Dicyanovinyl-substituted J147 analogue inhibits oligomerization and fibrillation of β-amyloid peptides and protects neuronal cells from β-amyloid-induced cytotoxicity

Article abstract of DOI:10.1039/c5ob01463h

A series of novel J147 derivatives were synthesized, and their inhibitory activities against β-amyloid (Aβ) aggregation and toxicity were evaluated by using the oligomer-specific antibody assay, the thioflavin-T fluorescence assay, and a cell viability assay in the transformed SH-SY5Y cell culture. Among the synthesized J147 derivatives, 3j with a 2,2-dicyanovinyl substituent showed the most potent inhibitory activity against Aβ₄₂ oligomerization (IC₅₀ = 17.3 μM) and Aβ₄₂ fibrillization (IC₅₀ = 10.5 μM), and disassembled the preformed Aβ₄₂ fibrils with an EC₅₀ of 10.2 μM. Finally, we confirmed that 3j is also effective at preventing neurotoxicity induced by Aβ₄₂-oligomers as well as Aβ₄₂-fibrils.

Full text of DOI:10.1039/c5ob01463h

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Dicyanovinyl-substituted J147 analogue inhibits
oligomerization and fibrillation of β-amyloid
peptides and protects neuronal cells from
β-amyloid-induced cytotoxicity†
Cite this: Org. Biomol. Chem., 2015,
13, 9564
Received 17th July 2015,
Accepted 13th August 2015
Kyoungdo Kim,‡a Kwang-su Park,‡a Mi Kyoung Kim,a Hyunah Choob,c and
DOI: 10.1039/c5ob01463h
www.rsc.org/obc
Youhoon Chong*a
A series of novel J147 derivatives were synthesized, and their culprit in AD, derives from the amyloid precursor protein
inhibitory activities against β-amyloid (Aβ) aggregation and toxicity (APP) through sequential cleavage by the two proteases β- and
were evaluated by using the oligomer-specific antibody assay, the γ-secretase.5 The Aβ monomers then start aggregating to even-
thioflavin-T fluorescence assay, and a cell viability assay in the tually become pathogenic oligomers6 and insoluble fibrillar
transformed SH-SY5Y cell culture. Among the synthesized J147 aggregates.7 Thus, blocking the aggregation of the Aβ peptide
derivatives, 3j with a 2,2-dicyanovinyl substituent showed the most is a potential disease-modifying approach to the treatment
potent inhibitory activity against Aβ42 oligomerization (IC50
17.3 μM) and Aβ42 fibrillization (IC50 = 10.5 μM), and disassembled
=
of AD.8–15
Curcumin (Fig. 1), the yellow pigment and primary curcu-
the preformed Aβ42 fibrils with an EC50 of 10.2 μM. Finally, we minoid found in turmeric, is well known for its potent anti-
confirmed that 3j is also effective at preventing neurotoxicity oxidant and anti-inflammatory activities. It has also been
induced by Aβ42-oligomers as well as Aβ42-fibrils.
reported that curcumin inhibits the formation of Aβ oligomers
and fibrils in vivo,16 and there have been several attempts to
apply curcumin to the treatment of AD.17 However, due to
poor bioavailability and low neurotrophic activity, the thera-
peutic use of curcumin for AD treatment has not been very suc-
cessful.18 Efforts have been made to optimize the potency and
pharmacokinetic properties of curcumin, which culminated in
the recent identification of J147 (Fig. 1) as an exceptionally
potent neurotrophic molecule that facilitates memory in
normal rodents, and prevents the loss of synaptic proteins
and cognitive decline in transgenic AD mouse models.19,20
However, the potent therapeutic effects of J147 against AD do
not seem to be directly associated with its anti-amyloidogenic
effects; even though J147 reduced soluble levels of Aβ, it was
attributed to down-regulation of β-secretase (BACE) rather than
inhibition of Aβ aggregation.19,20 Thus, in terms of an anti-
amyloidogenic effect, J147 has suboptimal properties, and
in the course of our ongoing efforts to discover new and more
effective inhibitors of Aβ aggregation, we anticipated that
structural modification of the J147 scaffolding might provide a
novel Aβ-aggregation inhibitor with potent anti-AD activity. For
this purpose, the J147 scaffold was compared with two high
affinity Aβ-binders, curcumin and DDNP (1,1-dicyano-2-[6-(di-
methylamino)naphthalene-2-yl]propene),21 which led to the
conclusion that appropriate substitution at the aromatic para-
position of the J147 scaffold might enhance its Aβ-binding
affinity and thereby the anti-amyloidogenic activity (Fig. 1).
