Synthesis and antioxidant activities of Coenzyme Q analogues

Article abstract of DOI:10.1016/j.ejmech.2014.09.042

A series of 2,3-dimethoxy-5-methyl-1,4-benzoquinones (Coenzyme Q) substituted at the C-6 position with various groups were designed and synthesized based on the Coenzyme Q₁₀ as potent antioxidant. In vitro antioxidant activities of these compounds were evaluated and compared with commercial antioxidant Coenzyme Q₁₀ employing DPPH assay. All these synthesized Coenzyme Q analogues are found to exhibit good antioxidant activities. Of which Compound 8b bearing a N-benzoylpiperazine group at the C-6 position showed more potent inhibition of DPPH radical than Coenzyme Q₁₀. All these results suggested the applicability of the Coenzyme Q analogues as potent antioxidants for combating oxidative stress.

Full text of DOI:10.1016/j.ejmech.2014.09.042

European Journal of Medicinal Chemistry 86 (2014) 710e713
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Short communication
Synthesis and antioxidant activities of Coenzyme Q analogues
,
b
,
, **
Jin Wang a *, Shuo Li c, Tao Yang a, Jian Yang a
a Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan, 650224, PR China
b
ꢀ
ꢀ
Universite de Toulouse, Universite Toulouse III e Paul Sabatier, 118 route de Narbonne, 31062 Toulouse Cedex 9, France
c The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, 210029, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 2,3-dimethoxy-5-methyl-1,4-benzoquinones (Coenzyme Q) substituted at the C-6 position
with various groups were designed and synthesized based on the Coenzyme Q10 as potent antioxidant.
In vitro antioxidant activities of these compounds were evaluated and compared with commercial
antioxidant Coenzyme Q10 employing DPPH assay. All these synthesized Coenzyme Q analogues are
found to exhibit good antioxidant activities. Of which Compound 8b bearing a N-benzoylpiperazine
group at the C-6 position showed more potent inhibition of DPPH radical than Coenzyme Q10. All these
results suggested the applicability of the Coenzyme Q analogues as potent antioxidants for combating
oxidative stress.
Received 22 June 2014
Received in revised form
9 September 2014
Accepted 11 September 2014
Available online 16 September 2014
Keywords:
Coenzyme Q analogues
DPPH assay
© 2014 Elsevier Masson SAS. All rights reserved.
Antioxidant activities
1. Introduction
inhibitory activity and 5-lipoxygenase suppressant activity, etc.
however, very few systematic studies have been reported on
Oxidative stress plays critical roles in the pathogenic mecha-
nisms of several neurodegenerative disorders including Alz-
heimer's disease (AD), increased levels of free radicals and reactive
oxygen species (ROS) would cause damage to cell membrane, lipids,
proteins and DNA [1]. Thus, much research effort has focused on
antioxidants as potential treatment agents for oxidative stress-
related diseases [2]. Coenzyme Q10 ( CoQ10), or ubiquinone, is a
lipid-soluble benzoquinone with a side-chain of 10 isoprenoid units
(Fig. 1), acts as a free radical scavenging antioxidant, widely
distributed in our dietary foods (beef, pork, fish, oils, etc). CoQ10
efficiently protect membrane phospholipids and LDL from damage
caused by peroxidation, it has been widely used as a dietary sup-
plement by health-conscious individuals and those who have ail-
ments including various cardiac disorders [3].
structure-antioxidant activity correlations in CoQ analogues. The
antioxidant activity is believed to originated from the quinone
nucleus, so we conceived that keeping the quinone nucleus and
introducing some hydrophilic group at the C-6 position of CoQ to
see whether it can increase its antioxidant activity and its solubility
in water. In order to better understand the structureeactivity
relationship of CoQ analogues as antioxidants and to find some
potential therapeutic agents for oxidative stress-related diseases,
we synthesized herein a series of 2,3-dimethoxy-5-methyl-1,4-
benzoquinones substituted at the C-6 position with various
groups (methoxy-, hydroxyl- and heterocyclic groups) and first
time investigated their antioxidant effects against 2,2-diphenyl-1-
picrylhydrazyl (DPPH) in vitro.
