RESUMO
Keto-substituted hydrocarbons with 11-19 methylene and bis-terminal hydroxyl and carboxyl groups have been synthesized and evaluated in both in vivo and in vitro assays for their potential to favorably alter lipid disorders including metabolic syndrome. Compounds were assessed for their effects on the de novo incorporation of radiolabeled acetate into lipids in primary cultures of rat hepatocytes as well as for their effects on lipid and glycemic variables in obese female Zucker fatty rats [Crl:(ZUC)-faBR] following 1 and 2 weeks of oral administration. The most active compounds were found to be symmetrical with four to five methylene groups separating the central ketone functionality and the gem dimethyl or methyl/aryl substituents. Furthermore, biological activity was found to be greatest in both in vivo and in vitro assays for the tetramethyl-substituted keto diacids and diols (e.g., 10c, 10g, 14c), and the least active were shown to be the bis(arylmethyl) derivatives (e.g., 10e, 10f, 14f). Compound 14c dose-dependently elevated HDL-cholesterol, reduced triglycerides, and reduced NEFA, with a minimum effective dose of 30 mg/kg/day. Compound 1 g dose-dependently modified non-HDL-cholesterol, triglycerides, and nonesterified fatty acids, with a minimum effective dose of 10 mg/kg/day. At this dose, compound 10g elevated HDL-cholesterol levels 2-3 times higher than pretreatment levels, and a dose-dependent reduction of fasting insulin and glucose levels was observed.
Assuntos
Álcoois/síntese química , Ácidos Dicarboxílicos/síntese química , Hidrocarbonetos/síntese química , Hipolipemiantes/síntese química , Cetoácidos/síntese química , Cetonas/síntese química , Lipídeos/biossíntese , Doenças Metabólicas/tratamento farmacológico , Álcoois/química , Álcoois/farmacologia , Animais , Células Cultivadas , HDL-Colesterol/biossíntese , HDL-Colesterol/sangue , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/metabolismo , Ácidos Dicarboxílicos/química , Ácidos Dicarboxílicos/farmacologia , Relação Dose-Resposta a Droga , Feminino , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hidrocarbonetos/química , Hidrocarbonetos/farmacologia , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/metabolismo , Hipolipemiantes/química , Hipolipemiantes/farmacologia , Cetoácidos/química , Cetoácidos/farmacologia , Cetonas/química , Cetonas/farmacologia , Masculino , Doenças Metabólicas/metabolismo , Ratos , Ratos Sprague-Dawley , Ratos ZuckerRESUMO
A system suitable for tracking the amounts and locations of ca. 10 000 chemicals is described.
RESUMO
A 1H nuclear magnetic resonance study of Sepia melanin, Sepia melanin free acid (Sepia MFA) and human hair melanin was carried out in deuterium oxide solution at pH 10-11. The empirical formula of Sepia MFA was calculated and used to estimate the number of protons in the aromatic region of the Sepia MFA polymeric chain and to suggest a possible monomeric unit profile.
