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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 133568
Funding scheme SNSF Professorships
Research institution
Institution of higher education University of Zurich - ZH
Main discipline Inorganic Chemistry
Start/End 01.03.2011 - 28.02.2015
Approved amount 1'554'716.14
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All Disciplines (2)

Discipline
Inorganic Chemistry
Biochemistry

Keywords (8)

Inorganic Chemical Biology; Bioorganometallic Chemistry; Medicinal Inorganic Chemistry; Metal Complexes; Peptide Nucleic Acid (PNA); Caged Compounds; Metal Bioconjugates; Photo-release

Lay Summary (English)

Lead
Lay summary
An important and useful strategy applied in Chemical Biology for the study of living 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), were introduced into living cells/organisms. Upon activation of light, the irreversible release of these biologically active molecules at a specific time and location could be achieved. Despite great success observed in these such studies, the examples of released metal complexes for biological purposes are rare. The idea of releasing metal complexes at a specific time and location, within a living cell, is very appealing. Numerous metal complexes are already being used/are in clinical trials for medicinal or biological applications (Cisplatin, Ferroquine, Auranofin, etc..) . However, many more could be employed if the “metal release” was achieved in a spatiotemporal, controlled manner. Indeed, the majority of the anticancer metallo-drugs on the market (e.g. cisplatin) are targeting DNA, which is ubiquitous in every living cell, both healthy and cancerous ones. Thus, if a derivative of this metallo anticancer drug was linked to a specific cancer cell receptor via a PLPG, therefore rendering it inactive, these metal-containing bioconjugates could be specifically delivered to cancer cells. Once in the cells, the metallo-drug could be released and exert its toxic activity upon light activation. Depending on the location of the tumour, the use of endoscopes or fiber optic catheters would be required to deliver the light necessary for the cleavage.With this in mind, my research group has recently embarked on a project to specifically release metal complexes of biological/medicinal relevance from metal-containing bioconjugates using UV light as an external trigger. In this project, we propose to extend this concept by using a two-photon excitation technique to release the metal complexes. This technique uses near-IR light irradiation (700-800 nm) to cleave the metal complex from the bioconjugate 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.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
A Photocaged Inositol-Pyrophosphate: Synthesis, Cellular Delivery, Photochemical Release, and its Effect on PH-Domain Translocation
Pavlovic I., Thakor D.T., Vargas J.R., McKinlay C.J., Haucke S., Anstaett P., Camuña R.C., Gasser G., Schultz C., Wender P.A., Jessen H.J. (2016), A Photocaged Inositol-Pyrophosphate: Synthesis, Cellular Delivery, Photochemical Release, and its Effect on PH-Domain Translocation, in Nature Commun., N/A.
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.
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.
Sedaxicenes: potential new antifungal ferrocene-based agents?
Rubbiani R., Blacque O., Gasser G. (2016), Sedaxicenes: potential new antifungal ferrocene-based agents?, in Dalton Trans., 45, 6619-6626.
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.
An Organometallic Structure-Activity Relationship Study Reveals the Essential Role of a Re(CO)3 Moiety in the Activity Against Gram-Positive Pathogens Including MRSA
Patra M., Wenzel M., Prochnow P., Pierroz V., Gasser G., Bandow J.E., Metzler-Nolte N. (2015), An Organometallic Structure-Activity Relationship Study Reveals the Essential Role of a Re(CO)3 Moiety in the Activity Against Gram-Positive Pathogens Including MRSA, in Chem. Sci., 6, 214-224.
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, 16, 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., 6, 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, 63, 128-136.
DNA intercalating RuII Polypyridyl Complexes as effective Photosentizers for Photodynamic Therapy
Mari C., Pierroz V., Rubbiani R., Patra M, Hess J., Spingler B., Oehninger L., Schur J., Ott I., Salassa L., Ferrari S., Gasser G. (2015), DNA intercalating RuII Polypyridyl Complexes as effective Photosentizers for Photodynamic Therapy, in Chem. Eur. J., 44, 14421-14436.
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., 6, 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., 54, 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, 16, 1302-1306.
Lightening up Ruthenium Complexes to Fight Cancer?
Mari C., Gasser G. (2015), Lightening up Ruthenium Complexes to Fight Cancer?, in Chimia, 69, 176-181.
