Synthesis, characterization, DNA binding, cytotoxicity, and molecular docking approaches of Pd(II) complex with N,O- donor ligands as a novel potent anticancer agent

https://doi.org/10.1016/j.molstruc.2020.128212Get rights and content

Highlights

  • A new watersoluble palladium(II) complex was synthesized and characterized.

  • DFT calculations results have a good confirmation with experimental results.

  • PDQ-DNA binding were extensively investigated in physiological condition.

  • Biological evaluation of PDQ on K562 indicated its potential as antitumor agent.

Abstract

A new potent anticancer agent of 2,2′-dipyridylamine8-hydroxyquinolinatopalladium(II) chloride, [Pd(dpa)(8Q)]Cl titled as PDQ, was synthesized by the reactions of Na2PdCl4 with the organic compounds of 2, 2′-dipyridylamine (D) and 8-hydroxyquinoline (Q). Also, the prepared complex was characterized by elemental analyses, FTIR, NMR spectroscopies and conductivity measurements. The characterization results were found in consistent with the proposed structure of PDQ and DFT methodology confirmed the experimental results. The cytotoxicity evaluation of complex against human chronic myelogenous leukemia (K562) cancer cells demonstrated that the CC50 value of PDQ (22 μM) was comparable with carboplatin and better than some palladium complexes, which were reported as potential anticancer agents. Moreover, PDQ-DNA binding properties were extensively performed by UV–vis, fluorescence, CD spectroscopies and viscosity measurement in physiological condition. Molecular docking technique was performed to provide more insights on binding mode. Overall, all evidence revealed that, PDQ spontaneously binds to DNA with intercalation mode and static mechanism.

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 Pdouble bondPd, 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.

References (75)

  • A. Zianna et al.

    Cadmium (II) complexes of 5-bromo-salicylaldehyde and α-diimines: synthesis, structure and interaction with calf-thymus DNA and albumins

    Polyhedron

    (2016)
  • V. Thamilarasan et al.

    Synthesis, molecular structure, theoretical calculation, DNA/protein interaction and cytotoxic activity of manganese (III) complex with 8-hydroxyquinoline

    J. Photochem. Photobiol. B Biol.

    (2015)
  • P. Karimi

    Investigation of intramolecular hydrogen bonding in conjunction with cation-π interactions in complexes involving 4-substituted-8-hydroxyquinolines

    J. Mol. Struct.

    (2019)
  • N. Cutillas et al.

    Anticancer cyclometalated complexes of platinum group metals and gold

    Coord. Chem. Rev.

    (2013)
  • K.G. Thorat et al.

    Modulating TICT to ICT characteristics of acid switchable red emitting boradiazaindacene chromophores: perspectives from synthesis, photophysical, hyperpolarizability and TD-DFT studies

    Dyes Pigments

    (2017)
  • R.N. Guzzo et al.

    Experimental and DFT evaluation of the 1H and 13C NMR chemical shifts for calix [4] arenes

    J. Mol. Struct.

    (2018)
  • M. Saeidifar et al.

    Mononuclear Pd(II) complex as a new therapeutic agent: synthesis, characterization, biological activity, spectral and DNA binding approaches

    J. Mol. Struct.

    (2017)
  • J.G. Malecki et al.

    Characterization of a Pd(II) complex with €-8-hydroxyquinoline-2-carbaldehyde O-benzyl oxime

    Mendeleev Commun.

    (2014)
  • A.K. Paul et al.

    Some potential antitumor 2, 2′-dipyridylamine Pt (II)/Pd (II) complexes with amino acids: their synthesis, spectroscopy, DNA binding, and cytotoxic studies

    J. Inorg. Biochem.

    (1993)
  • P. Štarha et al.

    Synthesis, characterization and in vitro cytotoxicity of the first palladium(II) oxalato complexes involving adenine-based ligands

    J. Inorg. Biochem.

    (2009)
  • P. Sathyadevi et al.

    Studies on the effect of metal ions of hydrazone complexes on interaction with nucleic acids, bovine serum albumin and antioxidant properties

    Inorg. Chim. Acta.

