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Biocompatible 17 e- Rhenium Dicarbonyl CO-Releasing Molecules on Natural Heme and Cobalamin Scaffolds

Applicant Zobi Fabio
Number 139424
Funding scheme Ambizione
Research institution Institut für Chemie Universität Zürich
Institution of higher education University of Zurich - ZH
Main discipline Inorganic Chemistry
Start/End 01.01.2012 - 30.06.2013
Approved amount 187'243.00
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All Disciplines (2)

Discipline
Inorganic Chemistry
Physical Chemistry

Keywords (4)

Carbon Momoxide; Transition Metals; CO-Releasing Molecules; Medicinal Applications

Lay Summary (English)

Lead
Lay summary

In the last decade, the use of carbon monoxide (CO) as a therapeutic agent molecule has received increasing attention in medicine due to its documented beneficial effects. There are three main areas where CO is evaluated as a clinically valuable medical agent: 1) inflammation, 2) cardiovascular diseases and 3) organ preservation and transplantation.

The anti-inflammatory properties of CO have been corroborated in a large number of animal models including rheumatoid arthritis, diabetes and acute hepatitis. The protective effects of CO as vasodilator have been successfully evaluated on several cardiovascular diseases including pulmonary arterial hypertension, for which there is no cure. Carbon monoxide proved effectiveness in prolonging organ graft survival, particularly in heart and kidney transplants for which CO inhalation has entered Phase II clinical trials.

Despite its current evaluation in novel therapies, the use of gaseous CO poses several problems related to safe handling and delivery to specific target sites in a controlled and measurable fashion. The challenges associated with clinical application of the gas by inhalation have sparked the design of CO-releasing molecules (CORMs) as an alternative approach to the administration of CO (e.g. orally or by injection). 

However, none of the characterized CO-releasing molecules displays drug-like acceptable properties such as: a) water solubility and biocompatibility, b) stability in aqueous aerobic media, c) slow decay of the M(CO)x fragment in the blood, d) low toxicity and rapid excretion of the metal scaffold after CO release.

In order to meet the above mentioned requirements for a pharmaceutically acceptable CORM, this research project intends to synthesize, investigate, develop and apply new Re-based CO-releasing molecules coupled to with biomolecules. In particular cyanocobalamin (vitamin B12) and other natural hemes will be investigated as the scaffolds for the targeted delivery of the new CORMs.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Carbon Monoxide and CO-Releasing Mole-cules in Medicinal Chemistry
Zobi fabio (2013), Carbon Monoxide and CO-Releasing Mole-cules in Medicinal Chemistry, in Future Medicinal Chemistry, 5, 175-188.
17 e− rhenium dicarbonyl CO-releasing molecules on a cobalamin scaffold for biological application
Zobi Fabio, Blacque Olivier, Jacobs Robert A., Schaub Marcus C., Bogdanova Anna Yu. (2012), 17 e− rhenium dicarbonyl CO-releasing molecules on a cobalamin scaffold for biological application, in Dalton Transactions, 41, 370-378.
Post-Protein-Binding Metal-Mediated Coupling of an Acridine Or-ange-Based Fluorophore
Santoro Giuseppe, Blacque Olivier, Zobi Fabio (2012), Post-Protein-Binding Metal-Mediated Coupling of an Acridine Or-ange-Based Fluorophore, in Metallomics, 4, 253-259.
Post-Protein-Binding Reactivity and Modifications of the fac-[Re(CO)3]+ Core
Zobi fabio, Spingler Bernhard (2012), Post-Protein-Binding Reactivity and Modifications of the fac-[Re(CO)3]+ Core, in Inorganic Chemistry, 51, 1210-1212.
Live-Fibroblast IR Imaging of a Cytoprotective PhotoCORM Activated with Visible Light
Zobi Fabio, Quaroni Luca, Zlateva Theodora, Blacque Olivier, Sarafimov Blagoj, Schaub Marcus C., Bogdanova Anna Yu., Live-Fibroblast IR Imaging of a Cytoprotective PhotoCORM Activated with Visible Light, in Journal of Medicinal Chemistry, jm-2013-00.

Collaboration

Group / person Country
Types of collaboration
Institutes of Pharmacology and Toxicology Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Institute of Veterinary Physiology Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Duke Univesity Medical School United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Rhemantec II Symposium Talk given at a conference Chemistry and Biology of Biocompatible Transition Metal-Based CO-Releasing Molecules on Cobalamin Scaffolds 24.02.2013 Saas-Grund, Switzerland, Switzerland Zobi Fabio;
6th International Symposium on Bioorganometallic Chemistry Talk given at a conference Chemistry and Biology of Biocompatible Transition Metal-Based CO-Releasing Molecules on Cobalamin Scaffolds 08.07.2012 Toronto, Canada, Canada Zobi Fabio;


Patents

Title Date Number Inventor Owner

Associated projects

Number Title Start Funding scheme
144700 Development of Biocompatible Site Specific Metal Based CO-Releasing Molecules for Medical Applications 01.07.2013 SNSF Professorships
144964 Upgrade of the UZH NMR Core Facility 01.12.2012 R'EQUIP
121989 Systematic Approach to Rhenium (II) Building Blocks via Ligand-Mediated Decarbonylation: Prospective and Applications in Medicinal Inorganic Chemistry and for Single-Molecule Magnets 01.01.2009 Ambizione
170589 Bio-Inspired Vectors and Materials for the Targeted Delivery of CO-Releasing Molecules and Chemotherapeutic Agents 01.07.2017 SNSF Professorships

Abstract

Carbonmonoxide releasing molecules (CO-RMs) are a newly emerging class of compounds of pharmacological interest. Medicinal applications of this new class of compounds are mainly focused on the anti-inflammatory and the anti-apoptotic properties of the gaseous molecule but efforts are also directed towards cardiovascular diseases and organ transplantation and preservation. The recently-established collaboration between this author and Institutes of Pharmacology and Toxicology and of Veterinary Physiology of the University of Zurich resulted in the disclosure of a new family of Re(II)-based CO-RMs which show unique characteristics that underline their potential for possible clinical applications. These characteristics include: a) ease of preparation; b) cardioprotective action against ischemia-reperfusion injury of cultured neonatal rat cardiomyocytes (NRCs); c) absence of toxicity; d) chemically tuneable rate of CO release. At present, however, a number of complexes show poor water solubility, an absolute requirement for potential medical applications. Testing of the therapeutic and cardioprotective potential of the newly synthesised class of Re(II)-based CO-RMs in a more relevant in vivo model, requires new synthetic strategies for the design of fully water soluble and biocompatible species. On this base, the objectives of this follow-up proposal are as follows:1.Chemically derivatize naturally occurring vitamins and hemes with pending ligands for the bioconjugation of Re(II)-based CO-RMs. 2.Explore Re(II) chemistry starting from synthons comprising the the cis-[ReII(CO)2]2+ with molecules obtained under 1. 3.Evaluate the CO-releasing properties and (in collaboration with the above-mentioned Institutes) the therapeutic and cardioprotective potential of species obtained under 2.
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