Multifunctional mercapto-tacrine derivatives for treatment of age-related neurodegenerative diseases

Article abstract of DOI:10.1021/jm300124p

Cooperating mercapto groups with tacrine in a single molecular, novel multifunctional compounds have been designed and synthesized. These mercapto-tacrine derivatives displayed a synergistic pharmacological profile of long-term potentiation enhancement, cholinesterase inhibition, neuroprotection, and less hepatotoxicity, emerging as promising molecules for the therapy of age-related neurodegenerative diseases.

Full text of DOI:10.1021/jm300124p

Brief Article
pubs.acs.org/jmc
Multifunctional Mercapto-tacrine Derivatives for Treatment of Age-
Related Neurodegenerative Diseases
Yue Wang,†,⊥ Xin-Lei Guan,†,⊥ Peng-Fei Wu,† Can-Ming Wang,† Hui Cao,† Lei Li,‡ Xiao-Juan Guo,‡
Fang Wang,†,§,∥ Na Xie,†,§,∥ Feng-Chao Jiang,‡,∥ and Jian-Guo Chen*,†,§,∥
†Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030,
China
‡Department of Medicinal Chemistry, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei
430030, China
§The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan 430030, China
∥Institutes of Biomedicine and Drug Discovery, Huazhong University of Science and Technology, Wuhan 430030, China
S
* Supporting Information
ABSTRACT: Cooperating mercapto groups with tacrine in a single molecular, novel multifunctional compounds have been
designed and synthesized. These mercapto-tacrine derivatives displayed a synergistic pharmacological profile of long-term
potentiation enhancement, cholinesterase inhibition, neuroprotection, and less hepatotoxicity, emerging as promising molecules
for the therapy of age-related neurodegenerative diseases.
(Figure 1), can facilitate the induction of LTP in the normal
rats and even reverse the LTP impairment in aged rats.9−11
INTRODUCTION
■
Age-related neurodegenerative diseases, especially Alzheimer’s
disease (AD), is a multifaceted disease characterized by the
progressive loss of memory and cognitive functions, which
depends on a combination of aging, genetic, and environmental
factors. AD is initiated by a cascade of molecular events creating
dysfunctions in different neurotransmitter systems.1 Currently,
the approved therapy for AD was based on enhancing
cholinergic transmission through inhibition of cholinesterase
(ChE). These anticholinesterase drugs, such as galantamine,
donepezil, and rivastigmine, have been shown to only offer a
modest improvement in memory and cognitive function.2,3
Because of the complexity of AD, it is unlikely that a unitary
mechanism of action will provide a comprehensive therapeutic
approach to such multifaceted neurodegenerative disease.4
Efficient therapy is more likely to be achieved by drugs that
incorporate several pharmacological effects into a single
chemical entity.
Synaptic plasticity, especially the long-term potentiation
(LTP) in hippocampus, is widely considered as a key cellular
mechanism underlying learning and memory.5 Deficits in
learning and memory accompanied by age-related neuro-
degenerative diseases are closely related to the impairment of
synaptic plasticity. Generally, many studies have revealed that
an impairment of hippocampal LTP usually occurred in aged
animals.6 Therefore, modulation of hippocampal LTP has been
proposed as a potential therapeutic strategy for improving
cognitive function of AD patients. More recently, it has been
reported that some natural compounds can improve cognitive
impairment via enhancing hippocampal LTP.7,8 It has been well
documented in our laboratory and other groups that chemical
entities containing mercapto group, such as dithiothreitol
(DTT), glutathione (GSH), and N-acetyl cysteine (NAC)
Figure 1. Chemical structure of GSH, DTT, Tiopronin, and NAC.
In addition, chemical entities containing mercapto group
have attracted our interest because of their multiple
pharmacological actions. Given that some exogenous sulfhydryl
compounds could maintain the level of intracellular glutathione,
the major antioxidant in nerve cells when exposed to the
reactive oxygen species (ROS) insults, they may also lead to
neuroprotection in the central nervous system (CNS).12 The
serious hepatotoxicity of tacrine was the main limitation for its
clinical use.13 Tacrine can cause ROS production stimulation
and glutathione depletion in the human liver cell, suggesting
that oxidative insults might be involved in the hepatotoxicity of
tacrine. It has been reported that tacrine-induced oxidative
stress can be prevented by glutathione or vitamin E.14,15
Additionally, some chemical entities containing mercapto
Received: February 3, 2012
Published: March 15, 2012
© 2012 American Chemical Society
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Journal of Medicinal Chemistry
Brief Article
group, such as Tiopronin (Figure 1), were clinically applied to
treat the liver injury caused by chemical insults.16 Therefore,
tacrine derivates cooperated with additional antioxidant frag-
ment might be favorable to conquer the toxicity of tacrine.
