Ruthenium(II) p-cymene complex bearing 2,2′-dipyridylamine targets caspase 3 deficient MCF-7 breast cancer cells without disruption of antitumor immune response☆
Graphical abstract
Synthesis and characterization of [Ru(η6-p-cym)Cl{dpa(CH2)4COOEt}][PF6] (cym = cymene; dpa = 2,2′-dipyridylamine; 2) as well as its antitumor activity and that of [Ru(η6-p-cym)Cl(dpa)][PF6] (1) is described. The most prominent activity was observed for 1 against caspase deficient MCF-7 breast cancer cells without affect to the immune cells and cytokine production.
Introduction
Over the last few decades many efforts have been made in the field of cancer therapy [1], [2], [3], [4]. The treatment of many types of cancer has cisplatin and its analogs as mainstay drugs in current clinical chemotherapy. However, the clinical drawbacks of cisplatin are apparent, including the limited applicability, the intrinsic or acquired resistance, and the serious side effects [5]. In recent years, ruthenium-based complexes have emerged as promising antitumor and antimetastatic agents with equal or even greater antitumor activity and lower toxicity [6].
Superiority of ruthenium complexes from the classical platinum-based drugs reflect not only in their cytotoxic activity, but also in the extremely low toxicity against normal cells [7], [8], [9]. Up to now, various ruthenium complexes were investigated as potential anticancer agents [10], [11], [12], [13], [14], [15], [16], [17], [18], [19]. Two families of ruthenium(II) complexes were the mostly investigated as potential agents in treatment of cancer. Thus, octahedral ruthenium(III) complexes, such as [LH]trans-[RuCl4(L-κ-N)n(S-DMSO)2–n] (n = 1, L = imidazole; n = 2, L = indazole) which reached clinical trials [20], [21], [22], [23], [24], [25] as well as ruthenium(II) arene complexes, “piano stool” type, i.e. [Ru(η6-arene)Cl(N∩N)]X (N∩N = chelating diamine ligand; X = Cl, PF6, BPh4), showed promising anticancer activity in both in vitro and in vivo studies [26], [27].
Inflammation and immunity affect all phases of tumor growth from initiation to progression and dissemination [28]. T helper (Th) cells are fundamental for optimal induction of both humoral and cellular effector mechanisms [29]. Both innate and adaptive immunity have been shown to participate in this response. Adaptive immune responses to Ags released by dying cells play a critical role in the spontaneous as well as therapy-induced tumor rejection [30]. Ample studies have identified proinflammatory cytokines as crucial mediators in cancer treatments. Recently, the binuclear ruthenium(II) complex, [{Ru(η6-p-cym)Cl2}2μ-{(3-py)COO(CH2CH2O)4CO(3-py)}] (py = pyridine), was reported, which modulates immune system cell functions in vitro by inhibiting T cell differentiation toward pathogenic Th1/Th17 phenotype and inducing a regulatory phenotype characterized by IL-10 and IL-4 production [31]. This ruthenium(II) complex was found ineffective against several tumor cell lines [32].
This paper focuses on the synthesis and characterization of [Ru(η6-p-cym)Cl{dpa(CH2)4COOEt}][PF6] (cym = cymene; dpa = 2,2′-dipyridylamine; complex 2) as well as its biological activity and of its structural analog [Ru(η6-p-cym)Cl(dpa)][PF6] (1). With the aim to contribute to the understanding of the antitumor action mechanism of ruthenium(II) compounds the in vitro activity of 1 and 2 was investigated against tumor cells along with normal cells of the adaptive immune system.
Section snippets
Materials and measurements
All reactions and manipulations were carried out under argon using standard Schlenk techniques. NMR spectra (1H, 13C, 31P) were recorded at 27 °C on Varian Gemini VXR 400 spectrometers. Chemical shifts are relative to solvent signals (acetone-d6, δΗ 2.06, δC 30.5, 206.8; CDCl3, δΗ 7.24, δC 77.0) as internal references; δ(31P) is relative to external H3PO4 (85%). Microanalyses (C, H) were performed in the Microanalytical Laboratory of the University of Halle using a CHNS-932 (LECO) elemental
Synthesis and characterization
[Ru(η6-p-cym)Cl(dpa)][PF6] (dpa = 2,2′-dipyridylamine; 1) was obtained by an adapted literature procedure (Scheme 1) [35]. Dichlorido(p-cymene)ruthenium(II) dimer was reacted with dpa(CH2)4COOEt in the presence of [PF6]− forming the cationic complex [Ru(η6-p-cym)Cl{dpa(CH2)4COOEt}][PF6] (2) in a good yield. The ruthenium(II) complex 2 was characterized by elemental analysis, IR and multinuclear (1H, 13C, 31P) NMR spectroscopy as well as single-crystal X-ray structure analysis.
