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

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.