Identification of 4,6-diaryl-1,4-dihydropyridines as a new class of neuroprotective agents

Article abstract of DOI:10.1039/c3md20345j

A library of 4,6-diaryl-1,4-dihydropyridines was synthesized using a CAN-catalyzed, Hantzsch-related three component reaction starting from ammonium acetate, β-dicarbonyl compounds and a variety of α,β-unsaturated ketones including chalcones, their vinylo

Full text of DOI:10.1039/c3md20345j

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Identification of 4,6-diaryl-1,4-dihydropyridines as a
new class of neuroprotective agents†
Cite this: Med. Chem. Commun., 2013,
4, 590
a
b
b
bc
*
´
Giammarco Tenti, Javier Egea, Mercedes Villarroya, Rafael Leon,
b
b
a
´
´
´
*
Jose Carlos Fernandez, Juan Fernando Padın, Vellaisamy Sridharan,
a
a
a
´
M Teresa Ramos and J. Carlos Menendez
A library of 4,6-diaryl-1,4-dihydropyridines was synthesized using a CAN-catalyzed, Hantzsch-related three
component reaction starting from ammonium acetate, b-dicarbonyl compounds and a variety of a,b-
unsaturated ketones including chalcones, their vinylogs and heteroanalogues. These compounds lack
the structural features needed for vascular activity and were found to prevent calcium overload and
behave as neuroprotective agents. One of the compounds, bearing a 2-thienyl substituent at C-4,
showed the highest neuroprotective activity and was also a moderate antioxidant, being a good lead
compound for further studies in this area.
Received 12th November 2012
Accepted 23rd January 2013
DOI: 10.1039/c3md20345j
www.rsc.org/medchemcomm
Our interest focused on the oxidative stress that besides
increasing with the age is clearly involved in the pathogenesis
1 Introduction
and evolution of a number of neurological disorders.2 This high
vulnerability of the brain to oxidative damage is related to its
high level of oxygen intake, the high content of redox-active
transition metal ions and a comparative lack of antioxidant
protective mechanisms.3 During the last decade, neuro-
protection has been increasingly considered as a useful
instrument to combat the progression of neurodegenerative
disorders. Owing to the involvement of a variety of factors in the
development of oxidative damage, varied strategies are being
pursued in order to nd molecules that could be employed as
neuroprotective agents.
Neurodegenerative disorders constitute an increasingly serious
health, social and economic problem all over the world. This
alarming situation has stimulated considerable research efforts
aimed at achieving a better understanding of these diseases.
The most common and extensively studied neurodegenerative
disorders include Alzheimer's, Parkinson's and Huntington's
diseases (AD, PD, HD, respectively), together with Multiple and
Amyotrophic Lateral Sclerosis (MS and ALS). In the last two
decades, extensive studies on this kind of diseases led to the
conclusion that these disorders show a multifactorial patho-
genic character caused by different factors, including genetic,
endogenous and environmental factors related to lifestyle.