Metal Complexes and Medicine: A Successful Combination
Gasser G. (2015), Metal Complexes and Medicine: A Successful Combination, in Chimia, 7, 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 Chemi., 26, 2397-2407.
Organometallic Complexes as Enzyme Inhibitors: A Conceptual Overview
Anstaett P., Gasser G. (2015), Organometallic Complexes as Enzyme Inhibitors: A Conceptual Overview, in Jaouen G., Salmain M. (ed.), Wiley-VCH, Weinheim, 1-42.
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, 16, 1863-1866.
Towards Organometallic Antischistosomal Drug Candidates
Hess J., Keiser J., Gasser G. (2015), Towards Organometallic Antischistosomal Drug Candidates, in Future. Med. Chem., 8, 821-830.
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., 23, 3879-3891.
Towards Tris(diimine)-Ru(II) and Bis(quinoline) Re(I)(CO)3 Complexes as Photoactivated Anticancer Drug Candidates
Joshi T., Gasser G. (2015), Towards Tris(diimine)-Ru(II) and Bis(quinoline) Re(I)(CO)3 Complexes as Photoactivated Anticancer Drug Candidates, in Synlett, 26, 275-284.
Towards Tris(diimine)-Ru(II) and Bis(quinoline) Re(I)(CO)3 Complexes as Photoactivated Anticancer Drug Candidates
Joshi T., Gasser G. (2015), Towards Tris(diimine)-Ru(II) and Bis(quinoline) Re(I)(CO)3 Complexes as Photoactivated Anticancer Drug Candidates, in Synlett, 26, 275-284.
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., 14, 1821-1825.
Unexpected High Photothemal Conversion Efficiency of Gold Nanospheres upon Grafting with Two-Photon Luminescent Ruthenium(II) Complexes: A Way Towards Cancer Therapy?
Zhang P., Wang J., Huang H., Yu B., Qiu K., Huang J., Wang S., Jiang L., Gasser G., Ji L., Chao H. (2015), Unexpected High Photothemal Conversion Efficiency of Gold Nanospheres upon Grafting with Two-Photon Luminescent Ruthenium(II) Complexes: A Way Towards Cancer Therapy?, in Biomaterials, 63, 102-114.
(Metallo)porphyrins as Potent Phototoxic anti-Cancer Agents after Irradiation with Red Light
Antoni P.M., Naik A., Albert I., Rubbiani R., Gupta S., Ruiz-Sánchez P., Munikorn P., Mateos J.M., Luginbuehl V., Thamyongkit P., Ziegler U., Gasser G., Jeschke G., Spingler B. (2014), (Metallo)porphyrins as Potent Phototoxic anti-Cancer Agents after Irradiation with Red Light, in Chem. Eur. J., 21, 1179-1183.
A Novel, Mercury-Free Synthetic Pathway for Trifluoromethylthio-Subsituted Metallocenes
Hess J., Konatschnig S., Morard S., Pierroz V., Ferrari S., Spingler B., Gasser G. (2014), A Novel, Mercury-Free Synthetic Pathway for Trifluoromethylthio-Subsituted Metallocenes, in Inorg. Chem., 53, 3662-3667.
Activity of Praziquantel Enantiomers and Main Metabolites Against Schistosoma mansoni
Meister I., Ingram-Sieber K., Cowan N., Todd M.H., Patra M., Gasser G., Keiser J. (2014), Activity of Praziquantel Enantiomers and Main Metabolites Against Schistosoma mansoni, in Antimicrob. Agents Chemother., 58, 5466-5472.
An Octadentate Bifunctional Chelating Agent for the Development of Stable Zirconium-89 Based Molecular Imaging Probe
Patra M., Baumann A., Mari C., Fischer C.A., Blacque O., Häussinger D., Gasser G., Mindt T.L. (2014), An Octadentate Bifunctional Chelating Agent for the Development of Stable Zirconium-89 Based Molecular Imaging Probe, in Chem. Commun., 50, 11523-11525.
Anticancer Profile of a Series of Gold(III) (2-phenyl)pyridine Complexes
Rubbiani R., Zehnder T.N., Mari C., Blacque O., Venkatesan K., Gasser G. (2014), Anticancer Profile of a Series of Gold(III) (2-phenyl)pyridine Complexes, in ChemMedChem, 9, 2781-2790.
