Differential Cytotoxic Activity of a New Cationic Pd(II) Coordination Compound with N4-Tetradentate Hybrid Ligand in Cancer Cell Lines

Year 2022, Volume: 12 Issue: 3, 188 - 201, 31.12.2022

Merve Erkısa Genel Selin Selvi Ismail Yılmaz Remzi Okan Akar İlhan Yaylım Abdurrahman Şengül Engin Ulukaya

https://doi.org/10.26650/experimed.1188586

Abstract

Objective: Successful cancer treatment still requires the discovery of novel compounds that hold promise for chemotherapeutics. The objective of this study was to examine the effectiveness of a newly synthesized cationic palladium(II) coordination compound that functions via several pathways to provide an efficient therapeutic option for various cancer cells.

Materials and Methods: A new cationic palladium(II) coordination compound, [Pd(L)]Cl2·H2O, denoted as Complex 1, where the ligand L is the compound 6,6'-bis(NH-benzimidazol-2-yl)-2,2'-bipyridine), was synthesized and characterized by the attenuated total reflectance (ATR) - fourier-transform infrared spectroscopy (FT-IR), proton nuclear magnetic resonance (1H NMR), electrospray ionization mass spectrometry (ESI-MS), and carbon-hydrogen-nitrogen (CHN) analyses. The density functional theory (DFT) calculations show the coordination sphere around the metal center in Complex 1 to be made up of tertiary N atoms of the pyridine (py) and benzimidazole (bim) rings completing the square-planar geometry with significant distortion. The anti-growth/cytotoxic activity of the complex was determined using the sulforhodamine B (SRB) and adenosine triphosphate (ATP) viability assays for 24 and 48 h in vitro. The study evaluates the determinations for annexin V-propidium iodide (PI) positivity, mitochondrial membrane potential loss, Bcl-2 protein inactivation, and deoxyribonucleic acid (DNA) damage to investigate the cell death mode and its partial mechanism.

Results: Complex 1 caused cytotoxicity in a dose-dependent manner in all the cell lines used, with IC50 values ranging from 2.6-8.8 μM for 48 h. Among the cancer models, colon and breast cancer cell lines underwent cell death by well-described apoptosis through the intrinsic pathway involving the mitochondria. However, the other cell lines did not show such a cell death modality. This implies that differential cell death modes operate based on the cancer type.

Conclusion: For the treatment of breast and colon cancers, the complex 1 appears to be a unique, promising complex. Therefore, complex 1 deserves further attention for proof of concept in animal models.

Keywords

Palladium complexes, N4-donor ligand, benzimidazole, bipyridine, apoptosis, anticancer effect.