Indeed, some tacrine−antioxidant hybrids have been reported
such as lipocrine that protects cells against oxidative stress and
NO-donor-tacrine hybrids that showed hepatoprotective
properties.3,13,17
In this context, we proposed that tacrine derivates
cooperating with metcapto group in a single molecular entity
may work in a synergistic manner. These compounds can serve
as a safer and more effective therapeutic method for treatment
of age-related neurodegenerative diseases. Thus, we designed
and synthesized a series of mercapto-tacrine derivatives (Figure
2) and then investigated their effects on ChE activity, synaptic
plasticity, neuroprotection, and liver function.
to yield 7, 9, and 11. Compounds 8, 10, and 12 were prepared
by deacetylation of 7, 9, and 11 in the presence of methanol/
hydrochloric acid mixture.
The ChE inhibitory activity of 7−12 was measured in vitro
by Ellman’s assay (Table 1).18 Acetylcholinesterase (AchE)
Table 1. Inhibition of AchE and BuchE (pIC50 Values) by
Mercapto-tacrine Derivatives
a
pIC50 SEM
b
b
compd
n
R1
R2
AchE
BuchE
7
1
1
2
2
4
4
acetyl
H
H
H
H
H
Cl
Cl
5.76 0.05
5.22 0.04
5.14 0.04
5.08 0.02
7.37 0.02
6.75 0.07
7.19 0.03
6.64 0.07
6.74 0.03
6.81 0.03
6.89 0.15
7.04 0.03
6.75 0.04
8.42 0.11
8
9
acetyl
H
10
11
acetyl
H
12
Tacrine
a
Data are the mean values of at least three determinations. pIC50
=
b
−log IC50. AchE from electric eel and BuchE from equine serum were
used.
from electric eel and butyrylcholinesterase (BuchE) from
equine serum were used. The results showed that 7−12
generally retained the ChE inhibitory effect (Table 1).
Compound 11 displayed the most potent inhibitory activity
against AchE among all the tested compounds. However,
compared with tacrine, 7−10 and 12 showed a decrease in the
inhibitory activity against AchE and BuchE. The mercapto-
tacrine derivatives were more potent inhibitors of BuchE than
AchE similar to that of tacrine, except for 11, which had higher
selectivity for AchE. The reduced potency of 11 against BuchE
may cause by steric hindrance of the chloride atom with specific
residues of the BuchE binding site.19,20 The IC50 for AchE
inhibition by 11 were not significantly different among 2, 10,
and 40 min incubation, suggesting that 11 inhibited AchE
activity in a nontime-dependent manner.3 An analysis of the
Lineweaver−Burk reciprocal plots of 11 against AchE in Figure
3 revealed that there were an increasing slope and an increasing
intercept with higher inhibitor concentration. This result
indicated that 11 caused a mixed-type inhibition, which was
similar to that of tacrine and other reported tacrine derivates.3
Figure 2. Design strategy for compounds 7−12.
RESULTS AND DISCUSSION
Compounds 7−12 were synthesized following the convergent
synthetic approach depicted in Scheme 1. Intermediates 1 or 2
■
a
Scheme 1. Synthesis of 7−12
a
Reaction conditions: (a) diaminealkane, pentanol, 180 °C,18 h; (b)
THF, 50 °C, 18 h; (c) EDC·HCl, HOBt, CH2Cl2, 25 °C, 12 h; (d)
MeOH/HCl, 40 °C, 10−12 h.
were reacted with alkylenediamines to produce the important
intermediates 9-aminoalkylamino-1,2,3,4-tetrahydroacridines
(3, 4, 5). 3-(Acetylthio) propanoic acid (6) was produced by
mixing propenoic acid with thioacetic acid in tetrahydrofuran.
