Book of Abstracts - Ruhr-Universität Bochum

P-44
ISBOMC `10 5.7 – 9.7. 2010 Ruhr-Universität Bochum
Ferrocenyl Flavonoids: A Novel Class of Cytotoxics
Jean-Philippe Monserrat, a Elizabeth A. Hillard, a and Gérard Jaouen *a
a Organometallic Medicinal Chemistry Team, UMR 7223, Laboratoire Charles Friedel
11, rue Pierre et Marie Curie
75231 Paris Cedex 05
Occupying the second step of the mortality podium in the western countries, cancer has become one of
the most widely studied diseases in the world, and one of the most challenging targets for scientists. In
order to combat the common problem of drug resistance, we have decided to approach the problem via
the redox machinery of the cell. It is now accepted that elevated levels of cellular oxidative stress and
dependence on ROS-signaling for mitosis and apoptosis represent a specific vulnerability of cancer
cells that can be targeted by redox modulators. 1
Ferrocene is an organometallic complex that possesses a stable and reversible redox couple, and
possesses many attractive qualities for use in medicinal chemistry. Ferrocene-tamoxifen derivatives, in
particular, are known to be highly toxic against cancer cells via a redox mechanism. 2
Fe
O
OH
hydroxyferrocifen
N
102
O
OH O
quercetin
Flavonoids are a large class of natural products, some of which are active against cancer and are
thought to act, at least partially, via a redox mechanism. For instance, quercetin, in the process of
scavenging free radicals, can be converted to four quinone forms (QQ), which can form adducts with
glutathione, thus disturbing the redox balance of the cell. 3 Other polyphenols specifically act as
prooxidants in oxidizing environments. 4 Because some cancer cells are under oxidative stress, these
properties could be useful in the design of selective cancer agents. 5,6 By the introduction of ferrocene,
we hope to modulate the flavonoids’ redox properties and enhance their antiproliferative effects.
We have recently discovered a novel reaction which gives easy access to the first reported ferrocenyl
flavones. Preliminary results show that the antiproliferative effects of ferrocene flavones against the
highly aggressive B16 mouse melanoma cell line are considerably stronger than those of organic
flavones, with IC50 values in the low micromolar range. The synthesis and biological results of this
original class of molecules will be presented.
References
1. G. T. Wondrak, Antiox. Redox. Sign. 2009, 11, 3013-3069.
2. E. A. Hillard, A. Vessières, L. Thouin, G. Jaouen and C. Amatore, Angew. Chem. Int. Ed. 2006,
45, 285-290.
3. W. Boots, H. Li, R. P. F. Schins, R. Duffin, J. W. M. Heemskerk, A. Bast and G. R. M. M.
Haenen, Toxicol. App.Pharmacol. 2007, 222, 89-96.
4. Simić, D. Manojlović, D. Šegan and M. Todorović, Molecules, 2007, 12, 2327.
5. H. Pelicano, D. Carney and P. Huang, Drug Resist. Update 2004, 7, 97-110.
6. Hoffman, L. M. Spetner and M. Burke, J. Theor. Biol. 2001, 211, 403-407.
HO
OH
OH
OH