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Caged Metal Complexes as Tools in Inorganic Chemical Biology

English title Caged Metal Complexes as Tools in Inorganic Chemical Biology
Applicant Gasser Gilles
Number 157545
Funding scheme SNSF Professorships
Research institution Institut für Chemie Universität Zürich
Institution of higher education University of Zurich - ZH
Main discipline Inorganic Chemistry
Start/End 01.03.2015 - 28.02.2017
Approved amount 690'978.00
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All Disciplines (2)

Discipline
Inorganic Chemistry
Biochemistry

Keywords (7)

Medicinal Inorganic Chemistry; Enzyme Inhibitors; Inorganic Chemical Biology; Metal Complexes; Bioorganometallic Chemistry; Photo-release; Caged Compounds

Lay Summary (French)

Lead
Le but cette prolongation de ma bourse de professeur boursier est d'explorer le potentil du concept développé durant ces trois premières années en utilisant la technique de "two-photon excitation" au lieu de la "one-photon excitation" pour libérer des inhibiteurs d'enzyme contenant un métal dans des cellules vivantes. De manière plus spécifique, des unités de reconnaissances cellulaires (par exemple bombesin, herceptin) seront couplées à des groupes protecteurs "two-photon" en utilisant différentes techniques de ligation (par exemple des couplages peptidique, des additions de Michael, etc.) auxquels des des inhibiteurs d'enzyme contenant un métal (par exemple histone deacetylase, COX-2, kinase) seront attachés. Une "prodrug" sera ainsi formée. Par application de lumière, l'inhibiteur d'enzyme sera libéré et sera capable de réducire l'activié de l'enzyme and ainsi induire une mort cellulaire.
Lay summary
In this grant extension application, I propose to further extend the scope of the concept developed during the first three years of my SNSF professorship by notably using the two-photon excitation technique instead of one-photon excitation to release specific (metal-based) enzyme inhibitors in living cells. More specifically, specific cellular recognition units (e.g. bombesin, herceptin) will be coupled to two-photon protecting groups (TPPGs) using different ligation techniques (e.g. peptide coupling, Michael addition, etc.) to which known (metal-based) enzyme inhibitors (e.g. histone deacetylase, COX-2, kinase) will be attached. A “prodrug” will hence be formed. Upon light activation, the enzyme inhibitor will be liberated and will therefore be able to turn down the activity of the enzyme (and hence induce cell death).
Direct link to Lay Summary Last update: 13.08.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
Biological Evaluation of Ru(II) Polypyridyl Complexes as Photosensitizers in Photodynamic Therapy
Mari C., Rubbiani R., Gasser G. (2017), Biological Evaluation of Ru(II) Polypyridyl Complexes as Photosensitizers in Photodynamic Therapy, in Inorg. Chim. Acta, 454C, 21-26.
Comparison of the octadentate bifunctional chelator DFO*-pPhe-NCS and the clinically used hexadentate bifunctional chelator DFO-pPhe-NCS for 89Zr-immuno-PET
Vugts Danielle J., Klaver Chris, Sewing Claudia, Poot Alex J., Adamzek Kevin, Huegli Seraina, Mari Cristina, Visser Gerard W. M., Valverde Ibai E., Gasser Gilles, Mindt Thomas L., van Dongen Guus A. M. S. (2017), Comparison of the octadentate bifunctional chelator DFO*-pPhe-NCS and the clinically used hexadentate bifunctional chelator DFO-pPhe-NCS for 89Zr-immuno-PET, in Eur. J. Nucl. Med. Mol. Imag., 44, 286-295.
Multi-Stimuli Responsive Block Copolymers as Smart Release Platform for a Polypyridyl Ruthenium Complexes
Appold M., Mari C., Lederle C., Elbert J., Schmidt C., Ott I., Stühn B., Gasser G., Gallei M. (2017), Multi-Stimuli Responsive Block Copolymers as Smart Release Platform for a Polypyridyl Ruthenium Complexes, in Polym. Chem., 8, 890-900.
A Disassembly Strategy for Imaging Endogenous Pyrophosphate in Mitochondria by Using an FeIII–salen Complex
Kumari Namita, Huang Huaiyi, Chao Hui, Gasser Gilles, Zelder Felix (2016), A Disassembly Strategy for Imaging Endogenous Pyrophosphate in Mitochondria by Using an FeIII–salen Complex, in ChemBioChem, 17, 1211-1215.
Assessment of the nematocidal activity of metallocenyl analogues of monepantel
Hess Jeannine, Patra Malay, Jabbar Abdul, Pierroz Vanessa, Konatschnig Sandro, Spingler Bernhard, Ferrari Stefano, Gasser Robin B., Gasser Gilles (2016), Assessment of the nematocidal activity of metallocenyl analogues of monepantel, in Dalton Trans., 45, 17662-17671.
