Direct Determination of Metal Complexes ... - ACS Publications

Letter pubs.acs.org/JPCL

Direct Determination of Metal Complexes’ Interaction with DNA by Atomic Telemetry and Multiscale Molecular Dynamics Joanna Czapla-Masztafiak,†,‡,# Juan J. Nogueira,§,# Ewelina Lipiec,†,⊥ Wojciech M. Kwiatek,† Bayden R. Wood,∥ Glen B. Deacon,∇ Yves Kayser,‡ Daniel L. A. Fernandes,○ Mariia V. Pavliuk,○ Jakub Szlachetko,*,‡,¶ Leticia González,*,§ and Jacinto Sá*,○,¤ †

Institute of Nuclear Physics, Polish Academy of Sciences, PL-31342 Krakow, Poland Paul Scherrer Institute (PSI), 5232 Villigen, Switzerland § University of Vienna, Faculty of Chemistry, Institute of Theoretical Chemistry, Währinger Str. 17, A-1090 Vienna, Austria ⊥ ETH Zurich, Vladimir-Prelog-Weg 1-5/10, 8093 Zurich, Switzerland ∥ Centre for Biospectroscopy, School of Chemistry, Monash University, 3800 Victoria, Australia ∇ School of Chemistry, Faculty of Science, Monash University, 3800 Victoria, Australia ○ Department of Chemistry-Ånsgtröm Laboratory, Uppsala University, 751 20 Uppsala, Sweden ¶ ́ Institute of Physics, Jan Kochanowski University in Kielce, Swiętokrzyska 15 St., 25-406 Kielce, Poland ¤ Institute of Physical Chemistry, Polish Academy of Sciences, ul. Kasprzaka 44/52, 01-224 Warsaw, Poland ‡

S Supporting Information *

ABSTRACT: The lack of molecular mechanistic understanding of the interaction between metal complexes and biomolecules hampers their potential medical use. Herein we present a robust procedure combining resonant X-ray emission spectroscopy and multiscale molecular dynamics simulations, which allows for straightforward elucidation of the precise interaction mechanism at the atomic level. The report unveils an unforeseen hydrolysis process and DNA binding of [Pt{N(p-HC6F4)CH2}2py2] (Pt103), which showed potential cytotoxic activity in the past. Pt103 preferentially coordinates to adjacent adenine sites, instead of guanine sites as in cisplatin, because of its hydrogen bond ability. Comparison with previous research on cisplatin suggests that selective binding to guanine or adenine may be achieved by controlling the acidity of the compound.

M

An additional drawback of cisplatin is its low selectivity that results in toxic side effects, including hepatotoxicity, nephrotoxicity, and cardiotoxicity.5 Promising alternatives to platinum (Pt) compounds are ruthenium-based complexes, which are also able to bind to DNA, disrupting DNA replication; have shown activity against cisplatin-resistant cells; and present lower toxicity.6 Moreover, some classes of ruthenium complexes act as sensitizers and can induce DNA photooxidation after absorption of light.7 The photophysical behavior of ruthenium compounds able to interact with DNA has been intensively investigated in the last years (for example, see refs 8−11). Another family of compounds with potential medical applications is formed by copper phenanthrene derivatives, which can promote oxidative DNA damage.12 Although different metals have been employed in the design of new complexes with potential antitumor activity, the develop-

etals and their compounds are essential for nearly all biological processes occurring in the human body, and novel roles in organisms’ homeostasis are discovered every year. Metals have also been used for centuries to diagnose and treat illnesses. In contrast, the study of metal interactions with biomolecules is a comparatively recent endeavor. This is a vast area of research, spanning from metal complexes used as molecular probes in radioisotope and magnetic resonance imaging, to complexes used in electronic devices, prosthetics, and therapies. Chemotherapy, for example, takes advantage of the coordination properties of metal ions to treat patients with cancer, and the efficacy of the most notorious treatments is ascribed to the interaction of platinum-containing metallodrugs, such as cisplatin,1,2 with DNA. The pioneering success of cisplatin in treating different cancer types sparked the synthesis of innumerable analogues.1−3 When some tumors were known to develop resistance to cisplatin with chemotherapy treatment progression, the development of new compounds4 with modes of action different from that of cisplatin became an urgent task. © 2017 American Chemical Society

