Abstract
A series of new platinum(II) bis-amidine derivatives were prepared by addition of primary and secondary aliphatic amines to coordinated nitrile ligands in cis- and trans-[PtCl2(NCR)2] (R=Me, Ph, CH2Ph). The bis-amidine complexes were tested for their in vitro cytotoxicity on a panel of various human cancer cell lines. The results indicated that the trans isomers are more effective than the cis species, and in particular the benzamidine complex trans-[PtCl2{E-N(H)=C(NMe2) Ph}2] was the most active derivative and was able to circumvent acquired cisplatin resistance, thus suggesting a different mechanism of action compared to that exhibited by cisplatin. New benzyliminoether derivatives cis- and trans-[PtCl2{E-N(H)=C(OMe)CH2Ph}2] were also prepared by addition of MeOH to cis- and trans-[PtCl2(NCCH2Ph)2] and the cytotoxic properties were evaluated in terms of cell growth inhibition against a panel of different types of human cancer cell lines. The complex cis-[PtCl2{E-N(H)=C(OMe)CH2Ph}2] was significantly more potent than cisplatin against all tumour cell lines, including cisplatin-resistant ones. Moreover, the in vivo studies, performed on two transplantable tumour models, showed that cis-[PtCl2{E-N(H)=C(OMe)CH2Ph}2] exhibited a marked activity against murine L1210 leukaemia and Lewis lung carcinoma in terms of survival prolongation and tumour growth inhibition, respectively.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Michelin RA, Mozzon M, Bertani R. Reactions of transition metal-coordinated nitriles. Chem. Rev 1996;147:299–338.
Kukushkin VY, Pombeiro AJL. Additions to metal-activated organonitriles. Chem. Rev 2002;102:1771–802.
Fannizzi FP, Intini FP, Natile G. Nucleophilic attack of methanol on bis(benzonitrile)dichloroplatinum: Formation of mono- and bis-imido ester derivatives. J. Chem. Soc. Dalton Trans. 1989;5:947–51.
Cini R, Caputo P A, Intini FP, Natile G. Mechanistic and stereochemical investigation of imino ethers formed by alcoholysis of coordinated nitriles: X-ray crystal structures of cis- and trans-bis(1-imino-1-methoxyethane)dichloroplatinum(II). Inorg. Chem. 1995;34:1130–7.
Bertani R, Catanese D, Michelin RA, Mozzon M, Bandoli G, Dolmella A. Reactions of platinum(II)-nitrile complexes with amines. Synthesis, characterization and X-ray structure of the platinum(II)-amidine complex trans-[PtCl2{Z-N(H)=C(NHMe)Me}2]. Inorg. Chem. Commun. 2000;3:16–18.
Michelin RA, Bertani R, Mozzon M, et al. Cis addition of dimethylamine to the coordinated nitriles of cis- and trans-[PtCl2(NCMe)2]. X-ray structure of the amidine complex cis-[PtCl2{E-N(H)=C(NMe2)Me}2]CH2Cl2. Inorg. Chem. Commun. 2001;4:275–80.
Belluco U, Benetollo F, Bertani R, et al. Stereochemical investigation of the addition of primary and secondary aliphatic amines to the nitrile complexes cis- and trans-[PtCl2(NCMe)2]. X-ray structure of the amidine complexes trans-[Pt(NH2Pri)2{Z-N(H)=C(NHPria,)Me}2]Cl24H2O and trans-[PtCl2(NCMe){E-N(H)=C(NMeBut)Me}]. Inorg. Chim. Acta 2002;330:229–39.
Belluco U, Benetollo F, Bertani R, et al. Addition reactions of primary and secondary aliphatic amines to the benzonitrile ligands in cis- and trans-[PtCl2(NCPh)2] complexes. X-ray structure of the amidine complex trans-[PtCl2{Z-N(H)=C(NHBut)Ph}2]. Inorg. Chim. Acta 2002;334:437–47.
Mazzega Sbovata S, Bettio F, Mozzon M, et al. Cisplatin and transplatin complexes with benzyliminoether ligands: Synthesis, characterization, structure-activity relationship, and in vitro and in vivo antitumor efficacy. J. Med. Chem. 2007;50:4775–84
Mazzega Sbovata S, Bettio F, Marzano C, et al. Synthesis, characterization and cytotoxic activity of substituted benzyl iminoether Pt(II) complexes of the type cis- and trans-[PtCl2{E-N(H)= C(OMe)CH2-p-C6H4-R}2] (X=Me, OMe, F). X ray structure of trans-[PtCl2{E-N(H)=C(OMe) CH2-p-C6H4-F}2]. J. Inorg. Biochem. 2008;102:882–91.
Marzano C, Mazzega Sbovata S, Bettio F, et al. Solution behaviour and biological activity of bisamidine complexes of platinum(II). J. Biol. Inorg. Chem. 2007;12:477–93.
Mazzega Sbovata S, Bettio F, Marzano C, et al. Benzylamidine complexes of platinum(II) derived by nucleophilic addition of primary and secondary amines. X ray crystal structure of trans-[PtCl{Z-N(H)=C(NHMe)CH2Ph}2]. Inorg. Chim. Acta 2008;361:3109–16.
Coluccia M, Natile G. Trans-platinum complexes in cancer therapy. Anti-cancer Agents Med. Chem. 2007;7:111–3.
Perego P, Camerini C, Gatti L, et al. A novel trinuclear platinum complex overcomes cisplatin resistance in an osteosarcoma cell system. Mol. Pharmacol. 1999;55:528–34.
Khazanow E, Barenholz Y, Gibson D, Najajreh Y. Novel apoptosis-inducing trans-platinum piperidine derivatives: Synthesis and biological characterization. J. Med. Chem. 2002;45:5196–204.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2009 Springer Science+Business Media, LLC
About this chapter
Cite this chapter
Bertani, R., Sbovata, S.M., Gandin, V., Michelin, R.A., Marzano, C. (2009). Synthesis of Cisplatin Analogues: Cytotoxic Efficacy and Anti-tumour Activity of Bis-Amidine and Bis-Iminoether Pt(II) Complexes. In: Bonetti, A., Leone, R., Muggia, F.M., Howell, S.B. (eds) Platinum and Other Heavy Metal Compounds in Cancer Chemotherapy. Cancer Drug Discovery and Development. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60327-459-3_7
Download citation
DOI: https://doi.org/10.1007/978-1-60327-459-3_7
Publisher Name: Humana Press, Totowa, NJ
Print ISBN: 978-1-60327-458-6
Online ISBN: 978-1-60327-459-3
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)