Interactions of the “piano‐stool” [ruthenium(II) (η6‐arene)(en)CL]+ complexes with water and nucleobases; ab initio and DFT study

Piano stool ruthenium complexes of the composition [Ru(II)(η6‐arene)(en)Cl]+/2+ (en = ethylenediamine) represent an emerging class of cisplatin‐analogue anticancer drug candidates. In this study, we use computational quantum chemistry to characterize the structure, stability and reactivity of these compounds. All these structures were optimized at DFT(B3LYP)/6‐31G(d) level and their single point properties were determined by the MP2/6‐31++G(2df,2pd) method. Thermodynamic parameters and rate constants were determined for the aquation process, as a replacement of the initial chloro ligand by water and subsequent exchange reaction of aqua ligand by nucleobases. The computations were carried out at several levels of DFT and ab initio theories (B3LYP, MP2 and CCSD) utilizing a range of bases sets (from 6‐31G(d) to aug‐cc‐pVQZ). Excellent agreement with experimental results for aquation process was obtained at the CCSD level and reasonable match was achieved also with the B3LYP/6‐31++G(2df,2pd) method. This level was used also for nucleobase‐water exchange reaction where a smaller rate constant for guanine exchange was found in comparison with adenine. Although adenine follows a simple replacement mechanism, guanine complex passes by a two‐step mechanism. At first, Ru‐O6(G) adduct is formed, which is transformed through a chelate TS2 to the Ru‐N7(G) final complex. In case of guanine, the exchange reaction is more favorable thermodynamically (releasing in total by about 8 kcal/mol) but according to our results, the rate constant for guanine substitution is slightly smaller than the analogous constant in adenine case when reaction course from local minimum is considered. © 2008 Wiley Periodicals, Inc. J Comput Chem, 2009

[1]  P. Dyson,et al.  Is the Aromatic Fragment of Piano‐Stool Ruthenium Compounds an Essential Feature for Anticancer Activity? The Development of New RuII‐[9]aneS3 Analogues , 2005 .

[2]  Erwin P. L. van der Geer,et al.  Controlling ligand substitution reactions of organometallic complexes: tuning cancer cell cytotoxicity. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[3]  A. Klamt,et al.  COSMO : a new approach to dielectric screening in solvents with explicit expressions for the screening energy and its gradient , 1993 .

[4]  Jerzy Leszczynski,et al.  How strong can the bend be on a DNA helix from cisplatin? DFT and MP2 quantum chemical calculations of cisplatin-bridged DNA purine bases. , 2003, Inorganic chemistry.

[5]  V. Brabec,et al.  Biophysical analysis of natural, double-helical DNA modified by anticancer heterocyclic complexes of ruthenium(III) in cell-free media , 2001, JBIC Journal of Biological Inorganic Chemistry.

[6]  P. Sadler,et al.  Insights into the mechanism of action of platinum anticancer drugs from multinuclear NMR spectroscopy , 2006 .

[7]  L. Ji,et al.  Enantiomeric ruthenium(II) complexes binding to DNA: binding modes and enantioselectivity , 2000, JBIC Journal of Biological Inorganic Chemistry.

[8]  J. Lau,et al.  Hydrolysis of the Anticancer Drug Cisplatin:  Pitfalls in the Interpretation of Quantum Chemical Calculations. , 2006, Journal of chemical theory and computation.

[9]  Jerzy Leszczynski,et al.  Activation barriers and rate constants for hydration of platinum and palladium square-planar complexes: an ab initio study. , 2004, The Journal of chemical physics.

[10]  Richard A Friesner,et al.  Theoretical study on the stability of N-glycosyl bonds: why does N7-platination not promote depurination? , 2002, Journal of the American Chemical Society.

[11]  B. Nordén,et al.  Binding of delta- and lambda-[Ru(phen)3]2+ to [d(CGCGATCGCG)]2 studied by NMR. , 1994, Biochemistry.

[12]  Antonio Fernández-Ramos,et al.  DOIT: a program to calculate thermal rate constants and mode‐specific tunneling splittings directly from quantum‐chemical calculations , 2001, J. Comput. Chem..

