The combination of sesamol and clofibric acid moieties leads to a novel potent hypolipidemic agent with antioxidant, anti-inflammatory and hepatoprotective activity

Article abstract of DOI:10.1016/j.bmcl.2021.128121

Oxidative stress and inflammation have been considered the main factors in the liver injury of clofibrate (CF). To obtain a novel antihyperlipidemic agent with antioxidant, anti-inflammation and hepatoprotection, the combination of sesamol and clofibric acid moieties was performed and achieved sesamol-clofibrate (CF-Sesamol). CF-Sesamol showed significant hypolipidemia effects in hyperlipidemia mice induced by Triton WR 1339, reducing TG by 38.8% (P < 0.01) and TC by 35.1% (P < 0.01). CF-Sesamol also displayed an alleviating effect on hepatotoxicity. The hepatic weight and hepatic coefficient were decreased. The amelioration of liver function was observed, such as aspartate and lactate transaminases (AST and ALT), alkaline phosphatase (ALP) and total proteins (TP) levels. Liver histopathological examination showed that hepatocyte necrosis, cytoplasmic loosening, nuclear degeneration and inflammatory cell infiltration reduced obviously by treatment with CF-Sesamol. Related molecular mechanisms on hepatoprotection showed that CF-Sesamol up-regulated Nrf2 and HO-1 expression and down-regulated p-NF-κB p65 expression in hepatic tissues. CF-Sesamol has significant antioxidant and anti-inflammatory effects. Plasma antioxidant enzymes such as SOD and CAT increased, anti-lipid peroxidation product MDA decreased. The expression of TNF-α and IL-6 inflammatory cytokines in liver was significantly lower than that in the CF group. The results indicated that CF-Sesamol exerted more potent antihyperlipidemic effects and definite hepatoprotective activity partly through the Nrf2/NF-κB-mediated signaling pathway.

Full text of DOI:10.1016/j.bmcl.2021.128121

Bioorg. Med. Chem. Lett. 44 (2021) 128121
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
The combination of sesamol and clofibric acid moieties leads to a novel
potent hypolipidemic agent with antioxidant, anti-inflammatory and
hepatoprotective activity
,
,
,
Yundong Xiea, Jiping Liua c, Yongheng Shia c, Bin Wanga c, Xiaoping Wanga, Wei Wanga,
Meng Suna, Xinya Xua, Haihui Jianga, Min Guoa, Yiyi Hea, Cuicui Renb *, Lifei Chengd
,
,*
a College of Pharmacy, Shaanxi University of Chinese Medicine, Shiji Ave., Xi’an-xianyang New Ecomic Zone, Shaanxi Province 712046, People’s Republic of China
b First Hospital of Xi’an, Xi’an, Shaanxi Province 710002, People’s Republic of China
c Key Laboratory of Pharmacodynamics and Material Basis of Chinese Medicine, Shaanxi Administration of Traditional Chinese Medicine, Xianyang 712046, People’s
Republic of China
d Shaanxi Traffic Hospital, 276 Daxue South Road, Beilin District, Xi’an, Shannxi Province 710068, People’s Republic of China
A R T I C L E I N F O
A B S T R A C T
Keywords:
Oxidative stress and inflammation have been considered the main factors in the liver injury of clofibrate (CF). To
obtain a novel antihyperlipidemic agent with antioxidant, anti-inflammation and hepatoprotection, the combi-
nation of sesamol and clofibric acid moieties was performed and achieved sesamol-clofibrate (CF-Sesamol). CF-
Sesamol showed significant hypolipidemia effects in hyperlipidemia mice induced by Triton WR 1339, reducing
TG by 38.8% (P < 0.01) and TC by 35.1% (P < 0.01). CF-Sesamol also displayed an alleviating effect on hep-
atotoxicity. The hepatic weight and hepatic coefficient were decreased. The amelioration of liver function was
observed, such as aspartate and lactate transaminases (AST and ALT), alkaline phosphatase (ALP) and total
proteins (TP) levels. Liver histopathological examination showed that hepatocyte necrosis, cytoplasmic loos-
ening, nuclear degeneration and inflammatory cell infiltration reduced obviously by treatment with CF-Sesamol.
Related molecular mechanisms on hepatoprotection showed that CF-Sesamol up-regulated Nrf2 and HO-1
expression and down-regulated p-NF-κB p65 expression in hepatic tissues. CF-Sesamol has significant antioxi-
dant and anti-inflammatory effects. Plasma antioxidant enzymes such as SOD and CAT increased, anti-lipid
CF-Sesamol
Hypolipidemic
Hepatoprotection
Nrf2/NF-κB signaling pathway
peroxidation product MDA decreased. The expression of TNF-α and IL-6 inflammatory cytokines in liver was
significantly lower than that in the CF group. The results indicated that CF-Sesamol exerted more potent anti-
hyperlipidemic effects and definite hepatoprotective activity partly through the Nrf2/NF-κB-mediated signaling
pathway.
With the improvement of people’s living standards and changes in
dietary structure, the incidence of hypertriglyceridemia (HTG) is placed
on the rise.1 The incidence of HTG in Asian countries is much higher
than that of hypercholesterolemia. Clinical data have indicated that the
prevalence rate of simple HTG in healthy people was about 20%. And
cardiovascular diseases such as type 2 diabetes mellitus and athero-
sclerosis caused by HTG were also substantially increased, so it is urgent
to effectively control and treat HTG. Clofibrate (CF) played an important
role in ameliorating HTG through activation of peroxisome proliferation
peroxisomal acyl-CoA oxidase, which increased the production of
H2O2.4 Moreover, peroxisome proliferation can affect mitochondria
function administrated with CF, resulting in elevating of the levels of
oxidative damage to mtDNA and proteins.3 These suggested that CF can
induce a large number of reactive oxygen species (ROS) and lead to
oxidative stress, resulting in the dysfunction of hepatocyte mitochon-
dria, and eventually lead to liver tissue damage. It was reported that
liver function disorder and liver weight increase (hepatocyte edema and
hypertrophy) after long-term treatment with CF. Furthermore, AST and
ALT and alkaline phosphatase (ALP) increased, while the contents of
antioxidant enzymes such as superoxide dismutase and catalase
activated receptor-α (PPAR-α). Because of the single target, although CF
has outstanding therapeutic effect, it has great side effects, particularly
the liver injury.2,3 Studies reported that CF can enhance the activity of
decreased.5,6 Moreover, ROS produced by activation of PPAR-
α can lead
* Corresponding authors.
E-mail addresses: rcc1990@163.com (C. Ren), 532413532@qq.com (L. Cheng).
https://doi.org/10.1016/j.bmcl.2021.128121
Received 17 March 2021; Received in revised form 10 May 2021; Accepted 13 May 2021
Available online 17 May 2021
0960-894X/© 2021 Elsevier Ltd. All rights reserved.

