Synthesis of a staurosporine analogue possessing a 7-azaindole unit instead of an indole moiety

The synthesis of a new staurosporine analogue possessing a 7-azaindole unit instead of an indole moiety is described. This synthesis could be achieved by coupling a sugar moiety previously tosylated in 2′ position to the azaindolocarbazole aglycone. Nucleophilic substitution on the carbon bearing the tosyl group yielded to the key cyclization leading to a compound in which the carbohydrate part is linked to both indole and azaindole nitrogen

A three-step synthesis from rebeccamycin of an efficient checkpoint kinase 1 inhibitor.

International audienceRebeccamycin derivative 1 bearing a sugar moiety linked to both indole nitrogens and an amino substituent on the carbohydrate unit was synthesized in three steps from the bacterial metabolite. This compound was found to be a highly potent checkpoint kinase 1 inhibitor with an IC50 value of 2.8 nM

Modèles de coût pour la sélection de vues matérialisées dans le nuage, application aux services Amazon EC2 et S3

National audienceDans les bases et entrepôts de données, la performance des requêtes est classiquement assurée grâce à des structures comme les caches, les index et les vues matérialisées. Dans ce contexte, des modèles de coût permettent de sélectionner un ensemble efficace de ce type de structures. Toutefois, cette tâche de sélection devient plus complexe dans le nuage, car en plus des temps de réponse, il faut simultanément optimiser le coût monétaire d'utilisation du nuage. En conséquence, nous proposons dans cet article de nouveaux modèles de coût qui intègrent le paradigme de paiement à la demande en vigueur dans les nuages informatiques. Sur la base de ces modèles, nous définissons un problème d'optimisation consistant à sélectionner, parmi un ensemble de vues candidates, celles qu'il faut matérialiser pour minimiser le coût d'interrogation et de maintenance de la base de données, ainsi que le temps de réponse à une charge de requêtes donnée. Dans un premier temps, nous optimisons les deux critères précédents séparément: le temps de réponse est optimisé sous contrainte de coût et vice versa. Les expériences que nous avons menées pour valider cette proposition montrent que la matérialisation de vues dans le nuage est toujours avantageuse

Synthesis of pyridino[3',2' :4,5]pyrrolo[3,2-g]pyrrolo-[3,4-e]indolizin-1,3-dione and pyrrolo[3,2-c]pyrazole skeletons

A three step synthesis of an isogranulatimide analogue, in which the imidazole moiety is replaced by a pyrrole unit and the indole heterocycle is replaced by a 7-azaindole moiety is described. Moreover, a novel synthetic pathway to the pyrrolo[3,2-c]pyrazole skeleton is reporte

Synthesis of dipyrrolo [3,4-a:3,4-c]carbazole-1,3,4,6-tetraones bearing a sugar moiety.

The synthesis of a series of dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6-tetraones, structurally related to the G2 checkpoint inhibitor granulatimide and bearing a sugar moiety, is described. Substitutions were carried out at the 6-position of the glycosyl unit to lead to an amino substituent as observed in many biologically active compounds such as anthracyclins or staurosporine

Accurate evolutions of inspiralling neutron-star binaries: assessment of the truncation error

We have recently presented an investigation in full general relativity of the dynamics and gravitational-wave emission from binary neutron stars which inspiral and merge, producing a black hole surrounded by a torus (see arXiv:0804.0594). We here discuss in more detail the convergence properties of the results presented in arXiv:0804.0594 and, in particular, the deterioration of the convergence rate at the merger and during the survival of the merged object, when strong shocks are formed and turbulence develops. We also show that physically reasonable and numerically convergent results obtained at low-resolution suffer however from large truncation errors and hence are of little physical use. We summarize our findings in an "error budget", which includes the different sources of possible inaccuracies we have investigated and provides a first quantitative assessment of the precision in the modelling of compact fluid binaries.Comment: 13 pages, 5 figures. Minor changes to match published version. Added figure 5 right pane

Synthesis, in vitro antiproliferative activities, and Chk1 inhibitory properties of indolylpyrazolones and indolylpyridazinedione

The synthesis of 5-indolylpyrazol-3-one, 4-indolylpyrazol-3-one and 4-indolyl-pyridazin-3,6-dione is reported. Their Chk1 inhibitory properties have been evaluated and their in vitro antiproliferative activities toward three tumor cell lines: murine leukemia L1210, human colon carcinoma HT29 and HCT116 have been determined. 4-Indolyl-pyridazin-3,6-dione is inactive against Chk1 and exhibits weak cytotoxicities toward the tumor cell lines tested. The IC50 values toward Chk1 of the two indolylpyrazolones are identical and are in the micromolar range, but the cytotoxicities of 4-indolylpyrazol-3-one are significantly stronger than those of 5-indolylpyrazol-3-one. Since 4-indolylpyrazol-3-one and 5-indolylpyrazol-3-one can present several conformers and tautomeric forms, molecular modelling in the ATP binding site of Chk1 has been carried out to investigate which form could induce the best stabilization in the active site of the enzyme. To get an insight into the kinase selectivity of these compounds, their inhibitory activities toward Src kinase were evaluate

Synthesis, in vitro antiproliferative activities, and Chk1 inhibitory properties of dipyrrolo[3,4-a:3,4-c]carbazole triones.

The syntheses of dipyrrolo[3,4-a:3,4-c]carbazole-1,4,6-triones and dipyrrolo[3,4-a:3,4-c]carbazole-3,4,6-triones are reported. These compounds can be considered as granulatimide analogues in which a maleimide replaces the imidazole moiety and a five-membered lactam ring replaces the upper maleimide. The Chk1 inhibitory properties of the more soluble compounds have been evaluated and their in vitro antiproliferative activities toward three tumor cell lines: murine leukemia L1210, and human colon carcinoma HT29 and HCT116. Due to their insolubility, the biological activities of the other compounds in this series could not be evaluated. All the tested compounds proved to be potent Chk1 inhibitor

Synthesis, in vitro antiproliferative activities, and Chk1 inhibitory properties of pyrrolo[3,4-a]carbazole-1,3-diones, pyrrolo[3,4-c]carbazole-1,3-diones, and 2-aminopyridazino[3,4-a]pyrrolo[3,4-c]carbazole-1,3,4,7-tetraone

The synthesis of substituted pyrrolo[3,4-a]carbazole-1,3-diones, pyrrolo[3,4-c]carbazole-1,3-diones, and 2-aminopyridazino[3,4-a]pyrrolo[3,4-c]carbazole-1,3,4,7-tetraone is reported. Their inhibitory properties toward Checkpoint 1 kinase (Chk1) have been evaluated and their in vitro antiproliferative activities toward three tumor cell lines: murine leukemia L1210, human colon carcinoma HT29 and HCT116 have been determined. From the biological results, it appears that, in contrast with the upper E heterocycle, the lower D heterocycle is not absolutely required for Chk1 inhibition. The ATP binding pocket of Chk1 seems to be adaptable to substitution of the nitrogen of the imide E heterocycle with a hydroxymethyl group, allowing the fundamental hydrogen bond with the Glu85 residue of the enzym

Synthesis and biological evaluation of new dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6-tetraones, substituted with various saturated and unsaturated side chains via palladium catalyzed cross-coupling reactions

The syntheses of a series of dipyrrolo[3,4-a:3,4-c]carbazole-1,3,4,6-tetraones, substituted in 10-position with saturated and unsaturated side chains, via palladium catalyzed cross-coupling reactions, are described. These compounds can be considered as granulatimide bis-imide analogues. Their inhibitory activity toward Chk1 kinase and their antiproliferative activities in vitro in four tumor cell lines are reporte