Synthesis and evaluation of multifunctional ferulic and caffeic acid dimers for Alzheimer’s disease

Article abstract of DOI:10.1080/14786419.2016.1219862

In this study, a series of novel ferulic and caffeic acid dimers was designed and synthesised, and their multifunctional properties against Alzheimer’s disease (AD) were evaluated. Results showed that our multifunctional strategy was great supported by en

Full text of DOI:10.1080/14786419.2016.1219862

Natural Product Research
Formerly Natural Product Letters
ISSN: 1478-6419 (Print) 1478-6427 (Online) Journal homepage: http://www.tandfonline.com/loi/gnpl20
Synthesis and evaluation of multifunctional ferulic
and caffeic acid dimers for Alzheimer’s disease
Xi-xin He, Xiao-hong Yang, Rui-ying Ou, Ying Ouyang, Sheng-nan Wang, Zi-
wei Chen, Shi-jun Wen & Rong-biao Pi
To cite this article: Xi-xin He, Xiao-hong Yang, Rui-ying Ou, Ying Ouyang, Sheng-nan Wang,
Zi-wei Chen, Shi-jun Wen & Rong-biao Pi (2016): Synthesis and evaluation of multifunctional
ferulic and caffeic acid dimers for Alzheimer’s disease, Natural Product Research, DOI:
10.1080/14786419.2016.1219862
To link to this article: http://dx.doi.org/10.1080/14786419.2016.1219862
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Date: 18 August 2016, At: 13:37

Natural Product research, 2016
http://dx.doi.org/10.1080/14786419.2016.1219862
SHORT COMMUNICATION
Synthesis and evaluation of multifunctional ferulic and caffeic
acid dimers for Alzheimer’s disease
Xi-xin Hea†, Xiao-hong Yangb,c†, Rui-ying Oua, Ying Ouyangd, Sheng-nan Wangb,c,
Zi-wei Chenb,c, Shi-jun Wenb,c and Rong-biao Pib,c
acollege of chinese Materia Media, Guangzhou university of chinese Medicine, Guangzhou, china;
bdepartment of Pharmacology, school of Pharmaceutical sciences, sun Yat-sen university, Guangzhou, china;
cInternational Joint laboratory (sYsu-Polyu hK) of Novel anti-dementia drugs of Guangdong, Guangzhou,
china; ddepartment of Pediatrics, sun Yat-sen Memorial hospital, sun Yat-sen university, Guangzhou, china
ABSTRACT
ARTICLE HISTORY
received 26 January 2016
accepted 6 July 2016
In this study, a series of novel ferulic and caffeic acid dimers was
designed and synthesised, and their multifunctional properties
against Alzheimer’s disease (AD) were evaluated. Results showed
that our multifunctional strategy was great supported by enhancing
the inhibition of Aβ1–42 self-induced aggregation. Moreover, 7b also
had potent protective effects against glutamate-induced cell death
without significant cell toxicity in mouse hippocampal neuronal
HT22 cells and 10c effectively scavenged diphenylpicrylhydrazyl
free radicals. Collectively, these data strongly encourage further
optimisation of 7b as a new hit to develop multifunctional agents
for the treatment of AD.
KEYWORDS
Ferulic acid; caffeic
acid; multifunctional
neuroprotective agents;
amyloid protein;
aggregation; free radicals
1. Introduction
Alzheimer’s disease (AD), the most common form of dementia, is a progressive neurodegen-
erative brain disorder resulting in loss of memory and cognitive functions, often accompa-
nied by behavioural disturbances like aggression and depression with the typical pathological
hallmarks, loss of cholinergic neurons, neurofibrillary tangles and beta-amyloid (Aβ) depo-
sition and affects about 6% of the population over the age of 65 (Querfurth & LaFerla 2010;
CONTACT Xi-xin he
mark07@gzucm.edu.cn; rong-biao Pi
pirb@mail.sysu.edu.cn
†the first two authors contributed equally to this work.
supplemental data for this article can be accessed at http://dx.doi.org/10.1080/14786419.2016.1219862.
© 2016 Informa uK limited, trading as taylor & Francis Group

