Elsevier

Polyhedron

Volume 210, 1 December 2021, 115477
Polyhedron

Mononuclear π-complexes of Pd(II) and Pt(II) with 1-allyl-3-(2-hydroxyethyl)thiourea: Synthesis, structure, molecular docking, DNA binding ability and genotoxic activity

https://doi.org/10.1016/j.poly.2021.115477Get rights and content

Highlights

  • Five novel π-complexes [M(HL)X2] (M = Pd2+, Pt2+; X = Cl, Br, I) have been obtained by the reactions of [MCl4]2− with 1-allyl-3-(2-hydroxyethyl)thiourea (HL) in the presence of HCl and/or KBr/KI.

  • The structures of all π-complexes were established by an X-ray diffraction study and characterized by IR, UV–Vis, 1H NMR spectra.

  • The cyclization of the organic ligand under the synthesis conditions for the iodide Pd(II) π-complexes was revealed.

  • Molecular docking, DNA binding ability and genotoxic activity studies of the complexes were performed.

Abstract

Five π-complexes [M(HL)X2] (M = Pd2+, Pt2+; X  = Cl, Br, I) have been obtained by the reactions of [MCl4]2− with 1-allyl-3-(2-hydroxyethyl)thiourea (HL) in the presence of HCl and/or KBr/KI. (Br/I)-Containing chelated π-type complexes of this type are presented for the first time. A comprehensive structural and spectral characterization has revealed an identical atomic arrangement, with the Cl- and Br-bearing phases adopting the same triclinic structure (space group P), while [Pt(HL)I2] crystallizes in the monoclinic P21/n space group. The molecules of HL are coordinated in a bidentate manner with the formation of six-membered chelate metallocycles. The diagonal arrangement of “soft-hard” donor atoms (S–X, C–X) in the coordination sphere leads to Pearson's effect of “molecular antisymbiosis in the trans effect” that causes the interaction of M:L in a ratio of 1:1. The similarity of the structures of the synthesized complexes with that of cisplatin implies the same mechanism for their antitumor action, whilst different halide anions in the coordination sphere of the metal affects the cytotoxic activity of the complexes. Among the new cisplatin analogues, two of the platinum π-complexes are promising compounds, the action of which slows or completely stops cell division, causes a decrease in nucleus size and increases the proportion of heterochromatin in the structure of interphase nuclei, thus reducing the activity of transcriptional processes. A molecular docking study showed that the general mechanism of action for the complexes can be characterized by the formation of single and double-stranded breaks of DNA plasmid. The presence of the OH-group has a positive impact on the “ligand – DNA binding”.

Introduction

The discovery of the antitumor activity of cis-diamminedichloroplatinum(II), also known as cisplatin (CisPt), in the 1960s stimulated a significant increase in attention to complex compounds of transition and platinum metals as potential antitumor agents. A large number of metal-coordination complexes have been designed, synthesized and tested in order to develop clinically effective anticancer drugs [1], [2], [3]. Despite this, the synthesis of novel Pd(II) and Pt(II) compounds remains relevant today, as evidenced by numerous publications over the past 5 years [4], [5], [6], [7], [8]. Coordination compounds exhibit high pharmacological activity and relative stability in physiological media due to the reduced hydrolysis processes compared to the starting metal salts [9], [10].

Over the last few decades, the use of biologically active organic compounds as ligands has become a promising approach for the design of new potential drugs, including antitumor agents, mostly because of the possible additive and/or synergistic effects occurring between the constituent parts of the complexes. This allows them to act on a wider range of specific molecular targets, which is beneficial for the development of novel antitumoral agents [6], [7], [8], [11], [12].

Numerous bioactive complexing agents have been used as ligands for the target synthesis of metal-based compounds for potential cancer treatments. Among these reagents, thiourea derivatives, which are known as effective antitumor agents, should be noted [13], [14], [15], [16]. The thiourea scaffold contains two nucleophilic reaction centers, the sulfur and nitrogen atoms of the carbothioamide group, which are capable of forming donor–acceptor bonds with many metal ions. Inclusion of various substituents into the thiourea ligands increases their chelating capacity and leads to the formation of stable complexes of interest for medicinal chemistry [17]. Biomedical studies have proved that complex compounds of thiourea derivatives with metal ions, such as Pt(II) [18], [19], [20], Pd(II) [21], [22], [23], Ru(II) [24], [25], Ir(II) [26], Cu(I) [27] and Co(III) [28], exhibit high antitumor activity.

The coordination of metal ions to the thiourea sulfur atom prevents their interaction with methionine and cysteine groups of intracellular sulfur-containing proteins, which leads to a decrease in toxicity of the complexes [29], [30]. Complexes modified with the thiourea moiety are less active, possibly due to the decreased rate of binding to the nucleobase nitrogen of DNA, but exhibit effectiveness at overcoming the resistance of tumor cells to metallopharmaceuticals [31], [32], [33].