Alzheimer’s disease (AD) is a chronic neurodegenerative
disease characterized by synaptic and neuronal loss, which
results in dementia, cognitive dysfunction, language problems,
and memory loss.1 These symptoms of AD generally appear in
people who are aged 65 and above, and the number of AD
patients is continually increasing.2 At present, acetylcholin-
esterase inhibitors are used to provide temporary relief of
symptoms, but there is no effective, long-term treatment for
AD.3 Pathologically, AD is characterized by the accumulation
of extracellular senile plaques containing β-amyloid peptides
(Aβ) and intracellular neurofibrillary tangles (NFTs) resulting
from tau fibrillogenesis.4 The Aβ peptide, the molecular
aDepartment of Bioscience and Biotechnology, Bio/Molecular Informatics Center,
Konkuk University, Hwayang-dong, Gwangjin-gu, Seoul 143-701, Korea.
E-mail: chongy@konkuk.ac.kr
bCenter for Neuro-Medicine, Korea Institute of Science and Technology, 39-1
Hawolgok-dong, Seoungbuk-gu, Seoul 136-791, Korea
cDepartment of Biological Chemistry, Korea University of Science and Technology,
Youseong-gu, Daejeon 305-350, Korea
†Electronic supplementary information (ESI) available: Synthetic procedures
and characterization of new compounds. Experimental details for Aβ42 oligomer-
ization, Aβ42 fibrillation, atomic force microscopy (AFM), ELISA assay for inhi-
bition of Aβ42 oligomerization, thioflavin T fluorescence assay for inhibition of
Aβ42 fibrillation, disruption assay of Aβ42 fibrils and Aβ42-induced cytotoxicity
assay. See DOI: 10.1039/c5ob01463h
‡These authors contributed equally on this work.
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Fig. 1 Structures of curcumin, DDNP and J147. Bold lines and dotted circles denote structural similarities and aromatic para-substituents,
respectively.
In this context, functional groups which mimic the aromatic
para-substituent of curcumin or DDNP (OH, OCH3, CH3, F,
CH(CN)2 and NMe2) were of particular interest.
In this proof-of-concept study, we embarked on a structural
modification study on the J147’s aromatic ring by introducing
various substituents at its para-position. Herein, we report the
synthesis of novel J147 derivatives and evaluation of their
inhibitory activity against Aβ aggregation and Aβ-induced
neurotoxicity by using the oligomer-specific antibody assay,
the thioflavin-T (ThT) fluorescence assay and a cell viability
assay in the transformed SH-SY5Y cell culture.
Results and discussion
Scheme 1 Synthesis of the J147 derivatives. Reagents and conditions:
(a) HNO3, H2SO4, rt; (b) TBDMSCI, lm, CH2Cl2, rt; (c) CH3l, K2CO3,
acetone, rt; (d) (i) Tf2O, TEA, CH2Cl2, 0 °C; (ii) PhB(OH)2, Pd(PPh)3)4,
K2CO3, MeOH, rt; (e) (i) DIBAL-H, THF, −78 °C; (ii) PCC, CH2Cl2, 0 °C; (f)
NHMe2, K2CO3, DMSO–H2O (7 : 3), 110 °C; (g) (i) HCl, NaNO2, H2O, 0 °C;
The J147 derivatives (3) were prepared by condensation of the
variously substituted 3-methoxybenzaldehydes (1) with the
commercially available (2,4-dimethylphenyl) hydrazine hydro-
chloride (2) followed by amidation with trifluoroacetic
anhydride (Scheme 1).19 Among the nine 3-methoxybenzalde-
hydes used for the condensation reaction, only three (1a, 1c,
1g) were commercially available; thus, the others were pre-
pared from other commercial sources. First, synthesis of
3-methoxy-4-nitrobenzaldehyde (1b) was accomplished by aro-
matic nitration of 3-methoxybenzaldehyde (1a). On the other
hand, 4-([tert-butyldimethylsilyl] oxy)-3-methoxybenzaldehyde
(1d), 3,4-dimethoxybenzaldehyde (1e) and 2-methoxy-[1,1′-
biphenyl]-4-carbaldehyde (1f) were prepared from vanillin (1c)
via silyl protection, methylation, and Suzuki coupling, respecti-
vely. Methyl 3-methoxy-4-methylbenzoate (1g) and 4-fluoro-
3-methoxybenzaldehyde (1i) were converted into the corres-
ponding benzaldehydes (1h and 1j) by reduction followed by
oxidation and nucleophilic aromatic substitution, respectively.
