Single-step synthesis of idebenone from Coenzyme Q0 via free-radical alkylation under silver catalysis

Article abstract of DOI:10.1016/j.tet.2014.10.017

Idebenone was synthesized directly by free-radical alkylation of 2,3-dimethyl-1,4-benzoquinone (Coenzyme Q₀) with commercially available 11-hydroxyundecanoic acid in the presence of potassium peroxodisulfate and silver nitrate in a mixed solvent (CH₃CN-H₂O, 1:1) under mild condition in good yields (65%, based on Coenzyme Q₀). The reaction is operationally simple and could be used in the preparation of other biologically Coenzyme Q analogues.

Full text of DOI:10.1016/j.tet.2014.10.017

Tetrahedron 70 (2014) 9029e9032
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Single-step synthesis of idebenone from Coenzyme Q0 via
free-radical alkylation under silver catalysis
,
b
, ,
,
Jin Wang a
y, 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:
Idebenone was synthesized directly by free-radical alkylation of 2,3-dimethyl-1,4-benzoquinone (Co-
enzyme Q0) with commercially available 11-hydroxyundecanoic acid in the presence of potassium per-
oxodisulfate and silver nitrate in a mixed solvent (CH3CNeH2O, 1:1) under mild condition in good yields
(65%, based on Coenzyme Q0). The reaction is operationally simple and could be used in the preparation
of other biologically Coenzyme Q analogues.
Received 6 September 2014
Received in revised form 25 September 2014
Accepted 7 October 2014
Available online 12 October 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Idebenone
Decarboxylative cross-coupling
CeH activation
Free-radical alkylation
1. Introduction
both in hydrophobic and hydrophilic environments. Theoretically,
idebenone may posses greater bioavailability than Coenzyme Q10
Idebenone (2,3-Dimethoxy-5-methyl-6-(10-hydroxydecyl)-1,4-
benzoquinone, Fig. 1) is a synthetic analog of Coenzyme Q10
due to its decreased molecular weight and increased water solu-
bility.3 More recently, idebenone has been recommended as a po-
tential treatment for Leber’s hereditary optic neuropathy (LHON)
and Duchenne muscular dystrophy (DMD).4
,
a free radical scavenger for reactive oxygen species (ROS) and fa-
cilitating electron transfer along the mitochondrial respiratory
chain.1 It has been widely used in the treatment of neurodegener-
ative and mitochondrial disorders, such as Alzheimer’s disease,
Parkinson’s disease, Friedreich’s ataxia, etc.2 In comparison with
Coenzyme Q10 (C40 side chain), idebenone (C10 side chain) has
a shorter carbon chain that facilitates interception of free radicals
To date, methods for the synthesis of idebenone are limited, few
synthetic processed to idebenone have been disclosed.5 The major
divergence of theses processes were the starting materials, either
FriedeleCrafts acylation of 3,4,5-trimethoxytoluene (or 2,3,4,5-
tetramethoxytoluene, 16% total yield),5a,b [Scheme 1, (1)] or Heck
coupling reaction of 2-bromo-3,4,5-trimethoxytoluene (20% total
yield)5c [Scheme 1, (2)]. However, both methods involve multistep
procedures under harsh reaction conditions, in which toxic re-
agents or metallic catalysts [NaCN, KMnO4, PtO2, Pd(AcO)2, etc.] are
often used.5 Therefore, a convenient and practical synthetic route
for the preparation of idebenone is highly demanded.
In recent years, transition-metal-catalyzed decarboxylative
cross-coupling reactions using carboxylic acids as coupling part-
ners have been widely studied in organic synthesis as novel
methods for the formation of carbonecarbon bonds.6 The Minisci
reactions, which involving the addition of radicals to hetero-
aromatic base under AgNO3 catalysis are valuable CeH function-
alization processes within medicinal chemistry.7 Although the
Minisci reaction is useful in coupling nitrogen-containing hetero-
cyclic compounds with aldehydes, carboxylic acids, and boronic
acids, it is associated with a few limitations.6,7 Radicals generated
Fig. 1. Coenzyme Q10 and idebenone.