    (2012)
  • E.-J. Gao et al.

    Hairpin-shaped tetranuclear palladium (II) complex: synthesis, crystal structure, DNA binding and cytotoxicity activity studies

    Eur. J. Med. Chem.

    (2010)
  • E. Sindhuja et al.

    DNA/protein interaction and cytotoxicity of palladium (II) complexes of thiocarboxamide ligands

    Inorg. Chim. Acta.

    (2014)
  • R. Mital et al.

    Synthesis, characterization and cytotoxic studies of diamine and diimine palladium (II) complexes of diethyldithiocarbamate and binding of these and analogous platinum (II) complexes with DNA

    Inorg. Chim. Acta.

    (1989)
  • S. Anbu et al.

    Phenyl carbohydrazone conjugated 2-oxoindoline as a new scaffold that augments the DNA and BSA binding affinity and anti-proliferative activity of a 1, 10-phenanthroline based copper (II) complex

    Inorg. Chim. Acta.

    (2014)
  • D. Ćoćić et al.

    New monofunctional platinum (II) and palladium (II) complexes: studies of the nucleophilic substitution reactions, DNA/BSA interaction, and cytotoxic activity

    J. Inorg. Biochem.

    (2018)
  • E.K. Efthimiadou et al.

    Mononuclear copper (II) complexes with quinolones and nitrogen-donor heterocyclic ligands: synthesis, characterization, biological activity and interaction with DNA

    Inorg. Chim. Acta.

    (2007)
  • M. Aminzadeh et al.

    Synthesis, crystal structure and DNA interaction of a new water-soluble derivative of pyrazino [2, 3-f][1, 10] phenanthroline; theoretical calculations, experimental and molecular docking studies

    J. Mol. Struct.

    (2018)
  • S. Murugavel et al.

    Synthesis, structural elucidation, antioxidant, CT-DNA binding and molecular docking studies of novel chloroquinoline derivatives: promising antioxidant and anti-diabetic agents

    J. Photochem. Photobiol. B Biol.

    (2017)
  • F.M. Muggia et al.

    Platinum antitumor complexes: 50 Years since barnett rosenberg’s discovery

    J. Clin. Oncol.

    (2015)
  • A.S. Abu-Surrah et al.

    Platinum group antitumor chemistry: design and development of new anticancer drugs complementary to cisplatin

    Curr. Med. Chem.

    (2006)
  • L. Cai et al.

    Anticancer platinum-based complexes with non-classical structures

    Appl. Organomet. Chem.

    (2018)
  • C. Sirlin et al.

    Molecular library obtained by allene insertion into the Pd−C bond of cyclopalladated complexes: biological and pharmacological evaluation

    Eur. J. Org Chem.

    (2004)
  • A.H. Velders et al.

    Synthesis and Chemical− Pharmacological Characterization of the Antimetastatic NAMI-A-Type Ru (III) Complexes (Hdmtp)[trans-RuCl4 (dmso-S)(dmtp)],(Na)[trans-RuCl4 (dmso-S)(dmtp)], and [mer-RuCl3 (H2O)(dmso-S)(dmtp)](dmtp= 5, 7-Dimethyl [1, 2, 4] triazolo [1, 5-a] pyrimidine)

    J. Med. Chem.

    (2004)
  • E. Gao et al.

    Impact of the carbon chain length of novel palladium (II) complexes on interaction with DNA and cytotoxic activity

    Inorg. Chem.

    (2010)
  • C. Icsel et al.

    New palladium (ii) and platinum (ii) 5, 5-diethylbarbiturate complexes with 2-phenylpyridine, 2, 2′-bipyridine and 2, 2′-dipyridylamine: synthesis, structures, DNA binding, molecular docking, cellular uptake, antioxidant activity and cytotoxicity

    Dalton Trans.

    (2015)
  • Z. Sorinezami et al.

    Synthesis of new ultrasonic-assisted palladium oxide nanoparticles: an in vitro evaluation on cytotoxicity and DNA/BSA binding properties

    J. Biomol. Struct. Dyn.

    (2019)
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