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 novel photosensitizers for Photodynamic Therapy (PDT)
2) Development of new light-based techniques to fight cancer.
3) Development of novel metal-based anticancer drug candidates
4) Development of novel organometallic-based antiparasitic drug candidates
5) Development of novel chelators for 89Zr

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 photosensitizers currently on the market have still important drawbacks which include, for example, a lack of selective uptake in cancer cells.

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

In this research project, we are aiming to develop new photosensitizers for PDT based on Ru(II) polypyridyl complexes.3-6 An example of a Ru(II) complex developed in our labs is presented in Figure 2. This complex was found to have an impressive phototoxic index (PI) of 150. One of our aims is also to render those complexes more selective to cancer cells.

Figure 2. Structure of Ru(II) polypyridyl complex used as a PDT agent.5
Very importantly, we recently described the use of similar complexes to kill bacteria.6 This is of high interest due to the emergence of bacterial resistance.
2) Development of novel light-based techniques to fight cancer
One of the drawbacks of PDT is its reliance on triplet oxygen (3O2) to produce the toxic singlet oxygen (1O2). This is a serious drawback since tumours are hypoxic (i.e. they lack oxygen). In this research project, we aim to develop a concept which relies only on the combination of light and a chemical to induce cell death. This concept is often referred as photoactivated phototherapy (PACT). Unlike PDT, in PACT, the presence of oxygen is not required. With this in mind, we recently developed “caged cytotoxic metal complexes”.7-10 As shown in Scheme 1, a cytotoxic Ru(II) polypyridyl complex developed in our labs11 could be release upon photo-irradiation. Importantly, as anticipated, the caged metal complex was found to be not cytotoxic.

Scheme 1. The cytotoxic Ru(II) complex is released upon light irradiation.
3) Development of novel metal-based anticancer drug candidates

Cisplatin and its derivatives are used in more than 50% of the treatments for patients suffering from cancer.12 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.12-15 Two complexes (i.e. NAMI-A and KP1039) are currently in clinical trial and another one (i.e. RAPTA-C) in clinical evaluation.
In this research project, novel Ru(II) complexes are synthesized, characterized and their biological activity investigated. Furthermore, the mechanism of action of these compounds is studied in depth using biochemical/molecular biological techniques as can be seen in Figure 3 with fluorescence co-localization studies of one of our Ru(II) complexes.
Figure 3. Fluorescence co-localisation studies of a cytotoxic Ruthenium complex.

More specifically, we could recently unveil a lead compound (Figure 4).11,16 In collaboration with Dr. Stefano Ferrari from the Institute of Molecular Cancer Research and Prof. Caroline Maake from the Institute of Anatomy of the University of Zurich, we are currently investigating in-depth its mechanism of action.

Figure 4. Structure of a cytotoxic Ru(II) complex developed in our labs.11
4) Development of novel organometallic-based antiparasitic drug candidates

Over the recent years, organometallic compounds have shown enormous potential in medicinal chemistry and chemical biology.12,17,18 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 5).19 The most successful example utilising this concept is undoubtedly the antimalarial drug candidate Ferroquine (Figure 5).20 Ferroquine is a ferrocenyl analogue of the antimalarial drug Chloroquine which is currently undergoing phase IIb clinical trial. 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.

Figure 5. Structures of Tamoxifen, Ferrocifen, Chloroquine and Ferroquine.

In this research project, we are currently using a similar concept to fight schistosomiasis. Schistosomiasis is the second most prevalent parasitic disease in the world after malaria. At the moment, schistosomiasis is treated with the organic drug Praziquantel (PZQ, Figure 6). However, PZQ has several drawbacks (i.e. low metabolic stability, inactivity against juvenile worms, etc.). But more worryingly, a decrease in activity has been observed in certain regions of the globe suggesting that PZQ could become (much less) effective in the future.21-24. Over the recent years, in collaborations with Prof. Jennifer Keiser from the Swiss Tropical and Public Health Institute in Basel, we have screened several organometallic compounds as novel antischistosomal drug candidates.25-28 Of high interest, two chromium tricarbonyl complexes were found to have a sub-nanomolar activity against S. mansoni worms (Figure 6).