* Corresponding authors. Tel.: þ33 0658273123; e-mail addresses: woongching@
gmail.com, jin.wang@ipbs.fr (J. Wang), pharmacistkg101@126.com (J. Yang).
y
Current address: Institut de Pharmacologie et de Biologie Structurale, UMR
5089, 205 route de Narbonne, 31077 Toulouse Cedex 04, France.
http://dx.doi.org/10.1016/j.tet.2014.10.017
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

9030
J. Wang et al. / Tetrahedron 70 (2014) 9029e9032
Then, the effect of the amount of 11-hydroxyundecanoic acid 2,
(a) known methods
AgNO3 and K2S2O8 was examined, and the results showed that an
increase in the amount of AgNO3 and K2S2O8 lead to higher con-
version of Coenzyme Q0. When we used 1.3 equiv of 2, 0.3 equiv of
AgNO3 and 2 equiv of K2S2O8, we obtained the highest yield (65%) of
idebenone 3 (Table 1, entries 10e13). Solvents were crucial for this
reaction, using THF-H2O, Acetone-H2O, DMF-H2O or CH2Cl2eH2O
as solvent led to a trace amount of idebenone 3 (Table 1, entries
14e17). Further screening of the reaction time showed that 3 h was
the best choice. On the basis of these screening studies, the optimal
condition was using 11-hydroxyundecanoic acid 2 (1.3 equiv),
AgNO3 (0.3 equiv), and K2S2O8 (2 equiv) in the mixed solvent of
CH3CNeH2O (v/v¼1:1) at 75 ꢀC for 3 h (Table 1, entry 11).
(b) this work
Scheme 2. Single-step synthesis of idebenone from Coenzyme Q0 via free-radical
alkylation.
Table 1
Scheme 1. Various approaches for idebenone.
a
Optimization studies of silver-catalyzed free-radical alkylation of Coenzyme Q0
by decarboxylaion of carboxylic acids with K2S2O8 and AgNO3 could
be used for the alkylation of quinones was reported by Liu et al.6b
and Fausta et al.,6c however, to the best of our knowledge, practi-
cal CeH functionalization of Coenzyme Q0 with long chain car-
boxylic acids were few reported,6deh which would provide a novel
CeC cross-coupling method of idebenone. Following our recent
work on synthesis of Coenzyme Q analogues,8 herein we describe
a one-step synthesis of idebenone by alkylation of Coenzyme Q0 1
with commercially available 11-hydroxyundecanoic acid 2 through
direct decarboxylative cross-coupling reaction under silver cataly-
sis [Scheme 1, (3)].
Entry
Catalyst (equiv.)
AgNO3 (0.1)
Oxidant (equiv.)
Mixed solvent
Yieldb (%)
1
K2S2O8 (1.5)
K2S2O8 (1.5)
K2S2O8 (1.5)
K2S2O8 (1.5)
K2S2O8 (1.5)
Na2S2O8 (1.5)
(NH4)2S2O8 (2)
H2O2 (2)
CH3CNeH2O
CH3CNeH2O
CH3CNeH2O
CH3CNeH2O
CH3CNeH2O
CH3CNeH2O
CH3CNeH2O
CH3CNeH2O
CH3CNeH2O
CH3CNeH2O
CH3CNeH2O
CH3CNeH2O
CH3CNeH2O
THF-H2O
34
0
2c
3
Ag2CO3 (0.1)
AgOAc (0.1)
Ag2O (0.1)
22
25
18
30
Trace
0
4
5
6
7
8
9
10
11
12d
13d
14
15
16
17
AgNO3 (0.1)
AgNO3 (0.1)
AgNO3 (0.1)
AgNO3 (0.1)
AgNO3 (0.2)
AgNO3 (0.3)
AgNO3 (0.4)
AgNO3 (0.5)
AgNO3 (0.3)
AgNO3 (0.3)
AgNO3 (0.3)
AgNO3 (0.3)
2. Results and discussion
TBHP (2)
0
K2S2O8 (2)
K2S2O8 (2)
K2S2O8 (3)
K2S2O8 (4)
K2S2O8 (2)
K2S2O8 (2)
K2S2O8 (2)
K2S2O8 (2)
44
65
62
60
Trace
Trace
0
We began our studies with the commercially available Co-
enzyme Q0 1 and 11-hydroxyundecanoic acid 2 (Scheme 2). 11-
hydroxyundecanoic acid 2 was selected because it is mono-
carboxylic acid and it could generate the 10 carbon alkyl radical
in the presence of silver (I) and peroxodisulfate, which may facili-
tate addition to the C-6 position of Coenzyme Q0 to form idebe-
