Christian Rivalle

Benzoindoloquinolines interact with DNA tetraplexes and inhibit telomerase

Telomeric G-rich single-stranded DNA can adopt a G-tetraplex structure which has been shown to inhibit telomerase activity. We have examined benzoindoloquinolines derivatives for their ability to stabilize an intramolecular G-quadruplex. The increase in T(m) value of the G-quadruplex was associated with telomerase inhibition in vitro.

Synthesis of 10-substituted 5H-pyrido[3′,4′ :4,5]pyrrolo[2,3-g]isoquinolines

The preparation of 6-amino-5-methyl isoquinolin-1 (2H)-one is described. Starting from this key intermediate, several derivatives of 5H-pyrido[3′,4′ :4,5]pyrrolo[2,3-g]isoquinoline substituted with various alkyl amino-groups at their 10-position have been synthesized.

Complementary advantages of fluorescence and SIMS microscopies in the study of cellular localization of two new antitumor drugs

Low light level fluorescence microscopy studies have been carried out on MCF7‐P human mammary tumor cells to localize the intracellular distribtion of two new anticancer drugs, Pazelliptine and Intoplicine, which are currently under clinical evaluation. These two molecules are thought to act at the nuclear level, through DNA topoisomerase interactions. Because fluorescence of these compounds appears strongly quenched by intercalation in double strand DNA, secondary ion mass spectrometry (SIMS) imaging was used to check the presence of the drugs in the nuclear compartment. In spite of chemical structure similitudes, pazelliptine and intoplicine appear to be distributed in quite different ways within the cells. Incubation for 1 and 24 hours also allowed us to bring to light strong differences in the distribution kinetics. Pazelliptine quickly enters into the nucleoli but is no longer present in the nucleus after 24 hours incubation. Intoplicine was not detected by fluorescence in the nucleus, however SIMS microscopy allowed us to show its accumulation within this cellular compartment as a function of time of exposure. This study shows the complementarity of fluorescence and SIMS microscopies. Microsc. Res. Tech. 36:287–295, 1997.

6,11-Dimethyl-5H-pyrido[3′,4′:4,5]pyrrolo[2,3-g]isoquinoline: a new aza-analogue of ellipticine

6,11-Dimethyl-5H-pyrido[3′,4′:4,5]pyrrolo[2,3-g]isoquinoline, an aza-analogue of ellipticine, has been prepared in four steps, starting from 4-chloro-3-nitropyridine and 6-amino-5,8-dimethylisoquinoline. Different unsuccessful attempts to prepare various pyrido[3′,4′:4,5]pyrrolo[2,3-g]isoquinolines by application of methods successfully used in the synthesis of several pyrido[4,3-b]carbazoles, are described.

Synthesis of 1-substituted ellipticines by a new route to pyrido[4,3-b]carbazoles

A new approach to pyrido[4,3-b]carbazole leading to 1-substituted ellipticines derivatives is described. A five-step synthesis starting from arenediazonium chlorides and 1-morpholinocyclohexenes gave 2-formyl-1-methyl-3,4-dihydrocarbazoles which were then aromatized by manganese dioxide to 2-formyl-1-methylcarbazoles. Knoevenagel malonic acid condensation afforded the corresponding trans-acrylic acids, the azides of which were cyclized in boiling diphenyl ether giving pyrido[4,3-b]carbazol-1 (2H)ones. These compounds were transfomed into 1-chlorojellipticines in boiling phosphorus oxychloride. Finally, the nucleophilic displacement of the chlorine atom by γ-diethylaminopropylamine provided the previously unknown 1-substituted pyrido[4,3-b]carbazoles.

Proton and charge transfer in the intercalating antitumour drug pazelliptine

The photophysical properties of the synthetic drug pazelliptine (PZE) have been investigated in order to characterize the geometric and electronic structure of the molecule bound to DNA. Whatever the pH of the solution, a proton tranfer reaction occurs in the excited state: this leads to the excited 9-N monoprotonated form of PZE. Deexcitation of this excited species is mainly non-radiative. A study of the fluorescence properties of sterically hindered derivatives allows us to propose the existence of a twisted internal charge transfer state to explain this non-radiative deexcitation. The formation of this state occurs on the picosecond timescale (τ∼ 200 ps) when PZE is fully protonated ring nitrogens (i.e. in acidic aqueous solutions).The acido-basic properties of PZE and five related amino and amino-substituted derivatives have been previously studied by spectroscopic measurements. The absorption, fluorescence spectra and the fluorescence quantum yields as a function of pH (range 2–12) and buffer concentration (50 mmol dm–3 to 1 mol dm–3) have been measured. Three pKa values have been determined, at 5.5, 6.5 and 9.2. This is good evidence for PZE having an appropriate pKa when bound to a hydrophobic and/or a hydrophilic structure.

Voie d'acces originale a des acetamido-3 amino-4 (IH) pyridones-2 par hydrogenation-rearrangement des nitro-3 amino-4 pyridines

Abstract 3-Nitro 4-alkyl (or aryl) amino pyridines were converted to 3-acetamido 4-a1ky1 (or aryl) amino (1H) pyridine-Z-ones by a catalytic hydrogenation-rearrangement in acetic acid medium.

N-1 substitution of 4-arylamino-3-nitropyridines by a heterocyclic ring-opening reaction

The normal substitution of 4-chloro-3-nitropyridine by primary aromatic amines is accompanied by the unexpected formation of 1-aryl-4-arylimino-3-nitropyridines. These products are formed via intermediate 4-arylamino-3-nitro-1-(3-nitro-4-pyridyl)pyridinium chlorides that are substituted by the primary amines by a mechanism involving addition–heterocyclic ring opening, closure, and elimination.

THERMOLYSE VON ALPHA‐ARYLOXY‐KETONEN 4. MITT. BLDG. VON ALPHA,BETA‐UNGESAETTIGTEN BENZOFURANONEN‐(2) DURCH ERHITZEN VON OMEGA‐ARYLOXY‐CROTONSAEUREESTERN

Der nach Reformatsky aus dem Keton (I) und dem Ester (II) erhaltene Hydroxyester (III) liefert durch Dehydratisierung ein Reaktionsgemisch, aus dem durch fraktionierte Destillation die isomeren Ester (IV) und (V) und das Benzofuranon (VI) isoliert werden.