Syntheses, neural protective activities, and inhibition of glycogen synthase kinase-3β of substituted quinolines

Article abstract of DOI:10.1016/j.bmcl.2014.05.085

A new series of fifteen 5-, 6-, and 8-appended 4-methylquinolines were synthesized and evaluated for their neural protective activities. Selected compounds were further examined for their inhibition of glycogen synthase kinase-3β (GSK-3β) and protein kina

Full text of DOI:10.1016/j.bmcl.2014.05.085

Accepted Manuscript
Syntheses, Neural Protective Activities, and Inhibition of Glycogen Synthase
Kinase-3β of Substituted Quinolines
Jianyu Lu, Izumi Maezawa, Sahani Weerasekara, Ramazan Erenler, Tuyen D.T.
Nguyen, James Nguyen, Luxi Z. Swisher, Jun Li, Lee-Way Jin, Alok Ranjan,
Sanjay K. Srivastava, Duy H. Hua
PII:
S0960-894X(14)00594-0
DOI:
http://dx.doi.org/10.1016/j.bmcl.2014.05.085
BMCL 21699
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
3 May 2014
20 May 2014
22 May 2014
Please cite this article as: Lu, J., Maezawa, I., Weerasekara, S., Erenler, R., Nguyen, T.D.T., Nguyen, J., Swisher,
L.Z., Li, J., Jin, L-W., Ranjan, A., Srivastava, S.K., Hua, D.H., Syntheses, Neural Protective Activities, and
Inhibition of Glycogen Synthase Kinase-3β of Substituted Quinolines, Bioorganic & Medicinal Chemistry Letters
(2014), doi: http://dx.doi.org/10.1016/j.bmcl.2014.05.085
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.

Syntheses, Neural Protective Activities, and Inhibition of Glycogen Synthase
Kinase-3β of Substituted Quinolines
Jianyu Lu,a Izumi Maezawa,b Sahani Weerasekara,a Ramazan Erenler,a Tuyen D. T. Nguyen,a
James Nguyen,a Luxi Z. Swisher,a Jun Li,a Lee-Way Jin,b Alok Ranjan,c Sanjay K. Srivastava,c
and Duy H. Hua*,a
aDepartment of Chemistry, 213 CBC Building, Kansas State University, Manhattan, KS 66506,
United States
bM.I.N.D. Institute and Department of Pathology, 2825 50th Street, UC Davis Health System,
Sacramento, California 95817, United States
cDepartment of Biomedical Sciences and Cancer Biology Center, Texas Tech University Health
Sciences Center, Amarillo, Texas 79106, United States
* Corresponding author. Tel.: +1 (785) 532 6699; fax: +1 (785) 532 6666.
E-mail address: duy@ksu.edu (D.H. Hua).
Key words: Alzheimer’s disease, amyloid β, glycogen synthase kinase-3β, neural protective
activity, protein kinase C, quinolines.
Abstract.
A new series of fifteen 5-, 6-, and 8-appended 4-methylquinolines were synthesized and
evaluated for their neural protective activities. Selected compounds were further examined for
their inhibition of glycogen synthase kinase-3β (GSK-3β) and protein kinase C (PKC). Two
1

