A new multifunctional hydroxytyrosol-clofibrate with hypolipidemic, antioxidant, and hepatoprotective effects

Article abstract of DOI:10.1016/j.bmcl.2018.06.010

Oxidative stress has been regarded as the leading mechanism of the hepatotoxicity of clofibrate (CF). To achieve multifunctional novel hypolipidemic agents with hypolipidemia, antioxidant, and ameliorating liver injury, clofibric acid derivative hydroxytyrosol-clofibrate (CF-HT) was synthesized by molecular hybridization. CF-HT exhibited significant hypolipidemia, reducing serum triglyceride (TG), total cholesterol (TC), and malonaldehyde (MDA) by 30%, 33%, and 29% in hyperlipidemic mice induced by Triton WR 1339. CF-HT also shown hepatoprotective effect, a significant decrease in hepatic indices toxicity was observed, i.e. aspartate and lactate transaminases (AST and ALT) activities, alkalines phosphatases (ALP), and total bilirubin (TBIL) levels. The liver weight and liver coefficient were also ameliorated. Serum superoxide dismutase (SOD) was significantly elevated, and serum catalase (CAT) and malondialdehyde (MDA) content were remarkably restored. The hepatic glutathione (GSH) content was obviously increased and hepatic oxidized glutathione (GSSG) content was reduced dramatically by CF-HT, as compared to the CF treated mice (p < 0.05). Moreover, the histopathological damage that hepatocyte hyperplasia and hypertrophy was also significantly ameliorated by treatment with CF-HT. Therefore, the results indicated that CF-HT exerted more potent hypolipidemic activity and definite hepatoprotective effect which may mainly be associated with its antioxidative property in mice.

Full text of DOI:10.1016/j.bmcl.2018.06.010

Accepted Manuscript
A new multifunctional hydroxytyrosol-clofibrate with hypolipidemic, antioxi-
dant, and hepatoprotective effects
Yun-Dong Xie, Zi-Zhang Chen, Li-Hua Shao, Qiu-Tang Wang, Na Li, Wen-
Fang Lu, Yan-Hong Xu, Yu-Qiong Gao, Li-Ying Guo, Hao-Le Liu, Yi-Ping Li,
Guang-De Yang, Xiao-Li Bian
PII:
S0960-894X(18)30496-7
https://doi.org/10.1016/j.bmcl.2018.06.010
BMCL 25891
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
3 March 2018
30 May 2018
4 June 2018
Please cite this article as: Xie, Y-D., Chen, Z-Z., Shao, L-H., Wang, Q-T., Li, N., Lu, W-F., Xu, Y-H., Gao, Y-Q.,
Guo, L-Y., Liu, H-L., Li, Y-P., Yang, G-D., Bian, X-L., A new multifunctional hydroxytyrosol-clofibrate with
hypolipidemic, antioxidant, and hepatoprotective effects, Bioorganic & Medicinal Chemistry Letters (2018), doi:
https://doi.org/10.1016/j.bmcl.2018.06.010
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A new multifunctional hydroxytyrosol-clofibrate with hypolipidemic,
antioxidant, and hepatoprotective effects
Yun-Dong Xiea,b, Zi-Zhang Chena, Li-Hua Shaoa, Qiu-Tang Wanga, Na Lic, Wen-Fang
Lud ,Yan-Hong Xua, Yu-Qiong Gaoa, Li-Ying Guoa, Hao-Le Liua, Yi-Ping Lia,
Guang-De Yanga*, Xiao-Li Biana*
a
College of Pharmacy, Xi’an Jiaotong University, No.76 Yanta West Road, Xi’an, Shaanxi Province 710061, People’s Republic
of China
b Department of Medicine, Tibet University of Nationalities, No.6 Wenhui East Road, Xianyang, Shaanxi Province 712082,
People’s Republic of China
c College of Pharmacy, Shaanxi University of Chinese Medicine, Shiji Ave., Xi’an-xianyang New Ecomic Zone, Shaanxi Province
712046, People’s Republic of China
d
Pharmacy department,Xianyang Central Hospital,No.78 Renmin East Road,Xianyang,Shaanxi Province 712000,People's
Republic of China
Abstract
Oxidative stress has been regarded as the leading mechanism of the
hepatotoxicity of clofibrate (CF). To achieve multifunctional novel hypolipidemic
agents with hypolipidemia, antioxidant, and ameliorating liver injury, clofibric acid
derivative hydroxytyrosol-clofibrate (CF-HT) was synthesized by molecular
hybridization. CF-HT exhibited significant hypolipidemia, reducing serum
triglyceride (TG), total cholesterol (TC), and malonaldehyde (MDA) by 30%, 33%,
and 29% in hyperlipidemic mice induced by Triton WR 1339. CF-HT also shown
1