CoQ10 has little solubility in aqueous systems duo to its high
molecular weight and poor water solubility, which limits its use. In
the past few years, there has been an extensive effort to improve
the oral bioavailability of CoQ10 in nutritional supplements [4].
Many studies [5,6] show that some metabolites of CoQ homologues,
and a number of synthetic CoQ analogues have shown significant
biological activities, such as electron carriers, collagen biosynthesis
2. Results and discussion
2.1. Chemistry
Seven CoQ analogues (2, 3, 6a, 6b, 6c, 8a, 8b) were synthesized
and the reaction route was shown in Scheme 1. 2, 3, 4, 5-
Tetramethoxytoluene 1 was employed as our initial starting ma-
terial, which was prepared by our previous method [6]. Compound
4 was obtained in high yield (96%) by blanc chloromethylation re-
action of 1 with paraformaldehyde and 37% HCl in absence of sol-
vent. The oxidation reaction of compound 1 or compound 4 were
carried out to offer Coenzyme Q0 2 or compound 7 in THF-H2O (1:1)
system, respectively, using cericammoniumnitrate (CAN) as
* Corresponding author. Present address: Institut de Pharmacologie et de Biologie
Structurale, UMR 5089, 205 route de Narbonne, 31077 Toulouse Cedex 04, France.
** Corresponding author.
E-mail addresses: jin.wang@ipbs.fr, woongching@gmail.com (J. Wang),
pharmacistkg101@126.com (J. Yang).
http://dx.doi.org/10.1016/j.ejmech.2014.09.042
0223-5234/© 2014 Elsevier Masson SAS. All rights reserved.

J. Wang et al. / European Journal of Medicinal Chemistry 86 (2014) 710e713
711
tested, compounds 8a and 8b showed better radical scavenging
activities than compound 2 (Coenzyme Q0), with IC50 values of
2980.78, 193.84
played better DPPH radical scavenging activity than Coenzyme Q10,
with IC50 values of 1121.59 M. Compound 6a, 6b, 6c, 3 showed less
radical scavenging activities than Coenzyme Q0, with IC50 values of
7685.25, 4089.06, 8939.94, 5504.73 M, respectively. Obviously, of
mM, respectively. In addition, compound 8b dis-
m
m
these compounds, 8b showed the best radical scavenging activity in
this assay, demonstrating great DPPH radical scavenging activities
of these compounds. On the basis of the above observation, Coen-
zyme Q analogues substituted at the C-6 position with a hetero-
cyclic substituent showed better DPPH radical scavenging activities
than the C-6 position with alkoxy group. Besides, the length of
carbon attached at the C-6 position appeared little effects on the
DPPH radical scavenging activities.
Fig. 1. Coenzyme Q.
3. Conclusions
In summary, a facile and efficient synthetic procedure has been
delineated for the synthesis of several novel Coenzyme Q analogues
substituted at the C-6 position. Among CoQ10 and its analogues
tested, those containing piperazine and morpholine at C-6 position
of CoQ analogues exhibited higher antioxidant activities than those
containing hydroxyalkyl or alkoxy-substituents at the same posi-
tion. Of all the compounds, 8b bearing a N-benzoylpiperazine
group at the C-6 position showed better radical scavenging activ-
ities than Coenzyme Q10 in DPPH assay, Moreover, compound 8b
bearing a piperazine group which make it more soluble in water,
which means compound 8b may displayed more potential anti-
oxidant activities than Coenzyme Q10 in hydrophilic environments.
The above results demonstrate that the rational design of Coen-
zyme Q analogues as novel antioxidant is feasible, and CoQ ana-
logues may be developed as potential therapeutic antioxidants for
oxidative stress-related diseases. Further studies on the water
solubility and problematic of the potential toxicity of these com-
pounds are in progress, and will be published in the future.
