Research

Our group is currently working on three different but complementary topics, namely Inorganic Chemical Biology, Medicinal Inorganic Chemistry and Medicinal Organometallic Chemistry. All projects undertaken in our group involve the preparation, characterisation and utilisation of metal complexes for biological or medicinal purposes. Our single objective is to understand, identify and/or influence biological processes in living cells using metal-based compounds. Our research therefore lies at the interface between inorganic chemistry, medicinal chemistry, chemical biology and biology. As a consequence, our group hosts not only chemistry students but also a biology student who jointly works between the Institute of Inorganic Chemistry and the Institute for Molecular Cancer Research at the University of Zurich.

The following topics are at the forefront of our current work:

1)
Development of new techniques to fight cancer
2) Development of novel metal-based anticancer drug candidates
3) Development of novel organometallic-based antiparasitic drug candidates

1) Development of new techniques to fight cancer
After surgery, chemotherapy is currently the frontline method to treat cancer. Although this technique is in many cases very successful, the patients undergoing such treatments often suffer from the severe side-effects associated with the intake of anticancer drugs which usually lack specificity. In other words, the drugs are killing both cancer and healthy cells. In this regard, Photodynamic Therapy (PDT) is a very interesting alternative to chemotherapy.1, 2 This medical technique typically results in fewer side-effects as the toxic singlet oxygen which destroys the cancer cells is produced only in the regions were the medical doctor has applied a light source (Figure 1). Nonetheless, the photosensitisers currently on the market have still important drawbacks which include, for example, a lack of selective uptake in cancer cells.

In
this research project, we are aiming to develop a novel method to overcome the current limitations of PDT.

Figure 1. Surgeons' hands in an operating room with a "beam of light" travelling along fibre optics for PDT.

2) Development of novel metal-based anticancer drug candidates

Cisplatin and its derivatives are used in more than 50% of the treatment regimes for patients suffering from cancer.3 Despite their high potency and tremendous success, however, these platinum compounds have three main disadvantages: they are inefficient against platinum-resistant tumours, they are non-specific and they often have severe side effects such as nephrotoxicity. As such, alternative metal-based drugs are still desperately sought. Among the potential metal complex candidates, ruthenium complexes have emerged as one of the leading players in this field.2-4

In this research project, novel Ru(II) complexes are synthesized, characterized and their cytotoxicity investigated. Furthermore, the mechanism of action of these compounds is studied in depth using biochemical/molecular biological techniques as can be seen in Figure 2 with fluorescence co-localisation studies of one of our Ru(II) complexes.


Figure 2. Fluorescence co-localisation studies of a cytotoxic Ruthenium complex.


3) Development of novel organometallic-based antiparasitic drug candidates

Over the recent years, organometallic compounds have shown enormous potential in medicinal chemistry and chemical biology.4-6 An interesting concept in these fields has been the replacement of an organic part (e.g. phenyl ring) of an existing drug by an organometallic complex (e.g. ferrocene). This idea has been pioneered by the group of Gérard Jaouen in Paris by manipulating the organic anticancer drug Tamoxifen to produce the so-called Ferrocifens (Figure 3).7 The most successful example utilising this concept is undoubtedly the antimalarial drug candidate Ferroquine (Figure 3).8, 9 Ferroquine is a ferrocenyl analogue of the antimalarial drug Chloroquine which completed clinical trial phase IIb in 2011. For both Ferrocifen and Ferroquine, the addition of a metal complex has allowed metal-specific modes of action to be uncovered, which has enabled resistance to be overcome and/or the bioactivity of the organic drug to be enhanced.

In this project, we are currently using a similar concept for antiparasitical purposes.

Figure 3. Structures of Tamoxifen, Ferrocifen, Chloroquine and Ferroquine.


References

1.
Dolmans, D. E. J. G. J.; Fukumura, D.; Jain, R. K. Photodynamic Therapy for Cancer. Nat. Rev. Cancer 2003, 3, 380–387.
2.
Dougherty, T. J.; Gomer, C. J.; Henderson, B. W.; Jori, G.; Kessel, D.; Korbelik, M.; Moan, J.; Peng, Q. Photodynamic Therapy. J. Nat. Cancer Inst. 1998, 90, 889–905.
3.
Lippert, B. Cisplatin, Chemistry and Biochemistry of a Leading Anticancer Drug. Verlag Helvetica Chimica Acta: Zürich, 1999.
4.
Patra, M.; Gasser, G. Organometallic Compounds, an Opportunity for Chemical Biology. ChemBioChem 2012, 13, 1232 – 1252.
5.
Gasser, G.; Ott, I.; Metzler-Nolte, N. Organometallic Anticancer Compounds. J. Med. Chem. 2011, 54, 3-25, and references therein.
6.
Gasser, G.; Metzler-Nolte, N. The Potential of Organometallic Complexes in Medicinal Chemistry. Curr. Opin. Chem. Biol. 2012, 16, 84-91.
7.
Hillard, E. A.; Vessières, A.; Jaouen, G. Ferrocene Functionalized Endocrine Modulators as Anticancer Agents. In Medicinal Organometallic Chemistry, Jaouen, G.; Metzler-Nolte, N., Eds. Springer-Verlag: Heidelberg, 2010; Vol. 32, pp 81-117.
8.
Biot, C.; Castro, W.; Botte, C. Y.; Navarro, M. The therapeutic potential of metal-based antimalarial agents: Implications for the mechanism of action. Dalton Trans. 2012, 41, 6335-6349.
9.
Biot, C.; Dive, D. Bioorganometallic Chemistry and Malaria. In Medicinal Organometallic Chemistry, Jaouen, G.; Metzler-Nolte, N., Eds. Springer-Verlag: Heidelberg, 2010; Vol. 32, pp 155-193.

Mise à jour le Jeudi, 21 Juin 2012 07:30