[13]  James A. Platts,et al.  Hydrogen bonding, solvation, and hydrolysis of cisplatin: A theoretical study , 2004, J. Comput. Chem..

[14]  P. Sadler,et al.  Kinetics of aquation and anation of ruthenium(II) arene anticancer complexes, acidity and X-ray structures of aqua adducts. , 2003, Chemistry.

[15]  P. Geerlings,et al.  Quantum similarity study of atoms: a bridge between hardness and similarity indices. , 2007, The Journal of chemical physics.

[16]  J. Lau,et al.  Loss of amine from platinum(II) complexes: implications for cisplatin inactivation, storage, and resistance. , 2005, Chemistry.

[17]  B. Keppler,et al.  Synthesis of water-soluble ruthenium porphyrins as DNA cleavers and potential cytotoxic agents , 1997, JBIC Journal of Biological Inorganic Chemistry.

[18]  P. Sadler,et al.  Structure-activity relationships for cytotoxic ruthenium(II) arene complexes containing N,N-, N,O-, and O,O-chelating ligands. , 2006, Journal of medicinal chemistry.

[19]  I. Tavernelli,et al.  Rational design of organo-ruthenium anticancer compounds , 2005 .

[20]  P. Sadler,et al.  Formation of platinated GG cross-links on DNA by photoactivation of a platinum(IV) azide complex , 2003, JBIC Journal of Biological Inorganic Chemistry.

[21]  L. Marzilli,et al.  New Concepts Relevant to Cisplatin Anticancer Activity from Unique Spectral Features Providing Evidence That Adjacent Guanines in d(GpG), Intrastrand-Cross-Linked at N7 by a cis-Platinum(II) Moiety, Can Adopt a Head-to-Tail Arrangement , 1999 .

[22]  J. Cummings,et al.  In vitro and in vivo activity and cross resistance profiles of novel ruthenium (II) organometallic arene complexes in human ovarian cancer , 2002, British Journal of Cancer.

[23]  K. Dunbar,et al.  Reactivity studies of anticancer active dirhodium complexes with 2-aminothiophenol. , 2002, Inorganic chemistry.

[24]  I. Tavernelli,et al.  Binding of Organometallic Ruthenium(II) and Osmium(II) Complexes to an Oligonucleotide: A Combined Mass Spectrometric and Theoretical Study , 2005 .

[25]  B. Nordén,et al.  DNA Binding Geometries of Ruthenium(II) Complexes with 1,10-Phenanthroline and 2,2‘-Bipyridine Ligands Studied with Linear Dichroism Spectroscopy. Borderline Cases of Intercalation , 1998 .

[26]  Stephen Neidle,et al.  Principles of nucleic acid structure , 2007 .

[27]  J. Šponer,et al.  A Systematic ab Initio Study of the Hydration of Selected Palladium Square-Planar Complexes. A Comparison with Platinum Analogues , 2001 .

[28]  P. Sadler,et al.  Organometallic ruthenium(II) diamine anticancer complexes: arene-nucleobase stacking and stereospecific hydrogen-bonding in guanine adducts. , 2002, Journal of the American Chemical Society.

[29]  A. Klamt Conductor-like Screening Model for Real Solvents: A New Approach to the Quantitative Calculation of Solvation Phenomena , 1995 .

[30]  M. Sip,et al.  Pentacoordinated transition states of cisplatin hydrolysis— ab initio study , 2000 .

[31]  Bernhard Lippert,et al.  Cisplatin : chemistry and biochemistry of a leading anticancer drug , 2006 .

[32]  P. Sadler,et al.  Highly selective binding of organometallic ruthenium ethylenediamine complexes to nucleic acids: novel recognition mechanisms. , 2003, Journal of the American Chemical Society.

[33]  H. Stoll,et al.  Energy-adjustedab initio pseudopotentials for the second and third row transition elements , 1990 .

[34]  Jaroslav V Burda,et al.  Cisplatin interaction with cysteine and methionine, a theoretical DFT study. , 2005, Journal of inorganic biochemistry.