Scheme 1. Synthetic route of Coenzyme Q analogues. Reagents and conditions: (a)
(HCHO)n, 37%HCl, 40 ꢀC; (b) CAN, THF/H2O, 25 ꢀC; (c) Na, KI, ROH, 60 ꢀC; (d) K2CO3,
DMF, 80 ꢀC; (e) 10-hydroxycapricacid, K2S2O8, AgNO3, CH3CN/H2O, 75 ꢀC.(f) 40% NaOH,
TBAB, KI, 100 ꢀC.
4. Experimental section
4.1. Chemistry
oxidant. It was important to note that compound 3 could be syn-
thesized directly by free-radical alkylation of Coenzyme Q0 2 with
10-hydroxycapricacid in the presence of K2S2O8 and AgNO3 under
solvent of CH3CNeH2O (1:1) condition in good yields (60%). Com-
pounds (5a, 5b) were obtained in good yield via Williamson reac-
tion of compound 4 with different alcohols (methanol, glycol)
catalysed by KI under solvent-free conditions, respectively. Com-
pound 5c was obtained by treatment of compound 4 with 40%
NaOH aqueous catalysed by KI and tetrabutyl ammonium bromide
(TBAB). Oxidation reaction of compounds (5a, 5b, 5c) with cer-
icammoniumnitrate (CAN) to afford the benzoquinones (6a, 6b, 6c)
in good yields. Directly N-alkylation of compound 7 with hetero-
cyclic compounds (morpholine, N-benzoylpiperazine) in the pres-
ence of K2CO3 gave benzoquinones (8a, 8b) via SRN1 reaction,
respectively [7].
General methods: The synthesized CoQ analogues were purified
by silica gel (80e120 mesh) column chromatography (Adamas-
beta, China) and identified by thin-layer chromatography (TLC), MS,
and NMR analysis. The melting points were measured with an YRT-
3 temp apparatus and are uncorrected. 1H NMR spectra and 13C
Table 1
Antioxidant activities of Coenzyme Q analogues.
Compounds
R
IC50
(
mM)
SD (mM)
2.2. Antioxidant evaluation
2
H
3565.75
7685.25
4089.06
8939.94
5504.73
2980.78
193.84
17.03
47.34
6.10
32.07
25.16
12.74
3.56
6a
6b
6c
CH2OCH3
CH2OCH2CH2OH
CH2OH
DPPH radical scavenging activity evaluation is a rapid and
convenient technique for screening the antioxidant activities of the
antioxidants [8]. The test results of CoQ analogues (2, 3, 6a, 6b, 6c,
8a, 8b) were shown in Table 1. Based on IC50 values, their DPPH
3
(CH2)9OH
8a
8b
CoQ10
CH2-morpholinyl
CH2-N-benzoylpiperazine
10 isoprenoid units
1211.54
1.59
radical-scavenging
activity
follows
the
order:
8b > CoQ10 > 8a > 2 > 6b > 3 > 6a > 6c, among the compounds
SD, standard deviation of three experiments.

712
J. Wang et al. / European Journal of Medicinal Chemistry 86 (2014) 710e713
NMR were recorded on a Bruker DRX NMR spectrometer respec-
tively, Mass spectra were obtained on a ZAB-2F mass spectrometer.
A UV-2550 UVeVis spectrophotometer from Shimadzu was used in
the scavenging assays. 2,2-Diphenyl-1-picrylhydrazyl free radical
(DPPH), Ceric ammonium nitrate (CAN), potassium persulfate
(K2S2O8) and silver nitrate (AgNO3) were purchased from Adamas-
beta, China. Other chemicals used were of analytical grade. Starting
material 1 was synthesized according to our previous procedures
[6].