Organometallic complex compounds of the platinum group metals (PGMs) have been found to be effective DNA intercalators. The formation of π-coordinate C-metal bonds with the π-electronic systems of aromatic scaffolds or the Cdouble bondC linkage of alkenes facilitates the penetration of the complexes through cell membranes, increases their stability in biological environments, reduces toxicity, and enhances selectivity against tumor cells, to make them promising antiproliferative and antimetastatic potential drugs [34], [35], [36], [37], [38], [39]. In previous studies we have synthesized four n,π-chelate complexes of Pd(II) and Pt(II) ions with N-allylthiourea derivatives and their cytotoxic, cytostatic and proapoptotic activities have been determined in vitro on the HeLa cell line and compared with cisplatin (CisPt) as an etalon drug [40]. All the compounds possessed pronounced cytotoxic activity with IC50 indexes in range 2 × 10−6–1.5 × 10−4 M (IC50 of CisPt is 5.7 × 10−5 M) and showed proapoptotic, cytostatic and antiproliferative influence higher or comparable with CisPt. In addition, they showed a high affinity to DNA, which correlates with the observed cytostatic and proapoptotic levels, with the Pd(II) complexes being more active than the Pt(II) ones. Next, we investigated the formation of the same π-complexes in solutions and their cytostatic and antiproliferative effects on meristem cells of Allium cepa (a test object widely used to evaluate the genetic potential of chemical compounds) [41]. Also, changes in spheroidal growth parameters, adhesive properties and gamma-glutamine transpeptidase activity in the model system of multicellular microspheroids of breast adenocarcinoma MCF-7 were studied under the influence of the Pt(II) and Pd(II) n,π-complexes [42]. Compared to CisPt, the test compounds reduced the activity of gamma-glutamine transpeptidase, increased the adhesive properties and inhibited the growth of multicellular spheroids in the model system. This indicated the feasibility of further research for potential analogues of anticancer drugs that do not cause resistance and reduce the level of metastasis in breast cancer [42].

In continuation of our previous research efforts, herein we report the synthesis, spectral data, molecular structures, DNA binding ability, cyto- and genotoxicity (Allium cepa test) of novel Pd(II) and Pt(II) π-complexes with 1-allyl-3-(2-hydroxyethyl)thiourea. In contrast to the previous studies, we changed the coordination environment of the square-planar coordination unit, extending the nature of halogens from chlorides to iodide anions. Although compounds of Pd(II) and Pt(II) ions containing of bromide and iodide anions in the coordination sphere are known, the chelated π-complexes containing these halogens are presented for the first time in this work. The main goal of our study was to theoretically substantiate the possibility of binding the synthesized compounds to DNA and to determine the possible influence of the nature of halide anions located in cis-positions in the coordination sphere of the square-planar polyhedron of the Pd(II) and Pt(II) n,π-chelate complexes on their cytotoxic activity.

Section snippets

Materials and methods

The initial reagents (PdCl2 and K2[PtCl4]) and solvents (ethanol, hydrochloric acid and diethyl ether) used in this work were of synthetic grade and used as purchased without further purification. Elemental analyses for carbon, hydrogen, nitrogen and sulfur were performed with a Carlo Erba Elemental Analyzer (Model 1106). The chlorine was measured by the Schoniger method. 1H NMR spectra were measured on a Bruker Avance DRX-400 spectrometer (400.00 MHz) in DMSO‑d6 solution using

Synthesis and characterization of the Pd(II)/Pt(II) π-complexes

The synthesis of the Pd(II) and Pt(II) π-coordination compounds was performed according to Scheme 1. The interaction of 1-allyl-3-(2-hydroxyethyl)thiourea (HL) with the complex ions [PdCl4]2− and [PtCl4]2− at an M:L ratio of 1:1 and 1:2 leads to the formation of π-complexes I and II. According to the effect of “antisymbiosis in the trans-influence” (Pearson [59]), the formation of coordination bonds with “soft” sulfur atoms in the trans-position to the allyl moiety is less advantageous, as we

Conclusion

Five novel mononuclear π-coordination complexes of Pd(II) and Pt(II) ions with the general formula [M(HL)X2] (M = Pd2+, Pt2+; X  = Cl, Br, I; HL = 1-allyl-3-(2-hydroxyethyl)thiourea) have been synthesized, structurally characterized and tested for the applicability of further biological studies. The allyl substituted thiourea molecules in all the complexes are coordinated in a bidentate manner via the sulfur atom of the thiourea group and the Cdouble bondC double bond of the allyl moiety with formation

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.

Acknowledgment

The publication contains the results of studies performed with the financial support of two Grants NAS of Ukraine (Projects 31/21-H and 52/21-H). The authors are grateful to Dr. Hlib Repich for early experimental work, to Mr. Olgerd Shtokvysh (IGIC NAS of Ukraine) for the assistance with the X-ray experiment, to Mr. Adam Balvanz (UD) for proof-reading the manuscript and to Dr. Glenn Yap (UD) for the helpful discussion.

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    • Synthesis, structural and spectral characteristics of novel n,π-chelate complexes of Pd(II) and Pt(II) with N-allylthioureas and their influence on the growth of spheroids cells MCF-7 and GGT activity

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      Citation Excerpt :

      At the same time, our previous studies showed that N-allyl-substituted thioureas form a π-bond under conditions when other donor atoms are in an unfavorable position for the formation of a chelate metallocycle. Otherwise, the «soft» Lewis acids will be coordinated to other donor centers [45–47]. Therefore, in the N,N-diethyl-N'-(2-propenyl)thiourea (HL1) and N-cyclohexyl-N'-(2-propenyl)thiourea (HL2) used in this work, the spatial arrangement of the N,S-nucleophilic centers to the allylic moiety is also favorable for the formation of the n,π-chelate metallocycle.

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