Received: January 11, 2017 Accepted: February 2, 2017 Published: February 2, 2017 805

DOI: 10.1021/acs.jpclett.7b00070 J. Phys. Chem. Lett. 2017, 8, 805−811

Letter

The Journal of Physical Chemistry Letters

Figure 1. (a) Representation of hydrolysis and DNA binding of Pt103. RXES map of Pt103 (b) in acetone, (c) in buffer solution, and (d) with DNA. (e) ΔRXES map resulting from the Pt103 hydrolysis in buffer solution and (f) subsequent binding to DNA. Color code for atoms: cyan for C, blue for N, red for O, pink for F, white for hydrogen, and ochre for Pt.

ment of new Pt drugs is still a prolific field of research, and several Pt complexes have exhibited promising results.1,2 The complex [Pt{N(p-HC6F4)CH2}2py2], known as Pt103, has shown anticancer activity both in vivo and in vitro against cisplatin-resistant cellular and animal models.13,14 This enhanced cytotoxicity in complex intracellular environments was attributed to greater cellular uptake13 and a larger number of DNA interstrand cross-links15 compared to cisplatin. The large biological activity of Pt103 is therefore related to the formation of DNA−Pt103 adducts. However, the molecular aspects of the DNA binding to Pt103 are largely unknown. This is not a specific problem for Pt103; it is a widespread problem for many metal complexes with potential interest in chemotherapy and other areas. Insight into the binding process and the prediction of structure−activity relationships not only is decisive for the design of novel antitumor compounds but also is required in any study of intermolecular interactions between metal complexes and biomolecules. Actually, the therapeutic effect of metallodrugs is not restricted only to DNA binding; it is acknowledged that many drugs have the ability to interact with proteins and enzymes, which may also vindicate the reported cytotoxicity. It is thus obvious that there is a need for robust methods capable of detecting interactions between metallodrugs and biotargets in a facile and accurate manner, and with drug dosages similar to the ones used in clinical applications. Herein, we report an original method to reveal the interactions of metal complexes with biocompounds based on resonant X-ray emission spectroscopy (RXES) and multiscale molecular dynamics (MD) simulations. The molecular mechanism involved in the hydrolysis of Pt103 and covalent binding of hydrolyzed Pt103 to DNA is used as a proof-ofconcept demonstration of the applicability and robustness of this novel strategy. Because of the rare ability of RXES to use

the metal center as a remote reporter of the mechanism of action, we will refer to this pioneering technique as atomic telemetry. Until now, the formation of metal−biomolecule adducts could be monitored only by indirect methods that evidence the existence of interactions. Structural features are typically accessed by X-ray crystallography or nuclear magnetic resonance (NMR),16−19 often in conjunction with theoretical methods.20−24 A limitation of these experimental techniques is the requirement of crystallization, in the case of X-ray crystallography, and the complexity of interpreting multiple and complex resonances in the NMR spectra. The interpretation of the results from these methods is not straightforward, as exemplified by the time delay between the discovery of cisplatin and the elucidation of its mechanism of action, some 15−25 years later.25−27 In contrast, atomic telemetry provides a clear-cut measure of the metal binding in situ. This approach was validated in a previous RXES study28 on cisplatin incubated with CT DNA. There it was shown that cisplatin coordinates preferentially to adjacent guanines, in agreement with the established mechanism of action of cisplatin.29 Here, we unequivocally demonstrate that Pt103 preferentially binds to adenine and not, as in case of cisplatin, to guanine29 (Figure 1a). Moreover, molecular dynamics simulations show that the antagonist behavior of Pt103 with respect to cisplatin is strongly connected with its ability to form hydrogen bonds during the DNA binding process. Figure 1b−d shows the RXES planes of Pt103 in acetone, aqueous buffer solution, and in the presence of DNA. The horizontal and vertical cuts along the RXES plane (Figure 1b) correspond to the Lα1 lines of the X-ray emission spectrum (XES) and high-resolution X-ray absorption spectrum (HRXAS) profiles, which provide information on occupied and unoccupied electronic states of the metal, respectively. According to the Nørskov’s model,30 chemical reactivity 806


