Design, synthesis, and evaluation of a water soluble C5-monoketone type curcumin analogue as a potent amyloid β aggregation inhibitor

Article abstract of DOI:10.1016/j.bmcl.2019.06.052

A structure activity relationship study of curcumin analogues for the inhibition of amyloid β aggregation is described. Optimization of the o-phenol and olefin spacer resulted in the identification of the C5-monoketone type curcumin analogue AY1319, which

Full text of DOI:10.1016/j.bmcl.2019.06.052

Accepted Manuscript
Design, synthesis, and evaluation of a water soluble C5-monoketone type cur-
cumin analogue as a potent amyloid β aggregation inhibitor
Mayumi Hotsumi, Misato Tajiri, Yuri Nikaido, Taki Sato, Koki Makabe,
Hiroyuki Konno
PII:
S0960-894X(19)30434-2
https://doi.org/10.1016/j.bmcl.2019.06.052
BMCL 26530
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
25 May 2019
18 June 2019
26 June 2019
Please cite this article as: Hotsumi, M., Tajiri, M., Nikaido, Y., Sato, T., Makabe, K., Konno, H., Design, synthesis,
and evaluation of a water soluble C5-monoketone type curcumin analogue as a potent amyloid β aggregation
inhibitor, Bioorganic & Medicinal Chemistry Letters (2019), doi: https://doi.org/10.1016/j.bmcl.2019.06.052
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Design, synthesis, and evaluation of a water soluble C5-monoketone
type curcumin analogue as a potent amyloid  aggregation inhibitor
Mayumi Hotsumi, Misato Tajiri, Yuri Nikaido, Taki Sato, Koki Makabe, Hiroyuki
Konno*
Department of Biochemical Engineering, Graduate School of Science and Engineering,
Yamagata University, Yonezawa, Yamagata 992-8510, Japan
E-mail: konno@yz.yamagata-u.ac.jp; Tel&FAX: +81-(0)238-26-3131
*Corresponding author should be addressed.
Abstract: A structure activity relationship study of curcumin analogues for the
inhibition of amyloid  aggregation is described. Optimization of the o-phenol and
olefin spacer resulted in the identification of the C5-monoketone type curcumin
analogue AY1319, which exhibited potent anti-amyloid  aggregation activity (leading
to nanorod-like fragments), sufficient water solubility, and low cytotoxicity.
Keywords: amyloid , curcumin, water soluble, aggregation
Amyloid  (A) is a heterogeneous mixture composed mainly of 40- and
42-mer peptides generated from amyloid beta precursor protein (APP).1,2 It is potently
neurotoxic and aggregates rapidly, from soluble oligomers and protofibrils to insoluble
amyloid fibrils with a -sheet structure, and inhibition of these processes has been
suggested as a therapeutic strategy for the treatment of Alzheimer’s disease.3 Studies
towards the inhibition of the soluble oligomer, the most toxic species, have been
ongoing for some time.
Curcumin (CUR) (1), a diarylheptanoid CUR (1) comprising two phenolic
rings, two olefin moieties, and a -diketone, is found in turmeric, and has been used as a
food and medicine in southeast Asia for thousands of years. More recently, a variety of
studies have concluded CUR (1) to impart antioxidant, anti-inflammatory, antitumor,
anti-A aggregation, and anti-Alzheimer’s disease activity.6-9 However a clinical trial of
CUR (1) for the treatment of Alzheimer’s disease patients ended in failure,10 perhaps
1

