RESUMO
Atropisomers with a biaryl dihydronaphthopyranone structure, dinapinones A1 (DPA1) (M position) and A2 (DPA2) (P position), were isolated from the fungus culture broth of Talaromyces pinophilus FKI-3864 as inhibitors of [14C]neutral lipid ([14C]triacylglycerol (TG) and [14C]cholesteryl ester (CE)) synthesis from [14C]oleic acid in Chinese hamster ovary-K1 (CHO-K1) cells. DPA2 inhibited [14C]TG and [14C]CE synthesis (IC50s, 0.65 and 5.6 µM, respectively), but DPA1 had no inhibitory activity on [14C]TG and [14C]CE synthesis even at 12 µM. However, a 1:1 mixture of DPA1 and DPA2 (DPAmix) had the most potent inhibitory activity on [14C]TG and [14C]CE synthesis (IC50s, 0.054 and 0.18 µM, respectively). The mechanism of action of DPAmix was investigated. DPAmix had no effects on the enzymes involved in neutral lipid synthesis, while DPAmix enhanced the degradation of [14C]neutral lipids with concomitant decrease in cytosolic lipid droplets accumulated in CHO-K1 cells. From analysis of autophagy marker proteins, DPAmix caused dose-dependent induction of microtubule-associated protein light chain 3-II (LC3-II) and degradation of p62. In the autophagic flux assay using bafilomycin A1, DPAmix upregulated autophagosome turnover. These results reveal that DPAmix enhances neutral lipid degradation together with induction of autophagy.
Assuntos
Autofagossomos/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Cumarínicos/farmacologia , Lipogênese/efeitos dos fármacos , Lipólise/efeitos dos fármacos , Animais , Ascomicetos/química , Autofagossomos/metabolismo , Células CHO , Ésteres do Colesterol/biossíntese , Cumarínicos/química , Cumarínicos/isolamento & purificação , Cricetulus , Células HeLa , Células Hep G2 , Humanos , Gotículas Lipídicas/efeitos dos fármacos , Gotículas Lipídicas/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Estereoisomerismo , Triglicerídeos/biossínteseRESUMO
A new bis-naphtho-γ-pyrone isomer named isochaetochromin A(1) was isolated along with known isochaetochromins B(1) and B(2) from the culture broth of Penicillium sp. FKI-4942 by solvent extraction, silica gel column chromatography and HPLC. Among them, isochaetochromin B(1) showed the most potent inhibitory activity of triacylglycerol synthesis with an IC(50) value of 5.6 µM, followed by isochaetochromins B(2) (IC(50), 11 µM) and A(1) (33 µM).
Assuntos
Inibidores Enzimáticos/isolamento & purificação , Naftóis/isolamento & purificação , Penicillium/química , Penicillium/metabolismo , Pironas/isolamento & purificação , Triglicerídeos/antagonistas & inibidores , Animais , Sequência de Bases , Células CHO , Sobrevivência Celular/efeitos dos fármacos , Cricetinae , Cricetulus , DNA Fúngico/química , DNA Fúngico/genética , DNA Espaçador Ribossômico/química , DNA Espaçador Ribossômico/genética , Diacilglicerol O-Aciltransferase/antagonistas & inibidores , Diacilglicerol O-Aciltransferase/metabolismo , Inibidores Enzimáticos/farmacologia , Fermentação , Microscopia Eletrônica de Varredura , Dados de Sequência Molecular , Naftóis/química , Naftóis/farmacologia , Penicillium/genética , Reação em Cadeia da Polimerase , Pironas/química , Pironas/farmacologia , Triglicerídeos/biossínteseRESUMO
The structure of a new congener of chaetochromin, an inhibitor of triacylglycerol synthesis in CHO-K1 cells produced by Penicillium sp. FKI-4942, was elucidated by spectroscopic methods, including various NMR experiments. Isochaetochromin A(1) has a bis-naphtho-γ-pyrone moiety.
Assuntos
Naftóis/química , Penicillium/química , Pironas/química , Modelos Moleculares , Ressonância Magnética Nuclear Biomolecular , Espectrometria de Massas por Ionização por Electrospray , Espectrofotometria Infravermelho , Espectrofotometria UltravioletaRESUMO
The structure of a new pentacecilide congener, pentacecilide D, produced by Penicillium cecidicola FKI-3765-1 was elucidated by various NMR experiments. The absolute stereochemistry of pentacecilides was elucidated by using the modified Mosher method for pentacecilide C. The inhibitory activity of all pentacecilides against lipid droplet formation and acyl-CoA:cholesterol acyltransferase isozymes was compared.