Synthesis, characterization, DNA binding, cytotoxicity, and molecular docking approaches of Pd(II) complex with N,O- donor ligands as a novel potent anticancer agent
Introduction
The platinum-based antitumor drugs provide wide applications in cancer treatment during the last decades [1,2]. Cisplatin is one of the leading chemotherapy drugs that used to treat different types of human cancers, especially those of genitourinary origin [3,4]. Despite the satisfied application of cisplatin as an anticancer platinum-based drug, it has encountered undesirable side effects including low solubility in water, nephrotoxicity, ototoxicity and peripheral neuropathy [5,6]. Over recent years, the drug design and development of new anticancer drugs with improved pharmaceutical properties as well as lower side effects have gained prominence for current researches in medicinal chemistry [[7], [8], [9], [10], [11]]. Palladium(II) derivatives were swiftly selected because of their structural analogy with those containing Pt(II) complexes, for treatment of cancer. A series of palladium complexes containing bidentate amine ligands have been reported which exhibited pharmacological properties and anticancer activity comparable with cisplatin [[12], [13], [14], [15]]. The aromatic N-containing ligand, dipyridylamines are a class of compounds with variable coordination behavior and promising biological properties. On the other hand, during recent years transition metal complexes containing 2,2′-dipyridylamine ligand have been synthesized and their cytotoxicity activity and binding behavior to DNA were studied [[16], [17], [18]]. Palladium complexes with 8-hydroxyquinoline are also of great interests due to considerable biological characteristics including anticancer activity, antiseptic, antimalarial and antifungal properties [[19], [20], [21], [22], [23], [24]]. Considering this findings, it was appreciate to utilize chelating ligands to reach palladium complexes which are thermodynamically stable with potent anticancer properties [25].
In the other hand, it is well known that the main biomolecule target for most cancer and viral treatment is deoxyribonucleic acid (DNA). Small molecules capable of cleaving DNA duplex at distinguished binding sites provide an area of interest as a result of decided advantages as potential drugs [26].
In order to design a novel water soluble agent with lower side effects is essential. Therefore, the synthesis and identification of palladium (II) complex containing planar aromatic ligands of 8-hydroxyquinoline and 2,2′-dipyridylamine, [Pd(dpa)(8Q)]Cl titled as PDQ (where PPd, D = dpa, Q = 8Q and Cl as counter ion was ignored) were performed. Density functional theory (DFT) calculations were carried out on PDQ to predict coordination geometry around Pd(II). Moreover, time dependent density functional theory (TD-DFT) calculations were applied to determine orbitals nature involved in the transition processes. To ascertain the pharmacological and chemotherapeutic behaviors of PDQ, its cytotoxicity was evaluated against human chronic myeloid leukemia cell lines, K562 and its interaction with DNA was performed by employing diverse types of biophysical methods of UV–vis, fluorescence, viscosity and circular dichroism. Furthermore, molecular docking analysis has been carried out as a complementary way to identify the binding nature.
Section snippets
Materials and methods
AgNO3, NaOH, calf thymus DNA (DNA), ethidium bromide (EB), 8-hydroxyquinoline (8Q), 2,2′-dipyridylamine and Tris-HCl buffer were obtained from Sigma Chemical Co., human leukemia cell line, K562 were employed from Pasteur Institute. All of the solvents were used of analytical grade.
Melting points were recorded on an Unimelt capillary melting point apparatus. CHN elemental analyses were carried out using LECO 600 elemental analyzer. Molar conductivity was performed with a Systronics conductivity
Characterization of PDQ
PDQ was prepared according to the reaction procedure (refer to Fig. 1) with an appropriate yield (60%). Anal. Calcd. for C19H15N4OClPd (457.22 g/mol): C, 49.91; H, 3.31; N, 12.25%. Found: C, 49.97; H, 3.25; N, 12.21%. Molar conductance, ΛM (10−3 M, H2O) was 116 Ω−1 cm2 mol−1 indicating 1:1 electrolytes [48].
Conclusion
In this study, preparation and characterization of novel water soluble palladium (II) complex bearing 2,2′-dipyridylamine and 8-hydroxyquinoline ligands, PDQ, with square-planar geometry were reported. Elemental analyses, FTIR, NMR spectroscopies confirmed the proposed structure of complex and also, the conductivity measurements showed that [Pd(dpa)(8Q)]Cl was 1:1 electrolyte. Theoretical calculations were performed with density functional theory (DFT) and time-dependent density functional
CRediT authorship contribution statement
Mohammad Aminzadeh: Methodology, Software, Writing - original draft. Maryam Saeidifar: Formal analysis, Validation, Writing - review & editing. Hassan Mansouri-Torshizi: Conceptualization, Supervision.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgment
The authors are grateful for all support provided by University of Sistan and Baluchestan and Materials and Energy Research Center.
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