title: Novel Nucleolipids of Pyrimidine β-D-Ribonucleosides: Combinatorial Synthesis, Spectroscopic Characterization, and Cytostatic/Cytotoxic Activities.
abstract: Four series of nucleolipids with either uridine, 5-methyluridine, 5-fluorouridine, and 6-azauridine as β-D-ribonucleoside component have been prepared in a combinatorial (not parallel!) manner (see Formulae). All compounds have been characterized by elemental analyses, ESI mass spectrometry as well as by (1) H-, and (13) C-NMR, and UV spectroscopy. A selection of eight nucleolipids with different lipophilizing moieties, based on earlier findings, as well as of 5-fluorouridine as control were first tested on their cytotoxic effect towards PMA-differentiated human THP-1 macrophages. Those compounds which did not exhibit a significant inhibitory effect on the survival of the macrophages were next tested on their cytostatic/cytotoxic effect towards the human astrocytoma/oligodendroglioma GOS-3 cells as well as against the rat malignant neuroectodermal BT4Ca cell line. Additionally, induction of apoptosis of the cell lines was evaluated. It turned out that particularly a combined lipophilization of the nucleosides by an 2',3'-O-ethyl levulinate residue plus a farnesyl moiety at N(3) of the pyrimidine moiety of the corresponding nucleolipids leads to an active compound with the highest probability.
authors.affiliation: Organic Chemistry I - Bioorganic Chemistry, Institute of Chemistry of New Materials, University of Osnabrück, Barbarastr. 7, DE-49069 Osnabrück.
authors.forename: Christine
authors.initials: C
authors.lastname: Knies
authors.affiliation: Anatomy and Cell Biology, Department of Medical Cell Biology, University of Marburg, Robert-Koch-Strasse 8, DE-35032 Marburg.
authors.forename: Katharina
authors.initials: K
authors.lastname: Hammerbacher
authors.affiliation: Anatomy and Cell Biology, Department of Medical Cell Biology, University of Marburg, Robert-Koch-Strasse 8, DE-35032 Marburg.
authors.forename: Gabriel A
authors.initials: GA
authors.lastname: Bonaterra
authors.affiliation: Anatomy and Cell Biology, Department of Medical Cell Biology, University of Marburg, Robert-Koch-Strasse 8, DE-35032 Marburg.
authors.forename: Ralf
authors.initials: R
authors.lastname: Kinscherf
authors.affiliation: Organic Chemistry I - Bioorganic Chemistry, Institute of Chemistry of New Materials, University of Osnabrück, Barbarastr. 7, DE-49069 Osnabrück. Helmut.Rosemeyer@uos.de.
authors.forename: Helmut
authors.initials: H
authors.lastname: Rosemeyer
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D020650:Combinatorial Chemistry Techniques; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D009369:Neoplasms / Q000188:drug therapy; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D012263:Ribonucleosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization; D013056:Spectrophotometry, Ultraviolet
chemical_list: D000970:Antineoplastic Agents; D011743:Pyrimidines; D012263:Ribonucleosides
keywords: BT4Ca; Combinatorial synthesis; Cytostatic/cytotoxic activity; GOS-3; Nucleolipids; THP-1