The factors that determine the stability and the effects of noncovalent interaction on the 6-arene ruthenium anticancer complexes are determined using DFT method. The intramolecular and intra-atomic properties were computed for two models of these half-sandwich ruthenium anticancer complexes and their respective hydrated forms. The results showed that the stability of these complexes depends largely on the network of hydrogen bonds (HB), strong nature of charge transfer, polarizability, and electrostatic energies that exist within the complexes. The hydrogen bonds strength was found to be related to the reported anticancer activities and the activation of the complexes by hydration. The metal–ligand bonds were found to be closed shell systems that are characterised by high positive Laplacian values of electron density. Two of the complexes are found to be predominantly characterised by LMCT while the other two are predominately characterised by MLCT. 1. Introduction There have been several research efforts to synthesize Ru-based anticancer complexes as alternative to cis-platin in cancer therapy [1–3]. Among the most studied compounds are the half-sandwich complexes of ruthenium due to their unique properties [4–6]. Among the most studied complexes are the half-sandwich complexes of ruthenium. Several of these half-sandwich ruthenium complexes have found numerous applications as catalysts for organic transformations, in the supramolecular field and in medicinal chemistry [7]. The applications of these complexes as anticancer agent have been reported [3, 8–12]. Some of the properties of interest are the existing noncovalent interactions and the effect of hydration on the interatomic interactions in the complexes. The noncovalent interactions such as hydrogen bonding, anion-π, cation-π, and π-π interactions and other weak forces are important in chemical reactions, molecular recognition, and regulation of biochemical processes [13, 14]. Deep understanding of these interactions has been pointed out to be of great importance in rationalizing their effects [14]. Using Bader’s quantum theory of atoms in molecules (QTAIM) [15], the atomic properties such as electronic population, energies, and (de)localization are evaluated over the atomic basins. Computer simulation is known to be helpful in giving detailed atomic structural properties and in interpreting experimental data at atomic level of interaction to show the mechanisms of biomolecular function [16]. Also, the quantum calculation plays significant roles in determination of force fields [17, 18]
References
[1]
E. Meggers, “Targeting proteins with metal complexes,” Chemical Communications, no. 9, pp. 1001–1010, 2009.
[2]
C. S. Allardyce, A. Dorcier, C. Scolaro, and P. J. Dyson, “Development of organometallic (organo-transition metal) pharmaceuticals,” Applied Organometallic Chemistry, vol. 19, no. 1, pp. 1–10, 2005.
[3]
P. J. Dyson and G. Sava, “Metal-based antitumour drugs in the post genomic era,” Dalton Transactions, no. 16, pp. 1929–1933, 2006.
[4]
Y. N. V. Gopal, D. Jayaraju, and A. K. Kondapi, “Inhibition of topoisomerase II catalytic activity by two ruthenium compounds: a ligand-dependent mode of action,” Biochemistry, vol. 38, no. 14, pp. 4382–4388, 1999.
[5]
C. S. K. Rajapakse, A. Martínez, B. Naoulou et al., “Synthesis, characterization, and in vitro antimalarial and antitumor activity of new ruthenium(II) complexes of chloroquine,” Inorganic Chemistry, vol. 48, no. 3, pp. 1122–1131, 2009.
[6]
M. Groessl, Y. O. Tsybin, C. G. Hartinger, B. K. Keppler, and P. J. Dyson, “Ruthenium versus platinum: interactions of anticancer metallodrugs with duplex oligonucleotides characterised by electrospray ionisation mass spectrometry,” Journal of Biological Inorganic Chemistry, vol. 15, no. 5, pp. 677–688, 2010.
[7]
B. Dutta, R. Scopelliti, and K. Severin, “Synthesis, structure, and reactivity of the methoxy-bridged dimer [Cp∧Ru(μ-OMe)]2 (Cp∧ = η5-1-methoxy-2,4-di-tert-butyl-3-neopentylcyclopentadienyl),” Organometallics, vol. 27, no. 3, pp. 423–429, 2008.
[8]
B. Dutta, C. Scolaro, R. Scopelliti, P. J. Dyson, and K. Severin, “Importance of the π-ligand: remarkable effect of the cyclopentadienyl ring on the cytotoxicity of ruthenium PTA compounds,” Organometallics, vol. 27, no. 7, pp. 1355–1357, 2008.