4.1.4. Synthesis of compounds 2, 6, 7; general procedure
A solution of compounds 1, 4, 5 (2.5 mmol) in THF (10 mL) was
diluted with water (5 mL), and an excess solution of cerric
ammonium nitrate (CAN) (3.9 g, 7 mmol) in 10 mL water was added
at 0 ꢀC. The mixture was stirred at room temperature for 2 h. The
progress of the reaction was monitored by TLC. After completion of
the reaction, the THF was removed under a vacuum at 40 ꢀC, and
the crude mixture was extracted with three portions of CH2Cl2
(20 mL). The orange extracts were washed with brine until
neutrality, then dried over anhydrous Na2SO4 and concentrated in
vacuo. The crude products were purified by a silica-gel column
chromatography with petroleum ether and EtOAc as eluent to give
the desired benzoquinones 2, 7, 6.
4.1.1. Synthesis of compound 4
Conc. HCl (3 mL) was added to a stirred mixture of 1 (2.12 g,
0.01 mol) and paraformaldehyde (0.45 g, 0.015 mol) at room tem-
perature. Then the mixture was stirred at 40 ꢀC for 1 h, Water
(10 mL) were added and the mixture was extracted with petroleum
ether (4 ꢁ 10 mL), and the combined extracts were washed with
brine (4 ꢁ 10 mL). The solution are dried over anhydrous sodium
sulphate and solvent was removed in vacuo to afford a yellow oil 4
(2.51 g) in 97% yield.
4.1.4.1. Coenzyme Q0 2. 1H NMR (500 MHz, CDCl3): 6.42 (s,1H), 4.00
(s, 3H, OCH3), 3.98 (s, 3H, OCH3), 2.02 (s, 3H, CH3). MS (ESI): m/
z ¼ 183 (MþþH).
4.1.4.2. Compound 7. 1H NMR (500 MHz, CDCl3): 4.68 (s, 2H,
CH2Cl), 3.92 (s, 3H, OCH3), 3.91 (s, 3H, OCH3), 3.89 (s, 3H, OCH3),
3.78 (s, 3H, OCH3), 2.28 (s, 3H, CH3). MS (ESI): m/z ¼ 231 (MþþH).
1H NMR (500 MHz, CDCl3): 4.68 (s, 2H, CH2Cl), 3.92 (s, 3H,
OCH3), 3.91 (s, 3H, OCH3), 3.89 (s, 3H, OCH3), 3.78 (s, 3H, OCH3),
2.28 (s, 3H, CH3). Identical with Ref. [6a].
4.1.4.3. Compound 6a. Orange solid; m.p. 33e34 ꢀC; 1H NMR
(500 MHz, CDCl3): 4.30 (s, 2H, CH2O), 3.98 (s, 3H, OCH3), 3.96 (s, 3H,
OCH3), 3.35 (s, 3H, OCH3), 2.09 (s, 3H, CH3); 13C NMR (125 MHz,
MeOD):184.3, 183.2, 144.4, 144.2, 143.0, 136.5, 64.0, 61.0, 60.9, 58.6,
11.9; MS (ESI): m/z ¼ 225 (MꢂꢂH).
4.1.2. Synthesis of compounds 5a, 5b; general procedure
Freshly cut sodium (0.5 g, 0.022 mol) was dissolved in the dry
ROH (10 mL). The catalyst KI (0.1 g) and 1-chloromethyl -2, 3, 4, 5-
tetramethoxy-6-methylbenzene 4 (0.7 g, 2.69 mmol) were added
under a N2 atmosphere .The mixture was refluxed for 1 h. The
progress of the reaction was monitored by TLC. After completion of
the reaction, the reaction mixture was cooled to room temperature
and water (50 mL) were added and then neutralized to pH 7 with
1% aqueous HCl. The mixture was extracted with CH2Cl2
(4 ꢁ 30 mL) and the combined organic layers were dried over
anhydrous Na2SO4 and concentrated in vacuo to give the desired
compounds 5.