Bis(dipyridophenazine)(2-(2′-pyridyl)pyrimidine-4-carboxylic acid)ruthenium(II) hexafluorophosphate: A Lesson in Stubbornness
Joshi T., Pierroz V., Ferrari S., Gasser G. (2014), Bis(dipyridophenazine)(2-(2′-pyridyl)pyrimidine-4-carboxylic acid)ruthenium(II) hexafluorophosphate: A Lesson in Stubbornness, in ChemMedChem, 9, 1419-1427.
DMSO-mediated Ligand Dissociation: Renaissance for Biological Activity of N-heterocyclic-[Ru(η6-arene)Cl2] Drug Candidates
Patra M., Joshi T., Pierroz V., Ingram K., Kaiser M., Ferrari S., Spingler B., Keiser J., Gasser G. (2014), DMSO-mediated Ligand Dissociation: Renaissance for Biological Activity of N-heterocyclic-[Ru(η6-arene)Cl2] Drug Candidates, in Chem. Eur. J., 19, 14768-14722.
Enantioselective Total Syntheses of the Proposed Structures of Prevezol B and Evaluation of Anti-Cancer Activity
Leung A.E., Rubbiani R., Gasser G., Tuck K.L. (2014), Enantioselective Total Syntheses of the Proposed Structures of Prevezol B and Evaluation of Anti-Cancer Activity, in Org. Biomol. Chem., 12, 8239-8246.
Enhanced Cytotoxicity through Conjugation of a “Clickable” Luminescent Re(I) Complex to a Cell-Penetrating Lipopeptide
Leonidova A., Pierroz V., Adams L., Borlow N., Ferrari S., Graham B., Gasser G. (2014), Enhanced Cytotoxicity through Conjugation of a “Clickable” Luminescent Re(I) Complex to a Cell-Penetrating Lipopeptide, in ACS Med. Chem. Lett., 5, 809-814.
In vitro and in vivo Antischistosomal Activity of Ferroquine Derivatives
Keiser J., Vargas M., Rubbiani R., Gasser G., Biot C. (2014), In vitro and in vivo Antischistosomal Activity of Ferroquine Derivatives, in Parasites & Vectors, 7, 424-424.
Inorganic Chemical Biology: Principles, Techniques and Applications
Gasser G. (2014), Inorganic Chemical Biology: Principles, Techniques and Applications, John Wiley & Sons, Ltd, UK.
Photo-Induced Uncaging of a Specific Re(I) Organometallic Complex in Living Cells
Leonidova A., Pierroz V., Rubbiani R., Lan Y., Schmitz A.G., Kaech A., Sigel R.K.O., Ferrari S., Gasser G. (2014), Photo-Induced Uncaging of a Specific Re(I) Organometallic Complex in Living Cells, in Chem. Sci., 5, 4044-4056.
Preparation of Metal-Containing Peptide Nucleic Acid Bioconjugates on the Solid Phase
Gasser G. (2014), Preparation of Metal-Containing Peptide Nucleic Acid Bioconjugates on the Solid Phase, in Nielsen P.E. Appella D.H. (ed.), Springer, -, 55-72.
Synthesis of Ferrocenyl and Ruthenocenyl Thioamide Derivatives Using a Single-Step Three-Component Reaction
Patra M., Hess J., Konatschnig S., Spingler B., Gasser G. (2014), Synthesis of Ferrocenyl and Ruthenocenyl Thioamide Derivatives Using a Single-Step Three-Component Reaction, in Organometallics, 32, 6098-6105.
Synthesis, Characterization and Biological Evaluation of New Ru(II) Polypyridyl Photosensitizers for Photodynamic Therapy
Frei A., Rubbiani R., Tubafard S., Blacque O., Anstaett P., Felgenträger A., Maisch T., Spiccia L., Gasser G. (2014), Synthesis, Characterization and Biological Evaluation of New Ru(II) Polypyridyl Photosensitizers for Photodynamic Therapy, in J. Med. Chem., 57, 7280-7292.
Synthesis, Characterization and Evaluation of Radiometal-containing Peptide Nucleic Acids
Stephan H., Förster C., Gasser G. (2014), Synthesis, Characterization and Evaluation of Radiometal-containing Peptide Nucleic Acids, in Nielsen P.E. Appella D.H. (ed.), Springer, -, 37-54.
