Abstract
Ruthenium-based metallotherapeutics is an interesting alternative for platinum complexes acting as anticancer agents after the entry of KP1019, NAMI-A, and TLD1339 in clinical trials. Herein, we have synthesized three new arene ruthenium(II)-tetrazole complexes viz. [Ru2(η6-p-cymene)2(2-pytz)2Cl2] (1), [Ru2(η6-p-cymene)2(3-pytz)Cl3] (2), [Ru2(η6-p-cymene)2(4-pytz)Cl3] (3) [2-pytzH = 2-pyridyl tetrazole; 3-pytzH = 3-pyridyl tetrazole; 4-pytzH = 4-pyridyl tetrazole] which have been characterized by different analytical techniques. To aid the understanding of the complex formation, reactions of the arene ruthenium(II) dimer with tetrazoles were investigated using the first principles-based Density Functional Theory (DFT) B3LYP method. Electronic structures, equilibrium geometries of the reactants and products with the first-order saddle points, reactions mechanism, the changes of enthalpy (∆H) and free energy (∆G), chemical stability, and reaction barriers of the complexes were computed using the B3LYP DFT approach. The in vitro cytotoxicity of these complexes was investigated by MTT assay on different cancer cell lines which reveal complex 2 as the most significant cytotoxic agent toward the HeLa cell line. The complexes have also shown a strong binding affinity towards CT-DNA and albumin proteins (HSA and BSA) as analyzed through spectroscopic techniques. Investigation of the mechanism of cell death by complex 2 was further performed by various staining techniques, flow cytometry, and gene expression analysis by RT-PCR. Inhibition of cell migration study has been also revealed the possibility of complex 2 to act as a prospective anti-metastatic agent.
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03 June 2021
A Correction to this paper has been published: https://doi.org/10.1007/s10534-021-00321-0
Abbreviations
- A549:
-
Adenocarcinomic human alveolar basal epithelial cells
- MCF-7:
-
Breast carcinoma cells
- HEK:
-
Human embryonic kidney cells
- U87:
-
Human primary glioblastoma
- HeLa:
-
Human cervical cancer
- NCCS:
-
National Centre for Cell Science
- RPMI:
-
Roswell Park Memorial Institute
- DMEM:
-
Dulbecco minimum essential medium
- FBS:
-
Fetal bovine serum
- NAMI-A:
-
[Trans-tetrachloro(DMSO) (imidazole)ruthenate(III)]
- KP1019:
-
[Trans-tetrachlorobis(1H-indazole)ruthenate(III)]
- NKP-1339:
-
Sodium trans-tetrachloride bis(1H-indazole) ruthenate(III)]
- NSAIDs:
-
Non-steroidal anti-inflammatory drugs
- COX:
-
Cyclooxygenase
- LOX:
-
Lipooxygenase
- HETEs:
-
Hydroxyeicosatetraenoic acids
- EGF:
-
Epidermal growth factor
- DCM:
-
Dichloromethane
- CT-DNA:
-
Calf thymus DNA
- MTT:
-
[3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide]
- EtBr:
-
Ethidium bromide
- RT-PCR:
-
Reverse transcription-polymerase chain reaction
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Acknowledgements
We acknowledge the Indo-Bulgaria cooperation project DST/INT/BLG/P-07/2019. We also acknowledge SIC IIT Indore for providing their instrumental facility. C. S. thank the Council of Scientific and Industrial Research (CSIR) for her doctoral fellowship. We are grateful to DST SERB India (Project No. SR/S1/IC-43/2012) for financially supporting this project. Dr. S.P. gratefully acknowledges the SERB-DST for support through the projects, highly prestigious Ramanujan Faculty Fellowship under the Scheme No. SB/S2/RJN-067/2017, and Early Career Research Award (ECRA) under Grant No. ECR/2018/000255. N.M. thanks to MHRD and IIT Indore for her postdoctoral fellowship. N.S thanks to MHRD, Govt. of India for providing her doctoral fellowship. We are thankful to flowcytometry solutions and Dr. Hemant Agrawal (Director of flowcytometry solutions) for his guidance in flow cytometry experiments. We are thankful to Dr. Rinky Singh (CSIR RA) for her guidance in UV spectrophotometric and fluorescence studies.
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Sonkar, C., Malviya, N., Sinha, N. et al. Selective anticancer activities of ruthenium(II)-tetrazole complexes and their mechanistic insights. Biometals 34, 795–812 (2021). https://doi.org/10.1007/s10534-021-00308-x
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DOI: https://doi.org/10.1007/s10534-021-00308-x