Although each disease is determined by its etiology and char-
acterized by its own molecular mechanism and different clinical
manifestations, there are some general traits that can be
considered to be common in these disorders, including protein
misfolding and aggregation, an increase of the free radical
formation and of oxidative stress and a dysregulation of ionic
homeostasis (especially of Ca2+), associated with a mitochon-
drial dysfunction.1
In recent years, an increasing body of evidence indicates that
calcium dysregulation in the neuron plays a key role in the
molecular mechanism of neurodegenerative disorders by
inducing abnormal Ca2+ homeostasis,4 which strongly suggests
that compounds that are able to regulate the intracellular ow
of calcium maintaining it within normal levels may be effective
as neuroprotective agents.5
Although 1,4-dihydropyridines (DHPs) can be considered a
privileged structure6 due to their pharmacological versatility,7
their action in ion channels is certainly the best known and
exploited property, and these compounds are broadly used to
regulate the inux of Ca2+ into the cells thanks to their antag-
onist activity on the voltage-dependent calcium channels
(VDCCs).8 Some well-known traditional dihydropyridines in
clinical use have neuroprotective properties; for instance,
amlodipine prevents cytotoxicity in cortical neurons isolated
from stroke-prone spontaneously hypertensive rats.9 Further-
more, the L-type voltage-sensitive calcium channel blocker
S-312-d is also a neuroprotector10 and some of the 6-amino-1,4-
dihydropyridines have been shown to prevent calcium overload
a
´
´
´
Departamento de Quımica Organica y Farmaceutica, Universidad Complutense,
28040 Madrid, Spain. E-mail: josecm@farm.ucm.es; Fax: +34-91-3941822; Tel: +34-
91-3941840
b
´
´
´
Instituto Teolo Hernando y Departamento de Farmacologıa y Terapeutica, Facultad
´
de Medicina, Universidad Autonoma, 28029 Madrid, Spain
c
´
Instituto de Investigacion Sanitaria, Hospital Universitario de la Princesa, Servicio de
´
´
Farmacologıa Clınica, 28006 Madrid, Spain. E-mail: rafael.leon@uam.es; Fax: +34-
91-4973543; Tel: +34-91-4972766
† Electronic supplementary information (ESI) available: Chemical and
pharmacological experimental procedures and copies of spectra of all
compounds. See DOI: 10.1039/c3md20345j
590 | Med. Chem. Commun., 2013, 4, 590–594
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Scheme 1 CAN-catalyzed, three-component synthesis of compounds 3.
Fig. 1 A summary of the structural features of the compounds studied in the
present work.
Table 1 Scope and yields of the dihydropyridine synthesis
and neuronal cell death.11 One major problem that needs to be
addressed in this area is the prevalence of vascular side effects.
Against this background, we describe here the synthesis and
pharmacological evaluation of a library of new dihydropyridine
derivatives that were designed not to satisfy the well-known
structure–activity relationships for vascular activity but which,
at the same time, have the capacity to prevent neuronal calcium
overload. Since vascular activity of dihydropyridines is known to
require an ester function at C-5 and a small alkyl or aminoalkyl
substituent at C-6,12 we decided to prepare compounds with the
structure shown in Fig. 1, which lack these features since they
are unsubstituted at C-5 and bear an aryl group at C-6. In
contrast to other families of dihydropyridines, which have been
extensively studied, 6-aryl-1,4-dihydropyridines have received
little attention in the medicinal chemistry literature beyond
their identication as antagonists of the adenosine A3 receptor13
and as enhancers of the vanilloid receptor.14 Most importantly
for our purposes, they have been shown to lack vascular
activity.13a
Entry Compound R1
R2
R3
R4
Yield (%)
1
2
3
4
5
6
7
8
9
10
3a (ref. 19) CH3 OEt C6H5
3b C2H5 OEt C6H5
3c (ref. 19) CH3 OEt C6H5
3d (ref. 21) CH3 CH3 C6H5
C6H5
C6H5
4-ClC6H4 71
C6H5
C6H5
95
92
56
99
69
3e
3f
3g
3h
3i
CH3 StBu C6H5
CH3 StBu 4-MeOC6H4 C6H5
CH3 StBu 4-BrC6H4
CH3 StBu 4-MeC6H4
CH3 StBu 4-MeC6H4
CH3 OEt 2-Thienyl
4-MeC6H4 67
C6H5 99
4-MeC6H4 97
4-MeC6H4 67
3j
11
3k
CH3 StBu
C6H5
52a
a
The corresponding pyridine derivative was also isolated in 35% yield.
most of them had two phenyl substituents, bearing either
electron-withdrawing or electron-releasing substituents (3a–i,
entries 1–9). To increase the structural diversity in the dihy-
dropyridine derivatives, we carried out the synthesis of
compounds bearing substituents other than phenyl at the
dihydropyridine C-4 position by using appropriately modied
2 Results and discussion
2.1 Chemistry
Organic and medicinal chemists are increasingly conscious of chalcones (entries 10 and 11), which led to the preparation of
the need to develop synthetic methods that go beyond the compounds 3j, having an heterocyclic moiety, and 3k, with a
traditional requirements of chemo-, regio- and stereoselectivity, styryl chain. In the latter case, the target dihydropyridine was
pursuing economical and environmental concerns. In this obtained together with the pyridine derivative arising from its
perspective, the need to increase the synthetic efficiency of the dehydrogenation, an undesired reaction that was presumably
existing methods has led to the development of the concept of prompted by the high degree of conjugation of the aromatized
multibond forming reactions,15 which minimize procedure product.
