Original articleSeven-membered cycloplatinated complexes as a new family of anticancer agents. X-ray characterization and preliminary biological studies
Graphical abstract
Highlights
► Seven-membered cyclometallated Pt(II) compounds as a new class of potential anticancer drugs. ► Non-planar arrangement of these compounds deduced from molecular structures. ► Remarkable antiproliferative activity in the human lung carcinoma, breast and colon cancer cell lines. ► These compounds modify the DNA tertiary structure, in a similar way than cisplatin.
Introduction
Since the discovery by Rosenberg that cis-[PtCl2(NH3)2] (cisplatin) inhibits cell division [1] the search for new and effective chemotherapeutic agents with anticancer properties has led to tremendous activity. Over the last three decades thousands of Pt-containing compounds have been designed and tested [2], [3] but just a few of them have entered clinical use (carboplatin, oxaliplatin and nedaplatin) or are in clinical trials [4]. Despite the therapeutic benefit of the approved platinum drug, the efficacy of the treatments is still limited due to side effects [5], [6] and intrinsic and acquired resistances [7].
Recent advances in the knowledge of how cisplatin induces its antitumor effects and how tumours are or become resistant [8], [9], [10], have contributed to a renewed interest [11] in the development of a cisplatin based therapy safer to patients, providing oral bioavailability and able to overcome drug resistance. It is believed that DNA is the main target of platinum drug and that cisplatin and its analogues form an intrastrand d(GpG) adduct with platinum cross-linking N7 atoms of neighbour guanine residues of DNA [8], [9], [12]. It has been also shown that carrier amine ligands of cisplatin analogues appear to modulate the antitumor properties of this class of drugs [2]. There are many possible roles for the carrier ligand of the platinum anticancer compounds, such as affect pharmacokinetics, rates and type of DNA adduct formation, influence on the recognition of damaged DNA by repair enzymes or regulatory/binding proteins [13]. Subsequently, cis- and trans-[Pt(L)2Cl2] complexes have been prepared with a wide variety of ligands, where L = pyridine and picoline derivatives [14], [15], pyrazole [16], [17], benzimidazole [18], purine derivatives [19], [20] and many others. On the other hand, cyclometalating N-donor ligands may offer an alternative approach to give structures quite different from that of cisplatin and analogs with the possibility that those could interact in a different way with DNA, and consequently show a different spectrum of activity and toxicity profile.
Cyclometallated compounds containing not only Pd(II) and Pt(II), but also Ru(II), Ir(III), Rh(III) and Au(III), have revealed promising anticancerous activities [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32]. It is noteworthy that the presence of a metal-carbon σ-bond appears to increase the stability of the complexes, and therefore the cyclometallated complexes would be more likely to reach their biological target intact [33]. The cytotoxicities of several platinum compounds containing bidentate [C,N] cyclometallated ligands such as 2-(dimethylaminomethyl)phenyl [34], 2-phenylpyridine, 2-phenylpyrazole, and analogues [35], [36], [37], [38], [39] or terdentate [C,N,N] ligands such as 6-phenyl-2,2′-bipyridine [40], [41] have been studied. In all reported cases, the platinacycle is a planar five-membered ring.
We have been involved recently in the synthesis of a novel class of seven-membered platinacycles [42], [43] and the lack of information on the biological activity of these compounds prompted us to undertake the present study. On the other hand it has been reported for chelated diamines that 1,4-butanediamine complex (seven-membered rings) show greater antiproliferative activity than 1,2-ethanediamine complex (five-membered rings) and 1,3-propanediamine complex (six-membered rings) [44], [45], [46], in front of L1210 cell line. Hence we want to compare the behaviour of the seven-membered platinacycles investigated in this study with the five-membered cyclometallated complexes previously reported [33], [34], [35], [36], [37], [38], [39], [40], [41].
