Optimization of rutaecarpine as ABCA1 up-regulator for treating atherosclerosis

Article abstract of DOI:10.1021/ml500131a

ATP-binding cassette transporter A1 (ABCA1) is a key transporter and receptor in promoting cholesterol efflux, and increasing the expression level of ABCA1 is antiatherogenic. In our previous study, rutaecarpine (RUT) was found to protect ApoE^-/- mice from developing atherosclerosis through preferentially up-regulating ABCA1 expression. In the present work, a series of RUT derivatives were synthesized and examined as ABCA1 expression up-regulators. Compounds CD1, CD6, and BCD1-2 were found to possess the most potential activity as antiatherosclerotic agents among all compounds tested.

Full text of DOI:10.1021/ml500131a

Letter
pubs.acs.org/acsmedchemlett
Optimization of Rutaecarpine as ABCA1 Up-Regulator for Treating
Atherosclerosis
Yongzhen Li, Tingting Feng, Peng Liu, Chang Liu, Xiao Wang, Dongsheng Li, Ni Li, Minghua Chen,
Yanni Xu,* and Shuyi Si*
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Tiantanxili No. 1,
Beijing 100050, China
S
* Supporting Information
ABSTRACT: ATP-binding cassette transporter A1 (ABCA1) is a key
transporter and receptor in promoting cholesterol efflux, and increasing the
expression level of ABCA1 is antiatherogenic. In our previous study,
rutaecarpine (RUT) was found to protect ApoE−/− mice from developing
atherosclerosis through preferentially up-regulating ABCA1 expression. In the
present work, a series of RUT derivatives were synthesized and examined as
ABCA1 expression up-regulators. Compounds CD1, CD6, and BCD1−2
were found to possess the most potential activity as antiatherosclerotic agents
among all compounds tested.
KEYWORDS: Rutaecarpine, ABCA1, RCT, atherosclerosis
Rutaecarpine (8,13-dihydroindolo[2′,3′:3,4]pyrido[2,1-b]-
quinazolin-5(7H)-one, RUT, Figure 1) was identified as a
therosclerosis is the main cause of cardiovascular disease
A(CVD). Statins are able to prevent only about one-third of
CVD cases through lowering low-density lipoprotein (LDL)
expression levels,1,2 and thus, additional therapeutic strategies
are still required. The limitless uptakes of modified low density
lipoprotein (mLDL) by scavenger receptor SR-A and CD36 in
the macrophages are key events in the initiation and
development of atherosclerosis.3−5 Removing excess cholester-
ol from foamed macrophage cells is considered to be one of the
antiatherosclerotic therapeutic strategies.6 Reverse cholesterol
transport (RCT) is an efficient means of lowering cholesterol in
the extra-hepatic tissues. Through RCT, high-density lip-
oproteins (HDL) carry cholesterol from peripheral tissues to
the liver, where it can be secreted directly into bile or converted
to bile acids.7−9 ATP-binding cassette A1 (ABCA1), which is
the key transporter in RCT,10,11 transports both free
cholesterol (FC) and phospholipids (PL) to apolipoprotein
A-I (ApoA-I).12,13 Therefore, it plays an important role in
atherosclerosis.14 On the basis of this consideration, up-
regulation of ABCA1 expression represents an attractive
strategy for combating atherosclerosis.15,16
Figure 1. Structure of RUT.
possible candidate, with an EC50 value of 0.27 μM and a
maximum up-regulating value of 240% in ABCA1p-LUC
HepG2 cells.18 We then demonstrated that RUT indeed
suppressed atherosclerosis through up-regulating ABCA1
within the RCT process in ApoE−/− mice.18 Recent studies
have also shown that RUT exhibits various pharmacological
effects,19,20 including cardiovascular protection,21 antithrom-
botic activity, and anti-inflammatory properties.22,23 All these
effects might be beneficial in terms of reducing atheroscle-
rosis.24 Taken together, these data suggested that RUT might
be of use in the treatment of atherosclerosis. In the present
study, a series of compounds based on the optimization of RUT
were designed with the aim of improving the ABCA1 up-
regulatory activity and antiatherosclerotic efficacy. The
structure−activity relationship (SAR) of these compounds
was also explored.