times and waste generation because of the elimination of
Mechanistically, the three-component reaction proceeds by a
intermediate purication steps. In this context, the synthesis of Hantzsch-related mechanism that involves the initial genera-
the target compounds was achieved via an efficient three- tion of an enamine from ammonia and the starting b-dicar-
component process16 starting from 1,3-diaryl-2-propen-1-ones bonyl compound 2, followed by Michael addition to the enone
(chalcones) 1, b-dicarbonyl compounds 2 and ammonium system in chalcone 1 and a nal 6-exo-trig cyclization–dehy-
acetate as an ammonia source. All the b-dicarbonyl compounds dration sequence. This was proved by the fact that isolated ethyl
employed, as well as some of the chalcones, were of commercial 3-aminocrotonate, a commercially available enaminone that is
origin, whereas non-commercially available chalcones were one of the putative intermediates of our reaction, gave
synthesized under literature conditions.17 Aer an optimization compound 3a in 90% yield upon treatment with chalcone under
study, we carried out the synthesis of a library of eleven 6-aryl- our standard reaction conditions.
1,4-dihydropyridine derivatives 3 in reuxing ethanol and using
To further validate our synthetic method, and also to extend
cerium(IV) ammonium nitrate (CAN)18 as a Lewis acid catalyst the range of structures available for the SAR study, we examined
(Scheme 1).19 As shown in Table 1, the reaction proceeds in good briey the preparation of fused dihydropyridine systems by
to excellent yields, and was successful when using b-ketoesters employing 1,3-cyclohexanedione as
a
cyclic b-diketone
(3a–c, 3j), b-ketothioesters (3e–i, 3k) and b-diketones (3d) as the substrate. This reaction afforded the previously known22
dicarbonyl reagent.20 Regarding the chalcone components, hexahydroquinoline derivative 4 in 81% yield (Scheme 2).
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Scheme
2
Three-component reaction leading to the hexahydroquinoline
derivative 4.
2.2 Pharmacology
To assess the neuroprotective effect of these new compounds
against [Ca2+] overload, we rst studied whether they had any
effect on the Ca2+ entry elicited by K+ promoted depolarization
in SH-SY5Y human neuroblastoma cells. The well-known 1,4-
dihydropyridine drug nifedipine (10 mM) was used as the
reference compound. A preliminary study involved assaying all
synthesized dihydropyridines as inhibitors of the Ca2+ entry at a
10 mM concentration. As shown in Table 2, most compounds 3
(with the exception of 3i), and also hexahydroquinoline 4,
showed statistically signicant activity with values of the
blockade of the Ca2+ entry ranging from 32% to 54%. Two of the
compounds, namely 3b and 3f, have a potency similar to that of
nifedipine and were studied in more detail. As shown in Fig. 2,
both of them exhibited a dose-dependent response with IC50
values of 12.8 and 26.8 mM, respectively. Ca2+ entry blockade
potencies were 9- and 20-fold less active, respectively, than
nifedipine (IC50 ¼ 1.35 mM) used as control under the same
conditions.
Aer assessing their activity as inhibitors of calcium over-
load, the neuroprotective activity of compounds 3 and 4 was
examined. As shown in Table 3, most of the dihydropyridines
induced a good neuroprotective effect at the assayed concen-
tration (5 mM). It is remarkable that most compounds 3 had
rather similar potencies, with values ranging between 30% and
Fig. 2 Blockade by 3b (A) and 3f (B) of the [Ca2+]c increase induced by high K+ in
SH-SY5Y cells. Panel C shows non-linear regressions of % of response to 70 mM K+
in the presence of increasing concentrations of compound 3b (circles, continuous
line) or compound 3f (triangle, dotted line) and calculated IC50. Data are
expressed as means ꢀ SEM of at least three independent experiments in triplicate.
