Short description
(English)
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In this project, we aim at developing the chemistry and the biomedicinal application of arene complexes of rhenium and technetium. As it is in the objective of COST action CM1105 to study 'Metal Complexes that Bind to Biomolecules', we propose to introduce new organometallic cores for widening the scope of metals in medicine. Arene complexes of ruthenium are very well studied and established and an integral and central part of CM1105. This contrasts rhenium and technetium arenes which are principally known but not at all investigated for their potential in the targeting of receptors or the delivery of drugs. The proposed chemistry will complement the endeavors with ruthenium. Besides studying the synthesis and fundamental chemistry of [M(arene)2]+ (M=Re, 99mTc), we will, from an early time point onwards, involve arenes which comprise targeting moieties or bioactive functionalities. These compounds will be biologically investigated in partner groups of the Action. In particular, biodistribution studies will be performed in the Santos group in Portugal. The ultimate goal of the project is to find and develop biologically active, homologous rhenium and technetium compounds. The two represent matched pairs in the low oxidation states. According to our concept and previous experiences, the rhenium compounds can be used for therapy and the technetium homologous for imaging, following thereby one of the possible strategies of the theranostic concept.
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Abstract
(English)
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The field of bioorganometallic chemistry is dominated by mono-arene complexes of ruthenium and ferrocene (derivatives). Major studies with respect to cytotoxicity, site-directed delivery by targeting or unspecific distribution are ongoing in many groups worldwide. These organometallic complexes complement studies with pure coordination compounds such as those of platinum or palladium. Recently, carbene compounds of silver and gold have been added to these studies but the goal of selectively binding metal complexes to biomolecules as requested from the title of the COST action CM1105, in which this project is a major part, has not been achieved yet. The combination of a biologically active metal complex with a site-specific compound as delivery carrier is challenging and one way to go for introducing metal containing drugs into therapeutic medicine. Alternatively, metal complexes can be an integral part of the overall active structure, as shown with ruthenium. These metal-essential compounds represent an own category of novel therapeutic agents. To extend this field, we introduced in a first part of the project bis-arene rhenium complexes, a widely unexplored class of organometallic complexes. According to the proposed aims of the project, we want to implement these kind of complexes in bioorganometallic chemistry, with or without metal-based reactivity according to the concepts outlined above. Rhenium is an alternative to the other elements mentioned above. Its lower homologue, technetium, is the most widely used radionuclide in imaging. The innovation and originality of this project is thus the fact, that rhenium complexes could be used for therapy while there technetium homologues are applied in diagnosis, thus, opening a novel approach in theranostics. During the first year of the project (see previous report), we explored a route for the preparation of the basic 99mTc and Re complexes and studied their physico-chemical properties. Functionalities were introduced in the arene rings for further conjugation to targeting molecules (milestones 1 and 2 and in part 7). Accordingly, the focus of the 2nd year of the project was on the introduction of further functionalities or targeting molecules respectively and the substitution of arene rings with either solvent molecules or additional ligands, e.g. amino acids, mono- or multidentate auxiliary ligands. However, with the exception of the bis-naphthalene complex [Re[napht)2]+, the arene rings are so tightly bound that their replacement was not yet possible. Reactions with [Re(napht)2]+ gave complexes with one naphthalene ring replaced by tripod ligands. These studies are pursued with solvent molecules such as acetonitrile and water. Preliminary cytotoxicity studies show high to moderate activities of a few basic bis-arene compounds. Some fundamental structure-activity relationships can be deduced from the corresponding IC50 values. A new, unprecedented ring contraction reaction from coordinated phenols opens up new opportunities for replacing ferrocene by mixed-ligand metallocene like compounds.
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