Letter


Figure 2. (a) Chemical formula of Pt103. (b) HR-XAS spectra for the intact and hydrolyzed Pt103 and their spectral difference. (c) HR-XAS spectra of hydrolyzed and DNA bonded Pt103 and their spectral difference. (d) Spectral differences resulting from the interaction of Pt103 with DNA, guanosine monophosphate (GMP), and adenosine mono- (AMP) and diphosphate (ADP).

triggering the electronic density decrease. This hypothesis has been tested with quantum mechanics/molecular mechanics MD (QM/MM-MD) simulations in combination with the umbrella sampling technique (see details in sections S2.1 and S2.2 of the Supporting Information). Previous theoretical simulations predicted that the rate-limiting step for the hydrolysis of cisplatin,33 carboplatin,34 nedaplatin,32 and oxaliplatin35 in neutral conditions is the first hydration process. Therefore, we commenced by simulating the first nucleophilic attack on Pt103, exploring the two different mechanisms: dissociation of pyridine and partial dissociation of the [N(pHC6F4)CH2]22− group opening the five-membered ring (Figure 3a). Both pathways are endergonic with reaction free energies of 21.2 and 17.7 kcal/mol and activation barriers of 34.2 and 32.2 kcal/mol for the detachment of pyridine and [N(pHC6F4)CH2]22−, respectively (Figure 3b). Hence, the release of [N(p-HC6F4)CH2]22− during the reaction is thermodynamically and kinetically more favorable than that of pyridine. However, the large endoergonicity of the reaction (17.7 kcal/ mol) indicates that the hydrolytic equilibrium is displaced toward the reactants, and only a small amount of the active form of Pt103 is formed. One of reasons for this thermodynamic instability is that the dissociating bond Pt−N (bond order 0.513) is intrinsically stronger than the formed bond Pt−O (bond order 0.407), resulting in a large reaction energy. The small amount of hydrolyzed Pt103 formed after hydrolysis likely affects the efficacy of the subsequent binding to DNA. A rational functionalization of Pt103 that weakens the

between molecules and metals solely depends on the electronic structure of the metal d orbitals. Thus, the analysis of the density of states involving the Pt 5d orbitals can reveal bond formation and rupture processes at the metal center.31 The most significant differences between the RXES spectra of Pt103 in the different environments are contained within the HR-XAS signal. These are more evident when looking at the RXES difference (ΔRXES) maps (Figure 1e,f). They show the difference between the signals of the hydrolyzed Pt103 and intact Pt103, and between the signals of the Pt103−DNA complex and hydrolyzed Pt103, respectively. In the following, we shall discuss the HR-XAS signal because this undergoes the most significant changes with the different environments. The first step in the mechanism is the hydrolysis of Pt103 leading to the formation of the active form of the compound. It is well-known that the hydrolysis of Pt complexes proceeds by two consecutive second-order nucleophilic substitution steps,32 in each of which a water molecule attacks the metal center to release a ligand from the metal complex. Pt103 contains two leaving groups, namely, pyridine and [N(p-HC6F4)CH2]22− (Figure 2a), which can be potentially detached during the nucleophilic attack. The HR-XAS spectra (Figure 2b) show a decrease of the whiteline intensity after hydrolysis, indicating a drop in the electronic density at the Pt atom. Because the N atom of [N(p-HC6F4)CH2]22− owns a larger negative charge than the pyridine N atom (the calculated Mulliken charges at the optimized geometry are −0.70 and −0.51 au, see Appendix S1), it is very likely that [N(pHC6F4)CH2]22− is the leaving group during hydrolysis, 807


Letter


Figure 3. (a) Representation of the possible pathways for the hydrolysis of Pt103: detachment of one nitrogen of [N(p-HC6F4)CH2CH2N(pHC6F4)] (pathway 1) and pyridine (pathway 2). (b) Free-energy profiles for both hydrolytic pathways. (c) Representative snapshots of the calculated transition-state structures. The blue and red dashed lines represent the dissociating (R1) and forming (R2) bonds for pathway 1 and 2, respectively. The reaction coordinate in the umbrella sampling simulations is the difference between these two distances, R1 − R2. The magenta arrow indicates a hydrogen bond with the direction of the arrow representing the electron donation from the hydrogen acceptor atom to the hydrogen atom.