In our previous study, a high through-put screening (HTS)
assay was performed to identify ABCA1 up-regulators using
ABCA1p-LUC HepG2 cells.17 ABCA1p-LUC HepG2 cell line
was a stably transformed clone from HepG2 cells, which were
cotransfected with pGL3-ABCA1P and pcDNA3 (Invitrogen)
plasmids. The constructed plasmid pGL3-ABCA1P contains
human ABCA1 promoter region (−819 bp to +71 bp;
nucleotide +1 corresponds to the transcription start site).17
Received: March 31, 2014
Accepted: June 24, 2014
Published: June 24, 2014
© 2014 American Chemical Society
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ACS Medicinal Chemistry Letters
Letter
a
RUT exhibits both high structural rigidity and poor solubility.
Therefore, a scaffold-opened structure was designed to improve
the ABCA1 up-regulatory activity and enhance solubility and
bioavailability at the same time. This process was also an
effective way to examine novel structures with improved
activity.
Scheme 2. Synthesis of CD and BCD Series Compounds
Initially, the structure of RUT was truncated at the C13a−
C13b bond to investigate the contribution of the indole and
quinalin-4-one moieties to the activity. Compounds C1−4 were
synthesized based on the design presented in Scheme 1.25,26
a
Reagents and conditions: (i, iii) EDCI HCl salt, DCM/DMF; (ii)
a
Scheme 1. Synthesis of C Series Compounds
CD16, CH3CN, Et3N; CD15, CD17−18 DCM, Et3N.
As an initial step, we changed the position of the amino
group of CD1 to produce CD2−3. The activities of CD1−3
(Table 1) indicated that the effect of the amino position was
greatest in the order of ortho > para > meta. The disappeared
activity of CD4 was probably due to the introduction of 5-
methoxy on the indole ring. Second, substitution of the amino
group of CD1 with hydrogen or with hydroxyl, methyl, and
N,N-dimethylamino groups resulted in compounds CD5−8
(Table 1) with the substituents maintained at the ortho
position. According to Table 1, CD6 exhibited the best
performance, CD5 and CD7 showed moderate activities, and
CD8 completely lost its activity. Therefore, it appeared that the
optimal activity occurred when the E ring had hydrogen-
donating substituents. Third, the amino group on the E ring
was acylated by trifluoroacetyl and n-propionyl to give
compounds CD9−14 (Table 1). The up-regulating ABCA1
activity showed that the order of activity with regard to the
acylation position remained ortho > para > meta.
For the most part, the CD series maintained good up-
regulating ABCA1 activities. To determine whether the E ring
of CD1 is important to maintaining the activity, the ring was
exchanged with a pyridine ring to give CD15. CD15 also
exhibited good ABCA1 activity (Table 1). This implied that the
E ring (benzene) could be replaced with different aromatic
rings without a loss in performance. The effects of changing the
molecule at the L position were also investigated by
synthesizing products CD16−18, in which the carbonyl group
was replaced with methylene, ester, and 2-oxoacetyl groups,
respectively (Table 1). CD16 was synthesized by the
substitution of tryptamine with benzyl chloride in acetonitrile.
CD15, CD17, and CD18 were obtained by the acylation of
tryptamine with the corresponding acyl chloride in the presence
of triethylamine in dichloromethane (Scheme 2). Among the L-
changed compounds, CD16 lost its activity without the
carbonyl, while CD17, with one oxygen atom inserted between
the benzene and carbonyl groups, maintained its activity.
CD18, with two atoms inserted between the benzene and
carbonyl groups, lost its effectiveness (Table 1). These data
indicated that the carbonyl group was critical with regard to
maintaining activity, and the length of the linker was also
important, based on a comparison of CD16−18. Finally, to
examine whether the indole ring was important to maintaining
activity, the indole rings of CD1 and CD6 were replaced with
benzene rings to give compounds BCD1 and BCD2,
respectively. Compounds BCD1−2 were synthesized simply
by condensation of 2-phenylethanamine with a substituted
benzoic acid (Scheme 2). Both BCD1 and BCD2 exhibited
reasonably high activities, close to the performance of CD1 and
a
Reagents and conditions: (a) tryptamine, EtOH, reflux; (b)
(CF3CO)2O, pyridine, 25 °C; (c) 5-methoxytryptamine, EtOH,
reflux; (d, g) triethoxy orthoformate, reflux; (e) ethyl chloroformate,
reflux; (f) tryptamine, pyridine, reflux.
CD1 was prepared by reflux of tryptamine and isatoic
anhydride in alcohol. CD1 then refluxed in triethoxy
orthoformate or ethyl chloroformate resulted in C1 and C3,
respectively. C2 was obtained when isatoic anhydride was
treated with trifluoroacetic anhydride in pyridine, and then
refluxed with tryptamine. C4 was obtained by 5-methoxytrypt-
amine using the same synthetic method as C1.