due to its poor water solubility.11 Accordingly, a CUR (1) derivative exhibiting
improved absorption and pharmacokinetics is needed. Dolai et al. reported the improved
water solubility of a “clicked” sugar-derivative of curcumin,12 and we reported the
potent anti A aggregation activity of the o-phenol CUR derivative AY1031 (2), which
was more soluble in water than CUR (1) by a factor of 160.13,14 Herein, we report our
pursuit of a water soluble CUR analogues with good anti A aggregation activity by
optimization of the o-phenol and olefin spacer moieties15 (Figure 1).
Figure 1. CUR (1) and AY1031 (2)
In previous work, we discovered that the anti A aggregation properties of
CUR (1) could be improved by substituting free hydroxy groups for the bis-phenols to
give 2; and that both the ketone and double bond moieties in the spacer were essential
for inhibitory activity - perhaps because their reduction introduced excessive flexibility
in the molecule. Accordingly, we produced the 2’,3,4-trihydroxy derivative (AY1031)
(2), which combined potent anti A aggregation and water solubility.13 To investigate
the importance of hydroxy groups of phenols and carbon length and carbonyl groups of
the spacer unit, a variety of CUR derivatives were in this study prepared, including the
C7-spacer-containing 2,3-dihydroxy derivative (3) and the 2,5-dihydroxy derivative (4).
The mono- and diketone C5-spacer-containing compounds (5), (6) and (7); and the
chalcone derivative (8) bearing with mono-ketone C3-spacers were also synthesized
(Figure 2).
2

Figure 2. Molecular design adopted for water-soluble A aggregation inhibitors.
The key step in the synthesis of CUR analogues 3 and 4 was the aldol
condensation of 2,4-pentanediones and benzaldehyde derivatives using Pabon’s
protocol;16 more conventional conditions afforded mainly 3-substituted-2,4-diketone
derivatives, Scheme 1. Accordingly, treatment of 3,4-dihydroxybenzaldehyde and 2,4-
pentanedione with B(EtO)3/B2O3/piperidine in dioxane gave the catechol derivative (9)
in 27% yield. Reaction of this with 2,3-dihydroxybenzaldehyde gave the 2,3-dihydroxy
type CUR (3a) in 35% yield (Scheme 1). Using this method, a variety of the C7-CUR
derivatives (3a-e, 4a-f) were prepared in support of the structure-activity relationship
study (Table 1) (see supporting information).
Scheme 1. Synthesis of designed CUR analogue (3a)
Next, the C5- and C3-spacer type CUR derivatives were prepared, Schemes
2 and 3. Treatment of acetone and 3,4-dimethoxymethoxybenzaldehyde (10) in the
presence of NaOH gave a separable mixture of unsaturated ketone (11) and -
hydroxyketone (12) in yields of 73% and 20%, respectively. In contrast, the proline-
catalyzed aldol reaction17 of acetone and 10 afforded 12 in a yield of 34%. It was noted
that the proline-catalyzed aldol reaction using 3,4-dihydroxybenzaldehyde proceeded
excessively slowly (11 was obtained in a yield only 5% yield after 2 days) and therefore
the protected benzaldehyde (10) was employed. Aldol reaction between the unsaturated
3

ketone (11) and 2,5-dimethoxymethoxybenzaldehyde (13) with MeONa followed by the
deprotection of MOM ethers gave the corresponding C5-monoketone CUR analogue
(5d) in 4% yield. Dess-Martin periodinane oxidation of -hydroxyketone 12 gave
diketone 14 in 48% yield, which was transformed C5-diketone CUR analogue (7c) in
15% yield. The very low yields of these reactions were attributed to the steric hindrance
of the MOM ether moiety on the 2-position of 13 (Scheme 2) (see supporting
information).
Scheme 2. Synthesis of C5-CUR analogues (5d) and (7c)
On the other hand, aldol coupling of 3,4-dimethoxymethoxybenzaldehyde
(10) and 2-hydroxy-5-methoxymethoxyacetophenone (15) with 1M NaOH/EtOH
followed by the deprotection of the MOM groups with 5M HCl/EtOH yielded chalcone
(8a) in 38% yield (Scheme 3). Both C5- (for 5a-d, 6a-d, 7a-d) and C3- (for 8a-b)
monoketone type CUR derivatives were synthesized using these protocol (Table 2 and
1
Figure 3). The structures of the synthetic CUR analogues were confirmed by H and
13C NMR, IR and ESI-MS (see supporting information).
Scheme 3. Synthesis of C3-monoketone CUR analogue (8a)
4