Bimodal X-ray and Infrared Imaging of an Organometallic Derivative of Praziquantel in Schistosoma mansoni
Clède S., Cowan N., Lambert F., Bertrand H.C., Rubbiani R., Patra M., Hess J., Sandt C., Trcera N., Gasser G., Keiser J., Policar C. (2016), Bimodal X-ray and Infrared Imaging of an Organometallic Derivative of Praziquantel in Schistosoma mansoni, in ChemBioChem, 17, 1004-1007.
Cellular Uptake and Photo-Cytotoxicity of a Gadolinium(III)-DOTA-Naphthalimide Complex “Clicked” to a Lipidated Tat Peptide
O’Malley W.I., Rubbiani R., Aulsebrook M.L., Grace M.R., Spiccia L., Tuck K.L., Gasser G., Graham B. (2016), Cellular Uptake and Photo-Cytotoxicity of a Gadolinium(III)-DOTA-Naphthalimide Complex “Clicked” to a Lipidated Tat Peptide, in Molecules, 21, 194-194.
Dual Mode of Cell Death upon the Photo-Irradiation of a RuII polypyridyl Complex in Interphase and Mitosis
Pierroz V., Rubbiani R., Gentili C., Patra M., Mari C., Gasser G., Ferrari S. (2016), Dual Mode of Cell Death upon the Photo-Irradiation of a RuII polypyridyl Complex in Interphase and Mitosis, in Chem. Sci., 7, 6115-6124.
Insertion of Organometallic Moieties into Peptides and Peptide Nucleic Acids using Alternative “Click” Strategies
Mari C., Mosberger S., Llorente N., Spreckelmeyer S., Gasser G. (2016), Insertion of Organometallic Moieties into Peptides and Peptide Nucleic Acids using Alternative “Click” Strategies, in Inorg. Chem. Frontiers, 3, 397-405.
Luminescent Alkyne-Bearing Terbium(III) Complexes and their Application to Bioorthogonal Protein and Peptide Labeling
O’Malley W.I., Abdelkader E.H., Aulsebrook M.L., Rubbiani R., Loh C.-T., Grace M.R., Spiccia L., Gasser G., Otting G., Tuck K.L., Graham B. (2016), Luminescent Alkyne-Bearing Terbium(III) Complexes and their Application to Bioorthogonal Protein and Peptide Labeling, in Inorg. Chem., 55, 1674-1682.
New insights into the pretargeting approach to image and treat tumours
Patra Malay, Zarschler Kristof, Pietzsch Hans-Jurgen, Stephan Holger, Gasser Gilles (2016), New insights into the pretargeting approach to image and treat tumours, in Chem. Soc. Rev., 45, 6415-6431.
N-Heterocyclic Carbene-Polyethyleneimine (PEI) Platinum Complexes show in vitro and in vivo Antitumor Efficacy
Chekkat N., Dahm G., Chardon E., Sitz J., Decossas M., Lambert O., Frisch B., Rubbiani R., Gasser G., Guichard G., Fournel S., Bellemin-Laponnaz S. (2016), N-Heterocyclic Carbene-Polyethyleneimine (PEI) Platinum Complexes show in vitro and in vivo Antitumor Efficacy, in Bioconjugate Chem., 27, 1942-1948.
Organometallic Derivatization of the Nematocidal Drug Monepantel Leads to Promising Antiparasitic Drug Candidates
Hess Jeannine, Patra Malay, Rangasamy Loganathan, Konatschnig Sandro, Blacque Olivier, Jabbar Abdul, Mac Patrick, Jorgensen Erik M., Gasser Robin B., Gasser Gilles (2016), Organometallic Derivatization of the Nematocidal Drug Monepantel Leads to Promising Antiparasitic Drug Candidates, in Chem. Eur. J., 22, 16602-16612.
Organometallic Rhenium Complexes Divert Doxorubicin to the Mitochondria
Imstepf S., Pierroz V., Rubbiani R., Felber M., Fox T., Gasser G., Alberto R. (2016), Organometallic Rhenium Complexes Divert Doxorubicin to the Mitochondria, in Angew. Chem. Int. Ed., 55, 2792-2795.
Synthesis of New Tumor Targeting Photosensitizers for Photodynamic Therapy and Imagining Applications
Mion G., Mari C., Da Ros T., Rubbiani R., Gasser G., Gianferrara T. (2016), Synthesis of New Tumor Targeting Photosensitizers for Photodynamic Therapy and Imagining Applications, in ChemistrySelect, 2, 190-200.
Synthesis, Characterization and Biological Activity of Ferrocenyl Analogues of the Anthelmintic Drug Monepantel
Hess J., Patra M., Pierroz V., Spingler B., Jabbar A., Ferrari S., Gasser R.B., Gasser G. (2016), Synthesis, Characterization and Biological Activity of Ferrocenyl Analogues of the Anthelmintic Drug Monepantel, in Organometallics, 35, 3369-3377.
Synthesis, Characterization and Biological Evaluation of novel Ru(II) Arene Complexes containing intercalating Ligands
Nikoli, Rangasamy, Gligorijević, Aranđelović S., Radulović, Gasser, Grgurić-Šipka (2016), Synthesis, Characterization and Biological Evaluation of novel Ru(II) Arene Complexes containing intercalating Ligands, in J. Inorg. Biochem., 160, 156-165.
Towards 99mTc-based imaging agents with effective doxorubicin mimetics: a molecular and cellular study