Figure 6. Structures of Praziquantel (PZQ) and of two chromium tricarbonyl complexes of PZQ.
5) Development of novel chelators for 89Zr

The radionuclide Zirconium-89 (89Zr) is an emerging new metallic radionuclide with promising characteristics for application in high resolution PET (positron emission tomography) diagnosis in the field of nuclear medicine.29 The physical half-life of 89Zr (t½ = 78.4 h) matches well the biological half-life of antibodies (Abs) and thus, their combination in immuno-PET agents shows great promise because optimal tumour to non-tumour ratios important for imaging at late time points can be achieved. Several preclinical studies and clinical trials have demonstrated the potential of 89Zr-based radiopharmaceuticals, in particular 89Zr-labeled Abs. A major limitation of the use of 89Zr for immuno-PET imaging is the lack of appropriate methods for the stable chelation of the 89Zr radionuclide. To date, the 89Zr labelling of Abs is obtained exclusively through derivatives of desferrioxamine (DFO). The use of DFO as a chelator is very attractive since it has been safely used in the clinic for many years for the treatment of acute iron poisoning. However, the production of 89Zr-DFO coupled antibodies is quite challenging and there is evidence that some 89Zr is released from the chelator in vivo and taken up in the bones of mice. The potential release of radioactive 89Zr in vivo and accumulation in radiation sensitive bones is a safety concern and the search for better chelators for zirconium is therefore highly desirable. In collaboration with the group of Prof. Thomas Mindt, we have recently described a highly stable octadentate chelator (DFO*.30 As can be seen in Figure 7, DFO* allows for an octadentate coordination of 89Zr.30