none. When 1 equiv of Coenzyme Q0 1 was treated with 2 in the
presence of 0.1 equiv of AgNO3 and 1.5 equiv of K2S2O8 in
CH3CNeH2O (v/v¼1:1) at 75 ꢀC, we were delighted to know that
our desired idebenone 3 was indeed formed in 34% yield (Table 1,
entry 1). The control experiment showed that a silver catalyst was
necessary for this reaction to proceed (Table 1, entry 2). Then,
several other silver catalysts were screened in the reaction, Ag2CO3,
AgOAc and Ag2O catalyzed the reaction with moderate efficiency
(Table 1, entries 3e5), and AgNO3 was ultimately chosen as the
catalyst because it formed idebenone in the best yield and is less
expensive than other silver catalysts. Other oxidants, such as
Na2S2O8, (NH4)2S2O8,5e,6eeg H2O2 and TBHP were also examined in
the reaction, unfortunately, only Na2S2O8 can catalyze this reaction
with a moderate yield (30%) (Table 1, entries 6e9). It is necessary to
note that the methodology to prepare idebenone reported pre-
viously in a patent from 1996 by Morimasa5e utilizing (NH4)2S2O8
gives the desired product in 88.8% yield, which is quite doubtful.
Acetone-H2O
DMF-H2O
CH2Cl2eH2O
0
a
Reaction Conditions: 1 (6 mmol), 2 (1.3 equiv), catalyst, oxidant and 80 mL of
mixed solvent (v/v¼1:1).
b
Yield of pure isolated products.
No AgNO3 added.
1.5 equiv of 2 added.
c
d
With the optimized conditions, some commercially available
short chain mono-carboxylic acids 4 were investigated in this
free-radical decarboxylative cross-coupling reaction and the re-
sults were summarized in Table 2. The free-radical alkylation
proceeded smoothly in the presence of AgNO3 and K2S2O8 in the
mixed solvent of CH3CNeH2O at 75 ꢀC, mono-carboxylic acids:
glycolic acid 4a, chloroacetic acid 4b, methoxyacetic acid 4c,
ethoxyacetic acid 4d all direct C-6 alkylation with Coenzyme Q0 1
to form the corresponding Coenzyme Q analogues 5 (Table 2,
entries 1e4).

J. Wang et al. / Tetrahedron 70 (2014) 9029e9032
9031
Table 2
a 65% yield is quite respectable for such a reaction. This protocol
provided a new avenue to form CeC bonds between Coenzyme Q0
and carboxylic acids for the preparation of Coenzyme Q analogues
5. The reaction was performed at 75 ꢀC with no requirement of
strict water- and oxygen-free conditions, and is amenable to the
gram-scale synthesis of idebenone. Therefore, this synthetic
method would have potential industrial application in the prepa-
ration of idebenone and other biologically Coenzyme Q analogues.
Free-radical alkylation of Coenzyme Q0 1 with different mono-carboxylic acids 4a
Entry
4
R
5
Yieldb (%)
4. Experimental section
4.1. General
1
2
3
4
4a
4b
4c
4d
CH2OH
CH2Cl
CH2OCH3
CH2OCH2CH3
5a
5b
5c
5d
20
18
32
35
The synthesized CoQ analogues were purified by silica gel
(80e100 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 NMR were
recorded on a Bruker DRX NMR spectrometer, respectively, Mass
spectra were obtained on a ZAB-2F mass spectrometer. Potassium
persulfate (K2S2O8) and silver nitrate (AgNO3) were purchased from
Adamas-beta, China. Coenzyme Q0 1, 11-hydroxyundecanoic acid 2
and mono-carboxylic acids 4 were purchased from Adamas-beta
and SigmaeAldrich. Other chemicals used were of analytical grade.
a
Reaction Conditions: 1 (6 mmol), 4 (1.3 equiv), AgNO3 (0.3 equiv), and K2S2O8
(2 equiv) and 80 mL of mixed solvent (v/v¼1:1).
b
Yield of pure isolated products.