determine the most likely nucleobase target of Pt103, the hydrolyzed complex was exposed not only to guanosine monophosphate (GMP) but also to adenosine monophosphate (AMP) and measured by HR-XAS (Figure 2d). Surprisingly, the interaction between Pt103 and AMP leads to an increase of the whiteline intensity and no energy shift with respect to the hydrolyzed Pt103 signal, consistent with what is observed with DNA. Interaction with GMP leads to a significant energy blueshift (ca. 2.5 eV), in disagreement with the spectrum for DNA. The platinum ionization energy threshold of Pt103−guanine is blue-shifted comparatively to the hydrolyzed form conveying an increase in electron donation from platinum in the adduct with guanine, making it harder to excite the core electron. Because guanine is the easiest nucleobase to oxidize, one expects a higher electron donation from it and therefore the reverse to happen. However, this qualitative assessment assumes that the electronic changes observed are related only to electron density donation and not other factors, such as electron density delocalization and redistribution. Clearly, this is not the case presently; thus, adduct formation is most likely linked with several parameters. Therefore, we are left to conclude that Pt103 mostly binds to adenine nucleobases when it is in the presence of CT DNA. Note that Pt103 binds to N7 in both guanine and adenine, leading to very similar complexes. Even so, RXES is able to detect subtle electronic density changes caused by the environment of the metal beyond the first coordination sphere. To determine whether Pt103 can also bind to DNA via phosphate groups, the difference spectrum for Pt103 interacting with monomeric adenosine diphosphate (ADP) was also

Pt−N bond would displace the equilibrium toward the hydrolyzed Pt103 region. The two hydrolysis pathways lead to two different products (Figure 3a), which can be rationalized by analyzing the corresponding transition states (Figure 3c). When [N(pHC6F4)CH2]22− is released, there is proton transfer from the entering water molecule to the exiting ligand. The proton transfer is mediated by a hydrogen bond between the two reactive moieties, generating a hydroxido derivative as a product. In contrast, proton transfer does not take place between water and pyridine because hydrogen bond formation at the corresponding transition state is not favorable. The small negative charge at the N atom of pyridine hinders the ability of the N atom to act as hydrogen acceptor. Thus, both HR-XAS measurements and MD simulations suggest that a dihydroxido derivative is formed after hydrolysis of Pt103. The possibility that other protonation states of the complex are formed is discussed in section S2.2 of the Supporting Information. After activation of Pt103 by hydrolysis, predominantly 1,2intrastrand cross-links within DNA are formed.36 Specifically, 1,2-d(GpG) intrastrand cross-links are the most prevalent lesions induced by cisplatin,37 carboplatin,38 and oxaliplatin.39 In the case of Pt103, NMR29 measurements indicated that the complex can bind to N7 sites when interacting with d(GpG) dinucleotides. However, there were no further structural analyses, and the dominant damage induced by Pt103 is unknown. Addition of calf thymus (CT) DNA to the hydrolyzed Pt103 leads to a significant increase of the whiteline intensity, which confirms that the complex binds to DNA,28 but no shift of the HR-XAS spectrum is observed (Figure 2c). To 808


Letter


Figure 4. (a) Representation of the nucleophilic attack of guanine and adenine on Pt103. (b) Free-energy profiles for both nucleophilic attacks. (c) Representative snapshots of the transition-state structures. The blue and red dashed lines represent the dissociating (R1) and forming (R2) bonds for the attack of guanine and adenine, respectively. The reaction coordinate in the umbrella sampling simulations is the difference between these two distances, R1 − R2. The magenta arrows show the presence of hydrogen bonds.