[35]  F. Caruso,et al.  Antitumor titanium compounds. , 2003, Mini reviews in medicinal chemistry.

[36]  N. Katsaros,et al.  Rhodium and its compounds as potential agents in cancer treatment. , 2002, Critical reviews in oncology/hematology.

[37]  M. Sabat,et al.  Model of the Second Most Abundant Cisplatin-DNA Cross-Link: X-ray Crystal Structure and Conformational Analysis of cis-[(NH(3))(2)Pt(9-MeA-N7)(9-EtGH-N7)](NO(3)).2H(2)O (9-MeA = 9-Methyladenine; 9-EtGH = 9-Ethylguanine). , 1996, Inorganic chemistry.

[38]  A. Wang,et al.  Molecular structure of the complex formed between the anticancer drug cisplatin and d(pGpG): C222(1) crystal form. , 1990, Journal of biomolecular structure & dynamics.

[39]  J. Leszczynski,et al.  The influence of a sugar-phosphate backbone on the cisplatin-bridged BpB′ models of DNA purine bases. Quantum chemical calculations of Pt(II) bonding characteristics , 2004 .

[40]  B. Nordén,et al.  Interactions of Tris(phenanthroline)ruthenium(II) Enantiomers with DNA: Effects on Helix Flexibility Studied by the Electrophoretic Behavior of Reptating DNA in Agarose Gel† , 2000 .

[41]  G. Erker,et al.  Bioorganometallic Chemistry: Reactions of Methyltitanocene Cation Complexes with a Singly Deprotected Methyl Glucopyranoside , 2005 .

[42]  James A Platts,et al.  Hydrogen bonding and covalent effects in binding of cisplatin to purine bases: ab initio and atoms in molecules studies. , 2005, Inorganic chemistry.

[43]  B. Keppler,et al.  Hydrolysis of the tumor-inhibiting ruthenium(III) complexes HIm trans-[RuCl4(im)2] and HInd trans-[RuCl4(ind)2] investigated by means of HPCE and HPLC-MS , 2001, JBIC Journal of Biological Inorganic Chemistry.

[44]  J. Lau,et al.  In silico evolution of substrate selectivity: comparison of organometallic ruthenium complexes with the anticancer drug cisplatin. , 2006, Chemical communications.

[45]  P. Sadler,et al.  DNA interactions of monofunctional organometallic ruthenium(II) antitumor complexes in cell-free media. , 2003, Biochemistry.

[46]  Jerzy Leszczynski,et al.  The influence of square planar platinum complexes on DNA base pairing. An ab initio DFT study , 2001 .

[47]  Jerzy Leszczynski,et al.  Hydration process as an activation of trans‐ and cisplatin complexes in anticancer treatment. DFT and ab initio computational study of thermodynamic and kinetic parameters , 2005, J. Comput. Chem..

[48]  Chuanbao Zhu,et al.  Theoretical study of cisplatin binding to DNA: the importance of initial complex stabilization. , 2005, The journal of physical chemistry. B.

[49]  P. Lincoln,et al.  AB INITIO AND SEMIEMPIRICAL CALCULATIONS OF GEOMETRY AND ELECTRONIC SPECTRA OF RUTHENIUM ORGANIC COMPLEXES AND MODELING OF SPECTROSCOPIC CHANGES UPON DNA BINDING , 1997 .

[50]  James A Platts,et al.  A QM/MM study of cisplatin-DNA oligonucleotides: from simple models to realistic systems. , 2006, Chemistry.

[51]  Calculations of hydrated titanium ion complexes: structure and influence of the first two coordination spheres , 2001 .

[52]  Michael Dolg,et al.  Ab initio energy-adjusted pseudopotentials for elements of groups 13-17 , 1993 .

[53]  X. You,et al.  Hydrolysis theory for cisplatin and its analogues based on density functional studies. , 2001, Journal of the American Chemical Society.

[54]  Anna F. A. Peacock,et al.  Tuning the reactivity of osmium(II) and ruthenium(II) arene complexes under physiological conditions. , 2006, Journal of the American Chemical Society.

