Structure Activity-Relationships (SARs) of the five possible isomers of RuCl2(Azpy)2 were predicted
thanks to DFT method. Azpy stands for 2-phenylazopyridine and the structure of the isomers
α-RuCl2(Azpy)2, β-RuCl2(Azpy)2, γ-RuCl2(Azpy)2, δ-RuCl2(Azpy)2 and ε-RuCl2(Azpy)2 call respectively α-Cl, β-Cl, γ-Cl, δ-Cl and ε-Cl are defined according to chlorine atoms orientations. Hence,
they are divided into two groups. In the first group comprising α-Cl, β-Cl and ε-Cl, both chlorine
atoms are in cis position and Azpy ligands are intervertical. Whereas the two others isomers (γ-Cl
and δ-Cl), they form the second group. Here, both chlorine are in trans position and Azpy are planar.
The five synthesized isomers were investigated as potential antitumor agents. Then, regarding
the DNA, its bases are stacked by pair. Therefore, complexes are assumed to insert and to stack
on them through intercalative mode. So the electronic and geometric structures become more
important to describe their SARs. Consequently, group 2 regarding γ-Cl and δ-Cl presents the best
structure to allow intercalation between DNA base-pairs. Besides, the energy order of the lower
unoccupied molecular orbital (LUMO) of the isomers is ELUMO(β-Cl) > ELUMO(α-Cl) > ELUMO(ε-Cl) >
ELUMO(γ-Cl) > ELUMO(δ-Cl). The energy gap between LUMO and HOMO was also sorted as Δ(L-H)(β-Cl) >
Δ(L-H)(α-Cl) > Δ(L-H)(ε-Cl) > Δ(L-H)(γ-Cl) > Δ(L-H)(δ-Cl). In addition, the total dipole moment was classified
as μ(ε-Cl) > μ(β-Cl) > μ(α-Cl) > μ(γ-Cl) > μ(δ-Cl). Finally, net charge of the ligand Azpy was also
classified as QL(δ-Cl) > QL(γ-Cl) > QL(ε-Cl) > QL(α-Cl) > QL(β-Cl). All those parameters show that δ-Cl
isomer displays the highest activity as antitumor drug when intercalating between the DNA basepairs
Cytosine-Guanine/Cytosine-Guanine (CG/CG).
References
[1]
Goswami, S., Chakravarty, A.R. and Chakravorty, A. (1981) Chemistry of Ruthenium. 2. Synthesis, Structure, and Redox Properties of 2-(Arylazo) Pyridine Complexes. Inorganic Chemistry, 20, 2246-2250.
http://dx.doi.org/10.1021/ic50221a061
[2]
Chakravarty, A.R. and Chakravorty, A. (1981) Synthesis, Structure, and Electrochemistry of Dihalobis (.Alpha.-Benzil Oximato) Ruthenium (III). Inorganic Chemistry, 20, 275. http://dx.doi.org/10.1021/ic50215a055
[3]
Krause, R.A. and Krause, K. (1982) Chemistry of Bipyridyllike Ligands. 2. Mixed Complexes of Ruthenium (II) with 2-(Phenylazo) Pyridine: A New.pi.-Bonding Probe. Inorganic Chemistry, 21, 1714-1720.
http://dx.doi.org/10.1021/ic00135a002
[4]
Jorna, A.J., Boelrijk, A.E.M., Hoorn, H.J. and Reedijk, J. (1996) Heterogenization of a Ruthenium Catalyst on Silica and Its Application in Alcohol Oxidation and Stilbene Epoxidation. Reactive & Functional Polymers, 29, 101.
http://dx.doi.org/10.1016/1381-5148(96)00005-3
[5]
Boelrijk, A.E.M., Jorna, A.M. and Reedjik, J. (1995) Oxidation of Octyl α-d-Glucopyranoside to Octyl α-d-Glucuronic Acid, Catalyzed by Several Ruthenium Complexes, Containing a 2-(Phenyl) Azopyridine or a 2-(Nitrophenyl) Azopyridine Ligand. Journal of Molecular Catalysis A-Chemical, 103, 73. http://dx.doi.org/10.1016/1381-1169(95)00112-3
[6]
Hotze, A.C.G., Velders, A.H., Ugozzoli, F., Biagini-Cingi, M., Manotti-Lanfredi, A.M., Haasnoot, J.G. and Reedijk, J. (2000) Synthesis, Characterization, and Crystal Structure of α-[Ru(azpy)2(NO3)2] (azpy = 2-(Phenylazo) Pyridine) and the Products of Its Reactions with Guanine Derivatives. Inorganic Chemistry, 39, 3838-3844.