Towards Cancer Cell-Specific Phototoxic Organometallic Rhenium(I) Complexes
Leonidova A., Pierroz V., Rubbiani R., Heier J., Ferrari S., Gasser G. (2014), Towards Cancer Cell-Specific Phototoxic Organometallic Rhenium(I) Complexes, in Dalton Trans., 43, 4287-4294.
Underestimated Potential of Organometallic Rhenium Complexes as Anticancer Agents
Leonidova A., Gasser G. (2014), Underestimated Potential of Organometallic Rhenium Complexes as Anticancer Agents, in ACS Chem. Biol., 9, 2180-2193.
Visible Light-Induced Annihilation of Tumour Cells Using Novel Platinum-Porphyrin Conjugates
Naik A., Rubbiani R., Gasser G., Spingler B. (2014), Visible Light-Induced Annihilation of Tumour Cells Using Novel Platinum-Porphyrin Conjugates, in Angew. Chem. Int. Ed., 53, 6938-6941.
An Environmentally Benign and Cost-Effective Synthesis of Aminoferrocene and Aminoruthenocene
Leonidova A., Joshi T., Nipkow D., Frei A., Penner J.-E., Konatschnig S., Patra M, Gasser G. (2013), An Environmentally Benign and Cost-Effective Synthesis of Aminoferrocene and Aminoruthenocene, in Organometallics, 32, 2037-2040.
Di-Heterometalation of Thiol-Functionalized Peptide Nucleic Acids
Joshi T., Patra M., Spiccia L., Gasser G. (2013), Di-Heterometalation of Thiol-Functionalized Peptide Nucleic Acids, in Artificial DNA PNA & XNA, 4, 11-18.
In Vivo Antischistosomal Activity Studies and In Vitro Metabolic Profile of (η-Praziquantel)Cr(CO)3 Derivatives
Patra M., Ingram K., Leonidova A., Pierroz V., Ferrari S., Robertson M., Todd M.H., Keiser J., Gasser G. (2013), In Vivo Antischistosomal Activity Studies and In Vitro Metabolic Profile of (η-Praziquantel)Cr(CO)3 Derivatives, in J. Med. Chem., 56, 9192-9198.
Novel water-soluble 99mTc(I)/Re(I)-porphyrin conjugates as potential multimodal agents for molecular imaging
Spagnul C., Alberto R., Gasser G., Ferrari S., Pierroz V., Bergamo A., Gianferrara T., Alessio E. (2013), Novel water-soluble 99mTc(I)/Re(I)-porphyrin conjugates as potential multimodal agents for molecular imaging, in J. Inorg. Biochem., 122, 57-65.
Synthesis of Stable Peptide Nucleic Acid-Modified Gold Nanoparticles and their Assembly onto Gold Surfaces
Anstaett P., Zheng Y., Thai T., Funston A.M., Bach U., Gasser G. (2013), Synthesis of Stable Peptide Nucleic Acid-Modified Gold Nanoparticles and their Assembly onto Gold Surfaces, in Angew. Chem. Int. Ed., 52, 4217-4220.
Electrochemical, Spectroscopic, Magnetic and Structural Studies of Complexes Bearing Ferrocenyl Ligands of N-(3-hydroxypicolinoyl)picolinamide
Gasser G., Mari C., Burkart M., Green S.J., Ribas J., Stoeckli-Evans H., Tucker J.H.R. (2012), Electrochemical, Spectroscopic, Magnetic and Structural Studies of Complexes Bearing Ferrocenyl Ligands of N-(3-hydroxypicolinoyl)picolinamide, in New. J. Chem., 36, 1819-1827.
Electrochemiluminescent monomers for solid support syntheses of Ru(II) PNA bioconjugates - multimodal biosensing tools with enhanced duplex stability
Joshi T., Barbante G.J., Francis P.S., Hogan C.F., Bond A.M., Gasser G., Spiccia L. (2012), Electrochemiluminescent monomers for solid support syntheses of Ru(II) PNA bioconjugates - multimodal biosensing tools with enhanced duplex stability, in Inorg. Chem., 51, 3302-3315.
Ferrocenyl Derivatives of the Anthelmintic Praziquantel: Design, Synthesis and Biological Evaluation
Patra M., Ingram K., Pierroz V., Ferrari S., Spingler B., Keiser J., Gasser G. (2012), Ferrocenyl Derivatives of the Anthelmintic Praziquantel: Design, Synthesis and Biological Evaluation, in J. Med. Chem., 55, 8790-8798.