Figure 7. DFT optimized structure of Zr-DFO* with the terminal primary amine protonated (atom colour coding: white = carbon; blue = nitrogen; red = oxygen; magenta = zirconium).30
References
[1] Dolmans, D. E. J. G. J.; Fukumura, D.; Jain, R. K. Nat. Rev. Cancer 2003, 3, 380.
[2] Dougherty, T. J.; Gomer, C. J.; Henderson, B. W.; Jori, G.; Kessel, D.; Korbelik, M.; Moan, J.; Peng, Q. J. Nat. Cancer Inst. 1998, 90, 889.
[3] Mari, C.; Gasser , G. Chimia 2015, 69, 176.
[4] Mari, C.; Pierroz, V.; Ferrari, S.; Gasser , G. Chem. Sci. 2015, DOI: 10.1039/C4SC03759F and  references therein.
[5] Mari, C.; Pierroz, V.; Rubbiani, R.; Patra, M.; Hess, J.; Spingler, B.; Oehninger, L.; Schur, J.; Ott, I.; Salassa, L.; Ferrari, S.; Gasser , G. Chem. Eur. J. 2014, 44, 14421.
[6] Frei, A.; Rubbiani, R.; Tubafard, S.; Blacque, O.; Anstaett, P.; Felgenträger, A.; Maisch, T.; Spiccia, L.; Gasser , G. J. Med. Chem. 2014, 57, 7280
[7] Mari, C.; Pierroz, V.; Leonidova, A.; Ferrari, S.; Gasser , G. Eur. J. Inorg. Chem. 2015, DOI: 10.1002/ejic.201500602.
[8] Leonidova, A.; Pierroz, V.; Rubbiani, R.; Lan, Y.; Schmitz, A. G.; Kaech, A.; Sigel, R. K. O.; Ferrari, S.; Gasser, G. Chem. Sci. 2014, 5, 4044.
[9] Joshi, T.; Pierroz, V.; Mari, C.; Gemperle, L.; Ferrari, S.; Gasser, G. Angew. Chem. Int. Ed. 2014, 53, 2960.
[10] Joshi, T.; Gasser , G. Synlett 2015, 26, 275.
[11] Pierroz, V.; Joshi, T.; Leonidova, A.; Mari, C.; Schur, J.; Ott, I.; Spiccia, L.; Ferrari, S.; Gasser, G. J. Am. Chem. Soc. 2012, 134, 20376.
[12] Gasser, G.; Ott, I.; Metzler-Nolte, N. J. Med. Chem. 2011, 54, 3.
[13] Süss-Fink, G. Dalton Trans. 2010, 39, 1673.
[14] Hartinger, C. G.; Zorbas-Seifried, S.; Jakupec, M. A.; Kynast, B.; Zorbas, H.; Keppler, B. K. J. Inorg. Biochem. 2006, 100, 891.
[15] Bratsos, I.; Jedner, S.; Gianferrara, T.; Alessio, E. Chimia 2007, 61, 692.
[16] Joshi, T.; Pierroz, V.; Ferrari, S.; Gasser , G. ChemMedChem 2014, 9, 1419.
[17] Gasser, G.; Metzler-Nolte, N. Curr. Opin. Chem. Biol. 2012, 16, 84.
[18] Patra, M.; Gasser, G. ChemBioChem 2012, 13, 1232.
[19] Hillard, E. A.; Vessières, A.; Jaouen, G. In Medicinal Organometallic Chemistry; Jaouen, G., Metzler-Nolte, N., Eds.; Springer-Verlag: Heidelberg, 2010; Vol. 32, p 81.
[20] Biot, C.; Dive, D. In Medicinal Organometallic Chemistry; Jaouen, G., Metzler-Nolte, N., Eds.; Springer-Verlag: Heidelberg, 2010; Vol. 32, p 155.
[21] Gasser , G. Chimia 2015, accepted.
[22] Ismail, M.; Botros, S.; Metwally, A.; William, S.; Farghally, A.; Tao, L. F.; Day, T. A.; Bennett, J. L. Am. J. Trop. Med. Hyg. 1999, 60, 932.
[23] Melman, S. D.; Steinauer, M. L.; Cunningham, C.; Kubatko, L. S.; Mwangi, I. N.; Wynn, N. B.; Mutuku, M. W.; Karanja, D. M. S.; Colley, D. G.; Black, C. L.; Secor, W. E.; Mkoji, G. M.; Loker, E. S. PLoS Negl. Trop. Dis. 2009, 3, e504.
[24] Greenberg, R. M. Parasitology 2013, 140, 1534.
[25] Hess, J.; Keiser, J.; Gasser , G. Future. Med. Chem. 2015, 8, 821.
[26] Patra, M.; Ingram, K.; Leonidova, A.; Pierroz, V.; Ferrari, S.; Robertson, M.; Todd, M. H.; Keiser, J.; Gasser, G. J. Med. Chem. 2013, 56, 9192.
[27] Patra, M.; Ingram, K.; Pierroz, V.; Ferrari, S.; Spingler, B.; Gasser, R. B.; Keiser, J.; Gasser, G. Chem. Eur. J. 2013, 19, 2232.
[28] Patra, M.; Ingram, K.; Pierroz, V.; Ferrari, S.; Spingler, B.; Keiser, J.; Gasser, G. J. Med. Chem. 2012, 55, 8790.
[29] Deri, M. A.; Zeglis, B. M.; Francesconi, L. C.; Lewis, J. S. Nucl. Med. Biol. 2013, 40, 3.
[30] Patra, M.; Baumann, A.; Mari, C.; Fischer, C. A.; Blacque, O.; Häussinger, D.; Gasser, G.; Mindt, T. L. Chem. Commun. 2014, 50, 11523.

Mise à jour le Vendredi, 17 Juillet 2015 11:56