http://dx.doi.org/10.1021/ic000066v
[7]
Velders, A.H., Kooijman, H., Spek, A.L., Haasnoot, J.G., De Vos, D. and Reedijk, J. (2000) Strong Differences in the in Vitro Cytotoxicity of Three Isomeric Dichlorobis (2-Phenylazopyridine) Ruthenium(II) Complexes. Inorganic Chemistry, 39, 2966-2967. http://dx.doi.org/10.1021/ic000167t
[8]
Hotze, A.C.G., Bacac, M., Velders, A.H., Jansen, B.A.J., Kooijman, H., Spek, A.L., Haasnoot, J.G. and Reedijk, J. (2003) New Cytotoxic and Water-Soluble Bis (2-Phenylazopyridine) Ruthenium (II) Complexes. Journal of Medicinal Chemistry, 1743-1750. http://dx.doi.org/10.1021/jm021110e
[9]
Misra, T.K., Das, D. and Sinha, C. (1997) Chemistry of Azoimidazoles: Synthesis, Spectral Characterization and Redox Properties of bis(N(1)-alkyl-2-(arylazo) Imidazole) Copper (I) and Silver(I) Complexes. Polyhedron, 16, 4163- 4170. http://dx.doi.org/10.1016/S0277-5387(97)00127-7
[10]
Lu, T.-H., Misra, T.K., Lin, P.-C., Liao, F.-L. and Chung, C.-S. (2003) Synthesis and X-Ray Characterization of Two Isomeric Dichloro Bis-{1-(phenylazo) isoquinoline} Complexes of Ruthenium (II). Polyhedron, 22, 535.
http://dx.doi.org/10.1016/S0277-5387(02)01436-5
[11]
Affi, S.T., Bamba, K. and Ziao, N. (2015) Computational Characterization of Organometallic Ligands Coordinating Metal: Case of Azopyridine Ligands. Journal of Theoretical and Computational Chemistry, 14, Article ID: 1550006.
http://dx.doi.org/10.1142/s0219633615500066
[12]
Velders, A.H., Van der Schilden, K., Hoste, A.C.G., Reedijk, J., Kooijman, H. and Speck, A.L. (2004) Dichlorobis (2-Phenylazopyridine) Ruthenium (II) Complexes: Characterisation, Spectroscopic and Structural Properties of Four Isomers. Dalton Transactions, 448-455. http://dx.doi.org/10.1039/b313182c
[13]
Bamba, K., Leger, J.-M., Garnier, E., Bachmann, C., Servat, K. and Kokoh, K.B. (2005) Selective Electrooxidation of D-Glucose by RuCl2(azpy)2 Complexes as Electrochemical Mediators. Electrochimica Acta, 50, 3341-3346.
http://dx.doi.org/10.1016/j.electacta.2004.12.007
[14]
Campbell, N., Henderson, A.W. and Taylor, D.J. (1953) Geometrical Isomerism of Azo-Compounds. Journal of the Chemical Society, 1281. http://dx.doi.org/10.1039/jr9530001281
[15]
Seal, A. and Ray, S. (1984) Structures of Two Isomers of Dichlorobis (2-Phenylazopyridine) Ruthenium (II), [RuCl2(C11H9N3)2]. Acta Crystallographica Section C, 40, 929-932. http://dx.doi.org/10.1107/s0108270184006302
[16]
Popov, A.M., Egorova, M.B., Lutovinov, V.A. and Dmitrieva, R.I. (1990) Directed Synthesis of Unknown Isomer of Ruthenium Bis-Chelate Complex with 2-(phenylazo)pyridine. Zhurnal Organicheskoi Khimii, 60, 2169-2170.