Molecular and Cellular Characterization of the Biological Effects of Ruthenium(II) Complexes Incorporating 2-Pyridyl-2-Pyrimidine-4-Carboxylic Acid
Pierroz V., Joshi T., Leonidova A., Mari C., Schur J., Ott I., Spiccia L., Ferrari S., Gasser G. (2012), Molecular and Cellular Characterization of the Biological Effects of Ruthenium(II) Complexes Incorporating 2-Pyridyl-2-Pyrimidine-4-Carboxylic Acid, in J. Am. Chem. Soc., 134, 20376-20387.
Organometallic Compounds, an Opportunity for Chemical Biology
Patra M., Gasser G. (2012), Organometallic Compounds, an Opportunity for Chemical Biology, in ChemBioChem, 13, 1232-1252.
Preparation and Biological Evaluation of Di-Hetero Organometallic-Containing PNA Bioconjugates
Gasser G., Neumann S., Ott I., Seitz M., Heumann R., Metzler-Nolte N. (2012), Preparation and Biological Evaluation of Di-Hetero Organometallic-Containing PNA Bioconjugates, in Eur. J. Inorg. Chem., 5471-5478.
Sandwich and Half-sandwich Derivatives of Platensimycin: Synthesis and Biological Evaluation
Patra M., Gasser G., Wenzel M., Merz K., Bandow J.E., Metzler-Nolte N. (2012), Sandwich and Half-sandwich Derivatives of Platensimycin: Synthesis and Biological Evaluation, in Organometallics, 31, 5760-5771.
Small Organometallic Compounds as Antibacterial Agents
Patra M., Gasser G., Metzler-Nolte N. (2012), Small Organometallic Compounds as Antibacterial Agents, in Dalton Trans., 41, 6350-6358.
Specific Uptake and Interactions of Peptide Nucleic Acid Derivatives with Biomimetic Membranes
Joshi T., Gasser G., Martin L.L., Spiccia L. (2012), Specific Uptake and Interactions of Peptide Nucleic Acid Derivatives with Biomimetic Membranes, in RSC Adv., 2 , 4703-4712.
Synthesis, Characterisation and Bioimaging of a Fluorescent Rhenium-Containing PNA Bioconjugate
Gasser G., Pinto A., Neumann S., Sosniak A.M., Seitz M., Merz K., Heumann R., Metzler-Nolte N. (2012), Synthesis, Characterisation and Bioimaging of a Fluorescent Rhenium-Containing PNA Bioconjugate, in Dalton Trans., 41, 2304-2313.
The Potential of Organometallic Complexes in Medicinal Chemistry
Gasser G., Metzler-Nolte N. (2012), The Potential of Organometallic Complexes in Medicinal Chemistry, in Curr. Opin. Chem. Biol., 16, 84-91.
Synthesis of Optically Active Ferrocene-Containing Platensimycin Derivatives with a C6–C7 Substitution Pattern
Patra M., Gasser G., Wenzel M., Merz K., Bandow J.E., Metzler-Nolte N. (2011), Synthesis of Optically Active Ferrocene-Containing Platensimycin Derivatives with a C6–C7 Substitution Pattern, in Eur. J. Inorg. Chem., 3295-3302.
A Bis(dipyridophenazine) (2-(2′-pyridyl)pyrimidine-4-carboxylic acid)ruthenium(II) Complex with Anticancer Action upon Photodeprotection
Joshi T., Pierroz V., Mari C., Gemperle L., Ferrari S., Gasser G., A Bis(dipyridophenazine) (2-(2′-pyridyl)pyrimidine-4-carboxylic acid)ruthenium(II) Complex with Anticancer Action upon Photodeprotection, in Angew. Chem. Int. Ed..
A Deadly Organometallic Luminescent Probe: Anticancer Activity of a Re(I) Bisquinoline Complex
Kitanovic I., Can S., Alborzinia H., Kitanovic A., Pierroz V., Leonidova A., Pinto A., Molteni R., Spingler B., Ferrari S., Steffen A., Metzler-Nolte N., Wölfl S., Gasser G., A Deadly Organometallic Luminescent Probe: Anticancer Activity of a Re(I) Bisquinoline Complex, in Chem. Eur. J..