The therapeutic potential of CUR (1) is severely limited by its poor water solubility and
bioavailability.11 UV-vis and HPLC analysis were conducted to evaluate the water
solubility of the synthetic compounds compared to those of CUR (1).12 Identical molar
quantities of both CUR (1) and the synthesized CUR analogues were vortexed in water,
and the resulting solution was centrifuged to remove undissolved material. The
supernatant liquid was concentrated and the residue dissolved in MeOH for analysis by
RP-HPLC. The results are summarized Tables 1 and 2 and Figure 3. The water
solubility of CUR (1) (the control) and AY1031 (2) were 0.19 μM and 31 μM,
respectively. As can be seen from Table 1, the C7-spacer type CUR analogues 3a-e, 4a-
f were as poorly water soluble as CUR (1). However, the water solubility of 4a and 4b
bearing a catechol unit and/or o-phenol motif as in AY1031 (2) were slightly improved,
and those of 5a-d, 6a-d incorporating a C5-monoketone moiety were significantly
better. It is noted that combination of 2,5-dihydroxy groups and catechol unit on two
phenyl rings improves the water solubility. On the contrary, it was reduced by the 4-
hydroxy group on phenyl ring. Derivative 6d in particular exhibited excellent water
solubility (271 μM), a value 1350 times that of CUR (1). The water solubility of the C5-
diketone CUR analogues (7a-d) did not exceed that of the monoketone derivatives (6a-
6d). In conclusion, incorporation of the catechol, o-phenol, and C5-monoketone
moieties together greatly improved water solubility.
The anti A aggregation activity was investigated by the widely-used ThT
method.18 Fresh A42 (25 M) was incubated at 37oC with ThT and the fluorescence of
the mixture measured over time. The fluorescence was found to follow a sigmoidal-like
curve, with a point of inflection. There was an initial lag time of about 2 h
(corresponding to the aggregation of monomeric A42 to oligomer and/or protofibrils),
whereupon the fluorescence sharply increased at about 6 h (corresponding to the
aggregation of protofibrils to amyloid fibrils). The extent of A42 aggregation after 20
h was defined to be 100%. Incubation of a mixture of 25 M monomeric A42 and 10
M CUR (1) at 37oC resulted in a similar sigmoidal-like curve with a final equilibrium
level of ~20%. Thus, CUR (1) at a concentration of 10 M was found to inhibit A
aggregation (25 M) at a ratio of 80%, a result similar to those previously reported.13,19
In addition, the final equilibrium level at 20 h of the mixture of 25 M A42 and 1 M
CUR (1) showed ~60% (40% inhibition). All the synthesized CUR analogues were
5

