Structure and anticancer activity of Cu(II) complexes with (bromophenyl)thiourea moiety attached to the polycyclic imide
Graphical abstract
Two thiourea complexes with pseudo-tetrahedral geometry have shown significant and selective activity to cancer cell lines SW480 (primary colon cancer) and PC3 (metastatic prostate cancer), being less toxic than the chemotherapy medicines: doxorubicin and cisplatin.
Introduction
Cancer is the second leading cause of death in the world. It is estimated that over 9 million people affected by this disease died in 2018, i.e. one in six deaths globally, according to the WHO. Prostate, colon, stomach, liver and lung cancer are the most common types of cancer in men, while women most often suffer from breast, colon, cervix, thyroid and lung cancer. These diseases are characterized by abnormal cell growth (often the reason is a disturbed cell cycle or the proteasome pathway) causing the tumor formation. Thus, the components of the cell cycle or proteasome pathway are potential molecular targets for therapeutics. For about 20 years, much effort has been put into the development of connection with physiologically relevant, endogenous metals such as copper [1,2] which are a promising alternative to highly effective but also very toxic platinum-based drugs [3]. Copper is an essential trace element in animals and as a critical component of enzymes and proteins plays an important role in many biological processes. It has been shown that copper has the unique role in angiogenesis, which is a critical process for tumor growth and metastasis [4]. Moreover, in numerous cancerous tissues, such us prostate, breast, brain and lung, the copper concentration exceeds the concentration of normal tissues [2,5]. In this field, copper complexes are highly perspective in the metal-based anticancer drug discovery [1,2].
Copper forms a rich variety of complexes with oxidation state +1 and +2. The coordination number varies from 2 to 6. The tetrahedral geometry dominate in Cu(I) complexes while square planar, trigonal bipyramidal and octahedral arrangements are most often observed in the crystal structure of Cu(II) complexes [2]. The variety of coordination numbers and geometries, redox state, thermodynamic and kinetic properties as well as properties of ligands themselves allow one to design new potential drugs. The appropriate choice of ligands is the key step in planning new syntheses. The ligands of different hapticity, from monodentate to heksadentate chelates, can be considered in the case of copper complexes with N, O, S and halides donor atoms.
Derivatives of thiourea are able to act as potent metal chelators and have been used in our research. These compounds possess ability to bind metal cations via S and N atoms, and (i) act as monodentate ligands through S or N atoms; (ii) bind to metal ions forming S,N or N,N bridges or (iii) chelate by S,N atoms. Moreover, thioureas themselves show a broad spectrum of biological activity, including anticancer, antibacterial and antituberculosis properties [[6], [7], [8]]. It was demonstrated that the biological activity of copper complexes with thiourea derivatives can be higher than that of parent ligands [[9], [10], [11], [12]]. Focusing only on anticancer activity, Rauf et al. [11] synthesized a series of copper(I) complexes with N,N′-disubstituted thioureas that exhibit a moderate cytotoxicity, comparable to that of cisplatin and etoposide, against several human cancer cell lines: A498 (renal), EVSA-T (breast), H226 (lung), IGROV (ovarian), M19 (melanoma-skin), MCF-7 (breast) and WiDr (colon). The structural studies reveal that neutral ligands (1-chloro-/dichloro-phenyl-3-benzoylthioureas) bind Cu(I) cations via the S atom and a distorted tetrahedral geometry is formed around metallic centers of mononuclear complexes. Yan et al. [12] report the biological activities of Cu(I), Ag(I) and Au(I) complexes with N,N′-disubstituted cyclic thiourea derivatives. They exert significant cytotoxicity to cancer cell lines: HeLa (cervical epithelioid), HepG2 (hepatocellular), SUNE1 (nasopharyngeal) and NCI-H460 (lung). Their potency is similar or higher than the reference drug – cisplatin, whereas the parent ligands are much less cytotoxic. For Ag(I) and Au(I) complexes the X-ray crystal structure analysis was performed showing the linear molecular geometry around metal ions with two monodentate S-donor thiourea ligands within the first coordination sphere.
Numerous therapeutic agents such as cisplatin and doxorubicin inhibit the growth of tumor cells by inducing apoptotic cell death. Apoptosis is a key process for controlling cell proliferation and maintaining tissue homeostasis in physiological and pathological conditions [13]. In cancer cells, changed regulation of apoptosis is observed resulting in the overgrowth of malignant cells [14].
It is also known that cancer cells expressed high level of Interleukin 6 (IL-6) in the tumor microenvironment. IL-6 contributes to the growth of tumor by inhibiting cancer cells apoptosis and the induction of angiogenesis of tumors such as colorectal, breast, melanoma, urinary bladder and prostate cancer in both paracrine and autocrine ways. IL-6 concentration can depend on the tumor stage and can correlate with patient survival [15].
In the present study, we have prepared nine Cu(II) complexes with (bromophenyl)thiourea system attached to the different cyclic imides as potent copper-based anticancer drugs. Their structural characterization has been performed based on elemental analysis, ATR-IR (Attenuated Total Reflection Infrared), XANES (X-ray Absorption Near Edge Structure), EXAFS (Extended X-ray Absorption Fine Structure) and UV–Vis spectroscopies as well as molecular modelling. The new complexes along with two well-known medicines: cisplatin and doxorubicin were evaluated for cytotoxic activity on the following cancer cell lines: SW480 (primary colon cancer), SW620 (metastatic colon cancer), PC3 (metastatic prostate cancer) and normal cell line - HaCaT as well as on apoptosis induction and interleukin-6 release.
Section snippets
Synthesis
The initial reagents were bought from Sigma-Aldrich. The parent ligands 1–9 were synthesized and characterized using the methods described elsewhere [16]. Next, the organic ligands (1 mmol) dissolved in a minimum amount of dimethylformamide (DMF) were mixed with copper(II) chloride (1 mmol). The reaction mixtures were kept under stirring at room temperature (approx. 23 °C) for 1 h. After the solvent had evaporated, the solids were collected, washed several times with distilled water and dried
Synthesis
The synthetic route for the preparation of copper complexes Cu1–Cu9 is shown in Fig. 1. The organic ligands 1–9 were synthesized using the methods described elsewhere [16].
In our work, the synthesis of new complexes was performed by reacting 1,3-disubstituted thioureas (1–9) with copper(II) chloride. The structural diversity of compounds was generated by choosing various substituent attached to the thiourea moiety, mainly three type of tricyclic imide's part (substituent R1) and p/o/m
Conclusions
The series of Cu(II) complexes have been synthesized by the reaction of the copper(II) chloride with thiourea derivatives. In each case the complexes have an overall neutral charge with two monoanionic ligands. The thioureas coordinate to the metal cation in bidentate fashion via deprotonated N and S atoms according to the ATR-IR and EXAFS spectroscopy. In such four-coordinate copper(II) complexes the metal cation is a part of two four-membered rings (Cu-S-C-N) which is quite unusual for that
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.
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