Bis(dipyridophenazine)(2-(2′-pyridyl)pyrimidine-4-carboxylic acid)ruthenium(II) hexafluorophosphate: A Lesson in Stubbornness
Joshi T., Pierroz V., Ferrari S., Gasser G., Bis(dipyridophenazine)(2-(2′-pyridyl)pyrimidine-4-carboxylic acid)ruthenium(II) hexafluorophosphate: A Lesson in Stubbornness, in ChemMedChem.
Other Applications of Metal Complexes in Chemical Biology
Joshi T., Patra M, Gasser G., Other Applications of Metal Complexes in Chemical Biology, in Gasser G. (ed.), John Wiley & Sons, Ltd, UK.
Peptide Nucleic Acids – an Opportunity for Bio-Nanotechnology
Anstaett P., Gasser G., Peptide Nucleic Acids – an Opportunity for Bio-Nanotechnology, in Chimia.
Towards Cancer Cell-Specific Phototoxic Organometallic Rhenium(I) Complexes
Leonidova A., Pierroz V., Rubbiani R., Heier J., Ferrari S., Gasser G., Towards Cancer Cell-Specific Phototoxic Organometallic Rhenium(I) Complexes, in Dalton Trans..
Towards matched Pairs of Porphyrin-Re(I)/99mTc(I) Conjugates that combine Photodynamic Activity with Fluorescence- and Radio-Imaging
Gianferrara T., Spagnul C., Alberto R., Gasser G., Ferrari S., Pierroz V., Bergamo A., Alessio E., Towards matched Pairs of Porphyrin-Re(I)/99mTc(I) Conjugates that combine Photodynamic Activity with Fluorescence- and Radio-Imaging, in ChemMedChem.

Associated projects

Number Title Start Funding scheme
126404 Synthesis of PNA-Metal Bioconjugates by "Copper-Free" and "Photo" Click Chemistry: An Approach towards the in Vitro Attachment of Organometallics to Biomolecules 01.03.2010 Ambizione
129910 Photo-Induced Uncaging of Metal Complexes in Living Cells 01.08.2010 Project funding (Div. I-III)
144964 Upgrade of the UZH NMR Core Facility 01.12.2012 R'EQUIP
146776 Photo-Induced Uncaging of Metal Complexes in Living Cells 01.08.2013 Project funding (Div. I-III)
157545 Caged Metal Complexes as Tools in Inorganic Chemical Biology 01.03.2015 SNSF Professorships

Abstract

Chemical Biology is the extraordinary endeavour of understanding, identifying and/or influencing biological processes in living cells using small molecules. Some metal-based compounds have been (and continue to be) selected to assist in this quest, for example, as anticancer agents, artificial proteases, artificial nucleases, artificial transporters of Ca(II), probes to demonstrate DNA charge transport, delivery vehicles for CO and NO, imaging agents and more. All these biological applications employing metal complexes/organometallics have recently been referred to as Inorganic Chemical Biology. An important and useful strategy applied in Chemical Biology for the study of living 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, can be introduced into living cells/organisms. Upon activation with light, 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, examples of the specific release of metal complexes for medicinal or biological purposes are rare.With this in mind, my research group has recently embarked on a project to specifically release metal complexes of biological/medicinal relevance from metal-containing bioconjugates using UV light as an external trigger. Preliminary experiments have shown promising results. We demonstrated that a fluorescent Re(I) organometallic-containing PNA bioconjugate was partially able to downregulate the production of the enhanced Green Fluorescent Protein (eGFP) in HeLa cells.In this application, I propose to extend this concept by using a two-photon excitation technique to release the metal complexes. This technique uses near-IR light irradiation (700-800 nm) to cleave the metal complex from the bioconjugate 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.More specifically, in the first stage of this project, biologically specific cellular transporters/recognition units (peptides, proteins, nucleic acids, peptide nucleic acids (PNAs), biotin, (poly)saccharides, hormones, lipids, etc.) will be coupled, using different synthetic methods (native chemical ligation, peptide coupling, click chemistry, etc.), to photoremovable protecting groups to which metal complexes with different properties will be attached. A “prodrug” will hence be formed. Upon light activation, the metal complexes will be liberated and will therefore be able to undertake a specific function within the cell (cytotoxicity, imaging, enzyme inhibition, DNA/RNA/protein cleavage, etc.). In a later stage, the knowledge acquired during the in vitro experiments will be transferred to model organisms such as Caenorhabditis elegans (C. elegans) and zebrafish.
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