most potent analogs, compounds 3 and 10, show nanomolar protective activities in amyloid β-
induced MC65 cells and enzymatic inhibitory activities against GSK-3β, but poor PKC
inhibitory activities. Using normal mouse model, the distribution of the most potent analog 3 in
various tissues and possible toxic effects in the locomotors and inhibition of liver transaminases
activities were carried out. No apparent decline of locomotor activity and no inhibition of liver
transaminases were found. The compound appears to be safe for long-term use in Alzheimer’s
disease mouse model.
Alzheimer’s disease (AD), a progressive neurodegenerative disorder, is the most common
form of dementia in the elderly.1 AD brains have three major lesions, (1) formation of
aggregates and plaques of amyloid-β (Aβ) peptide, a 39-43 residue protein, outside of neurons;
(2) formation of abnormal neurofibrillary tangles (NTFs) consists of hyperphosphorylated tau
protein inside the neurons; and (3) dysfunction of neurons including cholinergic, noradrenergic,
serotonergic and pyramidal neurons.2 Major strategies for experimental disease-modifying
therapies include targeting multiple sites in Aβ metabolism (Aβ synthesis, aggregation,
deposition and clearance), targeting tauopathy (modulation of tau phosphorylation and inhibition
of tau aggregation), regulating cholesterol homeostasis, anti-excitotoxicity, anti-inflammation
and modulating calcium homeostasis, among others.1-3 A number of compounds has shown
efficacy in AD transgenic mouse models,4-12 but their efficacy in AD patients remains uncertain.
Moreover, several drug candidates in clinical trials failed to show benefits.1-3 In our pursuit of
finding neural protective compounds for AD, we use MC65 cells protection assay as our primary
screen for bioactive compounds,13-15 and a class of quinolines containing various substituents
(Figure 1) were found to have submicromolar activities. MC65 cells assay generates few false
2

positive results and identifies leads that penetrate cells and ameliorate Aβ oligomer-induced
toxicity.13 Moreover, studies of the enzyme assay inhibition of glycogen synthase kinase-3β
(GSK-3β) revealed several quinoline molecules inhibited the enzyme in nanomolar ranges.
GSK-3β is abundant in neurons of the central nervous system and catalyzes the phosphorylation
of tau proteins, which are overexpressed in AD brains.16 Hyperphosphorylation of tau proteins in
brain from imbalanced activity of GSK-3β results in neurofibrillary tangles and leads to cell
death.16-18 Moreover, the “dual pathway” hypothesis19 suggests that GSK-3 affects both
hyperphosphorylation of tau and elevation of Aβ via the enhancement of enzymatic processing
of APP. A dual effect of reduction of Aβ toxicity and inhibition of GSK-3β may provide a
greater beneficial effect than conventional GSK-3β inhibitors and anti-Aβ molecules.20 Herein,
we reported the syntheses of quinolines 2 - 16 (Figure 1) and evaluation of their bioactivities
along with our previously reported quinoline 1.21 Several compounds possess dual effects of
inhibition of Aβ toxicity in MC65 cells and GSK-3β enzyme.
3

Figure 1. Synthesized and bioevaluated quinolines 1 - 16.
R1
O
Me
N
F3C
Me
O
Me
N
F3C
Me
O
Me
N
O
O
R2
F3C
Me
O
Me
O
O
5
8
4
1
HN
HN
N
HN
S
HN
NH2
N
MeO
OMe
1
OH
OH
2
3 : R1 = CF3; R2 = Me
10 : R1 = CF3; R2 = H
12 : R1 = F ; R2 = Me
14 : R1 = H ; R2 = Me
4
F3C
Me
O
Me
F3C
Me
O
Me
O
O
N
F3C
Me
O
Me
N
N
F3C
Me
O
Me
N
HN
O
HN
O
O
S
HN
NH2
HN
Ph
O
5
N
6
8
Me
7
O
F3C
Me
O
Me
Me
Me
N
R1
Me
O
Me
N
O
N
O
O
Me
HN
N
O
HN
HN
NH2
HN
NH2
O
11 : R1 = F
13 : R1 = H
OH
15
9
16
From an initial screening of synthesized substituted quinoline compounds using MC65
cells, we found that compound 1 possesses strong neuronal cell protective activity (vide infra).
Hence, its analogs, quinolines 2 – 16 possessing different heterocycle- or arene-appended
methylamino moiety at C8, different C5 aryloxy moieties, no C5 aryloxy group, and C6
hydroxyl function, were synthesized. A reductive amination reaction was used to assemble
4