Y. Xie et al.
Bioorganic & Medicinal Chemistry Letters 44 (2021) 128121
Chart 1. Design of compound CF-Sesamol and structures of Clofibrate (CF), Clofibric acid, and Sesamol.
Scheme 1. Synthesis route to compound CF-Sesamol. Reagents and conditions: (a) 6 M NaOH, 50 ◦C; (b) EDCI, DMAP, DMF.
to excessive production and accumulation of inflammatory factors such
as TNF- and IL-6 that may cause severe liver damage. Therefore, the
inflammatory response also involved in the process of hepatotoxicity
caused by CF. Oxidative stress and inflammation have been considered
as the main contributions to the hepatotoxicity of CF. Hence, amelio-
ration of oxidative stress and inflammation while CF decreased blood
α
Fig. 1. Effects of CF-Sesamol and CF on plasma levels of triglyceride (TG) and total cholesterol (TC) in Triton WR 1339 induced hyperlipidemic mice after ig
administration of CF-Sesamol (0.362 mmol/kg) and CF (0.362 mmol/kg) for 7 days. The results were expressed as mean ± SEM, n = 10, ##P < 0.01 vs normal group;
**P < 0.01 vs model group; △P < 0.05 vs CF group.
2

Y. Xie et al.
Table 1
Bioorganic & Medicinal Chemistry Letters 44 (2021) 128121
and CF group (positive control, 0.36 mmol/kg). The dosage in the
experiment was established according to the pre-experiment. The results
showed that CF-Sesamol reduced plasma TG by 38.6% (P < 0.01) and TC
by 35.1% (P < 0.01). While CF decreased TG by 25.5% (P < 0.01) and
TC by 21.2% (P < 0.01). It was quite interesting that compound CF-
Sesamol has stronger activity of reducing TG than CF (P < 0.05)
(Fig. 1). The findings revealed that sesamol can be optimized by binding
to the structure of clofibric acid, and CF-Sesamol has a potential anti-
hyperlipidemic effects. Sesamol has a synergistic effect in structural
modification.
CF- with their PPAR
α
receptor affinity activity by MOE
docking scores.a
Compounds
Scores (kJ/mol⋅K)
CF-Sesamol
Sesamol
ꢀ 5.3657
ꢀ 3.6841
ꢀ 7.3294
ꢀ 4.6738
GW409544b
Clofibrate (CF)c
a
PDB code: 1K7L.
b
The X-ray crystal structure of PPAR
α protein reported as
complex with GW409544 deposited in Brookhaven Protein.
Molecular docking research was performed on the protein PPARα for
c
Clofibrate (CF) was selected as reference.
the affinity activity, applying the docking procedure of MOE program
installed on Win 10 software. The PDB code was 1K7L. CF was selected
as the reference. The results were showed that CF-Sesamol (the score
was ꢀ 5.3657 kJ/mol⋅K) have been found to dock well in the active site
lipids will be of enormous significance for the application.
Natural products provide a variety of leading structures and domi-
nant efficacy structures for drug discovery and research and develop-
ment. It was one of the important ways of drug discovery to derive and
optimize their structures. Due to the complex structure of natural
products, active structural fragments of natural products provide a
leading structure for the structural simplification and derivation of
natural products. Benzodioxalene structure existed in a variety of nat-
ural product structures with obvious physiological effects, such as ses-
ame lignans have obvious antioxidant, anti-inflammatory, regulating
lipid metabolism and other effects. Sesamol (1,3-benzodioxole) was the
core component of sesame oil, which has the effects of antioxidation,
anti-inflammation and regulating blood lipids.7–10 Sesamol derivatives
