Synthesis of a series of novel 2,4,5-trisubstituted selenazole compounds as potential PLTP inhibitors

Article abstract of DOI:10.1016/j.bmcl.2010.07.017

Based on a homology-modeled structure of PLTP and characteristic structural features of reported cholesteryl ester transfer protein (CETP) inhibitors, we designed and synthesized a novel series of 2,4,5-trisubstituted selenazole compounds. Biological evaluation reveals that compounds 12 and 17 exhibit favorable PLTP activity, and their IC₅₀s are 8 μM and 10 μM, respectively.

Full text of DOI:10.1016/j.bmcl.2010.07.017

Bioorganic & Medicinal Chemistry Letters 20 (2010) 5123–5125
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis of a series of novel 2,4,5-trisubstituted selenazole compounds as
potential PLTP inhibitors
a
Cui Ling a, Zhibing Zheng a, Xian Cheng Jiang b, Wu Zhong a, , Song Li
*
a Laboratory of Computer-Aided Drug Design & Discovery, Beijing Institute of Pharmacology and Toxicology, Taiping Road 27, Beijing 100850, PR China
b Department of Cell Biology, State University of New York, Downstate Medical Center, Brooklyn, NY, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Based on a homology-modeled structure of PLTP and characteristic structural features of reported cho-
lesteryl ester transfer protein (CETP) inhibitors, we designed and synthesized a novel series of 2,4,5-tri-
substituted selenazole compounds. Biological evaluation reveals that compounds 12 and 17 exhibit
Received 30 March 2010
Revised 24 June 2010
Accepted 7 July 2010
favorable PLTP activity, and their IC50s are 8
l
M and 10
l
M, respectively.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Atherosclerosis
PLTP inhibitor
2,4,5-Trisubstituted selenazole
Complications of atherosclerosis are among the most common
causes of death in Western societies. Lipid imbalances are thought
to be important contributors to the progression of this complex dis-
ease. It is generally accepted that elevated levels of LDLc increase the
risk of developing atherosclerosis, whereas HDLc appears to be pro-
tective. Plasmaphospholipidtransferprotein(PLTP), a secreted plas-
ma protein with 476 amino acid residues, plays an essential role in
HDL metabolism.1 As one of the extracellular lipid transfer proteins,
PLTP has three distinct functions: (1) mediating the transfer of
remaining phospholipids and free cholesterol to HDL during the
lipolysis of triglyceride-rich lipoproteins; (2) modulating the con-
version of HDL subfractions; and (3) regulating the secretion of
ApoB-containing lipoproteins from the liver.2
The relationship between PLTP and human atherosclerosis is
still under investigation. Studies indicate that systemic PLTP defi-
ciency is atheroprotective in different strains of hypercholesterol-
emic mice and that sustained over-expression of plasma PLTP in
PLTP-transgenic or bone marrow-transplanted mice leads to an in-
creased risk of atherosclerosis.3–7 In further support of the proath-
erogenic potential of plasma PLTP in vivo, a positive correlation
between PLTP activity and the risk of coronary artery disease
was observed in humans.8 After assessing the current evidence
on the role of PLTP under all conditions, Vergeer et al. came to
the conclusion that PLTP could be an attractive therapeutic target.9
Although presently known risk factors have some predictive value
for coronary artery disease (CAD), a major part of the variability in
this process remains unexplained.10 Therapies aimed at lowering
LDL cholesterol only reduce a fraction (roughly 30%) of the burden
of atherosclerotic disease.11 It is extremely important to improve
our understanding and treatment of the disease. Exploration of
the PLTP inhibition is one such approach.
Since there are no reported three dimensional structures of
PLTP, molecular design based directly on protein structure is
impossible. Also, when this project started, there were no reported
structures of PLTP inhibitors, which could have provided potential
lead compounds. Our goal in this Letter is to describe our efforts to
discover compounds that exhibit PLTP inhibiting activity in vitro.
PLTP displays sequence homology to three other proteins: bac-
tericidal permeability increasing protein (BPI) (25%), lipopolysac-
charide binding protein (LBP), (24%) and cholesteryl ester
transfer protein (CETP) (19%). These proteins belong to the LPS-
binding/lipid transfer protein family. Among these family mem-
bers, human BPI and human CETP have X-ray 3-D structures re-
ported.12,13 Both PLTP and CETP are important HDL modulators.
Moreover, models of PLTP and CETP are similar to the structure
of BPI.14,15 Several CETP inhibitors have been reported, and some
of them exhibit both CETP and PLTP inhibition.16–20 Based on these
results, a molecular model of PLTP has been constructed. Taking
our constructed model and characteristics of reported CETP inhib-
itors into consideration, we designed a library of 2,4,5-trisubsti-
tuted thiazole compounds21 and selenazole compounds. After
synthesis, their PLTP inhibiting activities were evaluated. Selenaz-
ole compounds 12 and 17 exhibited PLTP inhibiting activities of
IC50
8 lM and 10 lM, respectively (Table 1). Since compound 12
is the most potent PLTP inhibitor, it might be considered the lead
compound. The general formula of 2,4,5-trisubstituted selenazole
compounds is shown in Figure 1.
* Corresponding author. Tel.: +86 10 68240321; fax: +86 10 68211656.
E-mail address: zhongwu@nic.bmi.ac.cn (W. Zhong).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.07.017