individually tested in this assay. AY1031 (2) at a concentration of 10 M resulted in a
final ratio of 99%; and at 1 M resulted in a ratio of 62%. These results were used as
controls. 10 M of the synthesized C7-spacer CUR analogues (3a-e, 4a-f) prevented A
fibril formation cleanly (inhibitory rates = 95-100%, data not shown). Therefore, the
mixture of 25 M monomeric A42 and 1 M each synthesized CUR analogues (3, 4),
except for 3a, 3d, 3e, was incubated at 37oC. The C7-spacer CUR analogues (3b, 3e)
bearing a 2,3-catechol moiety maintained potent inhibitory activities (inhibitory rates =
92-93%). Interestingly, the C7-spacer CUR analogues (4a-f) bearing a 2,5-catechol
moiety were classified in two categories. The CUR analogues contained 3’- and/or 4’-
hydroxy groups (4a, 4d, and 4e) have similar inhibitory activities with AY1031 (2)
(inhibitory rates = 53-57%). In contrast, the CUR analogues contained 2’-hydroxy
group (4b, 4c, and 4f) were potent aggregation inhibitors (inhibitory rates = 80-100%).
Therefore, an o-phenol unit is essential for good inhibitory potency. On the other hand,
the C5-monoketone CUR analogues (5a-d, 6a-d) showed potent A aggregation
inhibitory activities (inhibitory rates = 75-100%). There was no significant difference in
inhibitory activity between the mono- and diketone C5-CUR analogues.
The cytotoxicity of the synthesized CUR derivatives was ascertained by
testing them against highly differentiated rat pheochromocytoma (PC-12) cells in a
standard water soluble tetrazolium-8 (WST-8) assay.20 PC-12 cells were cultured in a
medium of DMEM with 10% fetal bovine serum at 37 oC in an atmosphere of 5% CO2.
For WST-8 assays, the PC-12 cells were plated in 96-well plates at a density of 1.0 ×
104 cells per well for 24 h. Then the synthesized CUR analogues (in 1% DMSO) added
to the well plates and co-cultured for 24 h. Thereafter, the PC-12 cells were treated with
o
WST-8 for 2 h at 37 C. The generated formazan was detected by measuring the
absorbance 450 nm. We evaluated the synthesized CUR analogues for cytotoxicity
alongside CUR (1), which served as the control (CC50 = 42 M). C7-CUR derivatives
(3a-e, 4a-f) showed moderate cytotoxicity in a similar manner of CUR (1) for PC12-
cells. As shown in Table 2, the cytotoxicities (CC50) of the C5-monoketone CUR
analogues (5a-d, 6a-d) were in the M range. Interestingly, the C5-diketone CUR
analogues (7a-d) were found to be only minimally cytotoxic.
Oxidative stress has been reported to hasten the onset of AD, and the
concentration of active oxygen in the vicinity of A aggregates is high.21,22 Accordingly,
the antioxidant activity of the synthesized CUR analogues was evaluated by 1,1-
6

diphenyl-2-picrylhydrazyl (DPPH) radical scavenger assay.23 Solutions of DPPH are
purple due to a strong absorption of 513 nm, but turn yellow when the radical of DPPH
is eliminated by antioxidants, and therefore DPPH can be used to quantitatively evaluate
an antioxidant effect. Sawai et al.23 reported that the antioxidative and radical-
scavenging activities of a variety of polyphenols by the DPPH assay and NMR analysis.
The radical-scavenging ability of o-dihydroxy phenolic compounds was superior and
the ability of those with conjugated carbonyl unit was inferior. CUR (1) served as the
control (IC50 = 45 M). All synthesized CUR analogues showed moderate radical
scavenging activities (IC50 = 10-99 M) and therefore structure activity relationships of
the designed CUR analogues with respect to radical scavenging cannot be inferred.
Table 1. The water solubility, aggregation inhibitory activity, cytotoxicity and
antioxidant activity of the synthesized CUR analogues (3a-e, 4a-f)
entry compound
solubility
(M)a
0.19
aggregation
Cytotoxicity
DPPH
inhibition (%)b
CC50 (M)
IC50 (M)
1
2
CUR (1)
40
62
42
-
45
-
AY1031
(2)
31
3
4
5
6
7
8
9
3a
3.8
5.3
11
98c
93
16
39
34
38
8.5
51
53
19
30
23
29
27
60
27
3b
3c
92
3d
8.2
4.8
54
100c
100c
57
3e
4a
4b
100
100
7

10
11
12
13
4c
4d
4e
4f
4.4
5.8
80
56
53
99
38
15
21
24
48
88
41
57
0.57
5.0
aWater solubilities were measured by the Dolai’s protocol to show the values with M.
bAggregation inhibition values of A42 after a 20 h incubation at 25 M were indicated using 1 M
inhibitors and calculated based on the ThT-based fluorescence spectroscopy assay (excitation = 440 nm,
emission = 490 nm). Values are mean values from three independent experiments.
cInhibitors were used 10 M.
Table 2. The water solubility, aggregation inhibitory activity, cytotoxicity, and
antioxidant activity of the synthesized C5-curcumin analogues.
entry compound
solubility
(M) a
111
60
aggregation
cytotoxicity
DPPH
inhibition (%)b
CC50 (M)
34
IC50 (M)
1
2
5a
5b
5c
5d
6a
6b
6c
6d
7a
7b
7c
7d
100
100
75
62
71
24
25
99
48
40
13
16
10
82
28
>100
12
3
19
4
123
151
184
120
271
77
100
98
39
5
54
6
90
46
7
96
12
8
100
90
59
9
>90
>100
>100
63
10
11
12
25
85
47
98
32
100
aWater solubilities were measured by the Dolai’s protocol to show the values with M.
8

