Organometallic SERMs (selective estrogen receptor modulators): Cobaltifens, the (cyclobutadiene)cobalt analogues of hydroxytamoxifen Kirill Nikitin a , Yannick Ortin a , Helge Müller-Bunz a , Marie-Aude Plamont b , Gérard Jaouen b , Anne Vessières b, * , Michael J. McGlinchey a, * a School of Chemistry and Chemical Biology, University College Dublin, Belfield,Dublin 4,Ireland b Laboratoire Charles Friedel, UMR CNRS 7223, Ecole Nationale Supérieure de Chimie de Paris, 11 rue Pierre et Marie Curie, F-75231 Paris Cedex 05, France a r t i c l e i n f o Article history: Received 7 September 2009 Received in revised form 21 October 2009 Accepted 3 November 2009 Available online 10 November 2009 Keywords: Bioorganometallic chemistry Cobalt Breast cancer Tamoxifen SERM a b s t r a c t The McMurry coupling of (tetraphenylcyclobutadiene)cobalt(cyclopentadienyl) ketones, (C 4 Ph 4 )Co- [C 5 H 4 C(@O)R], where R = Me, 3a, or Et, 3b, with a range of substituted benzophenones furnished a serie of cobaltifens, organometallic analogues of tamoxifen whereby a phenyl ring has been replaced by an or ano-cobalt sandwich moiety. These systems of the general formula ( g 4 -C 4 Ph 4 )Co[ g 5 -C 5 H 4 C(R)@C(Ar)Ar 0 ], where R = Me or Et, and Ar = Ar 0 = p-C 6 H 4 X where X is OH, 2a and 2b, OMe, 2c and 2d, OBn, 2e and 2f, or O(CH 2 ) 2 NMe 2 , 12a and 12b,and where Ar = C 6 H 4 OH and Ar 0 = C 6 H 4 O(CH 2 ) 2 NMe 2 , 2g and 2h,have been characterised by NMR spectroscopy and/or X-ray crystallography. The effect of 2a and 2b, 2g and 2h, and 12a and 12b on the growth of MCF-7 (hormone-dependent) and MDA-MB-231 (hormone-indepen- dent breast cancer cells) was studied. The dihydroxycobaltifens 2a and 2b exhibit a strong estrogenic effect on MCF-7 cells while the aminoalkyl-hydroxycobaltifens, 2g and 2h, were found to be only slightly cytotoxic on MDA-MB-231 cells (IC 50 = 27.5 and 17 l M); surprisingly, however, the bis-(dimethylamino- ethoxy)cobaltifens, 12a and 12b were shown to be highly cytotoxic towards both cell lines (IC 50 = 3.8 and 2.5l M). Ó 2009 Elsevier B.V. All rights reserved. 1. Introduction In the continuing battle against breast cancer, tamoxifen remains a vital component in the physician’s armoury. However, approximately 40% of tumours are resistant to this drug, and mod- ifications of the molecule that involve the incorporation of organo- metallic substituents are attracting considerable attention.Of course,metallo-drugs such as cis-platin and its successors are in wide clinical use, but biologically-active systems in which the me- tal is directly linked to a carbon atom – bio-organometallics – have been intensively studied only in recent years [1]. Early work fo- cussed on the synthesis of organometallic derivatives of estradiol [2], alkynyl-estradiols [3] and related steroidalframeworks [4], and was concerned primarily with the development of the metal- carbonyl-immuno-assay technique that uses infrared spectroscopy and electrochemical techniques rather than radiochemical meth- ods [5]. However,since that time,the focus has moved more towards the development of therapeutic agents, and the current status of organometallic SERMs has been reviewed recently [6]. Thus, tamoxifen-type systems containing such metals as titanium and manganese [7], iron [8],rhenium [9],ruthenium [10],or platinum [11] have been reported.At present,the most promising candi- dates are the ferrocifens [8] in which a b-phenyl ring in tamoxifen has been replaced by a ferrocenyl moiety (Chart 1). The antiprolif- erative effect of the ferrocifens matches the efficacy of tamoxifen on hormone-dependent breast cancer cells (MCF7), but they show an additional strong cytotoxicity on hormone-independent (MDA- MB-231) breast cancer cells. Currently, the ferrocifens, 1, in particular the hydroxyferrocifen, 1b, are the most well-studied and potentially most biologically via- ble metal-containing analogues of tamoxifen [6,12].It has been suggested that the strong antiproliferative effect of the hydroxyfer- rocifens is based on their facile oxidation to the ferrocinium ion [13], and the consequent generation of hydroxyl radicals which are known to be very genotoxic. However,the mode of action of the ferrocifens has yet to be fully elucidated. We here describe the syntheses, structural characterisation and preliminary biologicalactivity of the first cobaltifens, 2, whereby the b-phenyl ring in tamoxifen has been replaced by a (tetraphe- nylcyclobutadiene)cobalt(cyclopentadienyl) group, an organo-co- balt sandwich unit capable of ready multiple functionalisation allowing exquisite tuning of its electronic character, redox proper- ties and steric parameters [14]. 0022-328X/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.jorganchem.2009.11.003 * Corresponding authors. Tel.: +353 1 716 2880; fax: +353 1 716 1178 (M.J. McGlinchey). E-mail address: michael.mcglinchey@ucd.ie (M.J. McGlinchey). Journal of Organometallic Chemistry 695 (2010) 595–608 Contents lists available at ScienceDirect Journal of Organometallic Chemistry j o u r n a l homepage: w w w . e l s e v i e r . c o m / l o c a t e / j o r g a n c h e m