It was noted that C1 (EC50 = 1.28 μM and maximum value =
176%) and C3 (EC50 = 0.29 μM and maximum value = 149%)
showed moderate ABCA1 up-regulating activities in ABCA1
up-regulating assays, while C2 and C4 exhibited no activities at
all. Although both trifluoromethyl and carbonyl are electron-
withdrawing groups, their effects were evidently quite different.
Thus, it could be concluded that the steric effect was likely
more important than the electric effect at the 2 position of
quinalin-4-one moiety. Small variation between C1 and C4 led
to the activities being dramatically changed, which indicated
that introducing electron-donating groups on the indole moiety
was not good for improving the activity. These results indicated
that the ring-opened structures successfully maintained fairly
high activities similar to that of the original RUT molecule.
It was interesting to see that CD1, with both C and D rings
opened and obtained as the intermediate to form C1, showed
better activity than C1. It was concluded that modification of
the C and D rings might be beneficial in terms of improving up-
regulating ABCA1 activities. For this reason, both the C and D
ring-isolated structures were designed for improving the up-
regulating ABCA1 activities based on CD1. Thus, a further
series of CD1 were synthesized by the condensation of
tryptamine and substituted benzoic acid with EDCI hydro-
chloride salt in dichloromethane (DCM) or N,N-dimethylfor-
mamide (DMF) (Scheme 2).
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Table 1. ABCA1 Activity of CD and BCD Series Compounds
a
b
a
b
compd
EC50 (μM)
max (%)
compd
EC50 (μM)
max (%)
CD1
CD2
CD3
CD4
CD5
CD6
CD7
CD8
CD9
BCD1
0.81 0.09
10.72 0.08
6.55 0.07
203
138
239
CD10
CD11
CD12
CD13
CD14
CD15
CD16
CD17
CD18
BCD2
1.28 0.03
33.24 0.15
1.56 0.06
19.55 0.12
8.86 0.06
3.67 0.09
138
192
192
169
175
180
0.71 0.10
0.21 0.10
1.66 0.07
193
182
166
6.38 0.05
160
3.28 0.10
204
187
0.035 0.08
0.121 0.07
183
a
b
Data represent an average of multiple determinations (n ≥ 3) standard error of the mean (SEM). Maximum up-regulating value (%).
CD6 (Table 1), which implied that the indole ring was not
necessary to maintain the activity.
BCD1 both in HepG2 (220% of control) and RAW264.7 cells
(350% of control) (Figure 2B). Then the capability of
promoting cholesterol efflux to HDL induced by BCD1 was
then confirmed by the [3H]-cholesterol experiment. According
to Figure 2C, BCD1 significantly increased the cholesterol
efflux from RAW264.7 cells to HDL, which indicated that
compound BCD1 had a good antiatherosclerotic effect in vitro.
To this point, various compounds in the C, CD, and BCD
series had been obtained through varying the structure of RUT,
and compounds CD1, CD6, and BCD1−2 exhibited good up-
regulating ABCA1 activities. Considering the results obtained
for all the compounds noted above, we could attempt to
produce a preliminary structure−activity relationship. First, the
C and CD series maintained up-regulating ABCA1 activity
when the C and/or D ring of the RUT scaffold was truncated
or removed. As well, the compounds in which E ring
substituents were replaced with hydrogen-donating groups at
the ortho position showed the most pronounced performance.
C4 and CD4 both with a 5-methoxy group on the indole ring
(AB) exhibited no activities, which was likely because electron-
donating groups substituted on the indole ring were not helpful
in terms of activity. Second, a carbonyl group (amide or ester)
inserted between two phenyl rings (A and E) was critical for
maintaining activity. The distance of the carbonyl from these
rings was also important; the space from the carbonyl to E was
limited to one atom, while the distance from the amide to A
was restricted to two or three atoms. Third, the BCD series
showed excellent activity when the indole ring (AB) was
replaced with a benzene ring. It was also beneficial when
hydrogen-donating groups (such as hydroxyl, amino, hydroxyl-
alkyl, alkyl, and hydrogen) were introduced on the E ring.
Therefore, the indole and quinazolin-4-one rings of RUT are
not necessary for the ABCA1 up-regulating activity, and
simplification of the structure could afford novel compounds
with potent up-regulating activities.
To confirm ABCA1 up-regulation by the RUT derivatives in
the luciferase reporter assay, we examined the effect of BCD1
on ABCA1 mRNA and protein expression levels in HepG2 and
RAW264.7 cells. Western blot analysis showed that the protein
levels of ABCA1 significantly increased when incubated with
0.01, 0.1, 1.0, or 10.0 μM BCD1 (Figure 2A). Quantitative real-
time PCR analysis showed that BCD1 stimulated the
expression of ABCA1 at both mRNA and protein levels. The
mRNA levels of ABCA1 were significantly up-regulated by
So far, there are some ABCA1 up-regulators reported.
