RESUMEN
New alkyl imidazoline derivatives have been synthesized as potential anti-cancer agents. The anti-proliferative activity of these compounds, evaluated against representative human haematological and solid neoplastic cell lines, showed that N, N'-di (4,5-dihydro-1H-imidazol-2-yl)3-aza-1,10-decane-diamine (8) and N, N'-di (4,5-dihydro-1H-imidazol-2-yl)3-aza-1,10-dodecane-diamine (9) were the most active compounds; in fact, they inhibited the cell proliferation at submicromolar concentrations. In enzyme assays, compound 9 turned out to be an inhibitor of topoisomerase II at concentrations comparable with those of the reference topoisomerase II inhibitor, etoposide.
Asunto(s)
Alcanos/síntesis química , Proliferación Celular/efectos de los fármacos , ADN-Topoisomerasas de Tipo II/metabolismo , Diaminas/síntesis química , Alcanos/química , Alcanos/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Diaminas/química , Diaminas/farmacología , Humanos , Ligandos , Relación Estructura-ActividadRESUMEN
We investigated the structure-activity relationships for the interactions of fatty acid amide analogs of the endocannabinoid anandamide with human recombinant cannabinoid receptors. Thirty-five novel fatty acid amides were synthesized using five different types of acyl chains and 11 different aromatic amine 'heads.' Although none of the new compounds was a more potent ligand than anandamide, we identified three amine groups capable of improving the metabolic stability of arachidonoylamides and their CB(1)/CB(2) selectivity ratio to over 20-fold, and several aromatic amines capable of improving the affinity of short chain or monosaturated fatty acids for cannabinoid CB(1) receptors. For the first time a tertiary amide of arachidonic acid was found to possess moderate affinity (K(i)=300 nM) for cannabinoid CB(1), but not CB(2), receptors.
Asunto(s)
Amidas/química , Química Farmacéutica/métodos , Ácidos Grasos/química , Receptores de Cannabinoides/química , Amidohidrolasas/química , Ácido Araquidónico/química , Ácidos Araquidónicos/química , Moduladores de Receptores de Cannabinoides/química , Cannabinoides/química , Línea Celular , Cromatografía , Diseño de Fármacos , Endocannabinoides , Humanos , Concentración 50 Inhibidora , Cinética , Ligandos , Modelos Químicos , Alcamidas Poliinsaturadas , Unión Proteica , Estructura Terciaria de Proteína , Proteínas Recombinantes/químicaRESUMEN
The anti-amoebic power of a series of bis-thioureidic derivatives against amoeba, responsible for a serious form of keratitis of the cornea, has been analysed. The synthesis of these products is also described.
Asunto(s)
Acanthamoeba/efectos de los fármacos , Amebicidas/farmacología , Tiourea/análogos & derivados , Tiourea/química , Animales , Córnea/parasitología , Humanos , Técnicas In Vitro , Queratitis/parasitología , Espectroscopía de Resonancia Magnética , Pruebas de Sensibilidad Parasitaria , Relación Estructura-Actividad , Tiourea/farmacologíaRESUMEN
Recent developments in biomedical science have shown that free radicals are involved in many diseases. They attack the unsaturated fatty acids in the biomembrane resulting in membrane lipid peroxidation, which is strongly connected to aging, carcinogenesis and atherosclerosis. Free radicals also attack DNA and cause mutation leading to cancer. In addition lipid peroxidation is an important factor of deterioration in the processing and storage of food. Therefore, it is important to search for new effective radical scavengers (Sci. Rev. 2 (1997) 152; J. Nat. Prod. Rev. 63 (2000) 1035). In this manuscript we describe the antioxidant activity of new thioureidic compounds.
Asunto(s)
Antioxidantes/química , Tiourea/análogos & derivados , Tiourea/química , Cristalización , Depuradores de Radicales Libres/química , Humanos , Ácido Linoleico/química , Superóxidos/química , Xantina Oxidasa/química , beta Caroteno/químicaRESUMEN
The therapy of human cancer is one of the more pursued goals by medicinal chemistry research. Most of the compounds clinically used as a treatment owe their efficacy to their cytotoxic interaction (direct or indirect) with nuclear DNA. This interaction results in the inhibition of DNA synthesis and the degradation of nucleic strands. Ellipticine is a naturally occurring 6H-pyrido[4,3-b]carbazole alkaloid endowed with antitumor activity, and several ellipticine derivatives have been used in clinical trials. We previously reported some 1,4-dimethyl-9H-carbazole derivatives structurally related to ellipticine. The purpose of our research was to transform the pyridocarbazole in a prodrug so that it would have more penetration in the tumor cells and block their replication. Our prodrug is slowly hydrolyzed in human plasma in the corresponding acid. From these preliminary results, we deduce that our compound can block cellular replication. Our hypothesis is that the antitumoral activity is probably related to the induction of damage to DNA, without cellular lysis in the short term.
Asunto(s)
Antineoplásicos/síntesis química , Carbazoles/síntesis química , Sistemas de Liberación de Medicamentos/métodos , Piridonas/síntesis química , Timidina/síntesis química , Antineoplásicos/farmacología , Carbazoles/farmacología , Línea Celular Tumoral , Evaluación Preclínica de Medicamentos/métodos , Humanos , Piridonas/farmacología , Nucleósidos de Pirimidina/síntesis química , Nucleósidos de Pirimidina/farmacología , Timidina/farmacologíaRESUMEN
Seven morpholin derivatives were synthesized (compounds 1-7) and their behavioural effects were evaluated; the elements considered were locomotor activity, motor coordination, catalepsy, stereotyped behaviour and antinociception. All the compounds, at doses of 10-20-40 mg/kg/i.p., induced a reduction of all behavioural elements without a significant antinociceptive effect. These results indicate that these morpholin derivatives affect the central nervous system.