Compound 1a (Scheme 1) containing a terdentate [C,N,N′] cyclometallated ligand and a seven-membered platinacycle has been prepared from the reaction of ligand 2,6-Cl2C6H3CHNCH2CH2NMe2 (a) and cis-[Pt(4-C6H4Me)2(μ-SEt2)]2 [43].Compounds 2a and 2b (Scheme 1) have been previously prepared from the reactions of cis-[Pt(C6H5)2(SMe2)2] with imines 2,6-Cl2C6H3CHNCH2CH2NMe2 (a) and 2-ClC6H4CHNCH2CH2NMe2 (b), respectively [42]. Preliminary biological studies suggested a high activity for the synthesized seven-membered platinacycles and therefore, the synthesis of new compounds 1b, 1c and 2c (Scheme 1) was envisaged and it was undertaken in this study. In all cases our strategy has been the use of terdentate, cyclometallated ligands to form stable seven-membered cycloplatinated complexes. The square planar coordination around the platinum of compounds 1 (1a–1c) and 2 (2a–2c) contains always a strong platinum-carbon σ bond cis to a non-labile imine function and two mutually cis labile positions, the chloro ligand and the amine fragment. Platinacycles 1 (1a–1c) and 2 (2a–2c) differ from one another in the nature of the substituents R1 (H, F, Cl), and R2 (H, CH3) in order to evaluate how the modifications in the physico-chemical properties of the molecules (hydrophobicity, steric hindrance or binding capabilities [47]), provided by the substituents, influence the antiproliferative activity of these complexes. The cytotoxicity effectiveness of complexes 1 (1a–1c) and 2 (2a–2c) was evaluated in A549 lung, MDA MB231 breast and HCT116 colon human cancer cell lines. To gain insight into the action mechanism of the investigated complexes, studies of electrophoretic shift DNA-migration, cell cycle arrest and apoptosis were performed.
Section snippets
Synthesis and characterization of compounds 1b, 1c and 2c
Following the previously reported procedures for compounds 1a, 2a and 2b [41], [42], the reactions of cis-[Pt(4-C6H4Me)2(μ-SEt2)]2 with ligands2-ClC6H4CHNCH2CH2NMe2 (b), and 2-Cl,6-FC6H3CHNCH2CH2NMe2 (c) were carried out in toluene under reflux for 4 h and produced respectively compounds [PtCl{(MeC6H3)(C6H4CHNCH2CH2NMe2}] (1b) and [PtCl{(MeC6H3)(FC6H3CHNCH2CH2NMe2}] (1c) (Scheme 1). An analogous reaction carried out using cis-[Pt(C6H5)2(SMe2)2] and imine c produced compound [PtCl{(C6H4)(FC6H3
Conclusions
Six cyclometallated platinum(II) compounds containing a novel framework have been tested as a new class of antitumour drugs. Complexes 1b, 1c and 2c were synthesized in this work and characterized by spectral and elemental analysis. The molecular structures of the compounds 1b and 1c confirmed by X-ray analysis indicated a non-planar arrangement for both the seven-membered metallacycle and the five-membered chelate ring. Cytotoxicity studies revealed the high effectiveness of compounds 1 (1a–1c
Chemistry
General. Microanalyses were performed at the Serveis Cientifico-Tècnics (Universitat de Barcelona). Electrospray mass spectra were performed at the Servei d’Espectrometria de Masses (Universitat de Barcelona) in an LC/MSD-TOF spectrometer using H2O–CH3CN 1:1 to introduce the sample. NMR spectra were performed at the Unitat de RMN d’Alt Camp de la Universitat de Barcelona using a Mercury-400 (1H, 400 MHz; 19F, 376.5 MHz) spectrometer, and referenced to SiMe4 (1H) and CFCl3 (19F). δ values are
Acknowledgments
This work was supported by the Ministerio de Ciencia y Tecnología (projects CTQ2009-11501 and CTQ2009-07021/BQU) and the AGAUR, Generalitat de Catalunya (Grants 2009-SGR-1111, 2009SGR01308, 2006ITT-10007 and 2009CTP-00026). This study was also supported by the project SAF2011-25726 and by RD06/0020/0046 from Red Temática de Investigación Cooperativa en Cáncer (RTICC), Instituto de Salud Carlos III, both funded by the Ministerio de Ciencia e Innovación-Spanish government and European Regional
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