On the basis of the literature precedence,6,7,9 we assumed that
the reaction is proceeding through a radical mechanism as shown
in Scheme 3. Initially, an Ag(I) cation is oxidized to an Ag(II) cation
ꢂ
by peroxodisulfate [Eq. (1)] and a sulfate radical ion (SOꢁ4 ) [Eq. (2)].
Then, mono-carboxylic acids 4 reacted with the Ag(II) cation to
form alkyl radical (A) by losing a proton, one molecule of CO2 and
the Ag(I) cation. The obtained radical (A) subsequently underwent
hydrogen atom abstraction from the C-6 position of Coenzyme Q0 1
forming a coupling intermediate (B), which can transfer to the
hydroquinol radical (C), subsequently the hydroquinol radical (C) is
oxidized to Coenzyme Q 5 by peroxodisulfate.
4.2. General procedure for synthesis of idebenone 3 and Co-
enzyme Q analogues 5
To a solution of Coenzyme Q0 1 (1.09 g, 6 mmol) and 11-mono-
carboxylic acids 2 or 4 (7.8 mmol) in acetonitrile 40 mL and distilled
water 10 mL was added AgNO3 (0.31 g, 1.8 mmol). The mixture was
heated to 75 ꢀC and a solution of K2S2O8 (3.24 g, 12 mmol) in dis-
tilled water 30 mL was added dropwise over 2 h, then the reaction
mixture was stirred for another 1 h. The resulting mixture was
cooled and extracted with CH2Cl2 and the organic layer was washed
with water, then dried over anhydrous Na2SO4 and evaporated
under reduced pressure. The residue was purified by short column
chromatograph on silica gel (eluent: PE/EtOAc¼3:1 or 5:1) to give
idebenone 3 or Coenzyme Q analogues 5.
4.2.1. Idebenone 3. (1.32 g, 65%), yellow needles, mp 53e55 ꢀC
(Lit5a 55.5 ꢀC). 1H NMR (400 MHz, CDCl3): 4.01 (s, 3H, OCH3), 4.00 (s,
3H, OCH3), 3.66 (t, 2H, J¼6.4 Hz, CH2OH), 2.47 (t, 2H, J¼6.8 Hz, CH2-
CoQ0), 2.03 (s, 3H, CH3), 1.65e1.53 (m, 2H), 1.46e1.24 (m, 14H); 13
C
NMR (100 MHz, CDCl3): 184.7 (C]O), 184.2 (C]O), 144.3, 143.1
(2C), 138.7, 63.1 (CH2OH), 61.1 (OCH3), 32.8, 29.8, 29.5, 29.4, 29.3,
28.7, 26.4 and 25.7 (CH2-side chain), 11.9 (CH3).
4.2.2. Compound 5a. (0.25 g, 20%), orange solid, mp 50e51 ꢀC (Lit5g
53e55 ꢀC). 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 (C]O), 184.5 (C]O), 144.6, 144.1, 140.6, 138.6, 61.1
(OCH3), 56.5 (CH2OH), 11.6 (CH3).
4.2.3. Compound 5b.8c (0.24 g, 18%), orange oil, 1H NMR (500 MHz,
CDCl3): 4.29 (s, 2H, CH2Cl), 3.88 (s, 3H, OCH3), 3.86 (s, 3H, OCH3),
1.99 (s, 3H, CH3); 13C NMR (100 MHz, MeOD):183.7 (C]O), 181.6
(C]O), 144.7, 144.2, 142.3, 136.7, 61.2 (OCH3), 61.1 (OCH3), 35.0
(CH2Cl), 11.8 (CH3); MS (ESI): m/z¼231 (MþþH).
Scheme 3. Proposed mechanism for the silver-catalyzed decarboxylative cross-
coupling reaction for the synthesis of Coenzyme Q analogues.
