Novel pyrrolo[3,2-f]quinolines: synthesis and antiproliferative activity.

Novel pyrrolo[3,2,f]quinoline derivatives have been synthesized and tested as antiproliferative agents. They are characterized by an angular aromatic tricyclic system, to which a methyl group can be bound at position 7, and by a methanesulfon-anisidide side chain as such, or lacking the m-methoxy substituent at position 1. The novel compounds were shown to exhibit cell growth inhibitory properties when tested against the NCI panel of cell lines, in particular those obtained from leukemias. Although the compounds are able to stimulate topoisomerase II poisoning at high concentration, the cell growth inhibition properties do not appear to rest principally on this mechanism of action. Overall, the most active proved to be compound 9, having the m-methoxy substituent typical of amsacrine, followed by the 7-methyl derivative 10 and by the unsubstituted compound 8. Comparison with previously investigated regioisomers shows modulation of activity dictated by the position and conformational freedom of side-chain groups.     

Synthesis and antiproliferative activity of some new DNA-targeted alkylating pyrroloquinolines

Two novel DNA-direct alkylating agents, consisting of aniline mustard linked to an angular 3H-pyrrolo[3,2-f]quinoline nucleus, were synthetized and assayed for their in vitro antiproliferative activity. Simple convergent synthesis, consisting of separate preparation of 9-chloro-3H-pyrrolo[3,2-f]quinoline and p-amino-aniline derivatives, and following their linkage by substitution reactions 8a, b and 10, yielded the corresponding diol derivatives 7b and 9. Biological properties were evaluated with respect to cell growth inhibition, ability to form cross-links with DNA, and capacity to give rise to a molecular complex with the macromolecule for 7b, 8b, 9 and 10.     

Innovative combination strategy to enhance effect and diminish adverse effects of glucocorticoids: another promise?

In a paper by Zimmermann and colleagues in this issue of Arthritis Research & Therapy, results of extended laboratory research with the drug combination of prednisolone and dipyridamole are reported. There seems to be a boost and extension of the glucocorticoid effect by the combination, without a clear increase of adverse effects, potentially allowing the application of lower dosages. However, laboratory models are not patients and the glucocorticoid mechanisms leading to effects and adverse effects are manifold. The next required step will be to demonstrate the improved therapeutic window in patients in adequate comparative clinical trials, assessing predefined beneficial effects and adverse effects in a standardized way.     

Synthesis of new chelating surfactants from octyl d-glucopyranosiduronic acid and amino acids for metal flotation

A new family of surfactants with metal-chelating properties was synthesized in few steps from octyl d-glucopyranosiduronic acid. The complexing function was either a carboxylic acid or a hydroxamic acid function introduced after coupling with glycine, aspartic acid, or glutamic acid and finally hydroxylamine. Interfacial properties were determined. Flotation experiments on a laboratory scale have been performed with Fe(III) solutions as model contaminant metal.     

Mitochondrial inner membrane permeabilisation enables mtDNA release during apoptosis

During apoptosis, pro‐apoptotic BAX and BAK are activated, causing mitochondrial outer membrane permeabilisation (MOMP), caspase activation and cell death. However, even in the absence of caspase activity, cells usually die following MOMP. Such caspase‐independent cell death is accompanied by inflammation that requires mitochondrial DNA (mtDNA) activation of cGAS‐STING signalling. Because the mitochondrial inner membrane is thought to remain intact during apoptosis, we sought to address how matrix mtDNA could activate the cytosolic cGAS‐STING signalling pathway. Using super‐resolution imaging, we show that mtDNA is efficiently released from mitochondria following MOMP. In a temporal manner, we find that following MOMP, BAX/BAK‐mediated mitochondrial outer membrane pores gradually widen. This allows extrusion of the mitochondrial inner membrane into the cytosol whereupon it permeablises allowing mtDNA release. Our data demonstrate that mitochondrial inner membrane permeabilisation (MIMP) can occur during cell death following BAX/BAK‐dependent MOMP. Importantly, by enabling the cytosolic release of mtDNA, inner membrane permeabilisation underpins the immunogenic effects of caspase‐independent cell death.     

The mode of dislocation ofAstropecten aranciacus

Summary 1. The mode of dislocation of the sea starAstropecten aranciacus was investigated on 23 individuals at the NE-coast of Sardinia. All were small to medium-sized representatives of the species; their radius (R) varied between 5 and 15 cm. The observations were carried out on 2 level sediments with different sand-grain diameter. Each sea star was followed for 30 min and its locations were recorded every minute.2.A. aranciacus does not move continuously. It stops intermittently for an average duration of 2 minutes. On coarse grained sand, stops occur more frequently than on fine grained sand.3. The average distance travelled in 30 min was 3.7 m on fine sand, 1.6 m on coarse sand. Including the stops, the cruising speed varied mostly between 0 and 20 cm/min on fine sand, and between 0 and 10 cm/min on coarse sand.4. Generally, the observed paths were all or partially straight. In accord with this, the ratio W/D between the distance travelled (W) and the shortest between the starting and end position (D) was smaller than 2 for most animals.5. Small ripple marks (on fine sand) do not seem to influence the direction of dislocation. Single observations indicate, however, that more pronounced ripple marks (on coarse sand) may have an influence.

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Die Dislokationsweise vonAstropecten aranciacus

Kurzfassung An der Nordküste Sardiniens wurden auf einer Sandfläche in 8 m Tiefe Exemplare des SeesternsAstropecten aranciacus einzeln während einer 30minütigen Beobachtungsdauer verfolgt. Jede Minute steckte ein Taucher eine numerierte Steckmarke eine Handbreite hinter dem sich fortbewegenden Seestern in den Sand. Nachher wurden die Wege vermessen. Auf diese Weise wurden 23 Seesterne verfolgt. Die Auswertung der Beobachtungsdaten erbrachte Aufschlüsse über Wegrichtung und Richtungsänderung, Geschwindigkeit der Fortbewegung, Häufigkeit und Dauer des Anhaltens, Einfluß der Sandkorngröße auf Haltefrequenz und Geschwindigkeit der Fortbewegung und Einfluß des Verlaufs und der Höhe von Rippelmarken auf die Wegrichtung.