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Cyanide bridged heterodinuclear complexes of cobaltamin and cobalt free vitamin B12

English title Cyanide bridged heterodinuclear complexes of cobaltamin and cobalt free vitamin B12
Applicant Alberto Roger
Number 117658
Funding scheme Project funding (Div. I-III)
Research institution Institut für Chemie Universität Zürich
Institution of higher education University of Zurich - ZH
Main discipline Inorganic Chemistry
Start/End 01.10.2007 - 30.09.2008
Approved amount 56'571.00
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All Disciplines (2)

Discipline
Inorganic Chemistry
Biochemistry

Keywords (14)

Vitamin B12; B12 enzymes; Targeting; Cytotoxic Agents; Catalysis; Heterodinculear Complexes; Corrinoids; Cyanide; Surrogates; Technetium; cisplatin; Antagonist; Cancer; Imaging

Lay Summary (English)

Lead
Lay summary
Aims of the project: It was the objective of this project to use Vitamin B12 as a carrier for targeted drug delivery. Since rapidly proliferating cells such as cancer or microorganisms have a high demand for vitamin B12, one could achieve with B12 as a Trojan horse a selective uptake in the target tissue only. This would reduce undesired side effects and could give an improved therapeutic index. We therefore coupled biologically active drugs to B12 in order to achieve this goal.Methods and results: The drugs were in general metal complexes of known cytotoxic activity. These metal complexes were directly coordinated to the cyanide in B12. Thus, Pt(II) complexes were in the focus of our research. However, we also did extend the principle of directly coordinated metal complexes to rhenium, technetium and gold. We could show that the Pt(II) complexes, bound via a bridging cyanide to B12, were cleaved in the intracellular space via a reductive mechanism. The adenosylation reaction cascade was mainly involved in this enzymatic cleavage process. We showed that the released complexes had a comparable cytotoxicity than cisplatin. However, the cytotoxicity of the full conjugate {B12-CN-Pt} was substantially smaller. We assume that the receptor mediated uptake was responsible for this reduced cytotoxicity and that not sufficient amounts of {B12-CN-Pt} were entering the cell due to competition with native B12. We furthermore coupled antibiotics and fluorescent agents along the same coupling strategy to B12. A similar observation was made as with {B12-CN-Pt}, activity but substantial less than the free antibiotic. Finally, we could radioactively label B12 with radioiodine (131I) via ligand exchange directly on Pt(II). Most of the conjugates have been structurally characterized.Significance: Most of the drugs in actual clinical application are non-specific. This means that they are entering all cells unless they are binding to specific receptors or other biological sites. Many pharmaceuticals accumulate to a slightly higher extent in rapidly growing cells, just because of the enhanced metabolic activity of such sites. If it would be possible to guide the pharmaceutical with high target / non-target ratio, side effects would be substantially reduced. Since it has been shown that e.g. cancerous tissue can be visualized with radioactively labelled B12, it is likely that the combination of B12 with a cytotoxic agent would lead to the same results but in a therapy context.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

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Associated projects

Number Title Start Funding scheme
107518 Cyanide bridged heterodinuclear complexes of cobalamin and cobalt free vitamin B12 01.04.2005 Project funding (Div. I-III)

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