*** p < 0.001; ** p < 0.01 and * p < 0.05.
Table 2 Effects of 1,4-dihydropyridine derivatives on the [Ca2+]c increase elicited
by 70 mM K+ in SH-SY5Y cells (% inhibition with respect to a control without any
drug)
36%, with the hexahydroquinoline derivative 4 being slightly
less active. The most interesting compound in this regard was
3j, bearing a 2-thienyl substituent at C-4, which afforded a
neuroprotection above 50%.
K+ (70 mM)
Compound
% Blockade Ca2+ increase Statistical signicancea
The similar level of activity found for most compounds
hampers the deduction of clear-cut structure–activity relation-
ships for neuroprotection in our compounds. Nevertheless, our
data indicate that the presence of an electron-withdrawing
group at C-3 is necessary but its nature does not seem to be
important, with esters, thioesters and ketones leading to similar
activities. Similarly, both electron-withdrawing and electron-
releasing groups are tolerated in the aromatic rings. The higher
activity found for the 4-(2-thienyl) derivative 3j could be related
to the operation of additional mechanisms (see below).
Oxidative mechanisms are very important in neuro-
degeneration and antioxidant properties are considered as an
important feature of any potential neuroprotective compound.23
Indeed, owing to its multifactorial nature, neurodegeneration is
one of the therapeutic elds best suited to the multi-target
Nifedipine 10 mM 59.75 ꢀ 1.51
***
***
***
***
***
***
***
***
***
***
***
***
***
3a
3b
3c
3d
3e
3f
32.45 ꢀ 3.69
53.84 ꢀ 3.88
44.90 ꢀ 2.11
33.82 ꢀ 3.96
35.14 ꢀ 5.24
52.26 ꢀ 4.59
35.37 ꢀ 4.31
36.80 ꢀ 4.62
12.60 ꢀ 4.03
36.59 ꢀ 4.58
39.97 ꢀ 5.23
41.20 ꢀ 5.77
3g
3h
3i
3j
3k
4
a
Data are expressed as means ꢀ SEM of at least four different cultures
in triplicate. ***
p
<
0.001; all compounds were assayed at
a
concentration of 10 mM.
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approach to therapy.24,25 For these reasons, we also examined
the potential of our compounds in this regard by studying their
effect as neuroprotectants towards oxidative stress induced by
free-radical generation induced via oxygen and glucose depri-
vation (OGD). For this assay, nifedipine (0.3 mM) and melatonin
(0.1 mM) were used as reference Ca2+ entry blockade and anti-
oxidant compounds, respectively. In this case, we only obtained
Table 3 Neuroprotective effect of 1,4-dihydropyridine derivatives 3 and 4
(5 mM) in the presence of 70 mM [K+] in neuroblastoma cells
K+ (70 mM co-incubation)
Statistical
Compound
% Survival
% Protection
signicancea
Fig.
3
An explanation for the increased radical scavenging activity of
compounds 3j and 3k, based on the improved delocalization of an unpaired
BASAL
100
—
—
—
—
*
electron at C4.
70 mM K+
51.69 ꢀ 2.17
58.71 ꢀ 2.19
67.64 ꢀ 3.12
67.34 ꢀ 2.31
69.35 ꢀ 2.45
67.37 ꢀ 1.42
67.98 ꢀ 2.21
66.68 ꢀ 2.95
67.21 ꢀ 3.26
67.36 ꢀ 1.98
69.85 ꢀ 2.40
75.62 ꢀ 2.10
68.99 ꢀ 2.56
66.42 ꢀ 1.34
Nifedipine 0.3 mM
15.76 ꢀ 3.70
34.65 ꢀ 5.37
31.37 ꢀ 3.99
36.57 ꢀ 5.31
32.46 ꢀ 3.56
34.13 ꢀ 4.52
31.27 ꢀ 6.14
34.46 ꢀ 4.96
30.44 ꢀ 4.09
36.24 ꢀ 4.64
50.73 ꢀ 3.04
35.26 ꢀ 4.37
28.23 ꢀ 3.31
3a
3b
3c
3d
3e
3f
3g
3h
3i
***
***
***
***
***
***
***
***
***
***
***
***
statistically signicant results for two compounds (3j and 3k),
which afforded a moderate protection (Table 4). This activity
may help to explain the high potency of 3j as a neuroprotector,
which is not accompanied by the highest activity as an inhibitor
of the calcium entry. Regarding the mechanism for this neu-
roprotection, dihydropyridines have been proved to act as
radical scavengers,26 and in the case of compounds 3j and 3k
the antioxidant activity can be proposed to be associated with
the ability of the substituents at C-4 to delocalize an unpaired
electron at C-4 more efficiently than the aryl ring usually present
in our compounds, owing to delocalization onto the thiophene
ring sulfur atom (3j) or to the presence of a more extended
conjugate system at C-4 (3k) (Fig. 3). Further studies involving
dihydropyridines 3 with a higher capacity to stabilize radical
species are in progress, in order to provide additional data on
the role of radical scavenging as an additional mechanism
contributing to neuroprotection by these compounds.