ESI-MS of 2,
Conclusions
Herein, the synthesis of [Ru(η6-p-cym)Cl{dpa(CH2)4COOEt}][PF6] (2) is described. 2 was characterized by spectroscopic methods and X-ray structural analysis. Structural analog [Ru(η6-p-cym)Cl(dpa)][PF6] (1) and 2 were tested for their in vitro antitumoral potential. The most efficient complex 1 showed higher activity against MCF-7 cells (the caspase 3 deficient cell line, more resistant to chemotherapy). Decreased viability was due to blockade of cell division and subsequent apoptotic cell death
Acknowledgements
The authors would like to acknowledge financial support from the European Union and the Free State of Saxony (project No. 100099597) and the Ministry of Education, Science and Technological Development of the Republic of Serbia (project No. 173013). We would like to thank Dr. Peter Lönnecke (Leipzig University) for the X-ray structural measurement of complex 2.
References (63)
- et al.
Coord. Chem. Rev.
(2009) - et al.
Curr. Opin. Chem. Biol.
(2008) - et al.
J. Inorg. Biochem.
(2007) - et al.
J. Inorg. Biochem.
(2006) - et al.
The role of CD4+ T cell responses in anti-tumor immunity
Curr. Opin. Immunol.
(1998) - et al.
Polyhedron
(1997) - et al.
J. Organomet. Chem.
(2010) J. Immunol. Methods
(1983)- et al.
Eur. J. Med. Chem.
(2013) - et al.
Eur. J. Med. Chem.
(2010)
Blood
S. K kassim, a rashad, a. Khalifa
Clin. Biochem.
Eur. J. Med. Chem.
Dalton Trans.
Curr. Med. Chem.
Bioinorg. Chem. Appl.
Int. J. Oncol.
Platin. Met. Rev.
J. Med. Chem.
Chem. Commun.
Organometallics
J. Med. Chem.
Chem. Asian. J.
Chem. Eur. J.
Inorg. Chem.
Organometallics
Angew. Chem. Int. Ed.
Proc. Natl. Acad. Sci. U. S. A.
Organometallics
Pharmacol. Toxicol.
Int. J. Oncol.
Cited by (26)
Construction of homo and heteronuclear Ru(II), Ir(III) and Re(I) complexes for target specific cancer therapy
2022, Coordination Chemistry ReviewsHealth beneficial and pharmacological properties of p-cymene
2021, Food and Chemical ToxicologyCitation Excerpt :According tothe U.S. Food and Drug Administration, p-cymene also known as p-cymol is considered to be “Generally recognized as safe” (GRAS) when used as a flavoring agent (FDA, 2006). p-cymene has shown a variety of pharmacological properties, including antimicrobial (Bagamboula et al., 2004; Tian et al., 2018), antioxidant (Makgwane and Ray, 2016; de Oliveira et al., 2015), anti-inflammatory (Santana et al., 2015; Xie et al., 2012), antiparasitic (Adams et al., 2013; Shang et al., 2016), antidiabetic (Abbasi et al., 2018), antiviral (Sharifi-Rad et al., 2017), and antitumor activities (Kalu\djerović et al., 2015). Indeed, p-cymene has been shown to be a potential anti-inflammatory agent due to its effective action on cytokine production tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and interleukin-10(IL-10) through blocking nuclear factor-κB (NF-κB)and mitogen-activated protein kinase (MAPK) signaling pathways (Zhong et al., 2013).
Recent advances in cytotoxicity, cellular uptake and mechanism of action of ruthenium metallodrugs: A review
2020, PolyhedronCitation Excerpt :It has been noted that the complexes binding via intercalative modes show hypochromism due to strong interaction between the base pairs and aromatic planar chromophore [151]. Ravi Kumar et al. reported the binding of the ruthenium (II) polypyridyl complexes with (2-(4-(diethoxymethyl)-1H-imidazo[4,5–f1,10]phenanthroline)) intercalative ligand. The complexes were found to be good intercalators with high binding constants of about 4–6 × 106 M−1 [154].
Synthesis, characterization and in vitro biological evaluation of novel organotin(IV) compounds with derivatives of 2-(5-arylidene-2,4-dioxothiazolidin-3-yl)propanoic acid
2020, Journal of Inorganic BiochemistryCitation Excerpt :The staining process was deactivated with the addition of 1 mL of PBS, centrifuged at 1000 rpm for 3 min and then the supernatant was discarded. The cells were resuspended in 1 mL of PBS and then analyzed with flow cytometry [57]. The PC-3 cells were prepared in a 6 well plate.
Ru(II)/N-N/PPh <inf>3</inf> complexes as potential anticancer agents against MDA-MB-231 cancer cells (N-N = diimine or diamine)
2019, Journal of Inorganic Biochemistry
- ☆
Dedicated to Prof. Giovanni Natile on the occasion of his 70th birthday.