Tamoxifen derivatives for delivery of the antitumoral (DACH)Pt group: selective synthesis by McMurry coupling, and biochemical behaviour.

Abstract

The goal of our study was to potentiate the effects of the ((R,R)-trans-1,2-diaminocyclohexane)-platinum(II) fragment [(DACH)Pt], known for its cytotoxic properties, either with tamoxifen (Tam), the most widely used antiestrogen in the treatment of hormone-dependent breast cancers, or with its active metabolite hydroxytamoxifen (hydroxy-Tam). We coupled Tam or hydroxy-Tam derivatives bearing a malonato group at the para position of the beta aromatic ring with the (DACH)Pt fragment. The malonato-Tam and malonato-hydroxy-Tam compounds were prepared through McMurry coupling of the appropriate ketones. The presence of the malonate group resulted in a pronounced stereospecificity in the reaction, since malonato-Tam was obtained only as the Z isomer, while malonato-hydroxy-Tam was obtained as an 80/20 E/Z mixture. Attribution of the isomeric structures was achieved by 2D NMR spectroscopy. The platinum complexes (DACH)Pt-malonato-Tam and (DACH)Pt-malonato-hydroxy-Tam were then prepared by coupling the barium salts derived from the malonato-Tam and malonato-hydroxy-Tam with the nitrate derived from (DACH)PtCl(2). Study of the biochemical properties of these two platinum complexes showed that, while the hydroxy-Tam complex is satisfactorily recognized by the estrogen receptor (relative binding affinity, RBA=6.4 %), the Tam complex is less well recognized (RBA=0.5 %). The effects of these complexes on two hormone-dependent breast cancer cell lines (MCF7 and MVLN) were studied in vitro. Both complexes showed an antiproliferative effect on MCF7 cells, and an antiestrogenic effect on MVLN cells. The observed effects appear to be essentially antihormonal, since incorporation of the (DACH)Pt fragment into the tamoxifen skeleton did not cause an increase in the cytotoxicity of the complexes.

• Authors: Siden Top, El Bachir Kaloun, Anne Vessières, Guy Leclercq, Ioanna Laïos, Michèle Ourevitch, Christine Deuschel, Michael J McGlinchey, Gérard Jaouen
• Journal: Chembiochem : a European journal of chemical biology (Chembiochem) Vol. 4 Issue 8 Pg. 754-61 (Aug 04 2003) ISSN: 1439-4227 [Print] Germany
• PMID: 12898627 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents, Hormonal
• Organoplatinum Compounds
• Receptors, Estrogen
• Tamoxifen
• dichloro-1,2-diaminocyclohexane platinum complex

Topics

• Antineoplastic Agents, Hormonal (chemical synthesis, pharmacology)
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Cell Division (drug effects)
• Female
• Humans
• Organoplatinum Compounds (chemical synthesis, pharmacology)
• Receptors, Estrogen (metabolism)
• Tamoxifen (chemical synthesis, pharmacology)
• Tumor Cells, Cultured