Efficient breakage of DNA apurinic sites by the indoleamine related 9-amino-ellipticine.

The aromatic amine, 9-NH2-ellipticine, is a synthetic DNA intercalating derivative of the antitumor agent ellipticine, which breaks circular DNA containing apurinic sites. This breakage is inhibited when the apurinic (AP) sites are reduced. The concentration of 9-NH2-ellipticine required to get a significant effect (0.1 microM) is the lowest known among chemicals which induce the same breakage reaction. Comparison with the action of structurally related amines shows that the amino-indole structure is specific for AP sites. The ability of ellipticine derivatives to induce breakage in DNA containing apurinic sites is related to the nucleophile substituent in position 9. Two ellipticine derivatives with known antitumor activity, BD 40 and 9-OH-ellipticine, were able to break purified DNA at apurinic sites.

[Syntheses designed to produce 8-amino ellipticine. Synthesis and pharmacological properties of 8-nitro ellipticine]. / Synthèses en vue de l'obtention de l'amino-8 ellipticine: synthèse et propriétés pharmacologiques de la nitro-8 ellipticine.

The synthesis of 8-nitro ellipticine starting from 6-nitro indole is reported. It is the first derivative of ellipticine substituted in position 8 obtained by total synthesis. In contrast to 9-nitro ellipticine the 8-nitro derivative could until now not be reduced to 8-amino ellipticine. To obtain the latter it was intended to arylate an enamine of the 2,5,8-trimethyloctahydroisoquinolone-6 by 1-chloro 2,4-dinitrobenzene, followed by a reductive cyclization and N-demethylating aromatization. Since the yield of the arylation step was low, the isoquinolone was replaced by 2,5-dimethyl cyclohexanone and the synthesis would have to be completed by addition of a pyridine ring. In the case the yield of the aromatisation was 37%, but the carbazole derivative resisted all formylation attempts. 8-Nitro ellipticine was investigated for its DNA affinity, its cytotoxic activity on L 1210 tumors cells and its toxicity in the mouse. The results obtained were compared with those for 9-nitro ellipticine and in regard to cytotoxicity, with those for the 8- and 9-hydroxy ellipticines.

[9-Nitro- and 9-amino-ellipticines and derivatives: synthesis and pharmacologic properties]. / Nitro-9 et amino-9 ellipticines et dérivés: synthèse et propriétés pharmacologiques.

Preparation of 9-nitroellipticine starting from 1,4-dimethyl-6-nitrocarbazole and its reduction according to the Béchamp method followed by acetylation. The salts of 9-nitro-2-methyl- and 9-amino-2-methyl ellipticinium were tested for cytotoxic activity on different tumor strains for mutagenicity, for affinity for DNA and cytochrome P450 and for toxicity in the mouse. The results obtained were compared with those found under the same conditions with 9-hydroxyellipticine and its corresponding ellipticinium salt.

[Derivatives of 2,3,4,5,-tetrahydro-1H-pyrido-(3,2-b)azepine and 2,3,4,5-tetrahydro-1H-pyrido(2,3-b)azepine and their corresponding lactams. II. Synthesis and pharmacologic study of their psychotropic activity]. / Derivés de la tétrahydro-2,3,4,5 1H-pyrido[3,2-b]azépine, de la tétrahydro-2,3,4,5 1H-pyrido[2,3-b]azépine et de leurs lactames correspondants. II. Synthèse et étude pharmacologique de leur activité psychotrope.

Preparation of the N-(2-diethylaminoethyl) derivatives of lactam (II) and of the N-(3-dimethylaminopropyl) derivative of lactam (XI) is described. Synthesis of the N-[4-(2-hydroxyethyl)piperazinylacetyl]- and 1-carbothiamide derivatives of azepine (I) and of the n-(chloroformyl)- and N-(carbamoyl) derivatives of azepine (XII) are also described. Some pharmacological results indicate a partial tranquilizing activity.

[Tetrahydropyridoazepine and tetrahydropyridoazepinone derivatives. I. Derivatives of 2,3,4,5-tetrahydro-1H-pyrido[3,2b]azepine and of the corresponding lactam]. / Dérivés de tétrahydropyridoazépines et de tétrahydropyridoazépinones. I - Dérivés de la tétrahydro-2,3,4,5 1H-pyrido[3,2-b]azépine et du lactame correspondant.

Preparation of N-derivatives of 2,3,4,5-tetrahydro-1H-pyrido[3,2-b]azepine and, in one case, of 2,3,4,5-tetrahydro-1H-pyrido[3,2-b]azepine-2-one was achieved by introducing the substituents COCl, CONH2, CO2(CH2)3N(CH3)2, COCH2Br and (CH2)3N(CH3)2. The pharmacological results indicate some effect on the ANS.

[Azotized emetine analogues: synthesis and evaluation of the anti-amebic and anti-tumoral action of aza-3 emetine and attempted synthesis of aza-2 emetine]. / Analogues azotés de l'émétine: synthèse et évaluation de l'activite antiamibienne et antitumorale de l'aza-3 émétine, et essais d'obtention de l'aza-2 émétine.

The synthesis of the N,N-bis-(acetylhomoveratrylamido)-1-hydroxymethyl and 1-carboxypropylamines (III a) and (III b) is described. Until now, these molecules could not been cyclized to the corresponding isoquinoline compounds. An attempted synthesis of 3-azaemetine by condensing homoveratrylamine with acetonedicarboxylic acid or its esters did not yield the expected diamide (XIV). However, by subjecting 1,3-bis-(1,2,3,4-tetrahydro-6,7-dimethoxy-1-isoquinolyl)acetone (XV) to a reducing aminoalkylation, one obtained the corresponding ethylamino derivative (XVI) which could be cyclized through Mannich reaction to give 3-azaemetine. The pharmacological screening showed 3-azaemetine to be less toxic than emetine in the mouse and without antiamebic and antitumor activity against P 388 Leukaemia in the mouse (25).