5124
C. Ling et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5123–5125
Table 1
Results of the biological assay
Compound
R1
R2
R3
CETP IC50
(
lV)
PLTP IC50 (lV)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Ethyl-
Ethyl-
Ethyl-
Ethyl-
p-Hydroxyl-phenyl-
p-Methoxyl-phenyl-
p-Hydroxyl-phenyl-
p-Methoxyl-phenyl-
p-Methoxyl-phenyl-
p-Methoxyl-phenyl-
p-Hydroxyl-phenyl-
p-Methoxyl-phenyl-
p-Methoxyl-phenyl-
p-Hydroxyl-phenyl-
p-Hydroxyl-phenyl-
Phenyl-
Phenyl-
Phenyl-
Phenyl-
Phenyl-
p-Hydroxyl-phenyl-
p-Hydroxyl-phenyl-
p-Hydroxyl-phenyl-
p-Methoxyl-phenyl-
p-Methoxyl-phenyl-
3,4,5-Trihydroxyl-phenyl-
3,4-Dimethoxyl-phenyl-
p-Chloro-phenyl-
3,4,5-Trimethoxyl-phenyl-
p-Chloro-phenyl-
3,4-Dimethoxyl-phenyl-
3,4,-Dihydroxyl-phenyl-
p-Nitro-phenyl-
3,4,5-Trimethoxyl-phenyl-
3,4,5-Trihydroxyl-phenyl-
Pentyl-
3,4-Dihydroxyl-phenyl-
3,4,5-Trihydroxyl-phenyl-
Phenyl-
3,4,5-Trimethoxyl-phenyl-
3,4,5-Trifluoro phenyl-
3,4,5-Trihydroxyl-phenyl-
Methyl-
p-Chloro-phenyl-
3,4,5-Trimethoxyl-phenyl-
3,4-Dimethoxyl-phenyl-
No
No
No
No
No
No
30
No
No
25
No
25
No
No
No
No
No
No
No
No
No
32
100
60
No
No
80
35
85
No
32
60
8
25
No
No
No
10
60
60
150
80
Ethyl-
Benzyl-
Benzyl-
Benzyl-
Benzyl-
Benzyl-
Benzyl-
Phenyl-
Phenyl-
Phenyl-
Phenyl-
Phenyl-
Butyl-
Butyl-
Butyl-
Butyl-
Butyl-
After comparing the structure and PLTP activity assay results, it
is conceivable that the hydroxyl group is the key determinant for
PLTP inhibition, regardless of whether it is on R2 or R3. For exam-
ple, compounds 4, 5, and 9 showed no or weak inhibition, while 1,
3, and 10 showed much stronger inhibition. Compounds with hy-
droxyl group substitution on R3 were more potent than those
with a hydroxyl at R2. Compounds 12 and 13 exhibited good inhi-
bition without any methoxy or hydroxyl substitution in R2. At R1,
butyl- and phenyl-groups had better PLTP inhibition than
benzyl- and ethyl-groups. To give some examples, compounds
13 and 17 had much stronger PLTP inhibition than compounds
1 and 10.
In conclusion, a novel serial of 2,4,5-trisubstituted selenazoles
were synthesized as potent PLTP inhibitors. Among them, com-
pounds 12 and 17 exhibited favorable PLTP inhibiting activity,
and they could be the potential new lead compounds in the search
for useful PLTP inhibitors.
R1
R2
O
C
Se
N
H
N
R3
Figure 1. The general formula of 2,4,5-trisubstituted selenazole compounds.
As shown in Scheme 1, the starting carboxylic acid a was treated
with SOCl2 to yield compound b, which, without further purification,
was reacted with aromatic compounds to give compound c. Then
compound c was treated with bromine to give compound d. A sus-
pension of compound d, KSeCN/SiO2, and CH3COONH4/Al2O3 was
heated in toluene at 80 °C for 12 h to afford compound e.22 Then,
compound e was acetylated to give compound f. If compound f
had the methoxyl group, the compound was treated with BBr3 to
provide phenolic compounds as additional analogs for testing.23
The structure data of MS and 1H NMR were shown in the reference.24
O
O
O
1
2
R1
R1
R1
OH
Cl
R2
a
b
c
R1
R2
Se
O
d
R1
R2
O
C
Se
R1
5
3
4
NH2
R2
NH
R3
N
N
f
Br
e
R1= CH3-CH2-
Ar-CH2-
CH3-CH2-CH2-CH2-
R2= P-CH3-Ar- P-HO-Ar-
Ar-
R3= 3,4,5-trimethoxyl-benz-
3,4-dihydroxy-benz-
4-chloro-benz-
3,4,5-trihydroxy-benz-
3,4-dihydroxy-benz-
4-nitro-benz-
pentyl-
methyl-
Scheme 1. General synthesis route for PLTP inhibitors. Reagents and conditions: (1) SOCl2, CH2Cl2, reflux, 1 h; (2) CH2Cl2, AlCl3, room temperature, 2 h; (3) AlCl3, CH2Cl2, Br2,
0 °C, 2 h; (4) KSeCN/SiO2, CH3COONH2/Al2O3, toluene, 80 °C, 12 h.

