Synthesis and characterization of cyclometalated Pd(II) complex bearing tyrosine: Experimental and theoretical study of interaction with biomacromolecules

Document Type : Original Article


1 Faculty of Chemistry. Kharazmi University. Tehran. Iran

2 Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran


Considering the important role of bioactive ligands in designing antitumor complexes, mononuclear C^C-cyclometalated Pd (II) complex containing amino acid, tyrosine, was synthesized and identified using Fourier-transform infrared (FT-IR) and nuclear magnetic resonance (NMR) spectroscopic methods. The interaction of the synthesized mononuclear complex with the biomacromolecules, deoxyribonucleic acid (DNA) and bovine serum albumin (BSA), was studied by UV-Vis absorption and fluorescence emission. Based on the experimental studies, an intercalating mode was proposed for the interaction between the complex and DNA. The UV-Vis absorption and fluorescence emission spectroscopies indicated the high affinity of the complex for BSA binding. Molecular docking calculations revealed that the hydrophobic interactions play important roles in complex – BSA binding.


Main Subjects

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[1] Deo, S. V. S., Sharma, J., & Kumar, S. (2022). GLOBOCAN 2020 report on global cancer burden: challenges and opportunities for surgical oncologists. Annals of Surgical Oncology, 29(11), 6497-6500.
[2] Galanski, M., Jakupec, M. A., & Keppler, B. K. (2005). Update of the preclinical situation of anticancer platinum complexes: novel design strategies and innovative analytical approaches. Current Medicinal Chemistry, 12(18), 2075-2094.
[3] Jung, Y., & Lippard, S. J. (2007). Direct cellular responses to platinum-induced DNA damage. Chemical Reviews, 107(5), 1387-1407.
[4] Lee, S. Y., Kim, C. Y., & Nam, T. -G. (2020). Ruthenium complexes as anticancer agents: A brief history and perspectives. Drug Design, Development and Therapy, 5375-5392.
[5] Muhammad, N., & Guo, Z. (2014). Metal-based anticancer chemotherapeutic agents. Current Opinion in Chemical Biology, 19, 144-153.
[6] Mohammadi, N., Abedanzadeh, S., Fereidonnejad, R., Mahdavinia, M., & Fereidoonnezhad, M. (2023). Effects of diphosphine ligands on the anticancer behavior of cycloplatinated (II) complexes of 2, 2´-Bipyridine N-Oxide: in vitro cytotoxicity, apoptosis, genotoxicity, and molecular docking studies. Journal of Organometallic Chemistry, 122759.
[7] Fereidoonnezhad, M., Shahsavari, H. R., Abedanzadeh, S., Nezafati, A., Khazali, A., Mastrorilli, P., Babaghasabha, M.,   Webb, J.,   Faghih,   Z., Faghih, Z., Bahemmat S., & Beyzavi, M. H. (2018). Synthesis, structural characterization, biological evaluation and molecular docking studies of new platinum (ii) complexes containing isocyanides. New Journal of Chemistry, 42(11), 8681-8692.
[8] Sakamaki, Y., Ahmadi Mirsadeghi, H., Fereidoonnezhad, M., Mirzaei, F., Moghimi Dehkordi, Z., Chamyani, S., Alshami, M., Abedanzadeh, S., Shahsavari, H. R. & Beyzavi, M. H. (2019). trans‐platinum (II) thionate complexes: synthesis, structural characterization, and in vitro biological assessment as potent anticancer agents. ChemPlusChem, 84(10), 1525-1535.
[9] Carneiro, T. J., Martins, A. S., Marques, M. P. M. & Gil1, A. M. (2020). Metabolic aspects of palladium (II) potential anti-cancer drugs. Frontiers in Oncology, 10, 590970.
[10] Lazarević, T., Rilak, A., & Bugarčić, Ž. D. (2017). Platinum, palladium, gold and ruthenium complexes as anticancer agents: Current clinical uses, cytotoxicity studies and future perspectives. European Journal of Medicinal Chemistry, 142, 8-31.
[11] Vojtek, M., Marques, M. P. M., Ferreira, I. M. P. L. V. O., Mota-Filipe, H., & Diniz,  C. (2019). Anticancer activity of palladium-based complexes against triple-negative breast cancer. Drug Discovery Today, 24(4), 1044-1058.
[12] Kapdi, A. R., & Fairlamb, I. J. (2014). Anti-cancer palladium complexes: a focus on PdX2L2, palladacycles and related complexes. Chemical Society Reviews, 43(13), 4751-4777.