[17]
Hotze, A.C.G., Van der Geer, E.P.L., Caspers, S.E., Kooijman, H., Spek, A.L., Haasnoot, J.G. and Reedijk, J. (2000) Coordination of 9-Ethylguanine to the Mixed-Ligand Compound α-[Ru(azpy)(bpy) Cl2] (azpy = 2-Phenylazo-Pyridine and bpy = 2,2‘-Bipyridine). An Unprecedented Ligand Positional Shift, Correlated to the Cytotoxicity of This Type of [RuL2Cl2] (with L = azpy or bpy) Complex. Inorganic Chemistry, 43, 4935-4943. http://dx.doi.org/10.1021/ic035390f
[18]
Hotze, A.C.G., Caspers, S.E., De Vos, D., Kooijman, H., Spek, A.L., Flamigni, A., Bacac, M., Sava, G., Haasnoot, J.G. and Reedijk, J. (2004) Structure-Dependent in Vitro Cytotoxicity of the Isomeric Complexes [Ru(L)2Cl2] (L= O-Tolylazopyridine and 4-Methyl-2-phenylazopyridine) in Comparison to [Ru(azpy)2Cl2]. Journal of Biological Inorganic Chemistry, 9, 354-364. http://dx.doi.org/10.1007/s00775-004-0531-6
[19]
Chen, J.C., Li, J., Qian, L. and Zheng, K.C. (2005) Electronic Structures and SARs of the Isomeric Complexes α-, β-, γ-[Ru(mazpy)2Cl2] with Different Antitumor Activities. Journal of Molecular Structure: THEOCHEM, 728, 93-101.
http://dx.doi.org/10.1016/j.theochem.2005.05.005
[20]
Hartmann, M., Finhauser, T.J. and Keppler, B.K. (1996) Two Antitumour Ruthenium(III) Complexes Showing Selectivity in Their Binding towards Poly(dG)?poly(dC) and Poly(dA)?poly(dT). Chemical Communications, 1741-1742.
http://dx.doi.org/10.1039/cc9960001741
[21]
Velders, A.H., Ugozzoli, F., Biagini-Cingi, M., Manotti-Lanfredi, A.M., Haasnoot, J.G. and Reedijk, J. (1999) A Unique Fourfold Intramolecular Hydrogen Bonding Stabilises the Structure of trans-Bis(2-amino-5,7-dimethyl [1,2,4]triazolo [1,5-a]pyrimidine-N3) Aquatrichlororuthenium(III) Monohydrate. European Journal of Inorganic Chemistry, 1999, 213-215. http://dx.doi.org/10.1002/(SICI)1099-0682(19990202)1999:2<213::AID-EJIC213>3.0.CO;2-2
[22]
Hotze, A.C.G., Broekhuisen, M.E.T., Velders, A.H., Van der Schilden, K., Haasnoot, J.G. and Reedijk, J. (2002) Unusual Coordination of the Rare Neutral Imine Tautomer of 9-Methyladenine Chelating in the N6, N7-Mode to Ruthenium(II) Complexes. European Journal of Inorganic Chemistry, 2002, 369-376.
http://dx.doi.org/10.1002/1099-0682(20022)2002:2<369::AID-EJIC369>3.0.CO;2-H
[23]
Velders, A.H. (2000) “Ruthenium Complexes with Heterocyclic Nitrogen Ligands” Design, Synthesis, Structural and Conformational Characterization, Biological Activity and the Binding to DNA Model Bases. PhD Thesis, Leiden University, Leiden.
[24]
Hotze, A.C.G., Kooijman, H., Spek, A.L., Haasnoot, J.G. and Reedijk, J. (2004) Synthesis and Characterization of Ruthenium(II) Complexes with the New Ligand 2-Phenylazopyridine-5-Sulfonic Acid (Hsazpy): In Search for New Anticancer Agents. New Journal of Chemistry, 28, 565-569. http://dx.doi.org/10.1039/b313746e
[25]
Ji, L.N. and Zhang, Q.L. (2001) DNA Structure, Binding Mechanism and Biology Functions of Polypyridyl Complexes in Biomedicine. Science China (Series B), 44, 246-259. http://dx.doi.org/10.1007/BF02879615
[26]
Lawrence, D., Vaidyanathan, V.G. and Nair, B.U. (2006) Synthesis, Characterization and DNA Binding Studies of Two Mixed Ligand Complexes of Ruthenium(II). Journal of Inorganic Biochemistry, 100, 1244-1251.
http://dx.doi.org/10.1016/j.jinorgbio.2006.02.003
[27]
Kurita, N. and Kobayashi, K. (2000) Density Functional MO Calculation for Stacked DNA Base-Pairs with Backbones. Computers & Chemistry, 24, 351-357. http://dx.doi.org/10.1016/S0097-8485(99)00071-6
[28]
Becke, A.D. (1993) A New Mixing of Hartree-Fock and Local Density-Functional Theories. The Journal of Chemical Physics, 98, 1372-1377. http://dx.doi.org/10.1063/1.464304
[29]
Foresman, J.B. and Frisch, ?. (1996) Exploring Chemistry with Electronic Structure Methods. Second Edition, Gaussian Inc., Pittsburgh.
