Ferrocifen

The application of organometallic complexes of the other group 8 elements, iron and osmium, in anticancer drug design has until recently been almost exclusively focused on iron, with the ferrocenyl derivative of tamoxifen (ferrocifen) being the most prominent example (104). Organometallic osmium compounds have been little explored in this respect. 

Ferrocenyl ligands, via zinc reagents, 9, 120 Ferrocenylmethyl phosphonium salts, with gold(I), 2, 274 Ferrocenylmonophosphine, in styrene asymmetric hydrosilylation, 10, 817 Ferrocenyl oxazolines, synthesis, 6, 202 Ferrocenylphosphines with chromium carbonyls, 5, 219 in 1,3-diene asymmetric hydrosilylation, 10, 824-826 preparation, 6, 197 various complexes, 6, 201 Ferrocenylselenolates, preparation, 6, 188 Ferrocenyl-substituted anthracenes, preparation, 6, 189 Ferrocenyl terpyridyl compounds, phenyl-spaced, preparation 6, 188 Ferrocifens... 

Depending on the presence or absence of the oestrogen receptor in the cells, breast cancer is often treated by endocrine therapy (tamoxifen) or chemotherapy, respectively. Organometallic derivatives of hydroxytamoxifen (e.g. ferrocifen, 16, and its... 

Nguyen A, Vessieres A, Hillard EA, Top S, Pigeon P, Jaouen G (2007) Ferrocifens and ferrocifenols as new potential weapons against breast cancer. Chimia 61 716-724... 

Top S, Dauer B, Vaissermann J, Jaouen G (1997) Facile route to ferrocifen, 1-[4-(2-dimethy-laminoethoxy)]-l(phenyl-2-ferrocenyl-but-l-ene), first organometallic analogue of tamoxifen, by the McMurry reaction. J Organomet Chem 541 355-361... 

Top S, Vessieres A, Cabestaing C, Laios I, Leclercq G, Provot C, Jaouen G (2001) Studies on organometallic selective receptor modulators (SERMs). Dual activity in the hydroxy ferrocifen series. J Organomet Chem 637 500-506... 

Hillard EA, Vessieres A, Thouin L, Jaouen G, Amatore C (2006) Ferrocene-mediated proton-coupled electron transfer in a series of ferrocifen-type breast cancer drug candidates. Angew Chem Int Ed Engl 45 285-290... 

Michard Q, Jaouen G, Vessieres A, Bernard BA (2008) Evaluation of cytotoxic properties of organometallic ferrocifens on melanocytes, primary and metastatic melanoma cell lines. J Inorg Biochem 102 1980-1985... 

Zanellato I, Heldt J-M, Vessieres A, Jaouen G, Osella D (2009) Antiproliferative effect of ferrocifen drug candidates on malignant pleural mesothelioma cell lines. Inorg Chim Acta 362 4037 1042... 

Buriez O, Labbe E, Pigeon P, Jaouen G, Amatore C (2008) Electrochemical attachment of a conjugated amino-ferrocifen complex onto carbon and metal surfaces. J Electroanal Chem... 

The /3-phenyl ring of OH-Tam has also been substituted by a ferrocenyl group to give complexes 3a-e, called ferrocifens (see Figure 2). The synthesis of these complexes employs McMurry coupling reactions, similar to... 

The design concept for the anticancer-active ferrocifen mentioned above is replacement of a phenyl ring by a ferrocene substituent. The very same principle has previously been applied to a number of antimicrobial agents. The first ferrocene derivatives of penicillins and cephalosporins have been synthesized by Edwards and co-workers. Eurther derivatives were later investigated. Unlike the anti-malarials discussed below, there has been no real... 

Chapter 2, by G. Jaouen et al, underlines the renewed interest in research on organometallic steroids and their ability to bind with specific receptors, where they can also act as inhibitors as, for example, in the case of the estrogen receptor. But this is a vast area, whether in terms of radiopharmaceuticals or the topic of SERMs (selective estrogen receptor modulators), for example, as demonstrated by the ferrocifens. This research may prove to be of social benefit in addressing the problems caused by endocrine disrupters, where the organometallic component is still evolving. 

As shown in the case of the ferrocifens or the antimalarial drug candidate ferro-quine (Chapter 5), the additional activities gained with organometallic compounds can be used to circumvent resistances of piu-ely organic enzyme inhibitors, or even establish an inhibitory activity. 

Scheme 1.9 The antiestrogen tamoxifen 16, its active metabolite hydroxy tamoxifen 17 and hydroxy ferrocifens 18.

Fig. 3.3 Antiproliferative effect off pM of OH-tamoxifen (HO-Tam), ferrocene (Fc), ferrocifens 31a (n = 2), 31b (n = 3), 31d ( = 5) and 31 e (n = 8) in the absence or presence of 10 nM of 17p-estradiol (E2) on hormone dependent breast cancer cells (MCF7 cells with a high level of ERa) after five days of culture (adapted from [85]).

The novel feature of ferrocifens lies in the strong cytotoxic effect observed on M DA-M B231 cells, which are hormone-independent breast cancer cells (Fig. 3.4). In these cells without ERa, OH-tamoxifen has no effect, while ferrocifens 31b and 31d have a remarkable antiproliferative effect (ICjq = 0.5 (iM). 

The mechanism of action of ferrocifens in the cell has not yet been elucidated. However, molecular modeling studies have revealed that ferrocifens such as (Z)-31b may be inserted into the antagonist configuration of the active site of the estrogen receptor (Fig. 3.5 left). The interior of the active site is of sufEcient size to accommodate the ferrocenyl group, which is bulkier than a phenyl (respective volumes of (Z)-31b and OH-Tam are 572 A and 413 A), and interactions between... 

In order to examine the hypothesis of a mechanism of action for the ferrocifens based on oxidation of the iron, their equivalents in the ruthenium series, the ruthenocifens 34a-d were prepared (Scheme 3.14) [93]. In fact, ruthenium s position in group 8 just below iron would suggest that the corresponding complexes would be more easily oxidized and thus would have an increased antiproliferative effect relative to the ferrocifens. These complexes were prepared, like those of iron and rhenium, via McMurry coupling. 

---