Ferrocene Tamoxifen Derivatives Ferrodfens

In this series, the p-phenyl ring of hydroxytamoxifen was substituted by a ferrocenyl to give complexes 31a-e, also called ferrodfens. The synthesis of these complexes employs McMurry coupling reactions [81-85] identical to those described for rhenium. The complexes are obtained in the form of a mixture of the isomers Z+E), which can be separated by HPLC. However, since these complexes rapidly isomerize in solution, most of the biological studies were performed on mixtures of the two isomers. 

The complexes with the shortest dimethyl amino side chains (n = 2,3,4) retain the best affinity for the two forms of the estrogen receptor (RBA for ERa respectively 14.6,11.5,12). Substitution of a phenyl by a more lipophilic ferrocenyl, followed by an increase in the number of CH2 links in the side chain, produces as expected a corresponding progressive increase in the lipophilic value of the complexes compared to hydroxytamoxifen (log Pq tj, = 3.8 for (2)-31a and 6.0 for (Z)-31e). On MCF7 hormone-dependent breast cancer cells, the antiproliferative effect of these complexes at molarities of 1 iM is a little stronger than that of OH-Tam for complexes where n = 3 and 5 (31b and 31d) (Fig. 3.3) and this effect is not entirely suppressed by addition of estradiol. This seems to indicate that the 

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). 

Here again, ferrocene alone is not toxic. In addition, it has been shown that derivatives of estradiol bearing a ferrocenyl substituent in position 17a, 32 and 33 have an estrogenic effect in vitro, and are devoid of any cytotoxic effect either on hormone-dependent or hormone-independent ceUs [71]. Simply delivering an estrogenic molecule bearing a ferrocenyl substituent payload into the interior of a target cell is not sufficient to obtain a cytotoxic effect. The production of this effect seems to be linked to a spedfic structure that allows the ferrocenyl - double bond - phenol pattern to come into play. 

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 

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