compounds 2 – 7 via the coupling of amine 1721 and aldehydes 18 – 23 with sodium
cyanoborohydride in methanol in good to moderate yields (Scheme 1). Aldehydes 18 – 22 were
obtained from commercial sources while 23 was prepared as reported.22 Compounds 2 – 7
contain different heterocycle- or arene-appended methylamino functions at C8, which depart
from that of compound 1.
Scheme 1. Synthesis of Compounds 2 - 7 via reductive amination reactions.
F3C
O
F3C
O
NaCNBH3
MeOH, AcOH
O
O
O
+
H
R
N
N
HN
NH2
N
S
18 : R =
R
17
2 (72% yield)
3 (82% yield)
4 (75% yield)
5 (65% yield)
6 (78% yield)
7 (76% yield)
OH
19 : R =
20 : R =
OMe
OH
OMe
21 : R =
22 : R =
23 : R =
O
Ph
S
N
The C8 appended 3-aminopropylamine function of compound 1 was also modified by
introducing a 3-amino-3-oxopropylamine moiety at C8, i.e., compound 8, or varied by a 2-
furanylamide group, compound 9. Compound 8 was readily synthesized from a Michael
addition reaction of amine 17 with acrylamide in acetonitrile in a sealed tube at 120oC in a 57%
5

yield, and amide 9 was prepared in a 75% yield from the acylation reaction of amine 17 with 2-
furancarbonyl chloride (24) (Scheme 2). Among the tested quinolines using MC65 cell assays,
compounds 1 and 3 appear to be the most active quinolines (vide infra), hence the C6-hydroxyl
analog of 3 and molecules possessing different substituents at C5, i.e., compounds 10 - 16, were
examined. The C6-methyl ether group of 17 was removed with boron tribromide in
dichloromethane, and the resulting quinoline 25 condensed with aldehyde 19 to give hydroxyl
analog 10 in a 52% yield.
Scheme 2. Synthesis of Quinolines 8 - 10.
CH3CN
NH2
+
17
17
8
120oC
O
(57% yield)
(sealed tube)
O
O
THF
+
9
-78 - 25oC
Cl
(75% yield)
24
NaCNBH3
MeOH, AcOH
BBr3, CH2Cl2
0 - 25oC
F3C
O
17
10
HO
19
(52% yield)
N
NH2
25 (83% yield)
C5-Aryloxy analogs of 1 such as compounds 11 and 13 were obtained from a sequence of
reactions starting from bromide 26 (Scheme 3).21 Hence, nucleophilic aromatic substitution
reactions of bromide 26 with potassium 3-fluorophenoxide (27) and potassium phenoxide (28)
separately in DMF gave aryl ether 29 and 30 in 65 and 80% yield, respectively (Scheme 3).
6

Removal of the acetyl protecting group of 29 and 30 with HCl in ethanol followed by ring
closing reactions with 3-buten-2-one and arsenic acid in phosphoric acid provided quinolines 31
and 32 in 35 and 45% yield, respectively. Reduction of the nitro function of 31 and 32 separately
with iron in acetic acid followed by alkylation of the resulting 8-aminoquinolines 33 and 34 with
3-iodopropylphthalimide,21 and deprotection with hydrazine afforded 11 and 13, respectively.
Condensation of amines 33 and 34 separately with 4-hydroxybenzaldehyde and sodium
cyanoborohyride furnished amines 12 and 14, respectively.
Scheme 3. Synthesis of Quinolines 11 - 14.
Br
1) HCl, EtOH
2) H3AsO4,
DMF
120oC
R1
O
Me
N
R1
O
R1
KO
MeO
MeO
MeO
+
H3PO4
3-buten-2-one
NHCOCH3
NHCOCH3
NO2
NO2
NO2
27 : R1 = F
28 : R1 = H
26
31 : R1 = F (35% yield)
32 : R1 = H (45% yield)
29 : R1 = F (65% yield)
30 : R1 = H (80% yield)
1) 3-iodopropyl-
phthalimide
NaHCO3, DMF
R1
O
Me
N
11 : R1 = F (49% yield)
13 : R1 = H (53% yield)
Fe/AcOH
MeO
2) NH2NH2
EtOH
NH2
33 : R1 = F (92% yield)
34 : R1 = H (92% yield)
NaCNBH3
MeOH, AcOH
33
34
12 (65% yield)
14 (84% yield)
19
Quinolines without C5 aryloxy function, 1523 and 16, were similarly synthesized from the
ring closing reaction of 4-amino-3-nitroanisole with 3-buten-2-one followed by the reduction
with iron in acetic acid to give amine 3524 in an 85% overall yield (Scheme 4). Alkylation of
amine 35 with 3-iodopropylphthalimide followed by the treatment of hydrazine gave C5-H
7