hepatoprotective effect, a significant decrease in hepatic indices toxicity was observed,
i.e. aspartate and lactate transaminases (AST and ALT) activities, alkalines
phosphatases (ALP), and total bilirubin (TBIL) levels. The liver weight and liver
coefficient were also ameliorated. Serum superoxide dismutase (SOD) was
significantly elevated, and serum catalase (CAT) and malondialdehyde (MDA)
content were remarkably restored. The hepatic glutathione (GSH) content was
obviously increased and hepatic oxidized glutathione (GSSG) content was reduced
dramatically by CF-HT, as compared to the CF treated mice (p<0.05). Moreover, the
histopathological damage that hepatocyte hyperplasia and hypertrophy was also
significantly ameliorated by treatment with CF-HT. Therefore, the results indicated
that CF-HT exerted more potent hypolipidemic activity and definite hepatoprotective
effect which may mainly be associated with its antioxidative property in mice.
Keywords: hydroxytyrosol-clofibrate; hypolipidemic; antioxidant; hepatoprotective
Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase. AST,
aspartate transaminase; CA, clofibric acid; CAT, catalase; CF, clofibrate; CF-HT,
hydroxytyrosol-clofibrate 13C-NMR, 13C-nuclear magnetic resonance; DMAP,
4-dimethylaminopyridine;
DMF,
N,N-dimethylformamide;
EDCI,
1-ethyl-3-(3-dimethylaminopropyl) carbodimide hydrochloride; GPX, glutathione
1
1
peroxidase; GSH, glutathione; GSSG, oxidized glutathione; H-NMR, H-nuclear
magnetic resonance; HT, hydroxytyrosol; MDA, malondialdehyde; SOD, superoxide
2

dismutase; TC, totol cholesterol; TG, triglyceride; TBIL, total bilirubin.
Hyperlipidemia is the major risk factor of cardio-cerebrovascular diseases and
metabolic syndromes such as atherosclerosis, coronary heart disease, myocardial
infarction, and cerebral apoplexy. Morbidity of hypertriglyceridemia is higher than
hypercholesterolemia, which presents a rising tendency.1 It has been attracted more
and
more
attentions
on
hypertriglyceridemia,
the
contributor
to
cardio-cerebrovascular and other diseases. Therefore, it is important to ameliorate and
control hypertriglyceridemia. Clofibrate (CF), a synthetic agonist of peroxisome
proliferator activated receptor-α (PPAR-α), characterized by decreasing triglyceride,
plays an important role in reducing blood lipids and ameliorating the related diseases.
The previous related literature reported that a disturbance of metabolic function in the
liver were observed after long-term administration CF, which included a distinction
increase in liver weight (due to hepatocyte hyperplasia and hypertrophy), midzonal
mitoses, centrilobular hypertrophy, and changes in clinical pathology.2, 3 Moreover,
CF increased hepatic mitochondrial oxidative DNA and protein damage in mice.4
These results indicated that CF can induce hepatotoxicity in body after treatment.
Liver damage following the use of fibrates agents has been reported as a cellular
damage (increases in AST or ALT enzymes, bilirubin and or alkaline phosphatase
increases).5 Moreover, the superoxide anion (O2-) and hydrogen peroxide (H2O2) were
marked increase as well as superoxide dismutase (SOD) and glutathione peroxidase
(GPX) were significantly decreased in rat liver during treatment with CF.6 Oxidative
3