Compounds 3, 4, or 5 were condensed with 6 in the presence
of 1-ethyl-3-(3-diethylaminopropyl) carbodiimide (EDC·HCl)
and 1-hydroxy-7-azabenzo triazole (HOBt) in dichloromethane
Figure 3. Kinetic study on the mechanism of AchE inhibition by 11.
Lineweaver−Burk reciprocal plots of AchE initial velocity at increasing
substrate concentration (0.05−1 mM) in the absence of inhibitor and
in the presence of 11 (10−40 nM) are shown.
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To evaluate the regulation of mercapto-tacrine derivatives on
synaptic plasticity, 7, 8, and 12 with diverse substructure were
chosen to test their effects on high-frequency stimulation
(HFS)-induced LTP in the CA1 region of Sprague−Dawley
(SD) rat hippocampal slices. It was found that HFS induced a
dramatic increase in the magnitude of LTP when incubation of
hippocampal slices with 50 μM 8 for 10 min (control, 133.7
3.6% of baseline; 8, 160.8 4.4% of baseline; n = 9 for each
group, P < 0.01 vs control, Figure 4B). Likewise, application of
50 μM 12 also enhanced the magnitude of LTP (control, 134.3
3.9% of baseline; 12, 157.1 5.7% of baseline; n = 8 for each
group, P < 0.01 vs control, Figure 4C). However, when the
mercapto group was acetylated, 7 failed to enhance LTP
(control, 136.3 5.3% of baseline; 7, 136.2 3.1% of baseline;
n = 8 for each group, Figure 4A). Treatment of hippocampal
slices with the equimolar dose of tacrine also did not
significantly alter the induction of LTP (control, 132.6
4.6% of baseline; tacrine, 136.2 3.6% of baseline; n = 6 for
each group, Figure 4D). Additionally, we further investigated
the regulation of 12 on synaptic plasticity under the condition
of in vivo drug administration. Hippocampal slices were
recorded 3 h after intracerebroventricular (icv) injection of
12 (final concentration 50 μM). It was found that in vivo
injection of 12 also enhanced the hippocampal LTP (control,
126.0 3.6% of baseline; 12, 149% 4.5% of baseline; P <
0.01 vs control, n = 8 for each group, Figure 5). Above results
Figure 5. Effects of 12 on the magnitude of hippocampal LTP under
the condition of in vivo administration. Hippocampal slices were
recorded 3 h after intracerebroventricular injection of 12 (final
concentration 50 μM). The bar graph illustrating the fEPSPs slope
averaged from the last 15 min recordings of control and treated slices.
# P < 0.01 vs control, n = 8.
indicated that the mercapto-tacrine derivatives could strengthen
the induction of LTP via its mercapto group.
The neuroprotective action of mercapto-tacrine derivatives
against oxidative stress was measured in human neuroblastoma
cell line SH-SY5Y. Cells were incubated with 7−12 at four
concentrations (1, 3, 10, and 30 μM) 1 h before the addition of
200 μM hydrogen peroxide. Cell viability was measured by
using the MTT assay after treatment of 200 μM hydrogen
peroxide for 12 h. Trolox, the vitamin E antioxidant moiety, was
selected as a positive control. All tested compounds (Table 2)
displayed neuroprotection against hydrogen peroxide-induced
damage at 1, 3, 10, and 30 μM. Compounds 7, 9, and 11, the
mercapto group of which was covered with the acetyl group,
Table 2. Neuroprotection (%) in the Human Neuroblastoma
Cell Line SH-SY5Y against H2O2 (200 μM) at the Indicated
Concentrations
compd
1 μM
3 μM
10 μM
30 μM
a
a
b
b
7
32.4
35.9
38.2
50.6
c
a
a
8
45.9
22.0
16.7
34.0
a
c
b
9
21.7
30.1
43.6
56.5
a
a
a
10
23.8
5.8
21.5
38.2
Figure 4. Effects of mercapto-tacrine derivatives on the magnitude of
LTP in the hippocampal slices of rat. The bar graph illustrating the
fEPSPs slope averaged from the last 15 min recordings of control and
treated slices. (A) 7 (n = 8); (B) 8 (# P < 0.01 vs control, n = 9); (C)
12 (# P < 0.01 vs control, n = 8); (D) tacrine (n = 6).
