Beauveriolide

1. Discovery, producing organism and structures 1-5,10)
Beauveriolides I1-3), III2,3), IV, V, VI, VII, VIII and IX5) (beauveroplide Fa4)) were isolated fromthe culture broth of the fungal strain Beauveria sp. FO-6979 and identified by means of an intact
cell assay as inhibitors of macrophage foam cell formation. Beauveriolides have a cyclodepsipeptide structure consisting of three amino acids and a ß-hydroxylic acid. Beauveriolide I has
been reported as an insecticidal agent 1), beauveriolide IX was identified as beauveriolide Fa4),
and the planar structure of beauveH3CR1riolide VI was identical with that of5)
OO
beauveriolide M .
O
R4NHHNR2O
Beauveriolides
IIII
IVVVI
VIIVIIIIX

Beauveria sp. FO-6979
Bar: 10 µm

R3R1O
R2R3I
-CH3-CH3I
-CH3V
-CH3V
-CH3V
I
-CH3-(CH2)2CH3 V
I-CH3II
II
II
II
IIII
III

H3C

CH3CH3I

N
H

II

CH3H3C

III

R4III
IV

V
IV

III
VIV
IV

H3C

CH3VIV

2. Physical data (Beauveriolide III) 3)
White powder. C27H41N3O5; mol wt 487.30. Sol. in MeOH, EtOH, acetone, CH3CN, EtOAc,CHCl3. Insol. in H2O, hexane.

3. Fermentation6)
Addition of L-Leu or L-Ile, but not D-Leu or D-allo-Ile, to the culture medium yielded high andselective production of beuveriolide I or III.
Condition
Control+ L-Ile+ D-Ile+ L-allo-Ile+ D-allo-Ile+ L-Leu+ D-Leu+ L-Phe+ L-Ala+ L-Val

Production (µg/mL)
Beauveriolide I
25.0
5.6
25.0
24.0
14.0
127.0
24.0
66.0
15.4
6.8

III
50.0
172.0
50.0
42.0
33.0
26.048.0 X 5.1
79.0
26.6
7.9
L-Leu

I
H3C

H3C
III

O

H3C

H3C
D-Leu

H3C

HN

D-allo-IleO

CH3OO
NH

HNO
H3C

N
H
L-Ala

O
L-Phe

X 3.5

I & III
X1
L-IIe

I & III
X2
L-Ala

L-Phe

4. Structure-activity relationship8,9,11)
Comparison of ACAT inhibitory activity among natural beauveriolides and synthetic derivatives8,9,10) revealed the structure-activity relationship.

5. Biological activity2,12-14)
Inhibition of lipid droplet formation in mouse peritoneal macrophages.
In the early stages of atherosclerogenesis, macrophages that penetrate into the intima accumulatemassive lipid droplets in the cytosols, and are converted into foam cells, leading to the development of atherosclerosis in the arterial wall. Therefore, inhibitors of macrophage lipid droplet
formation would be expected to retard progression of atherosclerosis.
Inhibitory activity against lipid droplet formation in macrophages was tested in a cell assay using mouse peritoneal macrophages. Beauveriolides I and III led to a reduction in the numberand size of cytosolic lipid droplets in macrophages at 15 µM without any cytotoxic effect on themacrophages.

3 µM

Beauveriolide I

10 µM

Control

3 µM

Beauveriolide III

10 µM

6. References
1.		
K. Mochizuki et al., Bull. Chem. Soc. Jpn. 66, 3041-3046 (1993)
2. [707] I. Namatame et al., J. Antibiot. 52, 1-6 (1999)
3. [708] I. Namatame et al., J. Antibiot. 52, 7-12 (1999)
4.		
J. F. Grove et al., J. Chem. Soc. Perkin Trans I 1795-1799 (1980)
5.		
M. Kuzma et al., J. Mass Spectrom. 36, 1108-1115 (2001)
6. [820] I. Namatame et al., J. Antibiot. 55, 1048-1052 (2002)
7. [899] D. Nagai et al., J. Antibiot. 57, 1-9 (2004)
8. [904] K. Nagai et al., J. Comb. Chem. 8, 103-109 (2006)
9. [921] T. Ohshiro et al., J. Org. Chem. 71, 7643-7649 (2006)
10. [963] H. Tomoda & S. Ōmura, Pharmacol. Ther. 115, 375-389 (2007)
11. [997] K. Nagai et al., Bioorg. Med. Chem. Lett. 18, 4397-4400 (2008)
12.		
T. Doi et al., Bioorg. Med. Chem. Lett. 22, 696-699 (2012)
13. [1051] T. Ohshiro et al., Chem. Pharm. Bull. 57, 377-381 (2009)
14. [850] I. Namatame et al., Proc. Natl. Acad. Sci. USA 101, 737-742 (2004)