stress has been regarded as the major mechanism of the hepatotoxicity. Thus,
ameliorating oxidative stress is good for CF to treat hyperlipidemia.
In the recent years, antioxidant compounds have received more and more
attention to overcome the harmful effects caused by many toxic chemicals mainly
through their scavenging ability of free radicals.7 Virgin olive oil is the major
component of Mediterranean diet, and many researches showed that phenolic
compounds are a beneficial factor to the health Mediterranean diet.8-10 Accumulating
evidence indicates that its health benefits include cardioprotection, chemoprotection
against several types of cancer, modification of inflammatory responses, etc.
Hydroxytyrosol (HT, 3,4-dihydroxy phenylethyl alcohol), the simple phenolic
compound found in olive oil, was also shown to exhibit various pharmacological
health benefits such as antithrombotic, antiatherogenic, anti-inflammatory, and
hypolipidemic activities.11 It has been reported to inhibit oxidative stress induced by
various toxic chemicals and improvising the antioxidant defense system by
modulating several signaling pathways.12
CF has been widely used in the treatment of hypertriglyceridemia and mixed
hyperlipidemia in clinical practice. It was hydrolyzed by esterase to ethanol and CA
which modulates the expression of related genes involved in lipid metabolism through
the activation of PPAR-α in the body after its absorption.13,14
Based on these, we designed compound CF-HT containing CA and HT
pharmacophore.(Chart 1) We replaced the oxethyl of CF with 3,4-dihydroxy
phenylethyl to obtained compound CF-HT and expected that the new compound can
4

be hydrolyzed by esterase to CA and HT, which not only remains hypolipidemic
activity, but also exerts antioxidant activity.
Chart 1. Design of compound CF-HT and structures of Clofibrate (CF), Clofibric
acid (CA), and Hydroxytyrosol (HT).
The preparation of CF-HT was demonstrated in Scheme 1. The catechol of HT
was firstly prevented to the 1a using benzyl bromide and potassium carbonate in
acetone. Then CA was esterified with 1a to give 2b, which was deprotected to
CF-HT in hydrogen and Pd/C.15,16 The product was purified by column
chromatography and was identified by 1H NMR, 13C NMR, and EI-MS.
5

Scheme 1. Synthesis route to compound CF-HT. Reagents and conditions: (a) BnBr,
K2CO3, acetone, reflux; (b) EDCI, DMAP, DMF; (c) H2 , Pd/C, ethanol.
Antioxidant activities of compound CF-HT in vitro were determined through
DPPH radical scavenging, the Fenton reaction, and anti-lipid peroxidation.17-19 As
showed in Figure 1, CF-HT exhibited excellent antioxidant abilities, while CF did
not show antioxidant properties. The antioxidant abilities of CF-HT were improved in
vitro, compared to HT. Both CF-HT and HT have the structure of catechol which
was favorable for scavenging reactive free radicals. Furthermore, the antioxidant
activities may be associated with the lipid solubility.
6

Figure 1. The antioxidant effects of CF-HT were evaluated in vitro towards
scavenging free radicals (DPPH• and OH•) and inhibiting lipid peroxidation. Data are
presented as the mean±SEM, n = 3.
The hypolipidemic activity of the CF-HT in vivo was evaluated in acute
hyperlipidemic mice induced by Triton WR 1339.20, 21 CF-HT was found able to
decrease plasma TG by 30% and TC by 33%. While CF reduced plasma TG by 24%
and TC by 23%. (Figure 2) Therefore, CF-HT showed to be more significant effects
on antihyperlipedemia compared to that of CF. We inferred that compound CF-HT
that incorporate CF with HT contributes to a significantly synergistic hypolipidemic
effects. Moreover, CF-HT and CF reduced plasma MDA levels by 29% and 14%.
(Figure 3) CF-HT reduced MDA could be explained by antioxidant and
hypolipidemia. CF reduced MDA might be explained by antihypolipidemia. Thus, the
7

increased antioxidant activity in vitro of CF-HT was also confirmed in vivo.
Figure 2. Percent reduction of triglyceride and total cholesterol plasma levels of
Triton WR 1339 induced hyperlipidemic mice after ig administration of 240 μmol/kg
CF-HT and CF for 7 days. mean±SEM, n=8, ###P＜0.001 vs blank group; **P＜0.01,
***P＜0.001 vs model group.
Figure 3. Plasma MDA (nmol/mL) levels of Triton WR 1339 induced hyperlipidemic
mice in the presence of compounds CF-HT and CF. mean±SEM, n=8, ###P＜0.001
vs blank group; **P＜0.01, ***P＜0.001 vs model group.
Finally, the hepatoprotective effect of CF-HT in vivo was evaluated in normal
mice. Male ICR mice (20.0 ± 2.0 g) were distributed into the following groups: (1)
normal (the same volume of vehicle), (2) CF (240 μmol/kg/day), (3) CF-HT (240
μmol/kg/day). To assess liver function, liver coefficient and hepatic histopathology
were researched, as well as hepatic biochemical indexes (AST, ALT, AKP and TBIL)
8

