Pentacecilides, new inhibitors of lipid droplet formation in mouse macrophages, produced by Penicillium cecidicola FKI-3765-1: I. Taxonomy, fermentation, isolation and biological properties

Abstract

New compounds designated pentacecilides A to C were isolated from the fermentation broth of Penicillium cecidicola FKI-3765-1 by solvent extraction, silica gel column chromatography and preparative HPLC. Pentacecilides A and B dosedependently inhibited lipid droplet formation in mouse macrophages. Furthermore, pentacecilides A and B were found to inhibit the synthesis of cholesteryl ester in mouse macrophages with respective IC 50 values of 3.65 and 4.76 lM without any cytotoxic effect, but pentacecilide C showed almost no activity. The study of the mechanism of action strongly suggested that pentacecilides A and B inhibit acyl-CoA: cholesterol acyltransferase activity in macrophages.

Absolute stereochemistry of pentacecilides, new inhibitors of lipid droplet formation in mouse macrophages, produced by Penicillium cecidicola FKI-3765-1

“…Pentacecilide A is the most potent inhibitor of CE synthesis in the three assays, followed by pentacecilide B. 1 Unfortunately, pentacecilides D and 3 showed almost no inhibitory activity at 22.5-24.2 mM.…”

“…1,2 Pentacecilide D was from 13-day-old culture broth fermented as reported previously. 1 For determination of the amounts of pentacecilide D in culture broths, samples (ethyl acetate extracts) dissolved in methanol were analyzed by the HP1100 system (Hewlett-Packard, Palo Alto, CA, USA) under the following conditions: column, Symmetry (2.1Â150 mm; Waters, Milford, MA, USA); flow rate, 0.2 ml min À1 ; mobile phase, a 20-min linear gradient from 60% CH 3 CN to 100% CH 3 CN containing 0.050% H 3 PO 4 ; detection, UV at 210 nm. Under these conditions, pentacecilide D was eluted with a retention time of 3.59 min, respectively.…”

“…In the previous study, pentacecilides inhibited cholesteryl ester (CE) synthesis in mouse macrophages and ACAT1-and ACAT2-CHO cells, strongly suggesting that they were dual inhibitors of ACAT1 and ACAT2 isozymes. 1 Pentacecilide D and semisynthetic 3S * -hydroxy pentacecilide A (3) were evaluated in these three cellbased assays, and the IC 50 values of CE synthesis were compared. Pentacecilide A is the most potent inhibitor of CE synthesis in the three assays, followed by pentacecilide B.…”

“…Furthermore, pentacecilides appeared as dual inhibitors of ACAT1 and ACAT2 isozymes. 1,[3][4][5][6][7] The structures including the relative stereochemistry were also elucidated; 2 however, the indication of the relative stereochemistry at C-2 was revised 8,9 because erroneous structures of pentacecilides had been shown in our previous reports. 1,2 Further precise analysis of metabolites in the whole culture led to the discovery of a new congener named pentacecilide D (Figure 1).…”

“…1,2 From the biochemical study, 1 pentacecilides inhibited lipid droplet formation in mouse macrophages, probably due to the blockade of acyl-CoA:cholesterol acyltransferase (ACAT) activity. Furthermore, pentacecilides appeared as dual inhibitors of ACAT1 and ACAT2 isozymes.…”