adenine adduct is caused by the ability of the hydrolyzed Pt103 to be both hydrogen donor and hydrogen acceptor during the reaction (Figure 4c). This is not the case for the Pt103− guanine complex because the NH2 groups of the guanine nucleobases are oriented toward the minor groove of the helix and thus are not accessible to the complex, located within the major groove. As a result, the hydrolyzed Pt103 can act only as a hydrogen donor when interacting with guanine. A previous experimental kinetic study investigated the binding of different cisplatin hydrolytic derivatives to oligonucleotides, 41 finding that the reactivity of these compounds increases with increasing hydrogen-bond donating ability, with the diaqua [Pt(NH3)2(H2O)2]2+ species being the most reactive. This protonated form of the complex is not able to act as hydrogen acceptor with the nucleobases because the negative charge at the O atoms of the ligands is small. If the complex is only able to act as hydrogen donor, binding to guanine results in stronger hydrogen bonds than binding to adenine because the carbonyl group of guanine is a better hydrogen acceptor than the NH2 group of adenine.42 Thus, by considering previous results on cisplatin and our current study on Pt103, we can conclude that binding to guanine is energetically favorable for the diaqua form of the complex, while binding to adenine is favorable for the dihydroxido species. This means that the design of Pt-based compounds with particular pKa values in their hydrolytic forms could allow for the selective binding to guanine or adenine. It has been reported that electron-withdrawing π-acceptor ligands, such as pyridine, stabilize hydroxido species in comparison with the aqua species,43 in agreement with the hydrolytic mechanism suggested here. On the other hand, if the σ-donating ability of the ligands is enhanced, the acidity of the water ligands

measured. Interestingly, phosphates indeed interact with the hydrolyzed complex, but the resulting adduct is unrelated to that formed with DNA because the signal is shifted with respect to the one measured with DNA (Figure 2d). The preference of Pt103 for adenine over guanine has been explained with umbrella sampling QM/MM-MD simulations (see details in section S2.3 of the Supporting Information). The main step of bonding to DNA is the nucleophilic attack of the N7 of the imidazole ring of guanine or adenine on the Pt atom of the hydrolyzed Pt103 (Figure 4a). Hence, the reaction between dihydroxido Pt103 and N7 of guanine and adenine within two different solvated DNA dodecamers (5′-GCGCGGGGCGCG-3′ and 5′-GCGCGAAGCGCG-3) was simulated. The resulting free energy profiles (Figure 4b) clearly demonstrate that the reaction with adenine is both thermodynamically and kinetically more favorable than the reaction with guanine, confirming the experimental findings. The reaction with adenine proceeds via an earlier transition state (reaction coordinate −0.1 Å) than the reaction with guanine (reaction coordinate 0.2 Å), thus satisfying Hammond’s postulate40 that states that reactions with early transition states have lower energy barriers and are more exergonic than reactions with late transition states. An early transition state requires a strong stabilization of the transient species. Our analyses reveal that hydrogen bond formation between the hydrolyzed drug and the two central adenine residues is responsible for such strong stabilization. The ability of Pt103 to form hydrogen bonds with adenine is better than with guanine, demonstrated by the stabilization energy associated with hydrogen bond formation, 20.9 kcal/mol for Pt103−adenine versus 12.8 kcal/mol for Pt103−guanine (Table S1). The larger stabilization energy of the Pt103− 809


Letter

The Journal of Physical Chemistry Letters Author Contributions

decreases, and the aqua species is the predominant one. Thus, for example, if the pyridine ligands of Pt103 are functionalized with electron-donating groups, e.g., CH3O, the formation of the diaqua species would be favored, and it would likely react with guanine, instead of adenine. In conclusion, the mechanism of hydrolysis and DNA binding of Pt103 has been elucidated using resonant X-ray emission spectroscopy and molecular dynamics simulations. The spectroscopic method, termed atomic telemetry, is labelfree and can be employed for in situ and in vivo measurements, allowing the direct study of the interaction between the complex and biomolecules within times that are shorter than those of current practices. One important advantage of atomic telemetry with respect to other complementary methods currently used is that low drug dosages commonly used in the treatment of cancer can be detected and analyzed. As a consequence, this technique can be used as a valuable method for elucidating the relationship between structure and mechanism of action, which is crucial in the context of determining the biological activity of any external compound introduced into the human body, with special attention to metal complexes. Molecular dynamics simulations reinforce the conclusions extracted from atomic telemetry and provide additional mechanistic insight, making the overall experimental−theoretical procedure a very powerful technique. The X-ray emission spectrum of Pt103 shows electronic density drop at the Pt atom after hydrolysis, consistent with the formation of a dihydroxido derivative after the release of the [N(p-HC6F4)CH2]2 moiety during the water nucleophilic attack, which is corroborated by molecular dynamics simulations. The hydrolyzed drug reacts with DNA, but in contrast to cisplatin, the DNA binding targets are adenine sites instead of guanine sites, as revealed by the X-ray measurements. This is rationalized by our simulations, which show that the hydrogen bond ability of the drug is greater when it interacts with adenine than with guanine. Comparison of our study on Pt103 with previous results on cisplatin suggests that a selective binding of Pt compounds to guanine and adenine residues can be achieved via selective design of the electron-donating and -withdrawing ability of the hydrolyzed compounds. Further examples are required to corroborate the validity of this rule in other Pt-based complexes. In addition, new adenine-targeted compounds should be investigated to compare its cytotoxicity against conventional guanine-targeted drugs. Atomic telemetry will pave the way to perform such additional studies as well as on other metal−biomolecular systems of interest.

