and intrastrand crosslinks caused by cisplatin inside the DNA. 52,53 Thus, the Figure 9 Fabricated seON DeX-ha*cPt can be controlled with a neodymium magnet.…”

mentioning

confidence: 99%

Development and characterization of magnetic iron oxide nanoparticles with a cisplatin-bearing polymer coating for targeted drug delivery

Unterweger¹,

Tietze²,

Janko³

et al. 2014

IJN

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A highly selective and efficient cancer therapy can be achieved using magnetically directed superparamagnetic iron oxide nanoparticles (SPIONs) bearing a sufficient amount of the therapeutic agent. In this project, SPIONs with a dextran and cisplatin-bearing hyaluronic acid coating were successfully synthesized as a novel cisplatin drug delivery system. Transmission electron microscopy images as well as X-ray diffraction analysis showed that the individual magnetite particles were around 4.5 nm in size and monocrystalline. The small crystallite sizes led to the superparamagnetic behavior of the particles, which was exemplified in their magnetization curves, acquired using superconducting quantum interference device measurements. Hyaluronic acid was bound to the initially dextran-coated SPIONs by esterification. The resulting amide bond linkage was verified using Fourier transform infrared spectroscopy. The additional polymer layer increased the vehicle size from 22 nm to 56 nm, with a hyaluronic acid to dextran to magnetite weight ratio of 51:29:20. A maximum payload of 330 μg cisplatin/mL nanoparticle suspension was achieved, thus the particle size was further increased to around 77 nm with a zeta potential of −45 mV. No signs of particle precipitation were observed over a period of at least 8 weeks. Analysis of drug-release kinetics using the dialysis tube method revealed that these were driven by inverse ligand substitution and diffusion through the polymer shell as well as enzymatic degradation of hyaluronic acid. The biological activity of the particles was investigated in a nonadherent Jurkat cell line using flow cytometry. Further, cell viability and proliferation was examined in an adherent PC-3 cell line using xCELLigence analysis. Both tests demonstrated that particles without cisplatin were biocompatible with these cells, whereas particles with the drug induced apoptosis in a dose-dependent manner, with secondary necrosis after prolonged incubation. In conclusion, combination of dextran-coated SPIONs with hyaluronic acid and cisplatin represents a promising approach for magnetic drug targeting in the treatment of cancer.

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Theoretical Study of Cisplatin Binding to DNA: The Importance of Initial Complex Stabilization

Cited by 106 publications

References 53 publications

A QM/MM Study of Cisplatin–DNA Oligonucleotides: From Simple Models to Realistic Systems

A QM/MM Study of Cisplatin–DNA Oligonucleotides: From Simple Models to Realistic Systems

A DFT study of a novel oxime anticancer trans platinum complex: Monofunctional and bifunctional binding to purine bases

Development and characterization of magnetic iron oxide nanoparticles with a cisplatin-bearing polymer coating for targeted drug delivery

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