RESUMEN
2,2,2-Trifluoro-1-{4-[(4-fluorophenyl)amino]pyrimidin-5-yl}-1-[1-(methylsulfonyl)piperidin-4-yl]ethanol 1 was identified as a novel potent aldosterone synthase inhibitor. Despite large species differences, compound 1 inhibits both human and rodent CYP11B2 in a nano-molar range.
Asunto(s)
Compuestos de Anilina/química , Compuestos de Anilina/farmacología , Citocromo P-450 CYP11B2/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Citocromo P-450 CYP11B2/metabolismo , Células HEK293 , HumanosAsunto(s)
Trastorno Obsesivo Compulsivo , Trastornos de Tic , Adulto , Antipsicóticos/uso terapéutico , Femenino , Humanos , Masculino , Trastorno Obsesivo Compulsivo/complicaciones , Trastorno Obsesivo Compulsivo/diagnóstico , Trastorno Obsesivo Compulsivo/fisiopatología , Trastorno Obsesivo Compulsivo/psicología , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Trastornos de Tic/complicaciones , Trastornos de Tic/diagnóstico , Trastornos de Tic/fisiopatología , Trastornos de Tic/psicologíaRESUMEN
We previously reported that overexpressing connexin 26 (Cx26) enhances the spontaneous metastasis of mouse BL6 melanoma cells. In contrast, daily intraperitoneal injections of an oleamide derivative named MI-18 potently inhibits the spontaneous metastasis of BL6 cells. In the present study, we chemically synthesized a novel oleamide derivative named MI-22 and found that it also efficiently suppressed the spontaneous metastasis of BL6 cells. Both MI-18 and MI-22 inhibited the gap junction-mediated intercellular communications (GJIC) that are formed between HeLa cells by the ectopic expression of the hCx26 and hCx32 human connexin subtypes; however, they had no effect on GJIC mediated by hCx40, hCx43 or hCx45. Fluorescently labeled MI-18 primarily localized not only at plasma membrane but also at Golgi/endosome. This suggests that this oleamide derivative may also act on the Cx26 molecules that accumulate in the Golgi/endosome because of their overexpression. Notably, neither derivative had a cytotoxic effect on HeLa cells when they were added into the tissue culture medium. Taken together, we propose that the MI-18 and MI-22 oleamide derivatives may serve as prototypes for novel and clinically important anticancer drugs.
Asunto(s)
Conexinas/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Ácidos Oléicos/química , Ácidos Oléicos/farmacología , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Conexina 26 , Conexinas/clasificación , Conexinas/genética , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Estructura Molecular , Metástasis de la Neoplasia/patología , Metástasis de la Neoplasia/prevención & control , Ácidos Oléicos/síntesis químicaRESUMEN
The title domino reactions were developed to directly provide tetrahydrofuro[3,4-c]isoxazole derivatives (5 and 9) in > or =90% ee from racemic alpha-hydroxynitrones (2 and 6), which were used in the concise asymmetric total synthesis of (-)-rosmarinecine .