Inhibitory Activity to Protein Prenylation and Antifungal Activity of Zaragozic Acid D3, a Potent Inhibitor of Squalene Synthase Produced by the Fungus, Mollisia sp. SANK 10294.

Q4 · MEDICINE

Article

Author: Satoshi Ohya ; Tatsuo Tanimoto ; Yoshio Tsujita

Recently we found novel zaragozic acids (ZAs), F-10863A (zaragozic acid D3, ZAD3), B, C and D in the culture broth of the fungus Mollisia sp. SANK 10294 as potent inhibitors of squalene synthase. There are several other enzymes that use farnesylpyrophosphate as their substrate. Among them we chose farnesyl-protein transferase and examined whether ZAD3 and F-10863B inhibit this enzyme's activity. ZAD3 and F-10863B inhibited farnesyl-protein transferase with IC50 values of 0.60 and 3.7 microM, respectively. They also inhibited geranylgeranyl-protein transferase at similar concentrations. In addition, they exhibited potent antifungal activity.

01 Jan 1997·The Journal of AntibioticsQ4 · MEDICINE

Biological Activities of Novel Zaragozic Acids, the Potent Inhibitors of Squalene Synthase, Produced by the Fungus, Mollisia sp. SANK 10294.

Q4 · MEDICINE

Article

Author: Tomoko Hirayama ; Kiyoshi Hamano ; Mayumi Kakusaka ; Yoshio Tsujita ; Tatsuo Tanimoto ; Teiichiro Koga ; Yoko Shimada ; Kaori Onodera ; Tsuyoshi Hosoya

Four novel zaragozic acids, F-10863A, B, C and D, were isolated from a culture broth of the fungus Mollisia sp. SANK 10294. F-10863 compounds contain a 4,6,7-trihydroxy-2,8-dioxyobicyclo-[3.2.1]octane-3,4,5-tricarboxyl ic acid core like previously reported zaragozic acids, but the structures of the side chains are different. Recently, it was found that F-10863A is identical to zaragozic acid D3, while the other three are novel compounds. F-10863 compounds are potent inhibitors of squalene synthase like previously reported zaragozic acids, and, furthermore, they exhibit serum cholesterol-lowering activity in vivo.

01 Jan 1997·Folia Pharmacologica Japonica

Inhibitory action of natural compounds of microbial origin on cholesterol metabolism

Review

Author: Fujioka, T

1) Repeated administration of pravastatin significantly increased serum and liver cholesterol in rats. Hepatic LDL receptor activity was not changed and VLDL cholesterol secretion from the liver was increased. Net cholesterol synthesis in rat liver was increased after 7 days of repeated pravastatin administration. These results suggest that for rats, unlike other animals for which serum cholesterol is decreased, induced HMG-CoA reductase activity due to pravastatin treatment might overcome the inhibitory capability of pravastatin. 2) In the course of screening for squalene synthase inhibitors, novel zaragozic acids-F10863A, B, C and D-containing zaragozic acid D3 were isolated. F10863A was most potent and selectively inhibited cholesterol synthesis in freshly isolated rat hepatocytes among several cultured and isolated cells. It also showed in vivo serum cholesterol-lowering effects in hamsters and marmosets. However, the inhibition for squalene synthase proved to cause acidosis due to the accumulation of farnesol-derived dicarboxylic acids in urines. 3) A novel acyl-CoA: cholesterol acyltransferase (ACAT) inhibitor, designated epi-cochlioquinone A, a stereoisomer of cochlioquinone A, which has been previously reported as a nematocidal agent, was isolated from the fermentation broth of Stachybotrys bisbyi. It inhibited in vivo cholesterol absorption in rats by 50% at 75 mg/kg.

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Indication	Highest Phase	Country/Location	Organization	Date
Hyperlipidemias	Preclinical	JP	Sankyo Corp.	-

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