bAggregation inhibition values of A42 after a 20 h incubation at 25 M were indicated using 1 M
inhibitors and calculated based on the ThT-based fluorescence spectroscopy assay (excitation = 440 nm,
emission = 490 nm). Values are mean values of triplicate readings for from three independent
experiments.
Since the water solubilities of the CUR analogues were improved by
incorporation of the C5-monoketone motif, an even more remarkable improvement in
water solubility was expected for the C3-monoketone CUR analogues (8a-b), due to the
reduction in the length of the hydrophobic carbon spacer. However, this turned out not
to be the case: the water solubility and the Aβ aggregation inhibitory activities of 8a and
8b were both inferior to the C5-monoketone CUR analogues (Figure 3). The same was
noted for the C6-1,2-diketone CUR analogues,24 compared to the C5- and C7-spacer
CUR analogues (data not shown).
Figure 3. Chemical property of 8a and 8b
To summarize the results so far, the anti Aβ aggregation activity of 6d was
the highest of all the molecules tested (100% for 1 M 6d and 25 M A42); it was
also the most water soluble (271 M). In addition, 6d exhibited the radical scavenging
ability as a IC50 value of 13 M, and its sufficient water solubility correlated with lower
cytotoxicity (CC50 = 59 M). This is consistent with the results of AY1319 (6d), which
had more hydroxy groups and was more water soluble than other derivatives.
To investigate the morphology of the A aggregation and its inhibition by
CUR analogues, TEM studies of the selected CUR analogues were undertaken. Mature
amyloid fibrils with a length of 1 m or more could be readily discerned (Figure 4a). A
similar morphology was visualized upon treatment of the A fibrils with ThT in a 4:1
ratio (Figure 4b). In this case, the A fibrils/ThT complexed gave rise to a green signal
derived from ThT by fluorescence microscope. Interestingly, upon incubation of this
9

mixture with AY1319 (6d), these fibrils were transformed into nanorod-like fragments
with a length of 50-500 nm (Figure 4c). The solution of these nanorod-like fragments
exhibited reduced fluorescence intensity, compared to that with the fibrils. Since this
reduction of fluorescence intensity presumably resulted from the binding AY1319 (6d)
with the protofibrils and/or the amyloid fibrils, measurement of the CD spectra was
attempted. A decrease of -sheet structure was inferred from the CD spectrum. It is
noted that A aggregation was not eliminated, simply that the resulting structures
resembled nano-rods and not fibrils (Figure 4d). These nanorod-like fragments are
known to be less cytotoxic than amyloidogenic A intermediates, protofibrils and
amyloid fibrils, and much more susceptible to cellular internalization. Their
colocalization with lysosomal enzyme in vitro greatly indicated the possibility of
successfully cleaning nanorod-like A in a cell-participated and enzyme-mediated
pathway.15
a)
b)
c)
d)
Figure 4. (a-c) Negative-staining TEM images of A aggregation after 20 h incubation.
(a) A alone. (b) A aggregation with ThT. (c) A nanorod-like structure with AY1319
(6d). Scale bars = 50 nm. (d) CD spectrum of A nanorod-like structure with AY1319
(6d).
To better understand the mechanism of Aβ fibril binding, a molecular docking
analysis was undertaken. GOLD software25,26 was used to simulate the docking mode of
AY1319 (6d) on a 12-fold Aβ11-42 fibril structure (PDB ID: 2MXU). As shown in
Figure 5a, AY1319 (6d) located on the outer site of the Aβ fibrils; with the binding
between the two comprised mainly of hydrophilic interaction. Several significant
binding interactions were observed within the docked complex, Figure 5b. Two
phenolic hydroxy groups and a ketone of AY1319 (6d) were involved in hydrogen
bonding interactions of Phe19 and Glu22 of the A oligomers. We have already
10