[13] Karami, K., Abedanzadeh, S., Yadollahi, F., Büyükgüngör, O., Farrokhpour, H., Rizzoli, C., & Lipkowski, J. (2015). Mono-and binuclear orthopalladated complexes of phosphorus ylides containing nitrogen, phosphorus or bridging diphosphine ligands: Self-assembly, theoretical calculations and comparative catalytic activity. Journal of Organometallic Chemistry, 781, 35-46.
[14] Jamali, S., Abedanzadeh, S., Khaledi, N. K., Samouei, H., Hendi, Z., Zacchini, S., Kia, R., & Shahsavari, H. R. (2016). A cooperative pathway for water activation using a bimetallic Pt 0–Cu I system. Dalton Transactions, 45(44), 17644-17651.
[15] Karami, K., Abedanzadeh, S., Farrokhpour, H., & Lipkowski, J. (2016). Synthesis and characterization of the P, C-palladacycles with bridging and chelating dinitrogen ligands and ONIOM calculations on the pyrazine-bridged organometallic polymers (n= 1 to n= 10). Journal of Organometallic Chemistry, 805, 68-76.
[16] Shahsavari, H. R., Lalinde, E., Moreno, M. T., Niazi, M., Kazemi, S. H., Abedanzadeh, S., Barazandeh, M., & Halvagar, M. R. (2019). Half-lantern cyclometalated Pt (ii) and Pt (iii) complexes with bridging heterocyclic thiolate ligands: synthesis, structural characterization, and electrochemical and photophysical properties. New Journal of Chemistry, 43(20), 7716-7724.
[17] Beletskaya, I. P., & Cheprakov, A. V. (2004). Palladacycles in catalysis– a critical survey. Journal of Organometallic Chemistry, 689(24), 4055-4082.
[18] Dupont, J., Consorti, C. S., & Spencer, J. (2005). The potential of palladacycles: more than just precatalysts. Chemical Reviews, 105(6), 2527-2572.
[19] Herrmann, W. A., Öfele, K., Preysing, D. v., & Schneider S. K. (2003). Phospha-palladacycles and N-heterocyclic carbene palladium complexes: efficient catalysts for CC-coupling reactions. Journal of Organometallic Chemistry, 687(2), 229-248.
[20] Karami, K., Abedanzadeh, S., & Hervés, P. (2016). Synthesis and characterization of functionalized titania-supported Pd catalyst deriving from new orthopalladated complex of benzophenone imine: catalytic activity in the copper-free Sonogashira cross-coupling reactions at low palladium loadings. RSC Advances, 6(96), 93660-93672.
[21] Jamali, S., & Abedanzadeh, S. (2018). Organoplatinum (II) complexes containing bis-(N-heterocyclic carbene) ligands: Catalytic activity in hydrosilylation of α, β-unsaturated ketones. Applied Chemistry, 13(46), 295-310. (in Persian)
[22] Karami, K., Esfarjani, S., Abedanzadeh, S., & Lipkowski, J. (2014). P, C-palladacycle complexes of triphenylphosphite: Synthesis, characterization and catalytic activity in the Suzuki cross-coupling reaction. Polyhedron, 68, 249-257.
[23] Alonso, D. A., & Najera, C. (2010). Oxime-derived palladacycles as source of palladium nanoparticles. Chemical Society Reviews, 39(8), 2891-2902.
[24] Karami, K., Abedanzadeh, S., Vahidnia, O., Herves, P., Lipkowski, J., & Lyczko, K. (2017). Orthopalladated complexes of phosphorus ylide: Poly (N‐vinyl‐2‐pyrrolidone)‐stabilized palladium nanoparticles as reusable heterogeneous catalyst for Suzuki and Heck cross‐coupling reactions. Applied Organometallic Chemistry, 31(11), e3768.
[25] Jain, V.K. (2021). Cyclometalated group-16 compounds of palladium and platinum: Challenges and opportunities. Coordination Chemistry Reviews, 427, 213546.
[26] Cutillas, N., Yellol, G. S., de Haro, C., Vicente, C., Rodríguez, V., & Ruiz, J. (2013). Anticancer cyclometalated complexes of platinum group metals and gold. Coordination Chemistry Reviews, 257(19-20), 2784-2797.
[27] Abedanzadeh, S., Karami, K., Rahimi, M., Edalati M., Abedanzadeh, M., Tamaddon, A. M., Dehdashti Jahromi M., Amirghofran, Z., Lipkowskif J., & Lyczkog K. (2020). Potent cyclometallated Pd (II) antitumor complexes bearing α-amino acids: synthesis, structural characterization, DNA/BSA binding, cytotoxicity and molecular dynamics simulation. Dalton Transactions, 49(42), 14891-14907.
[28] Rúa-Sueiro, M., Munín-Cruz, P., Fernández, A., Ortigueira, J. M., Pereira, M. T., & Vila, J. M. (2022). Cyclometallated palladium (II) complexes: An approach to the first dinuclear bis (iminophosphorane) phosphane-[C, N, S] metallacycle. Molecules, 27(20), 7043.
