Book of Abstracts - Ruhr-Universität Bochum

P-25
R
OH
O
N
R = Ph : hydroxytamoxifen
R = Fc : hydroxyferrocifen
ISBOMC `10 5.7 – 9.7. 2010 Ruhr-Universität Bochum
On the Mechanism of Hydroxyferrocifen Cytotoxicity
Didier Hamels, a Patrick M. Dansette, b Elizabeth A. Hillard, a Siden Top, a Anne Vessières, a Gérard
Jaouen, a and Daniel Mansuy. b
a Chimie ParisTech, Laboratoire Charles Friedel, UMR 7223; 11, rue Pierre et Marie Curie
75231 Paris Cedex 05, France. b Université Paris Descartes, Laboratoire de Chimie et Biochimie
Pharmacologiques et Toxicologiques, UMR 8601; 45, rue des Saints Pères 75006 Paris, France.
E-mail : didier-hamels@chimie-paristech.fr
Breast cancer is one of the most common cancers of women in the Western World. When the estrogen
receptor (ER) is expressed in tumor cells, the breast cancer is categorized as hormone-dependent
(ER+). ER+ breast cancer is the most commonly diagnosed (2 out of 3 cases), and can be treated with
the help of selective estrogen receptor modulators (SERMs). Some SERMs act as ER antagonists in
the cancer cell, thus preventing cell division. Unfortunately, SERMs are not active against ER� breast
cancer cells, and alternative molecules have to be found.
Fe
Me
O
Me
A hydroxyferrocifen
derivative QM (QM-1)
In 1996, Jaouen et al. designed and synthesized “hydroxyferrocifen”,
a compound in which one of the phenyl groups of
hydroxytamoxifen had been replaced by a ferrocene moiety. 1
The original idea was to combine the antiestrogenic effect of
hydroxytamoxifen with the potentially cytotoxic effect of
ferrocene. Our expectations were rewarded by the discovery
that hydroxyferrocifen is indeed active against ER+ (MCF-7)
and ER� (MDA-MB-231) breast cancer cells. 2 When the side
chain was extended to three carbon atoms, the resulting Fc-OHTam[3] molecule was found to be even
more cytotoxic.
We thus decided to investigate the mechanism of action of the
hydroxyferrocifens and related molecules. We hypothesized that
their cytotoxicity is due to the in situ formation of highly
cytotoxic quinone methide (QM) species. This interpretation was
supported by electrochemical experiments 3 but neither
hydroxytamoxifen 4 nor hydroxyferrocifen QMs had ever been
isolated this far. Metabolic and chemical oxidation of Fc-
OHTam[3] and three related conjugated ferrocene phenols
allowed us to isolate and characterize the QMs by 1 H and 13 C
NMR spectroscopy, and by X-ray crystallography in one case.
The obtained QMs were then tested against ER� breast cancer
cells (MDA-MB231) and were found to be cytotoxic. 5 This strongly supports the hypothesis that QMs
are indeed relevant intermediates in the cytotoxicity of hydroxyferrocifens and related molecules
against breast cancer cells. We are currently investigating the reactivity of such QMs in order to identify
potential biological targets.
References
1. Top et al., Chem. Com. 1996, 955-956.
2. Top et al., Chem. Eur. J. 2003, 9, 5223-5236.
3. Hillard et al., Angew. Chem. Int. Ed. 2006, 45, 285-290.
4. Fan et al., Chem. Res. Toxicol. 2000, 13 (1), 45-52.
5. Hamels et al., Angew. Chem. Int. Ed. 2009, 48, 9124-9126.
83
QM-1 X-ray crystal structure