and antioxidant indexes (SOD, MDA, CAT, GSH, and GSSG) were measured using
commercial kits (Jian Cheng, Nanjing, China).
As showed in Table 1, the body weight of CF group and CF-HT group mice was
significantly lower than normal group mice, and the liver weight of CF mice were
higher than normal mice, while the liver weight of CF-HT mice was closed to normal
mice. Therefore, the liver coefficient of CF mice was clearly elevated (p<0.01) and
the liver coefficient of CF-HT mice was also obviously lifted (p<0.05) compared to
normal mice. Moreover, the liver coefficient of CF-HT mice was distinctly decreased
(p<0.01) in comparison with CF mice. The results suggested that CF-HT possesses
the hepatoprotective effect at the side of CF.
Table 1. Effects of CF and CF-HT on body weight, liver weight and liver coefficient in mice.a
Groups
Normal
CF
Body weight (g)
36.8±0.70
Liver weight (g)
1.49±0.42
Liver Coefficient (mg/g)
40.50±0.71
33.8±0.60##
33.4±0.44##
1.77±0.08
52.12±1.60##
1.48±0.04
44.17±1.23#**
CF-HT
a
The results are summarized as mean±SEM (n=10) and analyzed by independent
T-test.
# p＜0.05, ## p＜0.01 vs Normal group
** p＜0.01 vs CF group
Serum AST, ALT, ALP, and TBIL levels were analyzed as indications of hepatic
function. As shown in Table 2, the levels of AST, ALT, ALP, and TBIL were
9

significantly higher in the CF group when compared to the normal group (p<0.05 or
p<0.01). The administration of CF-HT significantly decreased AST, ALT, ALP, and
TBIL levels (p<0.05 or p<0.01), as compared with CF group. The levels of ALT, ALP,
and TBIL in CF-HT group did not show the significance compared to normal group,
while the level of AST was apparently increased (p<0.05). In addition, as shown in
Table 3, the serum SOD and CAT activities were significantly decreased, serum MDA,
an index of lipid peroxidation, was obviously increased, and hepatic GSH content was
clearly reduced and GSSG content was overtly elevated as well as the ratio of
GSH/GSSG was visibly decreased after administration with CF, as compared with the
normal group (p<0.01), suggesting that oxidative stress resulted from CF poisoning.
CF-HT treatment was found able to increase SOD and CAT activities and decrease
MDA concentrations as well as restore GSH contents and the ratio of GSH/GSSG
effectively in contrast to the CF group (p<0.05 or p<0.01), but GSSG contents was
not significantly decreased (p>0.05), thus ameliorating oxidative stress to some extent.
Especially, the CAT activity and MDA concentrations in CF-HT group which were
closed to the normal group showed no significance. Altogether, these findings
suggested that the hepatoprotective activity of CF-HT was regarded as due to its
antioxidant action.
Table 2. Effects of CF and CF-HT on serum ALT, AST, APK and TBIL levels in mice.a
10

Groups
Normal
CF
AST (U/L)
ALT (U/L)
APK (U/100mL)
20.02±0.61
TBIL (μM)
0.63±0.09
13.09±0.94#
0.95±0.20*
107.25±2.77
157.50±9.05##
121.37±4.59#**
36.25±1.08
63.13±11.52#
39.75±2.03*
28.64±2.42#
17.57±0.76**
CF-HT
a
The results are summarized as mean±SEM (n=10) and analyzed by independent
T-test.
# p＜0.05, ## p＜0.01 vs Normal group
* p＜0.05, ** p＜0.01 vs CF group
Table 3. Effects of CF and CF-HT on serum SOD, MDA, and CAT levels, and hepatic GSH and
GSSG levels in mice.a
Groups SOD (U/mL)
MDA (μM) CAT (U/mL) GSH (μM)
GSSG (μM) GSH/GSSG
2.91±0.31 16.4±2.34
6.24±0.56## 2.1±0.41##
4.1±0.70##*
337.64±4.82
228.32±15.97## 7.79±0.34## 3.86±0.18##
275.20±5.14##* 6.44±0.09** 2.04±0.29**
6.00±0.20
2.83±0.22
43.38±4.59
Normal
CF
11.60±1.86##
22.87±3.58##* 4.85±0.58#
CF-HT
a
The results are summarized as mean±SEM (n=10) and analyzed by independent
T-test.
# p＜0.05, ## p＜0.01 vs Normal group
* p＜0.05, * * p＜0.01 vs CF group
Furthermore, the hepatoprotective effect was further confirmed by
11