analog 15, and reductive amination of amine 35 with aldehyde 19 and sodium cyanoborohydride
afforded derivative 16.
Scheme 4. Synthesis of Quinolines 15 and 16.
1) 3-iodopropyl-
phthalimide
NaHCO3, DMF
Me
1) H3AsO4,
H3PO4
3-buten-2-one
MeO
MeO
15
NH2
2) NH2NH2
EtOH
N
2) Fe/AcOH
(85% yield)
NO2
NH2
(58% yield)
35
NaCNBH3
MeOH, AcOH
16
35
19
(73% yield)
MC65 cell line was used as a screen to search for neural protective compounds against
cell death induced by oligomeric Aβ peptides.13-15 On day three, the induction of SβC gene (in
the absence of tetracycline) in MC65 cells leads to the production of the C99 fragment of
amyloid precursor protein and subsequently to Aβ peptides from the proteolysis by γ-secretase,
resulting in cell death. Compounds that protect cell from death likely possess anti-Aβ property.
An addition of tetracycline, an antioxidant, to the media of MC65 cells suppresses the production
of C99 fragment and cells survive. Consequently, toxicity of the compound to MC65 cells is
determined. Table 1 tabulates the EC50 (median effective concentration) and TC50 (median toxic
concentration) values of quinoline compounds, 1 – 16. From our initial screen of compounds 1 –
9 having various functionalities at C8 of the quinoline, compounds 1 and 3 showed the greatest
activities with EC50 values of 0.15 and 0.12 µM, respectively. Results suggest that the presence
of a 3-aminopropylamine or p-hydroxyphenylmethylamine function leads to higher bioactivity.
8

Modifications at C5 and C6 were therefore carried out by keeping appended C8 with either 3-
aminopropylamine or p-hydroxyphenylmethylamine, such as compounds 10 - 16. Among these
seven derivatives, C6-hydroxy derivative 10 and C5-phenoxy 13 are the most active analogs with
EC50 values of 0.30 and 0.42 µM, respectively, while other analogs having EC50 values range
from 0.53 to 17.6 µM. The results indicate that compound 3 is a suitable candidate for
mechanistic investigation.
Table 1. EC50 and TC50 values of Compounds 1 – 16 from MC65 cell protection assays.25 Values
are expressed in mean standard deviation.
Compound
Compound
EC50 (µM)
TC50 (µM)
EC50 (µM)
3.47 0.32
0.30 0.01
0.60 0.02
0.70 0.08
0.42 0.01
0.53 0.01
17.62 0.37
2.62 0.15
TC50 (µM)
>50
1
2
3
4
5
6
7
8
9
0.15 0.02
2.39 0.06
2.10 0.03
20.32 1.22
3.31 0.30
7.28 0.26
2.60 0.20
8.16 0.01
4.01 0.38
>50
10
11
12
13
14
15
16
0.12 0.01
0.48 0.03
0.46 0.11
0.39 0.02
0.19 0.02
0.50 0.02
1.38 0.08
2.91 0.15
>50
14.50 1.68
>50
>50
20.54 0.21
Hyperphosphorylation of tau proteins by GSK-3β leads to the formation of
neurofibrillary tangles,16-20 hence inhibition of GSK-3β by selected quinoline compounds was
conducted in search of possible mechanism of action. Protein kinase C (PKC) mediates the
function of other proteins in signal-transduction pathways of different cell types through the
phosphorylation of hydroxyl functions of serine and threonine residues of these proteins.26 In
particular, phosphorylation of potent activators of transcription would increase oncogene
expressions resulting in the promotion of cancer progression.27 Therefore, the inhibition of PKC
9