References

• 1. Phillips MC, Mousa SA. Clinical application of nano-targeting for enhancing chemotherapeutic efficacy and safety in cancer management. Nanomedicine 2022; 17(6): 405-21. [CrossRef] google scholar
• 2. Racane L, Zlatar I, Perin N, Cindric M, Radovanovic V, Banjanac M, et al. Biological Activity of Newly Synthesized Benzimidazole and Benzothizole 2, 5-Disubstituted Furane Derivatives. Molecules 2021; 26(16): 4935. [CrossRef] google scholar
• 3. Roopashree B, Gayathri V, Gopi A, Devaraju KS. Syntheses, characterizations, and antimicrobial activities of binuclear ruthenium (III) complexes containing 2-substituted benzimidazole derivatives. J Coord Chem 2012; 65(22): 4023-40. [CrossRef] google scholar
• 4. Renouard T, Fallahpour RA, Nazeeruddin MK, Humphry-Baker R, Gorelsky SI, Lever ABP, et al. Novel ruthenium sensitizers containing functionalized hybrid tetradentate ligands: synthesis, characterization, and INDO/S analysis. Inorg Chem 2002; 41(2): 367-78. [CrossRef] google scholar
• 5. Yau HC, Chan HL, Yang M. Determination of mode of interactions between novel drugs and calf thymus DNA by using quartz crystal resonator. Sens Actuators B Chem 2002; 81(2-3): 283-88. [CrossRef] google scholar
• 6. Heringova P, Kasparkova J, Brabec V. DNA adducts of antitumor cisplatin preclude telomeric sequences from forming G quadruplexes. J Biol Inorg Chem 2009; 14(6): 959-68. [CrossRef] google scholar
• 7. Büyükekşi SI, Orman EB, Şengül A, Altındal A, Özkaya AR. Electrochemical and photovoltaic studies on water soluble triads: Metallosupramolecular self-assembly of ditopic bis (imidazole) perylene diimide with platinum (II)-, and palladium (II)-2, 2': 6', 2 "-terpyridyl complex ions. Dyes Pig 2017; 144: 190-202. [CrossRef] google scholar
• 8. Largy E, Hamon F, Rosu F, Gabelica V, De PE, Guédin A, et al. Tridentate N-Donor Palladium (II) Complexes as Efficient Coordinating Quadruplex DNA Binders. Chemistry 2011; 17(47): 13274-283. [CrossRef] google scholar
• 9. Burda JV, Zeizinger M, Leszczynski J. Activation barriers and rate constants for hydration of platinum and palladium square-planar complexes: An ab initio study. J Chem Phys 2004; 120(3): 1253-62. [CrossRef] google scholar
• 10. Muller G, Bunzli, JCG, Schenk KJ, Piguet C, Hopfgartner G. Influence of bulky N-substituents on the formation of lanthanide triple helical complexes with a ligand derived from bis (benzimidazole) pyridine: structural and thermodynamic evidence. Inorg Chem 2001; 40(12): 2642-51. [CrossRef] google scholar
• 11. Cusumano M, Di Pietro ML, Giannetto A. Stacking surface effect in the DNA intercalation of some polypyridine platinum (II) complexes. Inorg Chem 1999; 38(8): 1754-58. [CrossRef] google scholar
• 12. Wong, ELM, Fang GS, Che CM, Zhu N. Highly cytotoxic iron (II) complexes with pentadentate pyridyl ligands as a new class of anti-tumor agents. Chem Commun 2005; (36): 4578-80. [CrossRef] google scholar
• 13. Davidson JP, Faber PJ, Fischer JrRG, Mansy S, Peresie HJ, Rosenberg B, et al. " Platinum-pyrimidine blues" and related complexes: a new class of potent antitumor agents. Cancer Chemother Rep 1975; 59(2 Pt 1): 287-300. google scholar
• 14. Yılmaz I, Akar OR, Erkisa M, Selvi S, Şengül A, Ulukaya E. Highly promising antitumor agent of a novel Platinum (II) complex bearing a tetradentate chelating ligand. ACS Med Chem Lett 2020; 11(5): 940-8. [CrossRef] google scholar
• 15. Drew D, Doyle JR, Shaver AG. Cyclic diolefin complexes of platinum and palladium. Inorg Syn 1972; 13: 47-55. [CrossRef] google scholar
• 16. Russo TV, Martin RL, Hay PJ. Density functional calculations on first-row transition metals. J Chem Phys 1994; 101(9): 7729-37. [CrossRef] google scholar
• 17. Hay PJ. Methods of Electronic Structure Theory: Plenum Press, 1977. google scholar
• 18. Dennington RD, Keith TA, Millam JM. GaussView 5.0, Gaussian. Inc., Wallingford, 20, 2008. google scholar
• 19. Zhang IY, Wu J, Xu X. Extending the reliability and applicability of B3LYP. Chem Commun 2010; 46(18): 3057-70. [CrossRef] google scholar
• 20. Czarnecki MA, Wojtkow D. Effect of varying water content on the structure of butyl alcohol/water mixtures: FT-NIR two-dimensional correlation and chemometric studies. J Mol Struct 2008; 883: 2038. [CrossRef] google scholar
• 21. Yilmaz I, Acar NS, Coles SJ, Jengul A. Spectroscopic, EPR, X-ray structural, and DFT studies of the complex compound of N4-donor ligand with copper (II). J Mol Struct 2020; 1214: 128204. [CrossRef] google scholar
• 22. Buyukeksi SI, Erkisa Genel M, Jengul A, Ulukaya E. Oral AY. Structural studies and cytotoxic activity of a new dinuclear coordination compound of palladium (II)-2, 2: 6, 2-terpyridine with rigid dianionic 1, 2, 4-triazole-3-sulfonate linker. Appl Organomet Chem 2018; 32(8): e4406. [CrossRef] google scholar
• 23. Lee C, Yang W, Parr RG. Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density. Phys Rev B 1988; 37: 785-9. [CrossRef] google scholar
• 24. Kohn W, Sham LJ. Self-consistent equations including exchange and correlation effects. Phys Rev 1965; 140: A1133-8. [CrossRef] google scholar
• 25. Yurdakul J. Kurt M. Vibrational spectroscopic studies of metal (II) halide benzimidazole. J Mol Struct 2003; 650(1-3): 181-190. [CrossRef] google scholar
• 26. Bhattacherjee A, Wategaonkar S. Water bridges anchored by a C-H... O hydrogen bond: the role of weak interactions in molecular solvation. Phys Chem Chem Phys 2016; 18(40): 2774549. [CrossRef] google scholar
• 27. Miao SB, Ji BM, Deng DS, Xu C, Ma N. Crystal structures and luminescence of two zinc (II) complexes with benzimidazole ligands. J Struct Chem 2010; 51(2): 386-91. [CrossRef] google scholar
• 28. Yıldız U, Şengül A, Kandemir I, Cömert F, Akkoç S, Coban B. The comparative study of the DNA binding and biological activities of the quaternized dicnq as a dicationic form and its platinum (II) heteroleptic cationic complex. Bioorg Chem 2019; 87: 70-7. [CrossRef] google scholar
• 29. Kim JS, He L, Lemasters JJ. Mitochondrial permeability transition: a common pathway to necrosis and apoptosis. Biochem Biophys Res Commun 2003; 304(3): 463-70. [CrossRef] google scholar
• 30. Kumar A, Naaz A, Prakasham AP, Gangwar MK, Butcher RJ, Panda D, Ghosh P. Potent anticancer activity with high selectivity of a chiral palladium N-Heterocyclic Carbene Complex. ACS omega 2017; 2(8): 4632-46. [CrossRef] google scholar