RESUMO
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.
Assuntos
Compostos de Anilina/química , Compostos de Anilina/farmacologia , Citocromo P-450 CYP11B2/antagonistas & inibidores , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Citocromo P-450 CYP11B2/metabolismo , Células HEK293 , HumanosAssuntos
Transtorno Obsessivo-Compulsivo , Transtornos de Tique , Adulto , Antipsicóticos/uso terapêutico , Feminino , Humanos , Masculino , Transtorno Obsessivo-Compulsivo/complicações , Transtorno Obsessivo-Compulsivo/diagnóstico , Transtorno Obsessivo-Compulsivo/fisiopatologia , Transtorno Obsessivo-Compulsivo/psicologia , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Transtornos de Tique/complicações , Transtornos de Tique/diagnóstico , Transtornos de Tique/fisiopatologia , Transtornos de Tique/psicologiaRESUMO
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.
Assuntos
Conexinas/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Ácidos Oleicos/química , Ácidos Oleicos/farmacologia , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Conexina 26 , Conexinas/classificação , Conexinas/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Metástase Neoplásica/patologia , Metástase Neoplásica/prevenção & controle , Ácidos Oleicos/síntese químicaRESUMO
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 .