■

#

J.C.-M. and J.J.N. contributed equally to this work.

Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS The calculations have been in part performed in the Vienna Scientific Cluster (VSC). B.R.W. is funded by the Australian Research Council Future Fellowship FT120100926. J.S. is funded by Uppsala University, Starting Grant. Vera Krewald is thanked for fruitful discussions.

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jpclett.7b00070. Experimental information and computational details (PDF)

■

REFERENCES

(1) Kelland, L. The resurgence of platinum-based cancer chemotherapy. Nat. Rev. Cancer 2007, 7, 573−584. (2) Johnstone, T. C.; Suntharalingam, K.; Lippard, S. J. The next generation of platinum drugs: targeted Pt(II) agents, nanoparticle delivery, and Pt(IV) prodrugs. Chem. Rev. 2016, 116, 3436. (3) Medici, S.; Peana, M.; Nurchi, V. M.; Lachowicz, J. I.; Crisponi, G.; Zoroddu, M. A. Noble metals in medicine: latest advances. Coord. Chem. Rev. 2015, 284, 329−350. (4) Kartalou, M.; Essigmann, J. M. Mechanisms of resistance to cisplatin. Mutat. Res., Fundam. Mol. Mech. Mutagen. 2001, 478, 23−43. (5) Dasari, S.; Tchounwou, P. B. Cisplatin in cancer therapy: molecular mechanisms of action. Eur. J. Pharmacol. 2014, 740, 364− 378. (6) Hartinger, C. G.; Zorbas-Seifried, S.; Jakupec, M. A.; Kynast, B.; Zorbas, H.; Keppler, B. K. From bench to bedside–preclinical and early clinical development of the anticancer agent indazolium trans[tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019 or FFC14A). J. Inorg. Biochem. 2006, 100, 891−904. (7) Elias, B.; Creely, C.; Doorley, G. W.; Feeney, M. M.; Moucheron, C.; Kirsch-DeMesmaeker, A.; Dyer, J.; Grills, D. C.; George, M. W.; Matousek, P.; Parker, A. W.; Towrie, M.; Kelly, J. M. Photooxidation of Guanine by a Ruthenium Dipyridophenazine Complex Intercalated in a Double-Stranded Polynucleotide Monitored Directly by Picosecond Visible and Infrared Transient Absorption Spectroscopy. Chem. - Eur. J. 2008, 14, 369−375. (8) Chantzis, A.; Very, T.; Despax, S.; Issenhuth, J.-T.; Boeglin, A.; Hébraud, P.; Pfeffer, M.; Monari, A.; Assfeld, X. UV−vis absorption spectrum of a novel Ru(II) complex intercalated in DNA: [Ru(2,2′bipy) (dppz)(2,2′-ArPy)]+. J. Mol. Model. 2014, 20, 2082. (9) Very, T.; Despax, S.; Hébraud, P.; Monari, A.; Assfeld, X. Spectral properties of polypyridyl ruthenium complexes intercalated in DNA: theoretical insights into the surrounding effects of [Ru(dppz) (bpy)2]2+. Phys. Chem. Chem. Phys. 2012, 14, 12496−12504. (10) Véry, T.; Ambrosek, D.; Otsuka, M.; Gourlaouen, C.; Assfeld, X.; Monari, A.; Daniel, C. Photophysical Properties of Ruthenium(II) Polypyridyl DNA Intercalators: Effects of the Molecular Surroundings Investigated by Theory. Chem. - Eur. J. 2014, 20, 12901−12909. (11) Atsumi, M.; González, L.; Daniel, C. Spectroscopy of Ru(II) polypyridyl complexes used as intercalators in DNA: Towards a theoretical study of the light switch effect. J. Photochem. Photobiol., A 2007, 190, 310−320. (12) Molphy, Z.; Slator, C.; Chatgilialoglu, C.; Kellett, A. DNA oxidation profiles of copper phenanthrene chemical nucleases. Front. Chem. 2015, 3, 28. (13) Talarico, T.; Phillips, D. R.; Deacon, G. B.; Rainone, S.; Webster, L. K. Activity and DNA binding of new organoamidoplatinum (II) complexes. Invest. New Drugs 1999, 17, 1. (14) Webster, L. K.; Deacon, G. B.; Buxton, D. P.; Hillcoat, B. L.; James, A. M.; Roos, I. A. G.; Thomson, R. J.; Wakelin, L. P. G.; Williams, T. L. J. cis-Bis(pyridine)platinum(II) organoamides with unexpected growth inhibition properties and antitumor activity. J. Med. Chem. 1992, 35, 3349. (15) Talarico, T.; Cullinane, C. M.; Gray, P. J.; Webster, L. K.; Deacon, G. B.; Phillips, D. R. Nuclear and mitochondrial distribution