[9]
W. H. Ang and P. J. Dyson, “Classical and non-classical ruthenium-based anticancer drugs: towards targeted chemotherapy,” European Journal of Inorganic Chemistry, no. 20, pp. 4003–4018, 2006.
[10]
G. Gasser, I. Ott, and N. Metzler-Nolte, “Organometallic anticancer compounds,” Journal of Medicinal Chemistry, vol. 54, no. 1, pp. 3–25, 2011.
[11]
S. Betanzos-Lara, L. Salassa, A. Habtemariam et al., “Photoactivatable organometallic pyridyl ruthenium(II) arene complexes,” Organometallics, vol. 31, no. 9, pp. 3466–3479, 2012.
[12]
E. A. Hillard and G. Jaouen, “Bioorganometallics: future trends in drug discovery, analytical chemistry, and catalysis,” Organometallics, vol. 30, no. 1, pp. 20–27, 2011.
[13]
E. A. Meyer, R. K. Castellano, and F. Diederich, “Interactions with aromatic rings in chemical and biological recognition,” Angewandte Chemie, vol. 42, no. 11, pp. 1210–1250, 2003.
[14]
I. Alkorta, F. Blanco, and J. Elguero, “Simultaneous interaction of tetrafluoroethene with anions and hydrogen-bond donors: a cooperativity study,” Journal of Chemical Theory and Computation, vol. 5, no. 4, pp. 1186–1194, 2009.
[15]
J. A. Platts, J. Overgaard, C. Jones, B. B. Iversen, and A. Stasch, “First experimental characterization of a non-nuclear attractor in a dimeric magnesium(I) compound,” Journal of Physical Chemistry A, vol. 115, no. 2, pp. 194–200, 2011.
[16]
I. M. Kapetanovic, “Computer-aided drug discovery and development (CADDD): in silico-chemico-biological approach,” Chemico-Biological Interactions, vol. 171, no. 2, pp. 165–176, 2008.
[17]
Y. Duan, C. Wu, S. Chowdhury et al., “A point-charge force field for molecular mechanics simulations of proteins based on condensed-phase quantum mechanical calculations,” Journal of Computational Chemistry, vol. 24, no. 16, pp. 1999–2012, 2003.
[18]
N. Rai, S. P. Tiwari, and E. J. Maginn, “Force field development for actinyl ions via quantum mechanical calculations: an approach to account for many body solvation effects,” Journal of Physical Chemistry B, vol. 116, pp. 10885–10897, 2012.
[19]
K. Cobb, “Dock this: drug design feeds drug development,” Biomedical Computation Review, pp. 20–30, 2007.
[20]
A. L. Harvey, “Natural products in drug discovery,” Drug Discovery Today, vol. 13, no. 19-20, pp. 894–901, 2008.
[21]
S. Chatterjee, S. Kundu, A. Bhattacharyya, C. G. Hartinger, and P. J. Dyson, “The ruthenium(II)-arene compound RAPTA-C induces apoptosis in EAC cells through mitochondrial and p53-JNK pathways,” Journal of Biological Inorganic Chemistry, vol. 13, no. 7, pp. 1149–1155, 2008.
[22]
A. E. Egger, C. G. Hartinger, A. K. Renfrew, and P. J. Dyson, “Metabolization of [Ru(η6-C6H5CF 3)(pta)Cl2]: a cytotoxic RAPTA-type complex with a strongly electron withdrawing arene ligand,” Journal of Biological Inorganic Chemistry, vol. 15, no. 6, pp. 919–927, 2010.
[23]
M. Hanif, H. Henke, S. M. Meier et al., “Is the reactivity of M(II)-arene complexes of 3-hydroxy-2(1 H)-pyridones to biomolecules the anticancer activity determining paramete？,” Inorganic Chemistry, vol. 49, no. 17, pp. 7953–7963, 2010.
[24]
F. Wang, A. Habtemariam, E. P. L. van der Geer et al., “Controlling ligand substitution reactions of organometallic complexes: tuning cancer cell cytotoxicity,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 51, pp. 18269–18274, 2005.
[25]
A. García-Fernández, J. Díez, M. P. Gamasa, and E. Lastra, “Facile modification of 1,3,5-triaza-7-phosphatricyclo[3.3.1.1 3,7]decane phosphanes coordinated to ruthenium(II),” Inorganic Chemistry, vol. 48, no. 6, pp. 2471–2481, 2009.