[55]  Rafa Wysokiski,et al.  The performance of different density functional methods in the calculation of molecular structures and vibrational spectra of platinum(II) antitumor drugs: cisplatin and carboplatin , 2001, J. Comput. Chem..

[56]  J. Platts,et al.  Insights into DNA binding of ruthenium arene complexes: role of hydrogen bonding and pi stacking. , 2008, Inorganic chemistry.

[57]  J. Leszczynski,et al.  The interactions of square platinum(II) complexes with guanine and adenine: a quantum-chemical ab initio study of metalated tautomeric forms , 2000, JBIC Journal of Biological Inorganic Chemistry.

[58]  R. Bader Atoms in molecules : a quantum theory , 1990 .

[59]  R. Parr,et al.  Absolute hardness: companion parameter to absolute electronegativity , 1983 .

[60]  J. Burda,et al.  Pt-bridges in various single-strand and double-helix DNA sequences. DFT and MP2 study of the cisplatin coordination with guanine, adenine, and cytosine , 2007, Journal of molecular modeling.

[61]  J. Asara,et al.  Evidence for Binding of Dirhodium Bis-Acetate Units to Adjacent GG and AA Sites on Single-Stranded DNA , 2000 .

[62]  J. Reedijk Why does Cisplatin reach Guanine-n7 with competing s-donor ligands available in the cell? , 1999, Chemical reviews.

[63]  Peddaiahgari Seetharamulu,et al.  Comprehensive ab initio quantum mechanical and molecular orbital (MO) analysis of cisplatin: Structure, bonding, charge density, and vibrational frequencies , 1999, J. Comput. Chem..

[64]  U. Rothlisberger,et al.  Cisplatin binding to DNA oligomers from hybrid Car-Parrinello/molecular dynamics simulations , 2004 .

[65]  Dirk V Deubel,et al.  The chemistry of dinuclear analogues of the anticancer drug cisplatin. A DFT/CDM study. , 2006, Journal of the American Chemical Society.

[66]  E. Thiel,et al.  Phase I clinical and pharmacokinetic study of titanocene dichloride in adults with advanced solid tumors. , 1998, Clinical cancer research : an official journal of the American Association for Cancer Research.

[67]  David J. Williams,et al.  Potential multifunctional anti-cancer metal complexes II. Synthesis of some rhodium(II) and platinum(II) complexes of diamine-substituted acridine-4-carboxamides, and the X-ray structure of [Rh(CH3CO2)2L]2 (L=N-[2-(dimethylamino)hexyl]acridine-4-carboxamide) , 1990 .

[68]  Richard A Friesner,et al.  Theoretical study of cisplatin binding to purine bases: why does cisplatin prefer guanine over adenine? , 2003, Journal of the American Chemical Society.

[69]  Dirk V Deubel,et al.  Factors governing the kinetic competition of nitrogen and sulfur ligands in cisplatin binding to biological targets. , 2004, Journal of the American Chemical Society.

[70]  W. Rocha,et al.  Monte Carlo simulation of cisplatin molecule in aqueous solution. , 2006, The journal of physical chemistry. B.

[71]  M. Sundaralingam,et al.  Structure of the anti-cancer drug complex tetrakis (mu-acetato)-bis(1-methyladenosine)dirhodium(II) monohydrate. , 1991, Acta Crystallographica Section C: Crystal Structure Communications.

[72]  B. Nair,et al.  Synthesis, characterization and DNA binding studies of a ruthenium(II) complex. , 2002, Journal of inorganic biochemistry.

[73]  H. D. Dos Santos,et al.  Structure and properties of the 5a,6-anhydrotetracycline-platinum(II) dichloride complex: a theoretical ab initio study. , 2006, Journal of inorganic biochemistry.

[74]  W. Rocha,et al.  Linear free energy relationship for 4-substituted (o-phenylenediamine)platinum(II) dichloride derivatives using quantum mechanical descriptors. , 2005, Journal of inorganic biochemistry.