have significant preventive and protective effects on liver injury.11–13
Based on these, we designed compound CF-Sesamol by combination
of sesamol and clofibric acid pharmacophores. (Chart 1) Sesamol was
introduced to replace ethoxyl of CF to achieve compound CF-Sesamol.
We expected that CF-Sesamol not only retains the effects of regulating
blood lipid, but also has antioxidant and anti-inflammatory activity, and
has a role in hepatoprotection.
of PPARα, which has stronger PPARα affinity activity than that of pos-
itive drug CF (the score was ꢀ 4.6738 kJ/mol⋅K). The molecular docking
results were consistent with the results of lipid-lowering activity in
Triton WR 1339 induced hyperlipidemic mice (Table 1).
The compound CF-Sesamol has good hypolipidemia activity, and
then we further evaluate its hepatotoxicity. The experiment was con-
ducted in normal mice. KM mice (20.0 ± 2.0 g) were randomly divided
into the following groups: normal group (the same volume of ~0.5%
CMC-Na), CF group (300 mg/kg) and CF-Sesamol group (412 mg/kg).
The dosage of CF was converted according to the clinical maximum
dosage of CF, and the CF-Sesamol dosage was converted to the equal
molar dosage of CF. In order to evaluate hepatotoxicity, hepatic weight,
hepatic coefficient and liver histopathology were studied, as well as
biochemical indexes of liver function (AST, ALT, ALP and TP) was
measured by an automatic biochemical analyzer. In addition, antioxi-
dant indexes (SOD, CAT, GSH and MDA) and inflammatory cytokines
(TNF-α and IL-6) were also tested.
As demonstrating in Fig. 2, body weight of the CF group and CF-
Sesamol mice has no significant difference between the normal group
mice. The hepatic weight of CF group mice was higher than normal mice
(P < 0.01), while the hepatic weight of CF-Sesamol was obvious
decreased (P < 0.01) compared with CF group mice, and has no sig-
nificant difference with normal mice (P > 0.05). Therefore, the liver
coefficient of CF group mice was dramatically increased (P < 0.01) and
the live coefficient of CF-Sesamol was also elevated (P < 0.01) compared
with normal group mice. However, the liver coefficient of CF-Sesamol
was significantly reduced (P < 0.01). The results indicated that the
hepatotoxicity of CF-Sesamol was lower than that of CF.
The synthesis of CF-Sesamol was showed in Scheme 1. CF was hy-
drolyzed under alkaline condition to get clofibric acid, which was then
reacted with sesamol to synthesize CF-Sesamol under the action of ester
condensation agent. CF-Sesamol was purified by silica gel column
chromatography and determined by 1H NMR, 13C NMR, and HR-MS.
The mouse animal experiment meets the requirements of animal
ethics and has passed the approval of the experimental animal ethics
committee. The antihyperlipidemic property of compound CF-Sesamol
was assessed in Triton WR 1339 induced hyperlipidemia mice. KM
mice (20.0 ± 2.0 g) were randomly divided into the following groups:
normal group (the same volume of ~0.5% CMC-Na), model group (the
same volume of ~0.5% CMC-Na), CF-Sesamol group (0.36 mmol/kg)
Plasma levels of AST, ALT, ALP and TP were detected to assess liver
function. As depicted in Fig. 3, the plasma levels of AST, ALT, ALP and
Fig. 2. Effects of CF-Sesamol and CF on body weight, liver weight and liver coefficient after intragastrical gavage treatment for a month. The results were expressed
as mean ± SEM, n = 8, ##P < 0.01 vs normal group; **P < 0.01 vs CF group.
3