3j
3k
4
a
Data are expressed as means ꢀ SEM of at least four different cultures
in triplicate. *** p < 0.001; * p < 0.05; all compounds were assayed at a
5 mM concentration.
Table 4 Neuroprotective effect of 1,4-dihydropyridine derivatives 3 and 4
(5 mM) on SH-SH5Y cells subjected to oxygen and glucose deprivation (OGD)
conditionsa
OGD SH-SY5Y (4 h co-incubation + 20 h post-
incubation)
3 Conclusions
Statistical
signicancea
In conclusion, we have proved that 4,6-diaryl-1,4-dihydropyr-
idines are a new class of neuroprotective agents, which lack the
structural features needed for cardiovascular activity. They are
able to prevent calcium overload, but additional mechanisms
probably aid their activity as neuroprotecting agents. Thus, one
of the compounds, bearing a 2-thienyl substituent at C-4, shows
the highest neuroprotective activity against calcium overload
and is also neuroprotective in oxidative stress. This compound
can be considered as a good lead for further studies in this area,
where drugs acting on more than a single target offer distinct
advantages.
Compound
% Survival
% Protection
BASAL
OGD
Nifedipine 0.3 mM
Melatonin 0.1 mM
3a
3b
3c
3d
3e
3f
3g
3h
3i
100
—
—
ns
***
ns
ns
ns
ns
ns
ns
ns
ns
ns
*
52.04 ꢀ 1.63
55.03 ꢀ 2.78
65.75 ꢀ 2.08
60.76 ꢀ 3.17
57.62 ꢀ 3.70
58.90 ꢀ 2.93
53.89 ꢀ 1.61
61.48 ꢀ 3.59
57.56 ꢀ 2.95
60.33 ꢀ 2.00
64.68 ꢀ 5.13
56.05 ꢀ 2.42
64.70 ꢀ 2.90
63.85 ꢀ 4.02
62.10 ꢀ 3.82
12.40 ꢀ 3.81
28.85 ꢀ 2.87
22.76 ꢀ 5.97
17.69 ꢀ 6.50
19.26 ꢀ 5.07
9.06 ꢀ 3.30
24.91 ꢀ 5.99
17.38 ꢀ 3.97
21.83 ꢀ 3.93
31.16 ꢀ 8.27
12.66 ꢀ 5.64
31.04 ꢀ 4.61
35.82 ꢀ 7.18
26.80 ꢀ 6.62
Acknowledgements
3j
3k
4
*
We gratefully acknowledge nancial support from MICINN
(grant CTQ-2009-12320-BQU, to JCM), MINECO (CTQ2012-
33272-BQU grant to JCM) and UCM (predoctoral fellowship
to GT), European Commission, Marie Curie Actions FP7
ns
a
Data are expressed as means ꢀ SEM of at least four different cultures
in triplicate. *** p < 0.001; * p < 0.05; all compounds were assayed at a
5 mM concentration.
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(FP7-People-2012-CIG-322156 to RL) and IS Carlos III (Miguel 16 For representative recent reviews of multicomponent
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This journal is ª The Royal Society of Chemistry 2013