C. Ling et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5123–5125
5125
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Acknowledgment
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This work was supported by a Grant from National Nature Sci-
ence Foundation of China (No. 30701042).
12. Kleiger, G.; Beamer, L. J.; Grothe, R., et al. J. Mol. Biol. 2000, 299, 1019.
13. Qiu, X.; Mistry, A.; Ammirati, M. J., et al. Nat. Struct. Mol. Biol. 2007, 14, 106.
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16. Jiang, X. C.; Tall, A. R. PCT WO 2002048650, 2002.
Supplementary data
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24. Selected data for compounds 12: 1H NMR (400 MHz, CD3Cl) d = 12.76 (s, 1H),
7.55–7.56 (d, 1H), 7.54 (s, 1H), 7.41–7.42 (d, 2H), 7.28–7.32 (m, 8H), 6.82–6.84
(d, 1H). MS (FAB) [M+1]+: m/z = 437.1. Compound 17: 1H NMR (400 MHz,
CD3Cl) d = 12.33 (s, 1H), 9.52 (s, 1H), 9.23 (s, 2H), 9.01 (s, 1H), 7.34–7.36 (d, 2H),
7.09 (s, 2H), 6.79–6.81 (d, 2H), 2.80–2.81 (t, 2H), 1.58–1.62 (m, 2H), 1.33–1.35
(m, 2H), 0.84–0.88 (t, 3H). MS (FAB) [M+1]+: m/z = 449.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2010.07.017.
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