reported that Me-CUR or ThT located in the inner site of A fibrils by the hydrophobic
interaction and hydrogen bonding networks and therefore Me-CUR or ThT causes A
fibrils to stabilize and fluoresce. In contrast, the water-soluble CUR analogue AY1319
(6d) caused A fibrils to form nanorod-like fragments.
(a)
(b)
Figure 5. (a) Binding pose of AY1319 (6d) in the A fibrils; (b) Detailed view of the
docked AY1319 (6d) structure and the interacting amino acid moieties within the
binding site of Aβ fibrils.
Studies towards the synthesis of a novel and potent inhibitor of the
aggregation of A resulted in the preparation of a variety of curcumin analogues and
elucidation of their structure-activity relationships. The length of the spacer unit and
presence of a carbonyl group thereon, and the presence of hydroxy groups of the
phenols, were all found to be important. These studies culminated in the discovery of
AY1319 (6d), which incorporates a C5-monoketone spacer moiety and phenolic rings
bearing hydroxy groups at 2,3,2’,5’-positions, and exhibits potent A aggregation
inhibition and ideal water solubility. Molecular modeling, a ThT assay, and CD, and
TEM studies concluded that AY1319 (6d) binds hydrophilic sites of Aβ fibrils, leading
them to disaggregate into nanorod-like fragments. In addition, analogues incorporating
the CUR framework (including AY1319 (6d) showed potent radical scavenging activity.
The cytotoxicity of AY1319 (6d) was found to be similar to that of CUR (1). In vivo
studies of AY1319 (6d) are underway, and the results will be reported in due course.
11

ASSOCIATED CONCEPT
Supporting information.
Additional compound data, synthesis procedures and characterization of compounds
AUTHOR INFORMATION
Corresponding author
*E-mail: konno@yz.yamagata-u.ac.jp. Phone: +81 238-26-3131.
Author contributions
The manuscript was written through contributions of all authors. All authors have given
approval to the final version of the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGEMENTS
This work was supported in part by a Value Program through target driven R&D, Japan
Society and Technology Agency and a Grant-in-Aid from the Japan Society for the
Promotion of Science, KAKENHI (25450145) to H.K.
REFERENCES
1. Hashimoto, M.; Rockenstein, E.; Crews, L.; Masliah, E. Neuromol. Med. 2003, 4,
21-35.
2. Walsh, D. M.; Selkoe, D. J. J. Neurochem. 2007, 101, 1172-1184.
3. Ono, K.; Hamaguchi, T.; Naiki, H.; Yamada, M. BBA Mol. Basis Dis. 2006, 1762,
575-586.
4. Haass, C.; Selkoe, D. J. Nat. Rev. Moll. Cell Biol. 2007, 8, 101-112.
5. Viola, K. L.; Klein, W. L. Acta Neuropathol. 2015, 129, 183-206.
6. Shishodia, S.; Chaturvedi, M. M.; Aggrwal, B. B. Curr. Probl. Cancer 2007, 31,
243-305.
7. Ohtsu, H.; Xiao, Z.; Ishida, J.; Nagai, M.; Wang, H-K.; Itokawa, H.; Su, C.-Y.;
Shih, C.; Chiang, T.; Chang, E.; Lee, Y.; Tsai, M.-Y.; Chang, C.; Lee, H.-H. J. Med.
12

