ABSTRACT
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.
Subject(s)
Autophagosomes/drug effects , Autophagy/drug effects , Coumarins/pharmacology , Lipogenesis/drug effects , Lipolysis/drug effects , Animals , Ascomycota/chemistry , Autophagosomes/metabolism , CHO Cells , Cholesterol Esters/biosynthesis , Coumarins/chemistry , Coumarins/isolation & purification , Cricetulus , HeLa Cells , Hep G2 Cells , Humans , Lipid Droplets/drug effects , Lipid Droplets/metabolism , Microtubule-Associated Proteins/metabolism , Stereoisomerism , Triglycerides/biosynthesisABSTRACT
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.
Subject(s)
Naphthols/chemistry , Penicillium/chemistry , Pyrones/chemistry , Models, Molecular , Nuclear Magnetic Resonance, Biomolecular , Spectrometry, Mass, Electrospray Ionization , Spectrophotometry, Infrared , Spectrophotometry, UltravioletABSTRACT
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).
Subject(s)
Enzyme Inhibitors/isolation & purification , Naphthols/isolation & purification , Penicillium/chemistry , Penicillium/metabolism , Pyrones/isolation & purification , Triglycerides/antagonists & inhibitors , Animals , Base Sequence , CHO Cells , Cell Survival/drug effects , Cricetinae , Cricetulus , DNA, Fungal/chemistry , DNA, Fungal/genetics , DNA, Ribosomal Spacer/chemistry , DNA, Ribosomal Spacer/genetics , Diacylglycerol O-Acyltransferase/antagonists & inhibitors , Diacylglycerol O-Acyltransferase/metabolism , Enzyme Inhibitors/pharmacology , Fermentation , Microscopy, Electron, Scanning , Molecular Sequence Data , Naphthols/chemistry , Naphthols/pharmacology , Penicillium/genetics , Polymerase Chain Reaction , Pyrones/chemistry , Pyrones/pharmacology , Triglycerides/biosynthesisABSTRACT
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.