3. Conclusion
4.2.4. Compound 5c. (0.43 g, 32%), orange solid, mp 33e34 ꢀC (Lit5g
36 ꢀC); 1H NMR (500 MHz, D2O): 4.18 (s, 2H, CH2OCH3), 3.87 (s, 3H,
OCH3), 3.85 (s, 3H, OCH3), 3.24 (s, 3H, CH2OCH3), 1.97 (s, 3H, CH3);
13C NMR (100 MHz, MeOD):184.3(C]O), 183.2(C]O), 144.4, 144.2,
143.0, 136.5, 64.0(CH2OCH3), 61.0 (OCH3), 58.6 (OCH3),
In summary, a silver-catalyzed free-radical direct C-6 alkylation
of Coenzyme Q0
1
with commercially available 11-
hydroxyundecanoic acid 2 for the preparation of idebenone 3 has
been developed, the reaction is clean without by-products and

9032
J. Wang et al. / Tetrahedron 70 (2014) 9029e9032
11.9(CH2OCH3); HRMS-ESI: m/z (Mꢁ-H) Calcd for C 11H
225.0762. Found: 225.0759.
O5:
€
Navarro, J.; Moreno-Yanguela, M. Acta. Neurol. Scand. 2014, 129, 32; (d) Kerr, D. S.
Neurotherapeutics 2013, 10, 307; (e) Mecocci, P.; Polidori, M. C. Biochim. Biophys.
Acta 2012, 1822, 631.
13
3. Parkinson, M. H.; Schulz, J. B.; Giunti, P. J. Neurochem. 2013, 126, 125.
4. (a) Hargreaves, I. P. Int. J. Biochem. Cell Biol. 2014, 49, 105; (b) Buyse, G. M.;
Goemans, N.; van den Hauwe, M.; Thijs, D.; de Groot, I. J.; Schara, U.; Ceulemans,
B.; Meier, T.; Mertens, L. Neuromuscul. Disord. 2011, 21, 396.
5. (a) Goto, G.; Okamoto, K.; Okutani, T.; Isuke, I. Chem. Pharm. Bull. 1985, 33, 4422;
(b) Lu, L.; Chen, F. Synth. Commun. 2004, 34, 4049; (c) Tsoukala, A.; Bjørsvik, H.-R.
Org. Process Res. Dev. 2011, 15, 673; (d) Duveau, D. Y.; Arce, P. M.; Schoenfeld, R.
A.; Raghav, N.; Cortopassi, G. A.; Hecht, S. M. Bioorg. Med. Chem. 2010, 18, 6429;
(e) Morimasa, A. Jpn. Kokai Tokkyo Koho 1996, JP 08239340; (f) Ma, W.; Li, D.-W.;
Sutherland, T.-C.; Li, Y.; Long, Y.-T.; Chen, H.-Y. J. Am. Chem. Soc. 2011, 133, 12366;
(g) Okamoto, K.; Watsumoto, M.; Watanabe, M.; Kawada, M.; Imamoto, T.; Im-
ada, I. Chem. Pharm. Bull. 1985, 33, 3745.
4.2.5. Compound 5d. (0.50 g, 35%), orange oil, 1H NMR (400 MHz,
CDCl3): 4.30 (s, 2H, CH2OCH2CH3), 3.95 (s, 3H, OCH3), 3.93 (s, 3H,
OCH3), 3.50 (q, J¼7.1 Hz, 2H, CH2OCH2CH3), 2.07 (s, 3H, CH3),
1.19e1.16 (t, J¼7.1 Hz, 3H, CH2OCH2CH3); 13C NMR (100 MHz,
CDCl3): 184.5(C]O), 183.3(C]O), 144.5, 144.4, 143.1, 136.9, 66.6
(CH2OCH2CH3), 62.2(CH2OCH2CH3), 61.1(OCH3), 61.1(OCH3),
15.1(CH3), 12.0(CH2OCH2CH3); HRMS-ESI: m/z (MþþNa) Calcd for C
12H 16 O5Na: 263.0895. Found: 263.0892.
6. (a) Zhao, W.; Chen, X.-L.; Yuan, J.; Qu, L.; Duan, L.; Zhao, Y.-F. Chem. Commun.