Y. Xie et al.
Bioorganic & Medicinal Chemistry Letters 44 (2021) 128121
Fig. 3. Plasma levels of AST, ALT, ALP, and TP after intragastrical gavage treatment with CF-Sesamol and CF as well as 0.5% CMC-Na solution (normal group) for a
month. The results were expressed as mean ± SEM, n = 8, #P < 0.05, ##P < 0.01 vs normal group; **P < 0.01 vs CF group.
Fig. 4. Plasma levels of SOD, GSH, CAT, and MDA after intragastrical gavage treatment with CF-Sesamol and CF as well as 0.5% CMC-Na solution (normal group) for
a month. The results were expressed as mean ± SEM, n = 8, #P < 0.05, ##P < 0.01 vs normal group; **P < 0.01 vs CF group.
Fig. 5. Effects of CF-Sesamol and CF on TNF-α and IL-6 protein expression in liver tissue by western blotting analysis after intragastrical gavage treatment for a
month. The results were expressed as mean ± SEM, (n = 3 each group). ##P < 0.01 vs normal group; **P < 0.01 vs CF group.
TP were observably increased (P < 0.05 or P < 0.01) compared with the
normal group after treatment with CF for a month. It was therefore
suggested that long-term use of CF can lead to liver injury in mice. While
CF-Sesamol decreased plasma AST, ALT, ALP and TP in varying degrees
compared with CF group, and have not been markedly difference with
normal group except ALP. These indicated that the liver damage caused
by CF-Sesamol was very mild.
decreased obviously, plasma levels of MDA, the lipid peroxidation
products, was dramatically increased (P < 0.05) and GSH content was
clearly decreased (P < 0.05) after treatment with CF, compared with the
normal mice, indicating that long-term administration with CF will lead
to severe oxidative stress in mice. While the levels of plasma SOD (P <
0.01) and CAT (P < 0.01) in CF-Sesamol group were significantly higher
than those in CF group, the level of MDA in plasma was significantly
lower than that in CF group, and there was no significant difference in
CF-Sesamol group compared with normal group. However, the content
In addition, the antioxidant capacity was measured. As showed in
Fig. 4, the plasma levels of SOD (P < 0.01) and CAT (P < 0.05) was
4