According to the structures of these compounds, they mainly
could be classified as two classes. Class 1 includes oxysterols,27
(iso)flavonoids, xanthone, aclarubicin, and pyrromycin,17 which
can be classified as cyclic structures. Class 2 includes
trichostatin (TSA),28 9-cis retinoic acid (9-CRA), curcumin,29
mycophenolic acid (MPA),30 oleic acids, and linoleic acids,31,32
which can be classified as aryl unsaturated aldehyde/ketone
derivatives. Compared with these known compounds, N-aryl/
alkyl-substituted aromatic amide derivatives based on the
optimization of RUT were first synthesized and found as
ABCA1 expression up-regulators in this study, and the up-
regulating ABCA1 activities of compounds CD1, CD6, and
Figure 2. BCD1 induced ABCA1 expression in HepG2 and
RAW264.7 cells and promoted [3H] cholesterol efflux from
RAW264.7 cells to HDL. (A) Western blot analysis of ABCA1
expression level induced by BCD1 in HepG2 and RAW264.7 cells. A
representative immunoblot of three separate experiments is shown.
(B) Quantitative real-time PCR analysis of ABCA1 mRNA levels
induced by BCD1 in HepG2 and RAW264.7 cells. The average copy
numbers of ABCA1 were normalized to GAPDH. Data are expressed
as means SEM of three independent experiments and are expressed
relative to control. *P < 0.05 versus vehicle. (C) Potency of [3H]
cholesterol efflux induced by BCD1 to HDL in RAW264.7 cells. Data
are means SEM (*P < 0.05 versus vehicle).
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ABCA1 gene expression is transcriptionally regulated.33
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receptor gamma (PPARγ) enhances cholesterol efflux by
inducing transcription of the liver X receptor (LXRα) and
thus ABCA1.34 Our results showed that some compounds
optimized in this study could partly activate PPARα/γ or
LXRα/β (data not shown), which might explain the up-
regulating ABCA1 mechanism of these compounds and might
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of up-regulating ABCA1 expression induced by these
compounds will be further investigated in vitro and in vivo in
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In summary, a series of N-aryl/alkyl-substituted aromatic
amide derivatives were synthesized as ABCA1 expression up-
regulators based on the optimization of RUT. The carbonyl
group was identified critical for maintaining activity; the
distance of the rings (A and E) from the carbonyl group and
the position of the hydrogen-donating groups on the E ring
were identified beneficial to the up-regulating ABCA1 activity.
The C and D rings and the indole ring, however, could be
removed without affecting the up-regulating activity. Com-
pounds CD1, CD6, and BCD1−2 were found to be the best
up-regulators, and all had simplified structures compared with
RUT. BCD1 could significantly promote cholesterol efflux in
RAW264.7 cells. These four compounds showed promise as
potent compounds for the treatment of atherosclerosis.
ASSOCIATED CONTENT
■
S
* Supporting Information
Cell culture, ABCA1 transcriptional activity assay, real-time
quantitative PCR, Western blots assay, cholesterol efflux assay,
and the synthesis and identification of compounds C1−C4,
CD1−18, and BCD1−2. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Authors
*(Y.X.) E-mail: xuyanni2010@gmail.com.
*(S.S.) E-mail: sisyimb@hotmail.com.
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Funding
This work was supported by the Key New Drug Creation and
Manufacturing Program (2012ZX09301002-003 and
2012ZX09301002-001); the National Natural Science Founda-
tion of China (81102443, 81273515, and 81321004); PUMC
Youth Fund (3332013089); the Fundamental Research Funds
for the Central Universities (3332013089); and the National
Natural Science Foundation of China-Guangdong Provincial
People’s Government of the Joint Natural Science Fund
Projects (U1032007).
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Y.; Liu, J. K.; Wu, Y. X.; Li, Y. Z.; Li, N.; Feng, T. T.; Lai, F. F.; Zhang,
M. R.; Hong, B.; Jiang, J. D.; Si, S. Y. Rutaecarpine suppresses
atherosclerosis in ApoE−/−mice through up-regulating ABCA1 and
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(19) Jia, S.; Hu, C. Pharmacological effects of rutaecarpine as a
cardiovascular protective agent. Molecules 2010, 15 (3), 1873−81.
Notes
The authors declare no competing financial interest.
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