a
11
8.1
17.1
27.2
28.5
34.0
c
b
a
12
52.3
24.5
37.8
c
c
Trolox
44.2
59.1
a
b
c
P < 0.05. P < 0.01. P < 0.001 vs H2O2 group
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Journal of Medicinal Chemistry
Brief Article
exhibited the neuroprotective effect mostly in a concentration-
dependent manner, with the maximal effect at 30 μM (7,
50.6%; 9, 56.5%; 11, 34.0%). Interestingly, 8, 10, and 12
presented a U-shaped dose−effect curve. Compounds 8 and 12
showed significant protection at 1, 3, and 30 μM, and the
maximal efficacy was observed at 1 μM (8, 45.9%; 12, 52.3%).
It was worth mentioning that the neuroprotective effect was
decreased at higher concentrations, which was probably due to
additional interactions with other biological targets. These
phenomena were similar to those of some marketed
compounds (e.g., galantamine or donepezil), which also
showed a U-shaped concentration-dependent neuroprotective
properties.21
To determine whether mercapto-tacrine hybrids were more
safe than tacrine, 7 and 8 were chosen to test their
hepatotoxicity. Rats were treated at the highest tolerated dose
of tacrine (6 μmol/100 g body weight) or equimolar doses of 7
and 8. The aspartate aminotransferase (AST) and alanine
aminotransferase (ALT) activity in serum samples were
measured before administration (0 h) or 24, 36, 72, and 120
h after administration. As shown in Figure 6, administration of
8 did not dramatically increase the activities of AST and ALT
from 0 to 120 h. These results indicated that 7 and 8 had little
hepatotoxicity.
CONCLUSION
■
In the current study, we report a novel series of mercapto-
tacrine derivatives endowed with cholinesterase inhibition, LTP
enhancement, neuroprotective activity, and less hepatotoxicity.
It is expected that these multifunctional compounds are more
efficient to improve the memory and cognitive impairment with
fewer side effects and diminish the oxidative damage caused by
free radicals. Such interesting properties highlight them as good
candidates for further studies directed to the development of
novel drugs for age-related neurodegenerative diseases such as
AD.
EXPERIMENTAL SECTION
■
1H and 13C NMR spectra were recorded using TMS as the internal
standard in CDCl3 or DMSO-d6 with a Bruker spectrometer at 400
and 100 MHz, respectively. MS spectra were recorded on a Finnigan
LCQ Deca XPTM instrument with an ESI mass selective detector.
Reactions were monitored by thin layer chromatography and MS
spectra. Flash column chromatography was performed with silica gel
(200−300 mesh) purchased from Qingdao Haiyang Chemical Co. Ltd.
The purities of targeted compounds were confirmed by analytical
HPLC on a HITACHI L-2000 instrument and a Diamonsil ODS-C18
HPLC column (250 mm × 4.6 mm, 5 μm) at 340 nm, eluted with a
gradient of 70−80% solvent B (methanol) in solvent A (water)
containing 0.2% phosphate buffer (pH = 7.23) at a speed of 1 mL/
min. The purities of target compounds were determined to be ≥95%
by HPLC unless otherwise indicated. Melting points were obtained on
Taike X-5 microautomatic melting point detector and were
uncorrected.
General Procedures for the Synthesis of 7, 9, and 11. To a
stirred solution of 1.0 molar equiv of 6 in 30 mL of CH2Cl2 at 25 °C
was added 2 molar equiv of 1-ethyl-3-(3-diethylaminopropyl)
carbodiimide (EDC·HCl) and 2 molar equiv of 1-hydroxy-7-
azabenzotriazole (HOBt). The resulting mixture was stirred at room
temperature for 30 min before a solution of 1 molar equiv of
compounds 3, 4, or 5 in 15 mL CH2Cl2 were added. The resulting
mixture was stirred at 25 °C for 12 h before it was quenched with
brine (5 mL) and diluted with CH2Cl2 (50 mL). The combined
organic phase was washed with brine (3 × 50 mL), dried over Na2SO4,
and filtered. After removal of the solvent under vacuum, the residue
was purified by flash column chromatography with petroleum ether/
ethyl acetate to yield the products.
General Procedures for the Synthesis of 8, 10, and 12.