[30]
Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Montgomery Jr., J.A., Vreven, T., Kudin, K.N., Burant, J.C., Millam, J.M., Iyengar, S.S., Tomasi, J., Barone, V., Mennucci, B., Cossi, M., Scalmani, G., Rega, N., Petersson, G.A., Nakatsuji, H., Hada, M., Ehara, M., Toyota, K., Fukuda, R., Hasegawa, J., Ishida, M., Nakajima, T., Honda, Y., Kitao, O., Nakai, H., Klene, M., Li, X., Knox, J.E., Hratchian, H.P., Cross, J.B., Adamo, C., Jaramillo, J., Gomperts, R., Stratmann, R.E., Yazyev, O., Austin, A.J., Cammi, R., Pomelli, C., Ochterski, J.W., Ayala, P.Y., Morokuma, K., Voth, G.A., Salvador, P., Dannenberg, J.J., Zakrzewski, V.G., Dapprich, S., Daniels, A.D., Strain, M.C., Farkas, O., Malick, D.K., Rabuck, A.D., Raghavachari, K., Foresman, J.B., Ortiz, J.V., Cui, Q., Baboul, A.G., Clifford, S., Cioslowski, J., Stefanov, B.B., Liu, G., Liashenko, A., Piskorz, P., Komaromi, I., Martin, R.L., Fox, D.J., Keith, T., Al-Laham, M.A., Peng, C.Y., Nanayakkara, A., Challacombe, M., Gill, P.M.W., Johnson, B., Chen, W., Wong, M.W., Gonzalez, C. and Pople, J.A. (2003) Gaussian, Inc., Pittsburgh.
[31]
Shriver, D.F. and Atkins, P.W. (1999) Inorganic Chemistry. 3rd Edition, Oxford University Press, New York, 235-236.
[32]
Fleming, I. (1976) Frontier Orbital and Organic Chemical Reaction. Wiley, New York.
[33]
Zhao, R.I., Al-Said, N.H., Sternbach, D.L. and William Lown, J. (1997) Camptothecin and Minor-Groove Binder Hybrid Molecules:? Synthesis, Inhibition of Topoisomerase I, and Anticancer Cytotoxicity in Vitro. Journal of Medicinal Chemistry, 40, 216-225. http://dx.doi.org/10.1021/jm9605804
Hotze, A.C.G., Broekhuisen, M.E.T., Velders, A.H., Kooijman, H., Spek, A.L., Haasnoot, J.G. and Reedijk, J. (2002) Crystallographic and NMR Evidence of the Unusual N6, N7-Didentate Chelation of 3-Methyladenine Coordinated to the Cytotoxic α-Dichlorobis(2-Phenylazopyridine) Ruthenium(II) Complex. Journal of the Chemical Society, Dalton Transactions, 2809-2810. http://dx.doi.org/10.1039/b204665m
[36]
Jain, S.C., Tsai, C.C. and Sobell, H.M. (1977) Visualization of Drug-Nucleic Acid Interactions at Atomic Resolution. II. Structure of an Ethidium/Dinucleoside Monophosphate Crystalline Complex, Ethidium: 5-Iodocytidylyl (3’-5’) Guanosine. Journal of Molecular Biology, 114, 317-331. http://dx.doi.org/10.1016/0022-2836(77)90253-4
[37]
Zheng, K.C., Deng, H., Liu, X.W., Li, H., Chao, H. and Ji, L.N. (2004) Electronic Structures, DNA-Binding and Related Properties of Complexes [Ru(bpy)2L]2+ (L = ip, pip, hpip). Journal of Molecular Structure: THEOCHEM, 682, 225-233. http://dx.doi.org/10.1016/j.theochem.2004.05.026
[38]
Wu, W.J., Lai, R., Zheng, K.C. and Yun, F. (2005) Quantitative Structure-Activity Relationship of Indolo[1,2-b]qui- nazoline Derivatives with Antitumor Activity. Acta Physico-Chimica Sinica, 21, 28.