Finally, synthesis of 2-(4-formyl-2-methoxybenzylidene)-
malononitrile (1l) required complex synthetic steps. Thus,
starting from 4-bromo-3-methoxyaniline (1k), the amino func-
tionality was transformed into the formyl group by a series of
reactions including diazotization of aniline, replacement of
the diazonium cation with cyanide, and reduction of the
resulting aromatic cyanide to the corresponding aldehyde,
while the 4-bromo group was subjected to the formyl transfer
CuCN, KCN, H2O, 70 °C; (ii) DIBAL-H, tol. −78 °C; (iii) HO(CH2)2OH),
p-TsOH, tol. reflux; (iv) nBuLi, THF, −78 °C; N-formylpiperidine;
(v) malononitrile, lm, THF, rt; (vi) 2 N HCl, acetone, rt; (h) EtOH, rt; Tf2O,
TEA (or pyr), CH2Cl2, 0 °C; (i) TBAF, THF, 0 °C.
reaction with N-formylpiperidine followed by Knoevenagel con-
densation with malononitrile. The 3-methoxybenzaldehydes
(1a–1b, 1d–1f, 1h–1j, and 1l), thus prepared, were condensed
with (2,4-dimethylphenyl)-hydrazine hydrochloride (2) to yield
the unstable benzylidenehydrazines, which were directly
reacted with trifluoroacetic anhydride to obtain the desired tri-
fluorohydrazides (3a–3c, 3e–3j) in 45–50% yields. Cleavage of
silyl ether in 3c by treatment with TBAF (tetrabutylammonium
fluoride) proceeded smoothly to give 3d in 64% yield.
The prepared J147 derivatives were evaluated for their
activity to inhibit Aβ aggregation and to protect neuronal cells
from Aβ-induced cytotoxicity. For this purpose, the 42-residue
Aβ42 stock solutions (2 mM) were prepared by dissolving the
lyophilized peptide in 100 mM NaOH.22 For oligomerization,
the Aβ42 stock solution was diluted in phosphate-buffered
saline (PBS), pH 7.4 (100 μM final Aβ42 concentration) and
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with 1% dimethyl sulfoxide [DMSO]) or presence of the J147
derivatives (100 μM). Absorbance (OD) of each sample was
recorded at 450 nm in triplicate and the average absorbance of
samples treated with the J147 derivatives relative to that of the
control is shown in Fig. 3a. Among the J147 derivatives, 3j with
a 2,2-dicyanovinyl substituent showed the most potent inhibi-
tory activity against Aβ42 oligomer formation, while others
including 3a (J147) had only marginal effects. Compared with
the control, the amount of Aβ oligomers in the sample treated
with 3j decreased to 32% (Fig. 3a). The inhibitory potency of 3j
on Aβ42 oligomerization was then assessed at concentrations
Fig. 2 Aβ42 assembly under conditions that facilitate either oligomeri-
zation (a) or fibrillation (b). AFM images show formation of globular oli-
gomers (a) and fibrils (b) of Aβ42. Oligomers were analyzed by dot blot
analysis with A11 antibody (c, left) but fibrils were not detectable ranging from 0.1 to 200 μM, and the IC50 value was determined
(c, right).
from the dose–response curve (IC50 = 17.3 1.3 μM, Fig. 3b).
The Aβ42 incubated in the presence of 3j did not show globular
oligomers in the AFM image (Fig. 3c).