2
X.-X. He eT AL.
Huang & Mucke 2012). At present, effective therapeutics are urgently needed because there
is no efficacious disease-modified treatment available.
In AD patients, amyloid protein β (Aβ) deposition impairs mitochondria, which results in
the elevated level of reactive oxygen species (ROS) and ultimately leads to oxidative damage
(D’Autreaux & Toledano 2007; Gu et al. 2013; Luque-Contreras et al. 2014). Therefore, a drug
that can simultaneously decrease the ROS generation and the Aβ aggregation, in principle,
may effectively block the progression of AD. For inhibiting Aβ aggregation, chemical features
are the presence of two aromatic end groups, which are substituted by one or more polar
groups and combined with an appropriate linker with a reduced flexibility in order to confer
a good interaction with Aβ (Reinke & Gestwicki 2007). In addition, our previous study sug-
gested that cinnamic acid might be a good pharmacophore to develop agents against Aβ
aggregation with ROS scavengiability (Chao et al. 2012). Based on above, this paper described
the synthesis and the pharmacological evaluation of 3a–3d, 5a–5b (Sánchez, Guillén-Villar
et al. 2014; Sánchez, Martínez-Mora et al. 2014), 5c–5d, 7a–7d and 10a–10d, which com-
bined two cinnamic acids, caffeic acid (CA) and ferulic acid (FA), into an entity, and were
designed to simultaneously enhance the inhibition of Aβ self-induced aggregation and
preserve the ability to prevent oxidative damage.
2. Results and discussion
In vitro, 3c, 7b, 10a and 10c had a significant inhibition of Aβ1–42 self-induced aggregation
by using a single-dose thioflavin T (Th–T) assay, while 3a, 3c, 7a and 10a significantly scav-
enged diphenylpicrylhydrazyl (DPPH) free radicals than CA (Table 1). HT22 cell line is an
excellent model for the study of glutamate oxidative toxicity due to lacking ionotropic glu-
tamate receptors, which excludes glutamate receptor-mediated excitotoxicity. Our results
showed that 3a, 7b, 10a and 10d could protect HT22 cells against glutamate-induced oxi-
dative damage at 10 μM, while 3a, 3d, 5b, 7a, 7b, 10a and 10c showed cell toxicity at 30 μM.
But it seems hard to reach an agreement on scavenging DPPH free radicals and protecting
Table 1. the preliminary evaluation of test compounds in vitro.
Inhibition of Aβ1–42 aggregationa
DPPH radicals scavenging capacity (%)a
Chemicals
ca
Fa
30.9
n.t.c
94.7
n.t.
58.91
27.3
n.t.
crb
curcumin
3a
18.56
92.60
26.00
88.12
17.33
80
19.86
85.26
21.52
74.78
21.62
71.45
9.44
59.6
67.2
81.7
70.3
48.1
69.3
41.0
83.7
88.8
n.a.d
90.0
7.8
3b
3c
3d
5a
5b
7a
7b
10a
10b
10c
10d
athe measurements were carried out in the presence of 10 μM compounds.
bcr means congo red.
cn.t. means no test.
dn.a. means not active.

NATURAL PRODUCT ReSeARCH
3
against oxidative damage in HT22, particularly in 3d, 5b and 7b. Sodium ferulate protected
cultured cortical neurons against glutamate toxicity due to activations of the PI3K/Akt/
p70S6K pathway and the MeK/eRK1/2 pathway (Jin et al. 2007), while FA did not have a good
capacity in scavenging DPPH free radicals, only 27.3% (Kikuzaki et al. 2002). This indicated
that the ability to scavenge DPPH free radicals in vitro may not be closely related with the
protection against glutamate-induced oxidative damage in vivo.
Further study showed that 7b did not have a high solubility at the concentration of
100 μM, but had an excellent neuroprotective capacity at 10 μM. The release of lactate dehy-
drogenase demonstrated that 7b may inhibit the proliferation but not induce cell toxicity
at 30 μM. Measurement of intracellular ROS accumulation indicated that 7b instead of 7a
could decrease the level of oxidative stress-induced ROS accumulation. Additionally, it has
been reported that 10a showed a pharmacological properties in both anti-neuroinflamma-
tory (Lu et al. 2013) and anti-perglycemic effect (Weng et al. 2010).
3. Conclusion
In summary, our multi-target strategy is to combine two cinnamic acids, CA and FA, through
three different rigid groups with a limited flexibility in order to confer a good interaction
with amyloid-β. Our findings contribute to further optimise FA, such as 7b as a new hit to
develop multifunctional agents for the treatment of AD.
Disclosure statement
The authors declare that there is no conflict of interest.
Funding
This work was supported by Guangdong Provincial International Cooperation Project of Science &
Technology [grant number 2012B050300015], [grant number 2013B051000038]; National Natural
Science Foundation of China [grant number 31371070].
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