Imstepf S., Pierroz V., Raposinho P., Felber M., Fox T., Fernandes C., Gasser G., Santos I. R., Alberto R. (2016), Towards 99mTc-based imaging agents with effective doxorubicin mimetics: a molecular and cellular study, in Dalton Trans., 45, 13025-13033.
Caged Phosphate and the Slips and Misses in Determination of Quantum Yields for UV-A induced Photouncaging
Anstaett P., Leonidova A., Gasser G. (2015), Caged Phosphate and the Slips and Misses in Determination of Quantum Yields for UV-A induced Photouncaging, in ChemPhysChem, 1857-1860.
Combination of Ru(II) Complexes and Light: New Frontiers in Cancer Therapy
Mari C., Pierroz V., Ferrari S., Gasser G. (2015), Combination of Ru(II) Complexes and Light: New Frontiers in Cancer Therapy, in Chem. Sci., 2660-2686.
Direct Imaging of Biological Sulfur Dioxide Derivatives in Vivo Using a Two-Photon Phosphorescent Probe
Li G., Chen Y., Wang J., Wu J., Gasser G., Ji L., Chao H. (2015), Direct Imaging of Biological Sulfur Dioxide Derivatives in Vivo Using a Two-Photon Phosphorescent Probe, in Biomaterials, 128-136.
Highly Charged Ruthenium(II) Polypyridyl Complexes as Lysosome-Localized Photosensitizers for Two-Photon Photodynamic Therapy
Huang H., Yu B., Zhang P., Huang J., Chen Y., Gasser G., Ji L., Chao H. (2015), Highly Charged Ruthenium(II) Polypyridyl Complexes as Lysosome-Localized Photosensitizers for Two-Photon Photodynamic Therapy, in Angew. Chem. Int. Ed., 14049-14052.
In vivo Demonstration of a Tumor Pretargeting Approach with Peptide Nucleic Acids as Complementary System
Leonidova A., Foerster C., Zarschler K., Schubert M., Pietzsch H.-J., Steinbach J., Bergmann R., Metzler-Nolte N., Stephan H., Gasser G. (2015), In vivo Demonstration of a Tumor Pretargeting Approach with Peptide Nucleic Acids as Complementary System, in Chem. Sci., 5601-5616.
Induction of Cytotoxicity through Photo-release of Aminoferrocene
Leonidova A., Anstaett P., Pierroz V., Spingler B., Ferrari S., Gasser G. (2015), Induction of Cytotoxicity through Photo-release of Aminoferrocene, in Inorg. Chem., 9740-9748.
Internal Labeling Strategy of Large RNAs with Minimal Perturbation Using Fluorescent PNA
Schmitz A.G., Zelger-Paulus S., Gasser G., Sigel R.K.O. (2015), Internal Labeling Strategy of Large RNAs with Minimal Perturbation Using Fluorescent PNA, in ChemBioChem, 1302-1306.
Lightening up Ruthenium Complexes to Fight Cancer?
Mari C., Gasser G. (2015), Lightening up Ruthenium Complexes to Fight Cancer?, in Chimia, 176-181.
Metal Complexes and Medicine: A Successful Combination
Gasser G. (2015), Metal Complexes and Medicine: A Successful Combination, in Chimia, 442-446.
Nuclear Targeting with an Auger Electron Emitter Potentiates the Action of a Widely Used Antineoplastic Drug
Imstepf Sebastian, Pierroz Vanessa, Raposinho Paula, Bauwens Matthias, Felber Michael, Fox Thomas, Shapiro Adam B., Freudenberg Robert, Fernandes Célia, Gama Sofia, Gasser Gilles, Motthagy Felix, Santos Isabel R., Alberto Roger (2015), Nuclear Targeting with an Auger Electron Emitter Potentiates the Action of a Widely Used Antineoplastic Drug, in Bioconjugate Chem., 2397-2407.
Phototoxic Activity and DNA Interactions of New Water Soluble Porphyrins and their Re(I) Conjugates
Mion G., Gianferrara T., Bergamo A., Gasser G., Pierroz V., Rubbiani R., Vilar R., Leczkowska A., Alessio E. (2015), Phototoxic Activity and DNA Interactions of New Water Soluble Porphyrins and their Re(I) Conjugates, in ChemMedChem, 1901-1914.
Reply to the Commentary by Trentham et al. on “Caged Phosphate and the Slips and Misses in Determination of Quantum Yields for Ultraviolet-A-Induced Photouncaging” by Gasser and Co-Workers
Anstaett P., Leonidova A., Janett E., Bochet C., Gasser G. (2015), Reply to the Commentary by Trentham et al. on “Caged Phosphate and the Slips and Misses in Determination of Quantum Yields for Ultraviolet-A-Induced Photouncaging” by Gasser and Co-Workers, in ChemPhysChem, 1863-1866.
Towards Selective Light Activated Ru(II)-based Prodrug Candidates
Mari C., Pierroz V., Leonidova A., Ferrari S., Gasser G. (2015), Towards Selective Light Activated Ru(II)-based Prodrug Candidates, in Eur. J. Inorg. Chem., 3879-3891.
Two-Photon Uncageable Enzyme Inhibitors bearing Targeting Vectors
Anstaett P., Pierroz V., Ferrari S., Gasser G. (2015), Two-Photon Uncageable Enzyme Inhibitors bearing Targeting Vectors, in Photochem. Photobiol. Sci., 1821-1825.