The J147 derivatives were also evaluated for their activity to
incubated at 25 °C for four days.22 On the other hand, fibrilli-
zation was initiated by diluting the stock solution in 10 mM
HEPES, 100 mM NaCl, 0.02% sodium azide, pH 7.4 (50 μM
final Aβ42 concentration), which was incubated at 37 °C
without agitation for up to two days.22 The formations of
globular Aβ42 oligomers (Fig. 2a) and fibrillar Aβ42 (Fig. 2b)
were confirmed by AFM (atomic force microscopy). Oligomeric
and fibrillar Aβ42 were further confirmed by dot blot analysis
using a polyclonal antibody A11 that specifically recognizes
soluble, prefibrillar Aβ oligomers but not monomer, dimer,
trimer, tetramer or Aβ fibrils (Fig. 2c).22,23
inhibit fibril formation, and to disassemble preformed Aβ42
fibrils. The thioflavin T (ThT) fluorescence assay has been
widely used to detect the formation of amyloid fibrils, because
the binding of thioflavin dyes to amyloid fibrils enables
reduction of self-quenching by restricting the rotation of the
benzothiozole and benzaminic rings, leading to significant
increase in fluorescence quantum yield.24 Thus, Aβ42 solution
(50 μM), in the presence of 1% DMSO (control reaction) or the
J147 derivatives (3a, 3b, 3d–3i) (100 μM), was incubated at
37 °C for 24 h under fibrillation conditions22 (Fig. 4a). Strong
ThT emission was observed in the control reaction, but the
samples treated with 3e, 3i, and 3j showed a decreased fluore-
scence signal (Fig. 4a). In particular, 3j, which showed the
most potent inhibitory activity against Aβ42 oligomerization,
was also the most effective fibrillation inhibitor evaluated.
First, in order to examine the ability of the J147 derivatives
to inhibit Aβ42 oligomerization, an ELISA assay using the A11
antibody22 was performed. Thus, the oligomerization reaction
was conducted22 in the absence (control samples treated
Fig. 3 ELISA assay for inhibition of Aβ42 oligomerization by the J147 derivatives. (a) Amounts of the Aβ42 oligomers in the samples treated with 1%
DMSO (control) or the J147 derivatives (3a, 3b, 3d–3i) (100 μM) were determined by ELISA using the oligomer-specific A11 antibody. Vertical bars
represent optical density (OD) values SD relative to the control. *P < 0.05, **P < 0.001 relative to the control. (b) Concentration-dependent inhi-
bition of Aβ42 oligomerization by 3j. Y-Axis represent relative OD values SD obtained from Aβ42 oligomers (50 μM) treated with 3j. All measure-
ments were performed in triplicate. (c) AFM images of the control (left) and a sample treated with 3j (100 μM).
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Fig. 4 (a–c) ThT assay for assessing inhibition of Aβ42 fibrillogenesis by the J147 derivatives: (a) amounts of the Aβ42 fibrils in the samples treated
with 1% DMSO (control) or the J147 derivatives (3a, 3b, 3d–3i) (100 μM) were determined by fluorescence from ThT. Vertical bars represent fluore-
scence intensities SD relative to the control. *P < 0.05, **P < 0.001 relative to the control. (b) Fluorescence was measured from Aβ42 peptides
under fibrillization conditions in the presence of different concentrations (0.1–200 μM) of 3j. The Y-axis represents the fluorescence intensity SD
relative to the control (DMSO). All measurements were performed in triplicate. (c) AFM images of the Aβ42 peptides under fibrillization conditions in
the absence (control, left) or presence of 3j (100 μM) (middle), and preformed Aβ42 fibrils after treatment with 3j (50 μM) (right). (d) ThT assay for dis-
aggregation of preformed Aβ42 fibrils by 3j. Fluorescence was measured from the preformed Aβ42 fibrils in the presence of different concentrations
(0.1–200 μM) of 3j. The y-axis represents fluorescence intensity SD relative to the control (DMSO). All measurements were performed in triplicate.
*P < 0.05, **P < 0.001 relative to the control.
Fig. 4b shows dose-dependent inhibition of 3j against Aβ42 oligomers for 24 h led to significant toxicity (41 2% cell viabi-
fibrillation and, from the dose–response curve, the IC50 of 3j lity) (Fig. 5a). When the Aβ42 oligomer-treated cells were
for inhibition of fibril formation was determined (10.5 μM). co-incubated with an increasing concentration of 3j, the cell
Inhibition of fibrillation by 3j was further confirmed by the viability was recovered in a dose-dependent manner (Fig. 5a).