[26]
W. H. Ang, E. Daldini, C. Scolaro, R. Scopelliti, L. Juillerat-Jeannerat, and P. J. Dyson, “Development of organometallic ruthenium-arene anticancer drugs that resist hydrolysis,” Inorganic Chemistry, vol. 45, no. 22, pp. 9006–9013, 2006.
[27]
C. Adamo and V. Barone, “Toward reliable density functional methods without adjustable parameters: the PBE0 model,” Journal of Chemical Physics, vol. 110, no. 13, pp. 6158–6170, 1999.
[28]
W. J. Stevens, M. Krauss, H. Basch, and P. G. Jasien, “Relativistic compact effective potentials and efficient, shared-exponent basis sets for the third-, fourth-, and fifth-row atoms,” Canadian Journal of Chemistry, vol. 70, pp. 612–630, 1992.
[29]
D. Feller, “The role of databases in support of computational chemistry calculations,” Journal of Computational Chemistry, vol. 17, no. 13, pp. 1571–1586, 1996.
[30]
K. L. Schuchardt, B. T. Didier, T. Elsethagen et al., “Basis set exchange: a community database for computational sciences,” Journal of Chemical Information and Modeling, vol. 47, no. 3, pp. 1045–1052, 2007.
[31]
R. Marchal, P. Carbonnière, D. Begue, and C. Pouchan, “Structural and vibrational determination of small gallium-arsenide clusters from CCSD(T) and DFT calculations,” Chemical Physics Letters, vol. 453, no. 1–3, pp. 49–54, 2008.
[32]
R. Marchal, P. Carbonnière, and C. Pouchan, “Structural and vibrational properties prediction of SnnTen clusters (n = 2-8) using the GSAM approach,” Computational and Theoretical Chemistry, vol. 990, pp. 100–105, 2012.
[33]
A. D. Becke, “Density-functional thermochemistry. III. The role of exact exchange,” The Journal of Chemical Physics, vol. 98, no. 7, pp. 5648–5652, 1993.
[34]
K. D. Dobbs and W. J. Hehre, “Molecular orbital theory of the properties of inorganic and organometallic compounds 5. Extended basis sets for first-row transition metals,” Journal of Computational Chemistry, vol. 6, pp. 861–879, 1987.
[35]
A. A. Granovsky, “Firefly version 7. 1.G,” http://classic.chem.msu.su/gran/firefly/index.html.
[36]
M. W. Schmidt, K. K. Baldridge, J. A. Boatz, et al., “General atomic and molecular electronic structure system,” Journal of Computational Chemistry, vol. 14, no. 11, pp. 1347–1363, 1993.
[37]
M. J. Frisch, G. W. Trucks, H. B. Schlegel et al., G03a: GAUSSIAN03, Revision D. 01, Gaussian, Wallingford, UK, 2009.
[38]
T. A. Keith, “AIMAll (Version 12. 06. 03),” Overland Park, Kan, USA, TK Gristmill Software, 2012, http://aim.tkgristmill.com.
[39]
A. E. Reed, L. A. Curtiss, and F. Weinhold, “Intermolecular interactions from a natural bond orbital, donor-acceptor viewpoint,” Chemical Reviews, vol. 88, no. 6, pp. 899–926, 1988.
[40]
J. P. Foster and F. Weinhold, “Natural hybrid orbitals,” Journal of the American Chemical Society, vol. 102, no. 24, pp. 7211–7218, 1980.
[41]
E. D. Glendening and A. Streitwieser, “Natural energy decomposition analysis: an energy partitioning procedure for molecular interactions with application to weak hydrogen bonding, strong ionic, and moderate donor-acceptor interactions,” The Journal of Chemical Physics, vol. 100, no. 4, pp. 2900–2909, 1994.
[42]
Z. Chval, Z. Futera, and J. V. Burda, “Comparison of hydration reactions for “piano-stool” RAPTA-B and [Ru(η6- Arene)(en)Cl]+ complexes: density functional theory computational study,” Journal of Chemical Physics, vol. 134, no. 2, Article ID 024520, 2011.
[43]
I. C. de Silva, R. M. de Silva, and K. M. N. de Silva, “Investigations of nonlinear optical (NLO) properties of Fe, Ru and Os organometallic complexes using high accuracy density functional theory (DFT) calculations,” Journal of Molecular Structure, vol. 728, no. 1–3, pp. 141–145, 2005.