Compounds 7, 9, or 11 were dissolved in 10 mL of methanol
containing 1 mL of 6 M HCl. The reaction mixture was stirred at 40
°C for 10−12 h under the protection of N2 while being monitored by
TLC and LC-MS until 7, 9, or 11 completely reacted. The reaction
mixture was allowed to cool, diluted with 50 mL of CH2Cl2, and
washed with NaHCO3 aqueous solution and brine (3 × 50 mL). The
combined organic phase was dried over Na2SO4 and filtered. The
solvent evaporated to obtain the pure products.
Figure 6. Influence of equimolar doses (6 μmol/100 g bwt) of tacrine
and 7 and 8 on the activity of ALT (U/L), and AST (U/L). Results
are compared to control values before administration. Statistical
significant difference to control values before administration (Student’s
t test, n = 8−12). # P < 0.05. ## P < 0.01 vs 0 h.
ASSOCIATED CONTENT
the highest tolerated dose of tacrine caused a sharp rise in AST
and ALT activities at 24 h. Although decreased at 36 h, they
were still significantly higher than the level of before
administration. The increase in activities of AST and ALT by
single dose of tacrine returned to the normal levels at 3 days
after administration. However, administration of saline or 7 and
■
S
* Supporting Information
Spectroscopic data for 3−12, AchE and BuchE inhibition
assays, electrophysiological studies in hippocampal slices,
neuroprotection assays, and hepatotoxicity assays. This material
is available free of charge via the Internet at http://pubs.acs.org.
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Journal of Medicinal Chemistry
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Macvicar, B. A. Glutathione restores the mechanism of synaptic
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AUTHOR INFORMATION
Corresponding Author
*Phone: 86-27-83692636. Fax: 86-27-83692608. E-mail:
chenj@mails.tjmu.edu.cn.
■
(13) Fang, L.; Appenroth, D.; Decker, M.; Kiehntopf, M.; Lupp, A.;
Peng, S.; Fleck, C.; Zhang, Y.; Lehmann, J. NO-donating tacrine
hybrid compounds improve scopolamine-induced cognition impair-
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Author Contributions
⊥These authors contributed equally.
Notes
The authors declare no competing financial interest.
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Heymans, F.; Lelievre, L.; Ombetta, J. E.; Massicot, F. Study of
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ACKNOWLEDGMENTS
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PMS777, a new type of acetylcholinesterase inhibitor, in human
HepG2 cells. Comparison with tacrine and galanthamine on oxidative
stress and mitochondrial impairment. Toxicol. in Vitro 2006, 20, 824−
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tetrahydroaminoacridine in isolated rat hepatocytes: effect of
glutathione and vitamin E. Biochem. Pharmacol. 1988, 37, 2311−2313.
(16) Yue, J.; Dong, G.; He, C.; Chen, J.; Liu, Y.; Peng, R. Protective
effects of thiopronin against isoniazid-induced hepatotoxicity in rats.
Toxicology 2009, 264, 185−191.
This work was supported by grants from the Key Project of
National Natural Science Foundation of China (NSFC No.
30930104), International Science & Technology Cooperation
Program of China (No. 2011DFA32670) and The National
Science and Technology Major Project of the Ministry of
Science & Technology of China (No. 2012ZX09103-101-045)
to Dr. J.G. Chen.
ABBREVIATIONS USED
■
(17) Rosini, M.; Simoni, E.; Bartolini, M.; Tarozzi, A.; Matera, R.;
Milelli, A.; Hrelia, P.; Andrisano, V.; Bolognesi, M. L.; Melchiorre, C.
Exploiting the lipoic acid structure in the search for novel multitarget
ligands against Alzheimer’s disease. Eur. J. Med. Chem. 2011, 46,
5435−5442.
AD, Alzheimer’s disease; ChE, cholinesterase; LTP, long-term
potentiation; ROS, reactive oxygen species; DTT, dithiothrei-
tol; GSH, glutathione; NAC, N-acetyl cysteine; AchE,
acetylcholinesterase; BuchE, butyrylcholinesterase; HFS, high
frequency stimulation; SD, Sprague−Dawley; fEPSPs, field
excitatory postsynaptic potentials; AST, aspartate amino-
transferase; ALT, alanine aminotransferase
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M. A new and rapid colorimetric determination of acetylcholinesterase
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Ramírez, L.; Gomez, E.; Isambert, N.; Lavilla, R.; Badia, A.; Clos, M.
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