Y. Xie et al.
Bioorganic & Medicinal Chemistry Letters 44 (2021) 128121
Fig. 6. Effects of CF-Sesamol and CF on histopathological changes in liver tissues (H&E 200×). (a) The liver section from normal group. (b) The liver section from CF
group. (c) The liver section from CF-Seseal group.
Fig. 7. CF-Sesamol regulated antioxidant
and inflammation signaling pathway in mice
after intragastrical gavage treatment for a
month. (a) Expression of Nrf2 protein in the
nucleus of liver tissue by western blotting
analysis. (b) Expression of HO-1 protein in
the liver tissue by western blotting analysis.
(c) Expression of p-NF-κB p65 and NF-κB p65
protein in the cytoplasm and nucleus of liver
tissue by western blotting analysis. The re-
sults were expressed as mean ± SEM, (n = 3
each group). ##P < 0.01 vs normal group;
**P < 0.01 vs CF group.
of GSH was less than that of the normal group, and there was no sig-
nificant difference compared with the CF group. These results showed
that the oxidative stress brought about by CF-Sesamol was very weak.
The literature reported that CF can lead to inflammatory cell infil-
central vein of the liver tissue was obvious, the liver plate was arranged
neatly with the central vein as the center, the morphology of hepatocytes
was normal, the boundary was clear, and the nucleus was clearly visible
(Fig. 6(a)). On the contrary, large areas of hepatocyte swelling and ne-
crosis, loose cytoplasm, nuclear degeneration and dissolution, obvious
cell infiltration in the central vein and a large number of inflammatory
cells were observed in the liver tissue of CF group (Fig. 6(b)). There was
no central venous congestion and a large number of inflammatory cell
infiltration in the liver tissue of CF-Sesamol group, but hepatocyte
swelling was still observed (Fig. 6(c)). Observation results of liver his-
tomorphology were consistent with the results of liver coefficient,
biochemical indexes of liver function and inflammatory cytokines.
Because compound CF-Sesamol has good hepatoprotective activity,
we speculated that its hepatoprotective effect may be related to
tration in the liver of mice. Therefore, the expression of TNF-α and IL-6
inflammatory cytokines in mouse liver tissue was analysed by western
blotting. As displaying in Fig. 5, the TNF- (P < 0.01) and IL-6 (P < 0.01)
proteins of CF group were up-regulated compared with normal group,
α
and the TNF-α (P < 0.01) and IL-6 (P < 0.01) proteins of CF-Sesamol
group were down-regulated compared with CF group. These results
revealed that CF can be expected to result in severe inflammation, while
CF-Sesamol alleviated inflammatory response.
Moreover, hepatoprotective activity was further evaluated by his-
topathological examination. As showed in Fig. 6, in the normal mice, the
5

Y. Xie et al.
Bioorganic & Medicinal Chemistry Letters 44 (2021) 128121
antioxidant and anti-inflammatory properties. Therefore, we further
studied the biological mechanism of its hepatoprotective effect. The
expression of related antioxidant and anti-inflammatory signaling
pathway proteins was analysed by Western blotting. As showed in Fig. 7
(a) and (b), the expression of nuclear factor erythroid-2-related factor 2
(Nrf2) and heme oxygenase ꢀ 1 (HO-1) in CF-Sesamol group was obvi-
ously up-regulated (P < 0.01) compared with the CF group. While the
expression of Nrf2 and HO-1 proteins in the CF group has no significant
difference compared with the normal group. The up-regulation of Nrf2
and HO-1 proteins will cause the expression of downstream related
antioxidant enzymes and exert antioxidant activity. Moreover, the
expression of p-NF-κB p65 protein in CF group was significantly up-
regulated compared with the normal group, and the expression of p-
NF-κB p65 protein in CF-Sesamol group was significantly down-
regulated compared with CF group. These findings revealed that CF
can cause serious oxidative stress and inflammation in mouse liver, but
CF-Sesamol can alleviate the oxidative stress and inflammatory response
by Nrf2/NF-κB signaling pathway in mouse liver.
which could be used as a promising agent for hyperlipidemia patients
with hepatoprotection. This strategy may be outstanding for the sec-
ondary optimization and development of CF.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Acknowledgements
Thanks for the Natural Science Foundation of Shaanxi Province (No.
2021JQ-730; No. 2019JQ-401), start-up fund for doctoral scientific
research given by Shaanxi University of Chinese Medicine (NO.
124020057; NO. 17102031907). Subject Innovation Team of Shaanxi
University of Chinese Medicine (2019-YL13 to BW). Key Laboratory of
Pharmacodynamics and Material Basis of Chinese Medicine, Shaanxi
Administration of Traditional Chinese Medicine is gratefully acknowl-
edged. The authors sincerely thank the Wanlei Biotechnology Co. LTD
(Shenyang, China) for the detection of experimental results of Western
Blotting and histopathological examination.
These results presented in this study indicated that CF-Sesamol was
better than CF in alleviating hyperlipidemia, oxidative stress, inflam-
mation and hepatotoxicity in mice. Nrf2 plays a major role in the anti-
oxidant by regulating the transcription of various antioxidant enzymes
to eliminate ROS.14,15 Under physiological conditions, Nrf2 was fixed in
the cytoplasm through binding of Keap1. Once stimulated by ROS, Nrf2
was activated and transfer into the nucleus, bind to the ARE and pro-
moted HO-1 expression, then up-regulated the expression of antioxidant
enzymes (such as CAT and SOD) to maintain cellular functions.16,17 In
this study, CF-Sesamol showed significant antioxidant activity (Fig. 4)
via activation hepatic Nrf2 and HO-1. In addition, after the occurrence
of oxidative stress, NF-κB p65 was phosphorescent and transferred into
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.bmcl.2021.128121.
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