Bioorganic & Medicinal Chemistry Letters 18 (2008) 4397–4400
Bioorganic & Medicinal Chemistry Letters
Synthesis and biological evaluation of a focused library of beauveriolides
Kenichiro Nagai a, Takayuki Doi b, Taichi Ohshiro c, Toshiaki Sunazuka a, Hiroshi Tomoda c,
b
a,
*
¯
Takashi Takahashi , Satoshi Omura
a Kitasato Institute for Life Sciences and Graduate School of Infection Control Sciences, Kitasato University and The Kitasato Institute, 5-9-1 Shirokane, Minato-ku,
Tokyo 108-8641, Japan
b Department of Applied Chemistry, Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro, Tokyo 152-8552, Japan
c School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Fungal beauveriolide III (1b), discovered as an inhibitor of lipid droplet accumulation in mouse macro-
Received 15 May 2008
Revised 16 June 2008
Accepted 17 June 2008
Available online 20 June 2008
phages and showing antiatherogenic activity in mouse model, consists of
(3S, 4S)-3-hydroxy-4-methyloctanoic acid moieties. A combinatorial library of beauveriolide analogues
focusing on -Ala and -allo-Ile of 1b was synthesized by combinatorial synthesis. Among them, -Ala
analogues consisting of A{2} improved their solubility, while those with 7{1,3,2},7{2,3,1}, and 7{2,3,2}
were 20 times more potent than 1b.
L-Phe, L-Ala, D-allo-Ile, and
L
D
D
Keywords:
Ó 2008 Elsevier Ltd. All rights reserved.
Cyclic depsipeptide
Focused library
Antiatherogenic activity
ACAT
Lipid droplet accumulation in macrophages is a critical stage for
plaque formation, which limits blood flow and rupture of blood
vessels, ultimately leading to the development of atherosclerosis
in the arterial wall. Thus, inhibitors for lipid droplet accumulation
in macrophages would be useful for the treatment of atherosclero-
sis.1 Beauveriolides are a family of cyclic depsipeptides isolated
from a culture broth of Beauveria sp. FO-6979 during the course
of our screening program for inhibitors of lipid droplet accumula-
tion in mouse macrophages. In particular, beauveriolides I (1a) and
III (1b) were found to dose-dependently reduce the number and
size of lipid droplets in mouse macrophages without cytotoxicity,
and to inhibit cholesteryl ester (CE) synthesis with IC50 values of
4
3
R
O
O
O
Beauveriolide I (1a)
Beauveriolide III (1b)
R
NH
HN
O
N
O
H
Figure 1. Structures of beauveriolides I and III.
tionships.5a In the 3-hydroxy-4-methyloctanoic acid moiety, the
importance of stereochemistry of the 3-hydroxyl and 4-methyl
groups has been investigated. The configuration of the 3S hydroxyl
group is essential for the activity because isomers with an inverted
hydroxyl group at C-3 were inactive, while the stereochemistry of
the methyl group at C-4 did not affect the inhibition of CE synthe-
sis.5b Naturally occurring beauveriolides IV, V, and VI in which
0.78 and 0.41 l
M, respectively (Fig. 1).2a,b,3 In addition, beauverio-
lides decreased atherogenic lesions in the aorta and heart when
administrated orally to apoE and LDL receptor knockout mice. This
mode of action has been examined indicating that 1a and 1b inhi-
bit CE synthesis by blocking acyl-CoA:cholesterol acyltransferase
(ACAT) activity to suppress foam cell formation.2c
Synthetic ACAT inhibitors including amides, ureas, and imida-
zoles do not have structural similarity to beauveriolides, which
are expected to be promising lead compounds for the treatment
of atherosclerosis.4 We established a method for combinatorial
synthesis of beauveriolide analogues using a 2-chlorotrityl chloride
linker and evaluated their inhibitory activity against CE synthesis
in mouse macrophages to elucidate partial structure–activity rela-
L
-Phe is replaced with
L
-Val show remarkably decreased activity.2d
With regard to the -Phe moiety, p- and m-chloro substituents on
L
the phenyl ring enhanced the activity. Furthermore, the diphenyl
alanine analogue was 10-fold more potent than 1b.5 These results
indicate that the phenyl group can be replaced by aromatic rings to
increase the activity. To date, the effects of substituents on
and -Leu parts in 1a (or -allo-Ile in 1b) are unclear. Herein, we
report on the synthesis of beauveriolide analogues focusing on
the -Ala and -Leu (or -allo-Ile) parts and evaluation of their
ACAT inhibitory activity in cell- and enzyme-based assays.
L-Ala
D
D
L
D
D
* Corresponding author. Fax: +81 3 3444 8360.
¯
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.06.054