Volume 19, Issue 39 p. 13017-13029
Full Paper

Nucleoside Analogues with a 1,3-DieneFe(CO)3 Substructure: Stereoselective Synthesis, Configurational Assignment, and Apoptosis-Inducing Activity

Dr. Christoph Hirschhäuser

Dr. Christoph Hirschhäuser

Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Köln (Germany), Fax: (+49) 221-470-3064

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Dr. Juraj Velcicky

Dr. Juraj Velcicky

Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Köln (Germany), Fax: (+49) 221-470-3064

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Dr. Daniel Schlawe

Dr. Daniel Schlawe

Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Köln (Germany), Fax: (+49) 221-470-3064

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Dr. Erik Hessler

Dr. Erik Hessler

Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Köln (Germany), Fax: (+49) 221-470-3064

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Dr. André Majdalani

Dr. André Majdalani

Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Köln (Germany), Fax: (+49) 221-470-3064

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Dr. Jörg-Martin Neudörfl

Dr. Jörg-Martin Neudörfl

Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Köln (Germany), Fax: (+49) 221-470-3064

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Dr. Dr. Aram Prokop

Corresponding Author

Dr. Dr. Aram Prokop

Children's Hospital Cologne, Department of Paediatric Oncology, Amsterdamer Strasse 59, 50735 Köln (Germany)

Aram Prokop, Children's Hospital Cologne, Department of Paediatric Oncology, Amsterdamer Strasse 59, 50735 Köln (Germany)

Hans-Günther Schmalz, Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Köln (Germany), Fax: (+49) 221-470-3064

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Dr. Thomas Wieder

Dr. Thomas Wieder

Department of Dermatology, University Medical Center Tübingen, Liebermeisterstrasse 25, 72076 Tübingen (Germany)

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Prof. Dr. Hans-Günther Schmalz

Corresponding Author

Prof. Dr. Hans-Günther Schmalz

Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Köln (Germany), Fax: (+49) 221-470-3064

Aram Prokop, Children's Hospital Cologne, Department of Paediatric Oncology, Amsterdamer Strasse 59, 50735 Köln (Germany)

Hans-Günther Schmalz, Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Köln (Germany), Fax: (+49) 221-470-3064

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First published: 09 August 2013
Citations: 20

Graphical Abstract

I gotta Fe-ling: Iron-containing nucleoside analogues, which were first synthesized during an exercise in stereoselective π-complex chemistry, exhibited pronounced cytotoxic and apoptosis-inducing activities, even against resistant cancer cell lines. Both hetero- (X=O) and carbocyclic (X=CH2) compounds were studied, and a synthetic route to R′-labeled derivatives was developed as a precondition for future biological experiments. TDS=thexyldimethylsilyl.

Abstract

The synthesis and stereochemical assignment of two classes of iron-containing nucleoside analogues, both of which contain a butadieneFe(CO)3 substructure, is described. The first type of compounds are Fe(CO)3-complexed 3′-alkenyl-2′,3′-dideoxy-2′,3′-dehydro nucleosides (2,5-dihydrofuran derivatives), from which the second class of compounds is derived by formal replacement of the ring oxygen atom by a CH2 group (carbocyclic nucleoside analogues). These compounds were prepared in a stereoselective manner through the metal-assisted introduction of the nucleobase. Whilst the furanoid intermediates were prepared from carbohydrates (such as methyl-glucopyranoside), the carbocyclic compounds were obtained by using an intramolecular Pauson–Khand reaction. Stereochemical assignments based on NMR and CD spectroscopy were confirmed by X-ray structural analysis. Biological investigations revealed that several of the complexes exhibited pronounced apoptosis-inducing properties (through an unusual caspase 3-independent but ROS-dependent pathway). Furthermore, some structure–activity relationships were identified, also as a precondition for the design and synthesis of fluorescent and biotin-labeled conjugates.