Chem. 2002, 45, 5037-5042.
8. Hamaguchi, T.; Ono, K.; Murase, A.; Yamada, M. Am. J. Pathol. 2009, 175, 2557-
2565.
9. Begum, A. N.; Jones, M. R.; Lim, G. P.; Morihara, T.; Kim, P.; Heath, D. D.; Rock,
C. L.; Pruitt, M. A.; Yang, F.; Hudspeth, B.; Hu, S.; Faull, K. F.; Teter, B.; Cole, G.
M.; Frautschy, S. A. J. Pharmacol. Exp. Ther. 2008, 326, 196-208.
10. Ringman, J. M.; Frautschy, S. A.; Teng, E.; Begum, A. N.; Bardens, J.; Beigi, M.;
Gylys, K. H.; Badmaev, V.; Heath, D. D.; Apostolova, L. G.; Porter, V.; Vanek, Z.;
Marshall, G. A.; Hellemann, G.; Sugar, C.; Masterman, D. L.; Montine, T. J.;
Cummings, J. L.; Cole, G. M. Alzheimer’s Reseach & Therapy. 2012, 4, 43.
11. Anand, P.; Kunnumakkara, A. B.; Newman, R. A.; Aggarwal, B. B. Molecular
Pharmaceutics 2007, 4, 807-818.
12. Dolai, S.; Shi, W.; Corbo, C.; Sun, C.; Averick, S.; Obeysekera, D.; Farid, M.;
Alonso, A.; Banerjee, P.; Raja, K. ACS Chem. Neurosci. 2011, 2, 694-699.
13. Endo, H.; Nikaido, Y.; Nakadate, M.; Ise, S.; Konno, H. Bioorg. Med. Chem. Lett.
2014, 24, 5621-5626.
14. Konno, H.; Endo, H.; Ise, S.; Miyazaki, K.; Aoki, H.; Sanjoh, A.; Kobayashi, K.;
Hattori, Y.; Akaji, K. Bioorg. Med. Chem. Lett. 2014, 24, 685-690.
15. Zhang, Q.; Liu, J.; Hu, Xiaoyu, Wang, W.; Yuan, Z. ACS Macro Lett. 2015, 4, 339-
342.
16. Pabon, H. J. J. Recl. Trav. Chim. Pays-Bas. 1964, 83, 379.
17. List, B.; Lerner, R. A.; Barbas, C. F. III J. Am. Chem. Soc. 2000, 122, 2395-2396.
18. Levine, H., III Proteins 1993, 2, 404.
19. Yang, F.; Lim, G. P.; Begum, A. N.; Ubeda, O. J.; Simmons, M. R.; Ambegaokar,
S. C.; Chen, P. P.; Kayed, R.; Glabe, C. G.; Frautschy, S. A.; Cole, G. M. J. Biol.
Chem. 2005, 280, 5892-5901.
20. Ishiyama, M.; Miyazono, Y.; Sasamoto, K.; Ohkura, Y.; Ueno, K. Talanta. 1997,
44, 1299-1305.
21. Hanjo, F.; Mori, M.; Goto, K.; Hara, Y. Biosci. Biotechnol. Biochem. 1999, 63,
1621-1623.
22. Ono, K.; Takamura, Y.; Yoshiike, Y.; Zhu, L.; Han, F.; Mao, X.; Ikeda, T.;
Takasaki, J.; Nishijo, H.; Takashima, A.; Teplow, D. B.; Zagorski, M. G.; Yamada,
M. J. Biol. Chem. 2012, 287, 14631-14643.
13

23. Sawai, Y.; Moon, J.-H.; Sakata, K.; Watanabe, N. J. Agri. Food.Chem. 2005, 53,
3598-3604.
24. Long, L.; Wang, L.; Wu, Y. Int. J. Org. Chem. 2013, 3, 235-239.
25. Sato, T.; Hotsumi, M.; Makabe, K.; Konno, H. Bioorg. Med. Chem. Lett. 2018, 28,
3520-3525.
26. The software was prepared by the Cambridge Crystallographic Data Centre
(CCDC). http://www.ccdc.cam.ac.uk
14

15

Highlights:
AY1319 exhibits potent A aggregation inhibition and ideal water solubility
AY1319 binds hydrophilic sites of Aβ fibrils, leading them to disaggregate into
nanorod-like fragments
The cytotoxicity of AY1319 was found to be similar to that of natural CUR.
16