RESUMO
Analogues of the antitumor drug S 16020-2 modified at the 9, 10, or 11 position were synthesized and evaluated in vitro and in vivo on the P388 leukemia and B16 melanoma models. Starting from 9-methoxy-5, 11-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxylic acid ethyl ester, the 11-CH3 analogue of 9-hydroxy-5,6-dimethyl-6H-pyrido[4, 3-b]carbazole-1-carboxylic (2-(dimethylamino)ethyl)amide (1), compound 4, was synthesized using a four-step sequence, whereas its 10-CH3 analogue 5 was prepared using a two-step pathway, starting from compound 1. Finally starting from the 9-OH compounds 1, 4, and 5, a series of variously 9-O-substituted derivatives were synthesized. In these series, the most active compounds resulted from esterification of the 9-OH group with various aliphatic diacids, which led to 9-O-CO-( )-COOH derivatives of 1, 4, and 5. For these compounds, the number of long-term surviving mice obtained at the optimal dose were 60-100% in the ip/iv P388 leukemia and 10-35% in the ip/ip B16 melanoma, corresponding to an improved therapeutic index with respect to 1 and 4. This high antitumor activity, with curative examples in both models, was not due to a higher cytotoxicity since these compounds were equally or slightly less potent in vitro than 1 and 4. The most active compounds were thus selected for further in vivo evaluation.
Assuntos
Antineoplásicos/síntese química , Elipticinas/síntese química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Divisão Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Elipticinas/química , Elipticinas/farmacologia , Concentração Inibidora 50 , Leucemia P388/tratamento farmacológico , Leucemia P388/patologia , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/patologia , Metilação , Camundongos , Transplante de Neoplasias , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
Starting from 2-(6-methoxy-1-methylcarbazol-2-yl)ethylamine and diethyl-2,6-pyridine dicarboxylate, the title compounds were obtained through five or six steps. The new compounds retained significant cytotoxicity towards various tumor cell lines, but in vivo studies on murine P388 leukemia, B16 melanoma and Lewis lung carcinoma showed a lowered antitumor activity with respect to that of the related olivacine lead compound 1.
Assuntos
Antineoplásicos/síntese química , Piridinas/síntese química , Animais , Antibióticos Antineoplásicos/farmacologia , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Sobrevivência Celular/efeitos dos fármacos , DNA de Neoplasias/efeitos dos fármacos , Doxorrubicina/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Leucemia P388/tratamento farmacológico , Melanoma Experimental/tratamento farmacológico , Camundongos , Piridinas/farmacologia , Células Tumorais CultivadasRESUMO
Oxidative modification of low-density lipoprotein (LDL) is thought to play a key role in the formation of foam cells and in the initiation and progression of the atherosclerotic plaque. After evaluation of a large number of original drugs, S 12340 was found to be the most potent compound in inhibiting in a dose-dependent manner the human LDL oxidative modification induced either by copper ions or by cultured endothelial cells. Both the electrophoretic mobility and the thiobarbituric acid reactive substances returned to almost normal values in the presence of 0.5 microM of S 12340. Watanabe heritable hyperlipidemic rabbits were treated orally for 3 days or for 1 month with S 12340 to evaluate the potential protective effect of the compound on LDL oxidative modification induced ex vivo. Purified LDL from placebo and treated rabbits were submitted to oxidation, and S 12340 was effectively able to protect LDL in a dose-dependent manner and at doses as low as 10 mg/kg/day. Purified LDL from animals sacrificed at various times after oral administration of S 12340 were protected against oxidation for at least 6 h after the last administration of the compound. These findings are in good agreement with the plasma and LDL levels of S 12340 in these WHHL rabbits. S 12340, probucol and vitamin E were all able to decrease the optical density of the 1,1-diphenyl-2-picrylhydrazyl solution, demonstrating their free radical scavenging properties. The pharmacological properties of the compound suggest that S 12340 may be of potential interest for a new therapeutic approach to atherosclerosis.
Assuntos
Antioxidantes/farmacologia , Lipoproteínas LDL/efeitos dos fármacos , Probucol/análogos & derivados , Compostos de Espiro/farmacologia , Animais , Células Cultivadas , Cobre/metabolismo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Lipoproteínas LDL/metabolismo , Oxirredução/efeitos dos fármacos , Probucol/farmacologia , Coelhos , Vitamina E/farmacologiaRESUMO
Oxidative stress induced by reactive oxygen species is one aspect of the deleterious mechanisms involved in myocardial post-ischemic reperfusion injury. The antioxidant properties of the new molecule S12340 (8-[3-(3,5-diterbutyl-4-hydroxyphenyl-thio)propyl]-1-oxa-2- oxo-3,8-diazaspiro[4.5]decane) were evaluated using three successive in vitro approaches mimicking the cardiac cell damages induced by reactive oxygen species released into the reperfused myocardium. (i) The effects of S12340 on lipid peroxidation were evaluated using an original cell-free model of non-enzymatic peroxidation of 1.32 mM arachidonic acid induced by reactive oxygen species generated photochemically. S12340 (13.2 microM) inhibited by 29% the rate of oxidative fragmentation of monohydroperoxidized arachidonic acid into aldehydic products. (ii) S12340 (10 microM) inhibited by 96% and 58% the oxidative necrosis of cultured rat cardiomyocytes induced by xanthine oxidase (20 mU/ml) and monohydroperoxidized arachidonic acid (30 microM), respectively. (iii) Superfusion of guinea-pig papillary muscle with monohydroperoxidized arachidonic acid (20 microM) resulted in marked alterations of their electrophysiological and mechanical activities. These modifications, maximal 15-17 min after the addition of lipid hydroperoxide, were completely abolished by S12340 (30 microM).