histopathological analysis. As exhibited in Figure 4, the pathology slice examination
showed the liver tissue organization of the mice in normal comparison group is
normal and the hepatic lobules of them were well-arranged. In contrast, the
hepatocyte hyperplasia and hypertrophy, midzonal mitoses, and centrilobular
hypertrophy were observed in CF group. However, the histopathological changes
were not recorded in CF-HT group. Histological observations support biochemical
findings (hepatic and antioxidant indexes), as they visibly show morphological
changes in connection with oxidative stress.
Figure 4. Histopathological studies of liver in mice (H&E 200×). (a) Normal group
mouse liver. (b) CF group mouse liver. (c) CF-HT group mouse liver.
These findings reported in this research provide the first evidence that CF-TH is
better than CF in preventing hyperlipidemia, oxidative stress, and hepatoprotective
effectives in mice. Compared CF-HT with CF in the structure, we replaced oxethyl
with HT. The action of CF in body involves the hydrolyzation of ester bond to CA
and ethanol by esterase. The pharmacokinetics results of CF-HT in rats revealed that
compound CA and HT were determined in serum, which did not describe in the paper.
And the bioavailability of CF-HT was similar to CF. We deduced that CF-HT also
can be hydrolyzed by esterase to CA and HT. CA was the active metabolite of CF
12

and activated PPAR-α to regulate lipid metabolism. It has been reported that HT
showed marked hypolipidemic activities decreasing TG and TC. Treatment with
CF-HT and CF showed the significant hypotriglyceridemic ability compared to the
model group, furthermore, CF-HT exhibited obvious decrease in TC concentrations
in Triton WR 1339 induced mice. The hypolipidemic results of CF-HT can be
explained by the synergistic effects of CA and HT in mice. In liver protection
experiment, CF exhibited a significant hepatotoxicity by elevating hepatic coefficient
and biochemical findings (hepatic and antioxidant indexes) compared to normal group
mice, while CF-HT shown obviously hepatoprotective effects by reducing hepatic
coefficient and hepatic function indexes and ameliorating oxidative stress, as in
contrast to CF group mice. Moreover, the hepatoprotective effects of CF-HT were
also confirmed in histological observations. The possible interpretation may be
considered to be via the action of HT. The previous research shown that treatment
with HT significantly attenuated ROS-induced hepatotoxicity by inhibiting CYP1A1
expression, bolstering the tissue antioxidant defense system.10
In conclusion, a multi-target-directed approach in this study led us to design
compound CF-HT, which was distinguished by the unique multimodal profile.
CF-HT was able to significantly reduce TG, similar to that of CF. Moreover, CF-HT
could potently decrease TC and ameliorate oxidative stress. Additionally, the results
presented here demonstrated that treatment with CF-HT possesses hepatoprotective
effects. The beneficiary effect of CF-HT against oxidative damages may be the most
possible contributor to liver protection. All these properties of CF-HT were better
13

than CF, which could be conducive to amelioration of hyperlipidemia in patients.
This approach may be significant for the secondary development and optimization of
CF.
Acknowledgements
This work was supported by the National Natural Science Foundation of China
(Grant No. 21172177).
Supplementary data
Supplementary data associated with this article can be found in supplement
material.
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17

Highlights
1. Design of CF-HT with a significantly hypolipidemic activity.
2. CF-HT displayed potent antioxidant and hepatoprotective effects.
3. Study indicated that CF-HT was better than clofibrate toward antihypolipidemic
action.
18