[29] Geyl, K. K., Baykov, S. V., Kasatkina, S. O., Savko, P. Y., & Boyarskiy, V. P. (2022). Reaction of coordinated isocyanides with substituted N-(2-pyridyl) ureas as a route to new cyclometallated Pd (II) complexes. Journal of Organometallic Chemistry, 980, 122518.
[30] Albrecht, A. (2010). Cyclometalation using d-block transition metals: fundamental aspects  and recent trends. Chemical Review, 110(2), 576–623
[31] Urriolabeitia, E. P., (2010). Ylide ligands. Transition metal complexes of neutral meta1-carbon ligands (Vol. 30), 15-48.
[32] Liu, H. -K., & Sadler P., (2011). Metal complexes as DNA intercalators. Accounts of Chemical Research, 44(5), 349–359.
[33] Komora,  A. C., &  Barton, J. K. (2013). The path for metal complexes to a DNA target. Chemical Communication, 49, 3617-3630.
[34] Bruijnincx, P. C., & Sadler, P. J. (2008). New trends for metal complexes with anticancer activity. Current Opinion in Chemical Biology, 12(2), 197-206.
[35] Sudlow, G., Birkett, D., & Wade, D. (1975). The characterization of two specific drug binding sites on human serum albumin. Molecular Pharmacology, 11(6), 824-832.
[36] Scattolin, T., Voloshkin, V. A., Visentin, F., & Nolan, S. P. (2021). A critical review of palladium organometallic anticancer agents. Cell Reports Physical Science, 2(6), 100446.
[37] Karami, K., Rizzoli, C., & Borzooie, F. (2011). Orthopalladation of phosphorus ylides in endo position with bidentate ligands. Polyhedron, 30(5), 778-784.
[38] Morris, G. M., Huey, R., Lindstrom, W., Sanner, M. F., Belew, R. K., Goodsell, D. S., & Olson A. J. (2009). AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. Journal of Computational Chemistry, 30(16), 2785-2791.
[39] Berman, H. M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T. N., Weissig, H. I., Shindyalov, N., & Bourned, P. E. (2006). The protein data bank, 1999–.
[40] Froimowitz, M. (1993). HyperChem: a software package for computational chemistry and molecular modeling. Biotechniques, 14(6), 1010-1013.
[41] Wolber, G., Dornhofer, A. A., & Langer, T. (2006). Efficient overlay of small organic molecules using 3D pharmacophores. Journal of Computer-Aided Molecular Design, 20(12), 773-788.
[42] Aguilar, D., Aragüés, M. A., Bielsa, R., Serrano, E., Soler, T., Navarro, R., & Urriolabeitia, E. P. (2008). Synthesis and structure of orthopalladated complexes derived from prochiral iminophosphoranes and phosphorus ylides. Journal of Organometallic Chemistry, 693(3), 417-424.
[43] Boerner, L. J. K., & Zaleski, J. M. (2005). Metal complex–DNA interactions: from transcription inhibition to photoactivated cleavage. Current Opinion in Chemical Biology, 9(2), 135-144.
[44] Jurgens, S., Kuhn, F. E., & Casini, A. (2018). Cyclometalated complexes of platinum and gold with biological properties: state-of-the-art and future perspectives. Current Medicinal Chemistry, 25(4), 437-461.
[45] Sindhu, M., Kalaivani, P., & Prabhakaran, R. (2022). Enhanced anticancer property of bio‐organometallic nano composites: Design, characterization, and biological evaluation. Applied Organometallic Chemistry, 36(1), e6488.
[46] Khater, M., Brazier, J. A., Greco, F., & Osborn, H. M. (2023). Anticancer evaluation of new organometallic ruthenium (II) flavone complexes. RSC Medicinal Chemistry, 14(2), 253-267.
[47] Omae, I. (2014). Applications of five-membered ring products of cyclometalation reactions as anticancer agents. Coordination Chemistry Reviews, 280, 84-95.
[48] Liu, H. K., & Sadler, P. J. (2011). Metal complexes as DNA intercalators. Accounts of Chemical Research, 44(5), 349-359.
[49] Habibi Shabestary,  B., & Golbon Haghighi, M. (2023). Synthesis, Characterization and DNA binding studies of Platinum Complexes with Imine Ferrocene Ligand. Applied Chemistry, 18(66), 225-240. (in Persian)
[50] Movahedi,  E., Razmazma,  H., Rezvani,  A., & Nowroozi, A., (2021). Synthesis, characterization, and evaluation of the interaction of DNA with a new silver(I) complex with diazafluorene-based ligands: Experimental and theoretical studies. Applied Chemistry, 16(59), 32-50. (in Persian)