Collaboration

Group / person Country
Types of collaboration
PD Dr. Stefano Ferrari, University of Zurich, Institute of Molecular Cancer Research Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof. Peter Hamm, University of Zurich, Department of Chemistry Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof. Caroline Maake, University of Zurich, Institute of Anatomy Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Associated projects

Number Title Start Funding scheme
133568 Caged Metal Complexes as Tools in Inorganic Chemical Biology 01.03.2011 SNSF Professorships
146776 Photo-Induced Uncaging of Metal Complexes in Living Cells 01.08.2013 Project funding (Div. I-III)

Abstract

An important and useful strategy applied in Chemical Biology for the study of living cells/organisms is the use of light-responsive caged compounds. In these studies, biologically relevant molecules (glutamates, proteins, nucleic acids, etc.), rendered inactive by a photolabile protecting group (PLPG), are introduced into living cells/organisms. Upon light activation, the irreversible release of these biologically active molecules at a specific time and location can be achieved. Despite great success observed in the studies engaging organic compounds, the examples of the selective release of inert metal complexes were, to the best of my knowledge, inexistent at the time of my SNSF application in 2011. My group has recently been the first to demonstrate the efficient releases of an inert cytotoxic Ru(II) polypyridyl complex and of a luminescent Re(I) tricarbonyl complex using UVA light (one-photon excitation). In addition, in preliminary experiments, we have recently shown that two-photon excitation could be used to release an organic enzyme inhibitor in a cuvette. This technique uses near-IR light irradiation (700-800 nm) to release the molecule of interest instead of the typically used UV light, which is known to damage cells/living organisms over an extended and/or repeated exposure. This wavelength range is also the optimal window for both tissue transparency and classically available laser sources and therefore opens up new avenues for non-invasive imaging or therapy.In this grant extension application, I propose to further extend the scope of the concept developed during the first three years of my SNSF professorship by notably using the two-photon excitation technique instead of one-photon excitation to release specific (metal-based) enzyme inhibitors in living cells. More specifically, specific cellular recognition units (e.g. bombesin, herceptin) will be coupled to two-photon protecting groups (TPPGs) using different ligation techniques (e.g. peptide coupling, Michael addition, etc.) to which known (metal-based) enzyme inhibitors (e.g. histone deacetylase, COX-2, kinase) will be attached. A “prodrug” will hence be formed. Upon light activation, the enzyme inhibitor will be liberated and will therefore be able to turn down the activity of the enzyme (and hence induce cell death).
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