4.1.4.4. Compound 6b. Orange oil; 1H NMR (500 MHz, C5D5N-d5):
4.31 (s, 2H, CH2O), 3.90 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 3.62e3.61
(m, 2H, CH2OH), 3.51e3.50 (m, 2H, CH2), 2.80 (brs, 1H, OH), 2.01 (s,
3H, CH3); 13C NMR (125 MHz, MeOD):184.2, 183.4, 144.3, 144.1,
143.0, 136.4, 72.0, 62.6, 61.3, 61.0, 60.9, 11.9; MS (ESI): m/z ¼ 255
(MꢂꢂH).
4.1.4.5. Compound 6c. Orange oil; 1H NMR (500 MHz, CDCl3): 4.45
(s, 2H, CH2OH), 3.92 (s, 6H, OCH3), 2.92 (s, 1H, OH), 2.02 (s, 3H, CH3).
13C NMR (100 MHz, CDCl3): 184.9, 184.5, 144.6, 144.1, 140.6, 138.6,
61.1 (2C), 11.6. MS (ESI): m/z ¼ 213 (MþþH).
4.1.2.1. Compound 5a. Colourless oil; 1H NMR (500 MHz, DMSO-
d6): 4.34 (s, 2H, CH2O), 3.80 (s, 3H, OCH3), 3.78 (s, 3H, OCH3), 3.73 (s,
3H, OCH3), 3.67 (s, 3H, OCH3), 3.30 (s, 3H, OCH3), 2.15 (s, 3H, CH3);
13C NMR (125 MHz, C5D5N-d5):148.4, 147.5, 146.6, 144.1, 126.7,
124.5, 65.5, 61.1, 60.4, 60.3, 59.8, 57.5, 10.7; MS (EI): m/z ¼ 256
(MþþH).
4.1.5. Synthesis of compounds 8; general procedure
Compound 7 (0.30 g, 1.3 mmol), morpholine or N-benzoylpi-
perazine (0.27 g, 1.4 mmol), and K2CO3 (0.28 g, 2.0 mmol) in DMF
were heated at 80 ꢀC for 2 h, After completion of the reaction, the
crude was extracted with three portions of CH2Cl2 (10 mL). The
orange extracts were washed with brine until neutrality, then dried
over anhydrous Na2SO4 and concentrated in vacuo. The crude
products were purified by a silica-gel column chromatography with
petroleum ether and EtOAc (5:1) as eluent to give the desired
compound 8.
4.1.2.2. Compound 5b. Colourless oil; 1H NMR (500 MHz, C5D5N-
d5): 4.40 (s, 2H, CH2O), 3.77 (s, 3H, OCH3), 3.72 (s, 3H, OCH3), 3.70 (s,
3H, OCH3), 3.63 (s, 3H, OCH3), 3.56 (m, 2H, CH2O), 3.46e3.45 (m,
2H, CH2), 3.14 (brs, 1H, OH), 2.11 (s, 3H, CH3); 13C NMR (125 MHz,
MeOD): 148.7, 147.8, 146.9, 144.4, 127.1, 124.6, 71.5, 64.4, 61.6, 61.4,
60.9, 60.8, 60.4, 11.3; MS (ESI):m/z ¼ 285 (MꢂꢂH).
4.1.5.1. Compound 8a. Orange oil; 1HNMR (500 MHz, CDCl3): 3.96
(s, 3H, OCH3), 3.94 (s, 3H, OCH3), 3.63 (t, J ¼ 4.3 Hz, 4H), 3.38 (s, 2H,
CH2), 2.43 (t, J ¼ 4.3 Hz, 4H), 2.16 (s, 3H, CH3). MS (API): m/z ¼ 282
(MþþH), identical with Ref. [9].