2014, 2018; (b) Liu, B.; Gu, L.; Zhang, J. Recl. Trav. Chim. Pays-Bas 1991, 110, 104;
(c) Coppa, F.; Fontana, F.; Lazzarini, E.; Minisci, F. Chem. Lett. 1992, 1299; (d) Asin-
Cayuela, J.; Manas, A. R.; James, A. M.; Smith, R. A.; Murphy, M. P. FEBS Lett. 2004,
Acknowledgements
This study was supported by China Scholarship Council (CSC)
(No. 201208530032) and Science Foundation of Department of
Education of Yunnan Province (No. 2011J077).
€
571, 9; (e) Angerer, H.; Nasiri, H. R.; Niedergesaß, V.; Kerscher, S.; Schwalbe, H.;
Brandt, U. Biochim. Biophys. Acta 2012, 1817, 1776; (f) Pei, Z.; Gustavsson, T.; Roth,
€
€
R.; Frejd, T.; Hagerhall, C. Bioorg. Med. Chem. 2010, 18, 3457; (g) Ma, W.; Zhou, H.;
Ying, Y.; Li, D.; Chen, G.; Long, Y.; Chen, H. Tetrahedron 2011, 67, 5990; (h) Fuji-
wara, Y.; Domingo, V.; Seiple, I. B.; Gianatassio, R.; Del Bel, M.; Baran, P. S. J. Am.
Chem. Soc. 2011, 133, 3292.
Supplementary data
7. (a) Minisci, F.; Bernardi, R.; Bertini, F.; Galli, R.; Perchinummo, M. Tetrahedron
1971, 27, 3575; (b) Matthew, A. Med. Chem. Commun. 2011, 2, 1135; (c) Seiple, I. B.;
Su, S.; Rodriguez, R. A.; Gianatassio, R.; Fujiwara, Y.; Sobel, A. L.; Baran, P. S. J. Am.
Chem. Soc. 2010, 132, 13194.
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2014.10.017.
8. (a) Wang, J.; Yang, J.; Yang, B.; Sun, J.; Yang, T. J. Chem. Res. 2010, 34, 717; (b)
Wang, J.; Yang, J.; Yang, B.; Hu, X.; Sun, J.; Yang, T. J. Chem. Res. 2010, 34, 724; (c)
Wang, J.; Yang, J.; Zhou, R.-G.; Yang, B.; Wu, Y.-S. J. Chem. Res. 2011, 35, 431; (d)
Wang, J.; Yang, J.; Zhou, R.-G.; Yang, B.; Wu, Y.-S. J. Chem. Res. 2011, 35, 428; (e)
Wang, J.; Zhou, R.-G.; Wu, T.; Yang, T.; Qin, Q.-X.; Li, L.; Yang, B.; Yang, J. J. Chem.
Res. 2012, 36, 121; (f) Wang, J.; Hu, X.; Yang, J. Synthesis 2014, 46, 2371; (g) Wang,
J.; Li, S.; Hu, X.; Yang, J. Org. Prep. Proced. Int. 2014, 46, 469; (h) Wang, J.; Li, S.;
Yang, T.; Yang, J. Eur. J. Med. Chem. 2014, 86, 710.
References and notes
1. (a) Imre, Z.-M. Arch. Gerontol. Geriatr. 1990, 11, 177; (b) Mordente, A.; Martorana,
G. E.; Minotti, G.; Giardina, B. Chem. Res. Toxicol. 1998, 11, 54; (c) Giorgio, V.;
Petronilli, V.; Ghelli, A.; Carelli, V.; Rugolo, M.; Lenaz, G.; Bernardi, P. Biochim.
Biophys. Acta 2012, 1817, 363.
2. (a) Liu, J.; Wang, L. N. CNS Drugs. 2014, 28, 63; (b) Mancuso, M.; Orsucci, D.; Volpi,
L.; Calsolaro, V.; Siciliano, G. Curr. Drug. Targets 2010, 11, 111; (c) Arpa, J.; Sanz-
9. Xu, P.; Guo, S.; Wang, L.; Tang, P. Angew. Chem., Int. Ed. 2014, 53, 5955.
ꢀ
Gallego, I.; Rodríguez-de-Rivera, F. J.; Domínguez-Melcon, F. J.; Prefasi, D.; Oliva-