UPTAKE, METABOLISM, AND METABOLIC EFFECTS OF THE ANTITUMOR TRICYCLIC NUCLEOSIDE, 3-AMINO-1, 5-DIHYDRO-5-METHYL-1-BETA-D-RIBOFURANOSYL-1, 4, 5, 6, 8 PENTAAZAACENAPHTHYLENE

The uptake, metabolism, and metabolic effects of the antitumor tricyclic nucleoside (TCN, NSC-154020) were studied in vitro. Uptake of TCN by human erythrocytes was concentrative, resulting mainly from the rapid intracellular phosphorylation of TCN. At high TCN doses, however, unchanged TCN was also concentrated within the erythrocytes. The initial linear rate of TCN uptake was saturable and obeyed Michaelis-Menten kinetics. TCN was metabolized chiefly to its 5'-monophosphate not only by human erythrocytes but also by wild-type Chinese hamster ovary (CHO) cells. In addition, three other metabolites were detected by means of high-performance liquid chromatography. The structures of these metabolites were elucidated by ultraviolet spectroscopy, infrared spectroscopy, mass spectrometry, and further confirmed by incubations with catabolic enzymes and intact wild-type or variant CHO cells. All were novel types of oxidative degradation products of TCN. Two are proposed to be (alpha) and (beta) anomers of a D-ribofuranosyl nucleoside with a pyrimido{4,5-c}pyridazine-4-one base structure. The third metabolite is most likely the 5'-monophosphate of the (beta) anomer. A CHO cell line deficient in adenosine kinase activity failed to phosphorylate either TCN or the (beta) anomer. No further phosphorylation of the 5'-monophosphates by normal cells occurred. Although the pathways leading to the formation of these TCN metabolites have not been proven, a mechanism is proposed to account for the above observations. The same adenosine kinase-deficient CHO cells were resistant to 500 (mu)M TCN, while wild-type cells could not clone in the presence of 20 (mu)M TCN. Simultaneous addition of purines, pyrimidines, and purine precursors failed to reverse this toxicity. TCN-treatment strongly inhibited formate or glycine incorporation into ATP and GTP of wild-type CHO cells. Hypoxanthine incorporation inhibited to a lesser degree, with the inhibition of incorporation into GTP being more pronounced. Although precursor incorporation into GTP was inhibited, GTP concentrations were elevated rather than reduced after 4-hr incubations with 20 (mu)M or 50 (mu)M TCN. These results suggested an impairment of GTP utilization. TCN (50 (mu)M) inhibited leucine and thymidine incorporation into HClO(,4)-insoluble material to 30-35% of control throughout 5-hr incubations. Incorporation of five other amino acids was inhibited to the same extent as leucine. Pulse-labeling assays (45 min) with uridine, leucine, and thymidine failed to reveal selective inhibition of DNA or protein synthesis by 0.05-50 (mu)M TCN; however, the patterns of inhibition were similar to those of known protein synthesis inhibitors. TCN 5'-monophosphate inhibited leucine incorporation by rabbit reticulocyte lysates; the inhibition was 2000 times less potent than that of cycloheximide. The 5'-monophosphate failed to inhibit a crude nuclear DNA-synthesizing system. Although TCN 5'-monophosphate apparently inhibits purine synthesis de novo, its cytotoxicity is not reversed by exogenous purines. Consequently, another mechanism such as direct inhibition of protein synthesis is probably a primary mechanism of toxicity. ^

Structural Studies of Transition Metal Complexes with 4,5-Bis(2-pyridylmethylsulfanyl)-4‘,5‘-ethylenedithiotetrathiafulvalene: Probing Their Potential for the Construction of Multifunctional Molecular Assemblies

Three divalent transition metal complexes of 4,5-bis(2-pyridylmethylsulfanyl)-4‘,5‘-ethylenedithiotetrathiafulvalene have been prepared and crystallographically characterized. The isostructural Co(II) and the Ni(II) complexes show octahedral geometries around the metal ions with the coordination sites occupied by the pyridyl nitrogen atoms and the thioether sulfur atoms of the ligand and cis coordination of the halide ions. Cyclic voltammetry reveals that the complexation leads to a small anodic shift in the first oxidation potential of the TTF system.

Cantiques de Salomon Rossi : chants, psaumes et hymnes à 3, 4, 5, 6, 7 et 8 voix

Transcrits en notation moderne et publiés par S. Naumbourg

Der Aufruhr in Dresden am 3., 4., 5., 6., 7., 8. und 9. Mai 1849 : nach amtlichen Quellen geschildert

Boberach: Der Dresdner Mai-Aufstand wird als Teil einer "allgemeindeutschen Demokratenverschwörung" gedeutet, bei der die Deutschkatholiken sich der antikatholischen Stimmung in Sachsen bedienten

Programm für die Generalversammlung der Lehrer an den höheren Schulen der Provinz Brandenburg, welche zu Berlin am 3., 4., 5. October 1848 stattfinden wird

Boberach: Anträge und Thesen von Gerber, Krech, Seyffert, Bergmann, Mützell, Holäufer, Hamann, Graser: Die Schule soll Staatsanstalt unter Beteiligung der Gemeinden, Landkreise und Regierungsbezirke, der Religionsunterricht auf die Elementarklassen beschränkt sein. Der Direktor muß die Beschlüsse des Lehrerkollegiums ausführen. Die Lehrer sollen höhere Pensionen erhalten. Die Schulamtskandidaten sollen zuerst ein halbes Jahr lang hospitieren. Die Lehrerseminare sollen hinsichtlich der praktischen Ausbildung reformiert, an der Universität ein Lehrstuhl für Pädagogik errichtet werden. Außerdem sollen Lehr- und Stundenpläne der Gymnasien und die Gründung eines Provinzialvereins behandelt werden

Zur Kritik der Mischnot Edujot 1, 3. 4. 5. u. 6.

M. Schwarzauer

Abwehr und Berichtigung der in Engler's Bot. Jahrb. Bd. 31, Heft 4/5, 1902 von Prof. Dr. E. Warming aus Kopenhagen veröffentlichten >Anmerkungen< zu meiner Arbeit über die Vegetation der ostfriesischen Inseln

Von Dr. A. Hansen

Inc. hebr. 1 Bd. 4/5 - Canon

Vorbesitzer: Abraham Berliner;

Zweiter Wettstreit deutscher Männergesangvereine zu Frankfurt a. M., 4. 5. 6. Juni 1903

Signatur des Originals: S 36/F03763

Zweiter Wettstreit deutscher Männergesangvereine zu Frankfurt a. M., 4. 5. 6. Juni 1903

Signatur des Originals: S 36/F03764

Zweiter Wettstreit deutscher Männergesangvereine zu Frankfurt a. M., 4. 5. 6. Juni 1903

Signatur des Originals: S 36/F03767