Synthesis, characterization, DNA interactions and biological activity of new palladium(II) complexes with some derivatives of 2-aminothiazoles

https://doi.org/10.1016/j.jinorgbio.2022.111857Get rights and content

Highlights

  • Two new palladium(II) complexes were synthesized.

  • Characterization was performed by IR, 1H and 13C NMR and X-ray spectroscopy.

  • The kinetic of the substitution reactions were studied by stopped-flow technique.

  • The interactions of new complexes with calf thymus DNA and bovine serum albumin were investigated.

  • Cytotoxic and antimicrobial activities of palladium(II) complexes were evaluated.

Abstract

Newly palladium(II) complexes (C1, C2) with derivatives of 2-aminothiazoles (L1 = 2-amino-6-methylbenzothiazole, L2 = 2-amino-6-chlorobenzothiazole), general formula [PdL2Cl2] were synthesized and characterized by elemental microanalyses, IR, NMR spectroscopy and X-ray spectroscopy in case of [Pd(L2)2Cl2]. The kinetic of the substitution reactions of complexes and the nucleophiles, such as guanosine-5′-monophosphate (5’-GMP), tripeptide glutathione (GSH) and amino acid L-methionine (L-Met), were studied by stopped-flow technique. The complex C2 was always more reactive, while the order of the reactivity of the nucleophiles, due to the associative mode of the reaction, was L-Met > GSH > 5’-GMP. In order to determine the type of interactions between palladium(II) complexes and calf thymus DNA (CT-DNA), we used electronic absorption spectroscopy, viscosity measurements, and fluorescence spectroscopic studies, while interactions with bovine serum albumin (BSA) were determined only with fluorescence spectroscopic studies. The observed results confirmed that both complexes bound to DNA by groove binding. The significantly strong interaction with BSA, especially for complex C2, was also observed. In vitro cytotoxic activity was evaluated against four tumor cell lines, 4 T1, CT26, MDA-MB-468, HCT116 and mesenchymal stem cells (mMSC). C1 complex showed higher cytotoxic activity against CT26 cell line. Flow cytometry analysis showed that C1 stimulated apoptosis of tumor cells via inhibition of expression of antiapoptotic Bcl-2 molecule and decelerated proliferation by decreasing Cyclin-D and increasing expression of P21. In vitro antimicrobial activity for ligands and corresponding palladium(II) complexes was investigated by microdilution method and minimum inhibitory concentration (MIC) and minimum microbicidal concentration (MMC) were determined. Tested compounds exhibited selective and moderate activity.

Graphical abstract

Newly complexes [PdL2Cl2] (L1 = 2-amino-6-methylbenzothiazole, L2 = 2-amino-6-chlorobenzothiazole) were synthesized and characterized by elemental microanalysis, IR, 1H, 13C NMR and X-ray spectroscopy for [Pd(L2)2Cl2]. The kinetic of the substitution reactions and interactions of complexes with calf thymus DNA and bovine serum albumin were determined. In vitro cytotoxic and antimicrobial activity were tested.

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Introduction

As the leading cause of death, cancer is a global health problem, causing almost 10 million deaths in 2020 [1]. The era of antitumor drugs began with the discovery of cisplatin and its use in medicine. Considering the large number of side effects of cisplatin and the appearance of resistance, the goal of this paper was to synthesize new components that could be more selective and as such manifest the highest antitumor potencies and fewer side effects [[2], [3], [4]]. The replication and transcription of DNA is known to be very important for the biological processes of synthesis of different proteins and enzymes. Furthermore, DNA represents the primary intracellular target for some anticancer drugs, and the interactions of these drugs and DNA usually cause deformation of cancer cells by blocking their division leading to the cell death [5]. Therefore, the investigation of the interactions between small molecules and DNA can support the development of the new transition metal ion complexes in order to potentially reveal their better activity compared to the already known platinum(II) complexes. Additionally, the interactions between some transition metal ion complexes and sulfur containing biomolecules usually lead to the appearance of resistance and toxic side effects [6]. Therefore, the study of interactions of metal complexes with different biologically relevant nucleophiles could be very important for the further development of new potential drugs. Also, the most abundant protein in plasma is serum albumin (SA) which is the crucial albumin for transport of metal ions and other molecules through the blood stream. The nature and strength of interactions between transition metal ion complexes and serum albumin have a great impact on drug distribution, absorption, metabolism and finally on excretion [7]. Since the most direct structural analogues of cisplatin exibit similar side effects, it is nessesary to synthesize novel components that will bind to DNA in different ways and have different effects [8].

The discovery of Penicilin [9] was a turning point in the tretmant of infective diseases, as well as the starting point in the synthesis of new antimicrobial agents with a wide range of treatments. But, with time, the uncontrolled usage of antibiotic therapy has resulted in the appearance of resistance to a large number of already used drugs. Therefore the synthesis and investigation of new antimicrobial agents are very useful.

Thiazoles are a biologically significant class of compounds. They are heterocyclic compounds containing both a nitrogen atom and a sulfur atom as a part of the aromatic ring. From a biological point of view thazoles and their derivatives are quite an important class of compounds due to their wide range of activites. The tiazole ring is a component of Penicilin and vitamine B1–thiamine. They are also an integral part of a large number of already used drugs, as well as tiazofurin (anticancer effect) [10], ritonavir (HIV/AIDS drug) [11], bacitracin (antibiotic) [12], meloxicam (anti-inflammatory drug) [13], etc.