4.1.3. Synthesis of compound 5c
Compound 4 (1.30 g, 5 mmol), KI (0.1 g, 0.6 mmol) and tetrabutyl
ammonium bromide (0.20 g, 0.6 mmol) in 40% NaOH aqueous were
heated at 100 ꢀC for 12 h, then quenched with water 20 mL, the
crude was extracted with three portions of CH2Cl2 (10 mL). The
orange extracts were washed with brine until neutrality, then dried
over anhydrous Na2SO4 and concentrated in vacuo. The crude
products were purified by a silica-gel column chromatography with
petroleum ether and EtOAc (1:1) as eluent to give a yellow oil 5c
(0.2 g) in 17% yield.
4.1.5.2. Compound 8b. Orange solid, m.p. 122.7e124.3 ꢀC, 1H NMR
(500 MHz, C5D5N-d5): 7.35e7.33 (m, 5H, PhH), 3.95 (s, 3H, OCH3),
3.94 (s, 3H, OCH3), 3.69 (brs, 2H, CH2N), 3.37 (s, 2H, CH2), 3.32 (brs,
2H, CH2N), 2.49 (brs, 2H, CH2N), 2.33 (brs, 2H, CH2N), 2.07 (s, 3H,
CH3); 13C NMR (125 MHz, MeOD):184.4, 183.8, 170.2, 144.3, 144.2,
142.9, 137.3, 135.6, 129.6 (CH), 128.4 (2 ꢁ CH), 126.9 (2 ꢁ CH), 61.2
(2 ꢁ OCH3), 53.4 (CH2N), 52.9 (CH2N), 51.5 (CH2), 47.6 (CH2N), 42.0
(CH2N), 12.4. MS (ESI): m/z ¼ 383 (MꢂꢂH).
1H NMR (500 MHz, CDCl3): 4.68 (s, 2H, CH2OH), 3.92 (s, 3H,
OCH3), 3.90 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 3.78 (s, 3H, OCH3),
2.27 (s, 3H, CH3). MS (ESI): m/z ¼ 242 (MþþH).

J. Wang et al. / European Journal of Medicinal Chemistry 86 (2014) 710e713
713
4.1.6. Synthesis of compound 3
Education of Yunnan Province (No. 2011J077). We also thank Dr.
Sandro Da Silva Gomes and Alexiane Decout (Institut de Pharma-
cologie et de Biologie Structurale, CNRS UMR 5089) for the help in
the studies of antioxidant activity.
To a solution of Coenzyme Q0 2 (0.55 g, 3 mmol) and 10-
hydroxycapricacid (0.70 g, 3.6 mmol) in acetonitrile 10 mL and
distilled water 10 mL was added AgNO3 (0.50 g, 3 mmol). The
mixture was heated to 75 ꢀC, a solution of K2S2O8 (1.62 g, 6 mmol)
in distilled water 20 mL was added dropwise over 2 h. The reaction
was monitored by TLC until the starting material was consumed.
The resulting mixture was cooled and extracted with CH2Cl2 and
washed with water, then dried over anhydrous Na2SO4 and evap-
orated under reduced pressure, and the residue was purified by
column chromatograph on silica gel (PE/EtoAc 4:1) to give an or-
ange oil 3 (0.97 g) in 60% yield.
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.ejmech.2014.09.042.
1H NMR (400 MHz, CDCl3): 3.91 (s, 6H, OCH3), 3.55 (t, J ¼ 6.3 Hz,
2H, CH2OH), 2.52 (brs, 1H, OH), 2.37e3.35 (m, 2H), 2.00 (s, 3H, CH3),
1.48-1.47 (m, 2H), 1.22 (brs, 12H). 13C MR (100 MHz, (CD3)2CO):
184.5, 183.9, 144.0, 142.8 (2C), 138.5, 62.6, 60.9, 32.5, 29.6, 29.2, 29.1,
29.0, 28.5, 26.2, 25.5, 11.7. MS (ESI): m/z ¼ 325 (MþþH).
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Acknowledgements
This study was supported by China Scholarship Council (CSC)
(No. 201208530032) and Science Foundation of Department of
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