Hiroyuki Yamazaki

Synthesis and structure-activity relationship of pyripyropene A derivatives as potent and selective acyl-CoA:cholesterol acyltransferase 2 (ACAT2) inhibitors: part 1.

In an effort to develop potent and selective inhibitors toward ACAT2, structure-activity relationship studies were carried out using derivatives based on pyripyropene A (PPPA, 1). We have successfully developed novel PPPA derivatives with a 7-O-substituted benzoyl substituent that significantly exhibit more potent ACAT2 inhibitory activity and higher ACAT2 isozyme selectivity than 1.

Xanthoradones, new potentiators of imipenem activity against methicillin-resistant Staphylococcus aureus, produced by Penicillium radicum FKI-3765-2 : I. Taxonomy, fermentation, isolation and biological properties

The fungal strain FKI-3765-2, identified as Penicillium radicum, was found to produce potentiators of imipenem activity against methicillin-resistant Staphylococcus aureus (MRSA). Two new compounds, designated xanthoradones A and B, were isolated from the fermentation broth of the producing strain by solvent extraction, octadecyl silyl column chromatography and preparative HPLC. Xanthoradones A and B potentiated imipenem activity against MRSA by decreasing the MIC value of imipenem from 16u2009μgu2009ml−1 to 0.060 and 0.030u2009μgu2009ml−1, respectively.

New rugulosins, anti-MRSA antibiotics, produced by Penicillium radicum FKI-3765-2.

New rugulosins B (2) and C (3) were isolated together with known rugulosin (renamed rugulosin A in this paper, 1) from whole culture of Penicillium radicum FKI-3765-2, and their structures were elucidated by NMR spectroscopy. Rugulosins A and C were a homodimer of the same anthraquinone moieties, whereas rugulosin B was a heterodimer of analogous anthraquinone moieties. Rugulosins A to C showed antimicrobial activity against methicillin-resistant Staphylococcus aureus.

Pentacecilides, new inhibitors of lipid droplet formation in mouse macrophages, produced by Penicillium cecidicola FKI-3765-1: II. Structure elucidation

The structures of pentacecilides, new inhibitors of lipid droplet formation in mouse macrophages produced by Penicillium cecidicola FKI-3765-1, were elucidated by spectroscopic studies, including various NMR experiments. Pentacecilides have a common pentacyclic meroterpene core, which contains an aromatic ring and a δ-lactone ring.

Production of monapinones by fermentation of the dinapinone-producing fungus Penicillium pinophilum FKI-3864 in a seawater-containing medium

Five new monapinones, including a dinapinone monomer, were isolated from the culture broth of the dinapinone-producing Penicillium pinophilum FKI-3864 in a medium modified to contain seawater. The structures of these monapinones were elucidated by various NMR experiments. Monapinones possessed the same dihydronaphthopyranone skeleton as the dinapinones, with different hydroxyalkyl chains: monapinone A was identified as the monomeric portion of the atropisomer dinapinones A1 and A2, and monapinones A and B showed weak inhibition of triacylglycerol (TG) synthesis in intact mammalian cells, whereas the others showed almost no effect on TG synthesis.

Xanthoradones, new potentiators of imipenem activity against methicillin-resistant Staphylococcus aureus, produced by Penicillium radicum FKI-3765-2 II. Structure elucidation

The structures of xanthoradones A and B, new potentiators of imipenem activity against methicillin-resistant Staphylococcus aureus produced by Penicillium radicum FKI-3765-2, were elucidated by spectroscopic studies, including various NMR experiments. These compounds have an asymmetric biaryl skeleton, which contains dihydronaphthopyranone and naphthoquinone moieties.

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

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 dose-dependently 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 IC50 values of 3.65 and 4.76u2009μM 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.

Structure-activity Relationships of Stemphones, Potentiators of Imipenem Activity against Methicillin-resistant Staphylococcus aureus

From a further purification study, four new stemphones D to G were isolated along with previously reported stemphones B and C from the culture broth of Aspergillus sp. FKI-2136. Twenty-one derivatives were semisynthetically prepared from stemphones C, E and G. Potentiation of imipenem activity against methicillinresistant Staphylococcus aureus (MRSA) by all the stemphones including natural and semisynthetic ones was compared to study the structure-activity relationships. Derivatives with a free hydroxy or an O-acyl residue having a C2 to C5 carbon length at C-4 held the potentiating activity, but those with a longer acyl residue lost the activity. The presence of an oxo or a free hydroxy residue at C-10 is important for the potentiating activity because introduction of an alkyl or acyl residue at this position resulted in a loss of activity. Among them, stemphone E exhibited the most potent potentiation of imipenem activity against MRSA and the lowest cytotoxic activity against Jurkat cells.

Xanthoradone C, a new potentiator of imipenem activity against methicillin-resistant Staphylococcus aureus, produced by Penicillium radicum FKI-3765-2

Xanthoradone C, a new potentiator of imipenem activity against methicillin-resistant Staphylococcus aureus , produced by Penicillium radicum FKI-3765-2

Inhibition of Lipid Droplet Accumulation in Mouse Macrophages by Stemphone Derivatives

From a study on the biological activity of fungal stemphones and their derivatives, five derivatives having an O-alkyl moiety at C-11 of stemphone C were found to inhibit lipid droplet accumulation in macrophages without any cytotoxic effect. Among the derivatives, those having O-isopropyl and O-isobutyl were the most potent inhibitors by blocking the synthesis of both cholesteryl ester (CE) and triacylglycerol (TG), the main constituents of lipid droplets in macrophages.