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. *E-mail: [email protected]. ORCID

Joanna Czapla-Masztafiak: 0000-0001-7706-0296 Leticia González: 0000-0001-5112-794X 810


Letter

The Journal of Physical Chemistry Letters of organamidoplatinum(II) lesions in cisplatin-sensitive and − resistant adenocarcinoma cells. Anti-Cancer Drug Des. 2001, 16, 135. (16) Sturla, S. J. DNA adduct profiles: chemical approaches to addressing the biological impact of DNA damage from small molecules. Curr. Opin. Chem. Biol. 2007, 11, 293−299. (17) Oleksi, A.; Blanco, A. G.; Boer, R.; Uson, I.; Aymami, J.; Rodger, A.; Hannon, M. J.; Coll, M. Molecular recognition of a three-way DNA junction by a metallosupramolecular helicate. Angew. Chem., Int. Ed. 2006, 45, 1227−1231. (18) Jamin, N.; Toma, F. NMR studies of protein-DNA interactions. Prog. Nucl. Magn. Reson. Spectrosc. 2001, 38, 83−114. (19) Barone, G.; Terenzi, A.; Lauria, A.; Almerico, A. M.; Leal, J. M.; Busto, N.; García, B. DNA-binding of nickel(II), copper(II) and zinc(II) complexes: Structure−affinity relationships. Coord. Chem. Rev. 2013, 257, 2848−2862. (20) Pérez, A.; Luque, F. J.; Orozco, M. Frontiers in molecular dynamics simulations of DNA. Acc. Chem. Res. 2012, 45, 196−205. (21) Fantacci, S.; De Angelis, F.; Sgamellotti, A.; Marrone, A.; Re, N. Photophysical properties of [Ru(phen)2(dppz)2+ intercalated into DNA: An integrated Car-Parrinello and TDDFT study. J. Am. Chem. Soc. 2005, 127, 14144−14145. (22) Gkionis, K.; Platts, J. QM/MM investigation into binding of square-planar platinum complexes to DNA fragments. JBIC, J. Biol. Inorg. Chem. 2009, 14, 1165−1174. (23) Barone, G.; Fonseca Guerra, C.; Gambino, N.; Silvestri, A.; Lauria, A.; Almerico, A. M.; Bickelhaupt, F. M. Intercalation of daunomycin into stacked DNA base pairs. DFT study of an anticancer drug. J. Biomol. Struct. Dyn. 2008, 26, 115−129. (24) Gossens, C.; Tavernelli, I.; Rothlisberger, U. DNA structural distortions induced by ru-thenium-arene anticancer compounds. J. Am. Chem. Soc. 2008, 130, 10921−10928. (25) Sherman, S. E.; Gibson, D.; Wang, A.H-J.; Lippard, S. J. X-ray structure of the major adduct of the anticancer drug cisplatin with DNA: cis-[Pt(NH3)2(d(pGpG))]. Science 1985, 230, 412−417. (26) Takahara, P. M.; Rosenzweig, A. C.; Frederick, C. A.; Lippard, S. J. Crystal structure of double-stranded DNA containing the major adduct of the anticancer drug cisplatin. Nature 1995, 377, 649−652. (27) van der Veer, J. L.; Reedijk, J. Investigating antitumour drug mechanisms. Chem. Br. 1988, 20, 775−780. (28) Lipiec, E.; Czapla, J.; Szlachetko, J.; Kayser, Y.; Kwiatek, W.; Wood, B.; Deacon, G. B.; Sá, J. Novel in situ methodology to observe the interactions of chemotherapeutical Pt drugs with DNA under physiological conditions. Dalton Trans. 2014, 43, 13839. (29) Bloemink, M. J.; Heetebrij, R. J.; Ireland, J.; Deacon, G. B.; Reedijk, J. J. DNA-binding properties of antitumor-active cisbis(pyridine)platinum(II) organoamides. JBIC, J. Biol. Inorg. Chem. 1996, 1, 278. (30) Hammer, B.; Nørskov, J. K. Why gold is the noblest of all the metals. Nature 1995, 376, 238. (31) Sá, J. High-Resolution XAS/XES: Analyzing Electronic Structures of Catalysts; CRC Press INC, Francis & Taylor: Boca Raton, FL, 2014. (32) Alberto, M. E.; Lucas, M. F. A.; Pavelka, M.; Russo, N. J. The second-generation anticancer drug Nedaplatin: a theoretical investigation on the hydrolysis mechanism. J. Phys. Chem. B 2009, 113, 14473. (33) Lau, J. K. C.; Ensing, B. Hydrolysis of cisplatina firstprinciples metadynamics study. Phys. Chem. Chem. Phys. 2010, 12, 10348. (34) Pavelka, M.; Lucas, M. F. A.; Russo, N. On the hydrolysis mechanism of the second-generation anticancer drug carboplatin. Chem. - Eur. J. 2007, 13, 10108. (35) Lucas, M. F. A.; Pavelka, M.; Alberto, M. E.; Russo, N. J. Neutral and acidic hydrolysis reactions of the third generation anticancer drug oxaliplatin. J. Phys. Chem. B 2009, 113, 831. (36) Rabik, C. A.; Dolan, M. E. Molecular mechanisms of resistance and toxicity associated with platinating agents. Cancer Treat. Rev. 2007, 33, 9. (37) Fichtinger-Schepman, A. M. J.; Van Der Veer, J. L.; Den Hartog, J. H. J.; Lohman, P. H. M.; Reedijk, J. Adducts of the antitumor drug

