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 butadiene-Fe(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.
Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Köln (Germany), Fax: (+49) 221-470-3064.
Christoph
C
Hirschhäuser
Juraj
J
Velcicky
Daniel
D
Schlawe
Erik
E
Hessler
André
A
Majdalani
Jörg-Martin
JM
Neudörfl
Aram
A
Prokop
Thomas
T
Wieder
Hans-Günther
HG
Schmalz
D017209:Apoptosis / Q000187:drug effects; D001710:Biotin / Q000138:chemical synthesis* / Q000737:chemistry; D005456:Fluorescent Dyes / Q000138:chemical synthesis* / Q000737:chemistry; D007501:Iron / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008667:Metalloproteins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D009705:Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
D005456:Fluorescent Dyes; D008667:Metalloproteins; D009705:Nucleosides; D001710:Biotin; D007501:Iron
antitumor agents; apoptosis; carbonyl ligands; iron; nucleosides