AFM images, and fibrils could not be seen after treatment with Thus, upon treatment with 50 and 100 μM of 3j, cell viability
3j (100 μM) (Fig. 4c, middle). On the other hand, the J147 increased to 58 3% and 77 3%, respectively. The neuro-
derivative 3j was also effective in disassembling preformed protective effects of 3j against the cytotoxicity induced by Aβ42
Aβ42 fibrils, and the ThT fluorescence assay showed a concen- fibrils was also investigated (Fig. 5b). As reported previously,
tration-dependent decrease in the fluorescence signal with an Aβ42 fibrils were less cytotoxic (70
2% cell viability) than
EC50 of 10.2 μM (Fig. 4d). The AFM image of the disintegrated the oligomers, and 3j was effective at preventing Aβ42 fibril-
sample shows no fibrils but smaller spherical particles induced cytotoxicity in a dose-dependent manner (Fig. 5b).
(Fig. 4c, right), presumed oligomers.25
Next, we investigated the time course of neuroprotection
Taken together, the dicyanovinyl functionality, a mimic of induced by 3j. Thus, after treatment of SH-SY5Y cells with pre-
the aromatic substituent of DDNP, seems to enhance the formed Aβ42 fibrils and 3j (10 μM), the cell viability was esti-
binding affinity of the J147 scaffold to Aβ42 to provide the J147 mated by an MTT assay at various time points (Fig. 5c).
derivative 3j with potent anti-amyloidogenic activity.
Interestingly, a biphasic change was observed, and the
Soluble oligomers have been implicated as the primary SH-SY5Y cells exhibited an initial rapid decrease followed by
toxic species of amyloids.26–30 We examined whether the aggre- an increase in viability between 7 and 48 hours. The initial
gation inhibitor 3j could inhibit Aβ42-induced neurotoxicity in decrease in viability of the cells treated with Aβ42 fibrils is well
cell culture. Toxicity was assessed with a 3-(4,5-dimethyl- matched with the Aβ42 fibril-disaggregating activity of 3j
thiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in (Fig. 4d) to give the neurotoxic Aβ42 oligomers (Fig. 4c,
transformed human neuroblastoma SH-SY5Y cells.31 The J147 right panel). On the other hand, the ensuing increase in cell
derivative 3j was not cytotoxic up to 100 μM (Fig. S1 in the viability supports further disintegration of Aβ42 oligomers to
ESI†), but incubation of SH-SY5Y cells with 50 μM of Aβ42 smaller nontoxic pieces.
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Fig. 5 Dose-dependent effects of 3j on prevention of (a) Aβ42 oligomer-induced and (b) Aβ42 fibril-induced cytotoxicity. (c) Time-dependent effect
of 3j on Aβ42 fibril-induced cytotoxicity. Vertical bars represent cell viability SD (%) relative to the control (untreated cells). All measurements were
performed in triplicate. *P < 0.05, **P < 0.001 relative to the control.
2 Alzheimer’s Association, Alzheimer’s Dementia, 2014, 10, e47.
3 B. Lam, E. Hollingdrake, J. L. Kennedy, S. E. Black and
Conclusions
J147 has strong potential to be an anti-AD therapeutic by
slowing disease progression and reversing memory deficits,
but its therapeutic effect does not seem to be directly associ-
ated with an anti-amyloidogenic effect. In this study, in the
course of our ongoing efforts to discover new and more
effective inhibitors of Aβ aggregation, we have undertaken a
structural modification study on a J147 scaffold. Thus, various
J147 derivatives were synthesized by introducing a substituent
at the para position of the J147’s aromatic functionality and
evaluated their activity to inhibit Aβ42 oligomerization and
fibrillization, to disassemble the preformed Aβ42 fibrils, and to
prevent Aβ42-induced neurotoxicity. Among them, 3j with a 2,2-
dicyanovinyl substituent showed the most potent inhibitory
activity against Aβ42 oligomerization (IC50 = 17.3 μM). The J147
derivative 3j was also effective in inhibiting Aβ42 fibrillization
(IC50 = 10.5 μM) as well as disassembling the preformed Aβ42
fibrils (EC50 = 10.2 μM). The potent anti-amyloidogenic activity
of 3j might be attributed to its dicyanovinyl functionality to
enhance the binding affinity of the J147 scaffold to Aβ42.
Finally, we confirmed that 3j is also effective at preventing
neurotoxicity induced by Aβ42-oligomers as well as Aβ42-fibrils.
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Acknowledgements
This study was supported by a grant of the Korean Health
Technology R&D project, Ministry of Health & Welfare, Repub-
lic of Korea (HI14C2341), and by a grant from the Priority
Research Centers Program through the National Research
Foundation of Korea (NRF) funded by the Ministry of
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