Compounds of Pd(II) ion showed antifungal, antitubercular and antimicrobial activities [14,15]. Due to the presence of sulfur and nitrogen atoms in the structure, derivatives of thiazole are good candidates for the complexation with Pd(II) ion as a soft Lewis acid. Also, due to the fact that compounds od Pd(II) ions and compounds of thaizoles have already exibited wide range of biological effects, we wanted to synhesize new complexes of Pd(II) ion with some derivatives of thiazole. The aim of this paper was also to present the results of testing of antimicrobial and cytotoxic capacities of new compounds. To compare reactivity of synthetized complexes and selected nucleophiles, such as amino acid L-methionine (L-Met), tripeptide glutathione (GSH) and guanosine-5′-monophosphate (5’-GMP), substitution reactions were examined by stopped-flow technique. To get more insight into the mode of substitution, three different temperatures were used for measurements. The interactions with calf thymus DNA (CT-DNA) were examined by three different techniques (UV–Vis spectroscopy, fluorescence spectrometry as well as viscosity), while interaction with bovine serum albumin (BSA), protein important for transport of ions through blood, was examined by fluorescence spectroscopy.

Section snippets

Reagents and instruments

All reagents used for synthesis were purchased commercially and used without further purification. Elemental microanalyses for C, H, N and S were done by standard methods by an Elemental Vario EL III Microanalyzer. Infrared spectra were recorded by Perkin-Elmer Spectrum One, using KBr pellet technique (4000-400 cm−1). 1H and 13C NMR spectra were recorded by a Varian Gemini-2000 (200 MHz) spectrometer in DMSO-d6, using tetramethylsilane as an internal standard.

Perkin-Elmer Lambda 35 double beam

Chemistry

The prepared palladium(II) complexes [PdL2Cl2] were synthesized as presented in the reaction scheme (Scheme 1). The prepared complexes are not soluble in water, but well soluble in dimethylsulfoxide. The structures of complexes were proposed by elemental microanalysis, IR and NMR spectral analysis for both complexes and confirmed based on crystal structure for complex C2.

Spectroscopic analysis

IR spectra of synthesized complexes contains bands from asymmetric (for C1 at 3411 cm−1 and for C2 at 3458 cm−1) and

Conclusion

Two novel Pd(II) complexes with derivatives of 2-aminothiazoles (C1 and C2) were synthesized and characterized by elemental microanalysis, infrared, 1H and 13C NMR spectroscopy. The structure of complex C2 was confirmed by X-Ray structural analyses. Concerning the results of the substitution reactions of complexes with biologically relevant nucleophiles it can be concluded that complex C2 is more reactive than C1, while the order of the reactivity of the nucleophiles was L-Met > GSH >5’-GMP.

Accession code

CCDC 2103077 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

Declaration of Competing Interest

None

Acknowledgements

This work was supported by the Serbian Ministry of Education, Science and Technological Development (Agreements No. 451-03-68/2022-14/200122, No 451-03-68/2022-14/200378 and ON175069), bilateral project with PR China (06/2018), the Faculty of Medical Sciences, University of Kragujevac (MP02/19, JP15/19, JP11/18, JP02/20).

References (60)

  • P. Amo-Ochoa et al.

    J. Inorg. Biochem.

    (1996)
  • R.N. Bose et al.

    J. Inorg. Biochem.

    (1997)
  • P.K. Wu et al.

    J. Inorg. Biochem.

    (1996)
  • F. Arjmand et al.

    Eur. J. Med. Chem.

    (2012)
  • M. Miernicka et al.

    J. Inorg. Biochem.

    (2008)
  • M. Popsavin et al.

    Bioorganic Med. Chem. Lett

    (2006)
  • A. Garoufis et al.

    Coord. Chem. Rev.

    (2009)
  • W. Guerra et al.

    J. Inorg. Biochem.

    (2005)
  • S.D. Sarker et al.

    Methods.

    (2007)
  • G.P. Radić et al.

    Inorganica Chim. Acta.

    (2012)
  • M.T. Vujčić et al.

    Int. J. Biol. Macromol.

    (2013)
  • G. Zhang et al.

    J. Photochem. Photobiol. B Biol.

    (2012)
  • J.B. Lepecq et al.

    J. Mol. Biol.

    (1967)
  • A.G. Krishna et al.

    Biochim. Biophys. Acta - Gen. Subj.

    (1998)
  • L. Pérez-Flores et al.

    Spectrochim. Acta - Part A Mol. Biomol. Spectrosc.

    (2008)
  • K.J. Kilpin et al.

    Inorganica Chim. Acta.

    (2009)
  • V.G. Vaidyanathan et al.

    J. Inorg. Biochem.

    (2003)
  • R.E. Olson et al.

    Annu. Rep. Med. Chem.

    (1996)
  • C. Tan et al.

    J. Inorg. Biochem.

    (2008)
  • A. Zianna et al.

    J. Inorg. Biochem.

    (2019)
  • A. Karimian et al.

    DNA Repair (Amst)

    (2016)
  • World Health Organization

    International Agency for Reasearch on Cancer, Cancer today

  • Ž.D. Bugarčić et al.

    Dalt. Trans.

    (2012)
  • T. Topală et al.

    Clujul Med.

    (2014)
  • F. Alexander

    ATW - Int. Zeitschrift Fur Kernenergie.

    (1929)
  • M.V.N. de Souza et al.

    Quim Nova

    (2003)
  • T. Moulard et al.

    J. Pharm. Pharmacol.

    (1993)
  • M. Zia-ur-Rehman et al.

    Bull. Korean Chem. Soc.

    (2005)
  • CrysAlis PRO

    Rigaku Oxford diffraction Ltd: Yarnton, Oxfordshire

    (2020)
  • G.M. Sheldrick

    Acta Crystallogr. Sect. A Found. Crystallogr.

    (2015)
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