[44]
P. J. Mendes, J. P. Prates Ramalho, A. J. E. Candeias, M. P. Robalo, and M. H. Garcia, “Density functional theory calculations on η5- monocyclopentadienylnitrilecobalt complexes concerning their second-order nonlinear optical properties,” Journal of Molecular Structure, vol. 729, no. 1-2, pp. 109–113, 2005.
[45]
I. N. Stepanenko, A. Casini, F. Edafe et al., “Conjugation of organoruthenium(ii) 3-(1h-benzimidazol-2 yl)pyrazolo[3,4-b]pyridines and indolo[3,2-d]benzazepines to recombinant human serum albumin: a strategy to enhance cytotoxicity in cancer cells,” Inorganic Chemistry, vol. 50, no. 24, pp. 12669–12679, 2011.
[46]
M. J. Calhorda and P. E. M. Lopes, “An “atoms in molecules” (AIM) analysis of the dihydrogen bond in organometallic compounds,” Journal of Organometallic Chemistry, vol. 609, no. 1-2, pp. 53–59, 2000.
[47]
D. Tiana, Organometallic Chemistry from the Interacting Quantum Atoms Approach [Ph.D. thesis], Università degli Studi di Milano, Milan, Italy, 2009/2010.
[48]
I. Rozas, I. Alkorta, and J. Elguero, “Behavior of ylides containing N, O, and C atoms as hydrogen bond acceptors,” Journal of the American Chemical Society, vol. 122, no. 45, pp. 11154–11161, 2000.
[49]
I. Alkorta, I. Rozas, and J. Elguero, “Non-conventional hydrogen bonds,” Chemical Society Reviews, vol. 27, no. 2, pp. 163–170, 1998.
[50]
S. Hammerum, “Alkyl radicals as hydrogen bond acceptors: computational evidence,” Journal of the American Chemical Society, vol. 131, no. 24, pp. 8627–8635, 2009.
[51]
J. E. D. Bene, I. Alkorta, G. Sanchez-Sanz, and J. Elguero, “Variations in the structures and binding energies of binary complexes with HBO,” Chemical Physics Letters, vol. 538, pp. 5–9, 2012.
[52]
K. Tang and F. Q. Shi, “Comparative analysis of blue-shifted hydrogen bond versus conventional hydrogen bond in methyl radical complexes,” International Journal of Quantum Chemistry, vol. 107, no. 3, pp. 665–669, 2007.
[53]
E. S. Shubina, N. V. Belkova, and L. M. Epstein, “Novel types of hydrogen bonding with transition metal π-complexes and hydrides,” Journal of Organometallic Chemistry, vol. 536-537, pp. 17–29, 1997.
[54]
M. Solimannejad, M. Malekani, and I. Alkorta, “Theoretical study of the halogen-hydride complexes between XeH2 and carbon halogenated derivatives,” Journal of Molecular Structure, vol. 955, no. 1–3, pp. 140–144, 2010.
[55]
L. J. Farrugia and H. M. Senn, “On the unusual weak intramolecular C？C interactions in Ru3(CO)12: a case of bond path artifacts introduced by the multipole model?” Journal of Physical Chemistry A, vol. 116, no. 1, pp. 738–746, 2012.
[56]
Q. K. Timerghazin, I. Rizvi, and G. H. Peslherbe, “Can a dipole-bound electron form a pseudo-atom? An atoms-in-molecules study of the hydrated electron,” Journal of Physical Chemistry A, vol. 115, no. 45, pp. 13201–13209, 2011.
[57]
K. E. Edgecombe, R. O. Esquivel, V. H. Smith Jr., and F. Müller-Plathe, “Pseudoatoms of the electron density,” The Journal of Chemical Physics, vol. 97, no. 4, pp. 2593–2599, 1992.
[58]
A. García-Fernández, J. Díez, á. Manteca, J. Sánchez, M. P. Gamasa, and E. Lastra, “Novel hydridotris(pyrazolyl)borate ruthenium(II) complexes containing the water-soluble phosphane 1,3,5-triaza-7-phosphaadamantane: synthesis and evaluation of DNA binding properties,” Polyhedron, vol. 27, no. 4, pp. 1214–1228, 2008.
