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Bis(triazinyl)pyridine complexes of Pt(II) and Pd(II): studies of the nucleophilic substitution reactions, DNA/HSA interactions, molecular docking and biological activity

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Abstract

Four new complexes of Pt(II) and Pd(II), [Pd(L1)Cl]Cl 1, [Pd(L2)Cl]Cl 2, [Pt(L1)Cl]Cl 3 and [Pt(L2)Cl]Cl 4 (where L1 = 2,6-bis(5,6-diphenyl-1,2,4-triazin-3-yl)pyridine and L2 = 2,6-bis(5,6-dipropyl-1,2,4-triazin-3-yl)pyridine), were synthesized. Characterization of the complexes was performed using elemental analysis, IR, 1H NMR spectroscopy and MALDI-TOF mass spectrometry. The substitution reactions of 1–4 complexes with l-methionine (l-met), l-cysteine (l-cys) and guanosine-5ʹ-monophosphate (5ʹ-GMP), were studied spectrophotometrically at physiological conditions. Complexes with ligand L1 (1 or 3) were more reactive than those with ligand L2 (2 or 4) by a factor ranging up to 1.57 and 3.71, respectively. The order of reactivity of the nucleophiles was: l-met > l-cys > 5ʹ-GMP. The interactions of complexes with calf thymus-DNA (CT-DNA) and human serum albumin (HSA) were studied by Uv–Vis absorption and fluorescence emission spectroscopy. Competitive binding studies with intercalative agent ethidium bromide (EB) and minor groove binder Hoechst 33258 were performed as well. All studied complexes can interact with DNA through the intercalation and minor groove binding, where the latter was preferred. The binding constants (103 and 104 M−1) for the interaction of complexes with HSA indicate the moderate binding affinity of complexes 1–4 to protein. The trends in the experimental results of binding studies between complexes 3 and 4 with DNA and HSA were compared to those obtained from the molecular docking study. Biological evaluation of cytotoxicity of 1 and 2 on HCT-116 and MDA-MB-231 cell lines showed significant cytotoxic and prooxidative character, while 2 also exerted extraordinary selectivity towards colon cancer in comparison to breast cancer cells.

Graphic abstract

The nucleophilic substitution reactions, DNA/HSA interactions, molecular docking and biological activity of bis(triazinyl)pyridine complexes of Pt(II) and Pd(II) were studied.

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Fig. 1
Scheme 1
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Abbreviations

L1:

2,6-Bis(5,6-diphenyl-1,2,4-triazin-3-yl)pyridine

L2:

2,6-Bis(5,6-dipropyl-1,2,4-triazin-3-yl)pyridine

L-met:

L-methionine

L-cys:

L-cysteine

5′-GMP:

Guanosine-5′-monophosphate

CT-DNA:

Calf thymus-DNA

HAS:

Human serum albumin

EB:

Ethidium bromide

Hoechst 33258:

2-(4-hydroxyphenyl)-5-[5-(4-methylpipera-zine-1-yl)-benzimidazo-2-yl]-benzimidazole

DMF:

Dimethylformamide

HCT-116:

Human colorectal carcinoma cells

MDA-MB-231:

Human breast cancer cells

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Acknowledgements

The authors gratefully acknowledge financial support from the Ministry of Education, Science and Technological Development of the Republic of Serbia (Agreement No. 451-03-9/2021-14/200378 and Agreement No. 451-03-9/2021-14/200122). MALDI-TOF mass spectrometry was conducted by Research Professor Dr. Marijana Petković at CQM-Madeira Chemistry Research Centre, University of Madeira, Funchal, Portugal, supported by the FCT-Fundação para a Ciência e a Tecnologia (CQM Base Fund—UIDB/00674/2020, and Programmatic Fund—UIDP/00674/2020), Madeira 14-20 Program (project PROEQUIPRAM-Reforço do Investimento em Equipamentos e Infrastructures Científcas na RAM-M1420-01-0145-FEDER-000008) and by ARDITI-Agência Regional para o Desenvolvimento da InvestigaçãoTecnologia e Inovação, ARDITI-CQM_2019-018-ISG.

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Authors and Affiliations

  1. Department of Natural Science, University of Kragujevac, Institute for Information Technologies Kragujevac, Jovana Cvijića Bb, 34000, Kragujevac, Serbia

    Snežana Jovanović-Stević, Biljana Šmit, Marko N. Živanović & Katarina Virijević

  2. Faculty of Science, University of Kragujevac, R. Domanovića 12, P. O. Box 60, 34000, Kragujevac, Serbia

    Snežana Radisavljević, Dušan Ćoćić & Biljana Petrović

  3. Inorganic Chemistry, Department of Chemistry and Pharmacy, University of Erlangen-Nürnberg, Erlangen, Germany

    Andreas Scheurer

  4. “Vinča” Institute of Nuclear Sciences, National Institute of the Republic of Serbia, University of Belgrade, Mike Petrovića Alasa 12-14, 11001, Belgrade, Serbia

    Marijana Petković

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  1. Snežana Jovanović-Stević
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  9. Biljana Petrović
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Contributions

All authors contributed to the study conception and design. SJ-S: supervision, validation, writing—review, and editing; SR: investigation; AS: investigation, methodology; DĆ: investigation, software; BŠ: formal analysis; MP: formal analysis; MNŽ: investigation, methodology; KV: investigation; BP: investigation, resources, methodology. All authors read and approved the final manuscript.

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Correspondence to Snežana Jovanović-Stević.

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Jovanović-Stević, S., Radisavljević, S., Scheurer, A. et al. Bis(triazinyl)pyridine complexes of Pt(II) and Pd(II): studies of the nucleophilic substitution reactions, DNA/HSA interactions, molecular docking and biological activity. J Biol Inorg Chem 26, 625–637 (2021). https://doi.org/10.1007/s00775-021-01879-3

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