Original article
Seven-membered cycloplatinated complexes as a new family of anticancer agents. X-ray characterization and preliminary biological studies

https://doi.org/10.1016/j.ejmech.2012.06.002Get rights and content

Abstract

A series of seven-membered cyclometallated Pt(II) complexes containing a terdentate [C,N,N′] ligand (1a–1c and 2a–2c) have been developed as potential monofunctional DNA binding agents. By reactions of cis-[Pt(4-C6H4Me)2(μ-SEt2)]2 or cis-[Pt(C6H5)2(SMe2)2] with imines 2-ClC6H4CHdouble bondNCH2CH2NMe2 (b) or 2-F,6-ClC6H3CHdouble bondNCH2CH2NMe2 (c) the new compounds 1b, 1c and 2c were synthesized and characterized. Complex 1b and 1c were further characterized by X-ray crystallography. The cytotoxicity assessment of the seven-membered platinacycles 1 (1a–1c) and 2 (2a–2c) against a panel of human cancer cell lines (A549 lung, HCT116 colon, and MDA MB231 breast adenocarcinomas) revealed that the six cycloplatinated complexes exhibit a remarkable antiproliferative activity, even greater than cisplatin in the three human cancer cell lines. From a pharmacological point of view, platinacycles 1 (1a–1c) and 2 (2a–2c) may represent compounds for a new class of antitumor drugs. Electrophoretic DNA migration studies showed that all of them modify the DNA tertiary structure. Induction of S-G2/M arrest and apoptosis were also observed for one of the representative compounds (1c) of the series.

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-Cl2C6H3CHdouble bondNCH2CH2NMe2 (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-Cl2C6H3CHdouble bondNCH2CH2NMe2 (a) and 2-ClC6H4CHdouble bondNCH2CH2NMe2 (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-ClC6H4CHdouble bondNCH2CH2NMe2 (b), and 2-Cl,6-FC6H3CHdouble bondNCH2CH2NMe2 (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

References (66)

  • I.M. El-Mehasseb et al.

    Platinum (II) complex with cyclometalating 2-phenylpyridine ligand showing high cytotoxicity against cisplatin-resistant cell

    J. Inorg. Biochem.

    (2001)
  • J. Ruiz et al.

    Novel C, N-chelate platinum(II) antitumor complexes bearing a lipophilic ethisterone pendant

    J. Inorg. Biochem.

    (2011)
  • H. Samouei et al.

    A cyclometalated diplatinum complex containing 1,1′-bis(diphenylphosphino)ferrocene as spacer ligand: antitumor study

    J. Organomet. Chem.

    (2011)
  • J.M. Pérez et al.

    Apoptosis induction and inhibition of H-ras overexpression by novel trans-[PtCl2(isopropylamine)(amine’)] complexes

    J. Inorg. Biochem.

    (1999)
  • S. Moradell et al.

    Platinum complexes of diaminocarboxylic acids and their ethyl ester derivatives: the effect of the chelate ring size on antitumor activity and interactions with GMP and DNA

    J. Inorg. Biochem.

    (2003)
  • B.E. Smart

    Fluorine substituent effects (on bioactivity)

    J. Fluorine Chem.

    (2001)
  • M. Malumbres et al.

    Is Cyclin D1-CDK4 kinase a bona fide cancer target?

    Cancer Cell

    (2006)
  • F.J. Ramos-Lima et al.

    The role of p53 in the cellular toxicity by active trans-platinum complexes containing isopropylamine and hydroxymethylpyridine

    Eur. J. Med. Chem.

    (2010)
  • A.K. Hammill et al.

    Annexin V staining due to loss of membrane asymmetry can be reversible and precede commitment to apoptotic death

    Exp. Cell Res.

    (1999)
  • D. Song et al.

    Structures of Pt2(CH3)4(S(CH3)2)2 and [PtPh2(S(CH3)2)]n (n=2,3)

    J. Organomet. Chem.

    (2002)
  • T. Mosmann

    Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays

    J. Immunol. Methods

    (1983)
  • B. Rosenberg et al.

    Inhibition of cell division in Escherichia coli by electrolysis products from a platinum electrode

    Nature

    (1965)
  • Á.M. Montaña et al.

    The rational design of anticancer platinum complexes: the importance of the structure-activity relationship

    Curr. Med. Chem.

    (2009)
  • E. Wong et al.

    Current status of platinum-based anticancer drugs

    Chem. Rev.

    (1999)
  • N.J. Wheate et al.

    The status of platinum anticancer drugs in the clinic and in clinical trials

    Dalton Trans.

    (2010)
  • R.Y. Tsang et al.

    Cisplatin overdose: toxicities and management

    Drug Safety

    (2009)
  • M.J. Sullivan

    Hepatoblastoma, cisplatin, and ototoxicity: good news on deaf ears

    Cancer

    (2009)
  • D. Wang et al.

    Cellular processing of platinum anticancer drugs

    Nat. Rev. Drug Discov.

    (2005)
  • D. Gibson

    The mechanism of action of platinum anticancer agents - What do we really know about it?

    Dalton Trans.

    (2009)
  • L. Kelland

    The resurgence of platinum-based cancer chemotherapy

    Nat. Rev. Cancer

    (2007)
  • Y. Jung et al.

    Direct cellular responses to platinum-induced DNA damage

    Chem. Rev.

    (2007)
  • J.T. Reardon et al.

    Efficient nucleotide excision repair of cisplatin, oxaliplatin, and bis- acetoammine-dichloro-cyclohexylamine-platinum(IV) (JM216) platinum intrastrand DNA diadducts

    Cancer Res.

    (1999)
  • Y. Chen et al.

    Stereospecific and kinetic control over the hydrolysis of a sterically hindered platinum picoline anticancer complex

    Chem. Eur. J.

    (1998)
  • Cited by (0)

    View full text