RESUMO
We have previously reported compound 2 as a inhibitor of acyl-coenzyme A:cholesterol O-acyltransferase (ACAT) and up-regulator of the low density lipoprotein receptor (LDL-R) expression. In this study we focused on compound 2, a unique LDL-R up-regulator, and describe the discovery of a novel class of up-regulators of LDL-R. Replacement the methylene urea linker in compound 2 with an acylsulfonamide linker kept a potent LDL-R up-regulatory activity, and subsequent optimization work gave compound 39 as a highly potent LDL-R up-regulator (39; EC(25) = 0.047 microM). Compound 39 showed no ACAT inhibitory activity even at 1 microM. The sodium salts of compound 39 reduced plasma total and LDL cholesterol levels in a dose-dependent manner in an experimental animal model of hyperlipidemia. Moreover, we revealed in this study using RNA interference that autosomal recessive hypercholesterolemia (ARH), an adaptor protein of LDL-R, is essential for compound 39 up-regulation of LDL-R expression.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Hipolipemiantes/síntese química , Pirimidinas/síntese química , Receptores de LDL/biossíntese , Ácidos Sulfônicos/síntese química , Animais , Disponibilidade Biológica , Linhagem Celular Tumoral , LDL-Colesterol/sangue , Cricetinae , Humanos , Hiperlipidemias/sangue , Hiperlipidemias/tratamento farmacológico , Hipolipemiantes/farmacocinética , Hipolipemiantes/farmacologia , Masculino , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Interferência de RNA , Esterol O-Aciltransferase/antagonistas & inibidores , Relação Estrutura-Atividade , Ácidos Sulfônicos/farmacocinética , Ácidos Sulfônicos/farmacologia , Triglicerídeos/sangue , Regulação para CimaRESUMO
Enediyne model compounds possessing photo-triggering devices were developed. These enediynes afforded biradicals by UV irradiation and showed DNA cleaving activity. The DNA damage was confirmed to be mainly caused by the biradical, not singlet oxygen.