cis-diamminedichloroplatinum(II) with DNA: formation, identification, and quantitation. Biochemistry 1985, 24, 707. (38) Blommaert, F. A.; Van Dijk-Knijnenburg, H. C. M.; Dijt, F. J.; Den Engelse, L.; Baan, R. A.; Berends, F.; Fichtinger-Schepman, A. M. J. Formation of DNA adducts by the anticancer drug carboplatin: different nucleotide sequence preferences in vitro and in cells. Biochemistry 1995, 34, 8474. (39) Woynarowski, J. M.; Chapman, W. G.; Napier, C.; Herzig, M. C. S; Juniewicz, P. Sequence- and region-specificity of oxaliplatin adducts in naked and cellular DNA. Mol. Pharmacol. 1998, 54, 770. (40) Hammond, G. S. J. Correlation of Reaction Rates. J. Am. Chem. Soc. 1955, 77, 334. (41) Legendre, F.; Bas, V.; Kozelka, J.; Chottard, J. C. A complete kinetic study of GG versus AG platination suggests that the doubly aquated derivatives of cisplatin are the actual DNA binding species. Chem. - Eur. J. 2000, 6, 2002. (42) Baik, M. H.; Friesner, R. A.; Lippard, S. J. J. Theoretical study of cisplatin binding to purine bases: Why does cisplatin prefer guanine over adenine? J. Am. Chem. Soc. 2003, 125, 14082. (43) Hofmann, A.; Jaganyi, D.; Munro, O. Q.; Liehr, G.; Van Eldik, R. Electronic tuning of the lability of Pt(II) complexes through πacceptor effects. Correlations between thermodynamic, kinetic, and theoretical parameters. Inorg. Chem. 2003, 42, 1688.

811


Direct Determination of Metal Complexes ... - ACS Publications

Recommend Documents