was also carried out. Table 2 summarizes results of the inhibition of GSK3β and PKC and the
selectivity index (SI) by selected quinolines using the respective GSK-3β kinase assay and
PepTag® non-radioactive PKC assay kits (both obtained from Promega Co.). Interestingly, the
gap junction enhancer compound 121 inhibited PKC with half maximum inhibitory concentration
(IC50) value of 35 nM but does not inhibit GSK-3β up to 1 mM. A similar finding is observed
with quinoline 7 except with much higher IC50 value of 400 µM against PKC. Quinolines 3 and
10 on the other hand show excellent selectivity for GSK-3β. The IC50 values of 3 and 10 against
GSK-3β are 35 nM and 158 nM, respectively, while the values against PKC are 240 and 750 µM,
respectively. The SI values of these two compounds are 6,857 and 4,747, respectively, suggesting
kinase specificity. Under similar assay conditions, staurosporine26,28 show potent but non-
discriminating inhibitions with IC50 values against GSK-3β and PKC of 38 and 33 nM.
Table 2. Enzyme inhibitory activities of GSK-3β and PKC by selected quinoline compounds
and selectivity index (SI) values.25 Values are expressed in mean standard deviation.
Compounds
IC50 value,
GSK-3β
IC50 value,
PKC
SI
(PKC IC50/GSK3β IC50)
< 3.5 x 10-5
> 1 mM
35 8 nM
240 21.2 µM
400 13.7 µM
750 9.3 µM
33 5 nM
1
3
35 6.36 nM
6,857
> 1 mM
158 19.1 nM
38 7 nM
< 0.4
4,747
0.87
7
10
Staurosporine
10

Compound 3 possesses strong neuronal cell protection and inhibitory activity against
GSK-3β, therefore, to examine whether 3 is suitable for future in vivo efficacy study, the
distribution of 3 in various tissues and possible toxic effects in the locomotors and inhibition of
liver enzymes activities in mice were carried out. The amounts of 3 in various tissues were
quantified by following a reported procedure,29 and results are summarized in Table 3 from an
oral gavage administration each day of 5 mg/Kg body weight of CD1 mice of 3 (two untreated
and four treated mice were used) for 75 days. The amounts of 3 in various organs and plasma
remained in low concentrations after 75 days and appeared to accumulate in brain and pancreases
in greater amounts than other tissues and plasma.
Table 3. Distribution of compound 3 in various tissues and plasma from an oral route
administration of 3 into CD1 mice with 5 mg/Kg body weight daily for 75 days (n = 4). Values
are expressed in mean standard deviation, and ND is not detectable.
Tissues
Brain
Pancreases
26.5 6.6
Liver
Kidney
Lung
ND
Plasma
Concentration 24.4 6.4
7.1 0.6
16.1 2.1
4.5 0.3
of 3 (µM)
After 75 days of treatment, behavioral activity was monitored using Versamax
(AccuScan Instruments Inc., Columbus, OH, USA), where readings were taken before and after
administration of 3. The Versamax chamber is ventilated and equipped with infrared sensors
along the side wall. Prior to the reading, each mouse was left in the chamber for 15 minutes for
acclimatization. Administration of 3 for 75 days did not showed any effect on the overall
locomotors activity of mice in terms of clockwise or counter-clockwise activity, total covered
distance, rest time, vertical activity, and horizontal activity when compared with control mice
11

(Figure 2). Results suggest that chronic administration of 3 did not have any behavioral side
effects in mice.
Figure 2. Effect of chronic administration of compound 3 on the locomotors activity of mice.
Control and compound 3 (5mg/Kg daily by oral gavage for 75 days) treated mice were
acclimatized for 15 min inside Versamax chamber followed by monitoring their movements. (A)
Clockwise revolution, (B) total distance covered, (C) rest time, (D) vertical activity, and (E)
horizontal activity.
Possible liver toxicity was examined by measuring enzymatic activities of liver
transaminases, aspartate aminotransferase (AST) and alanine transaminase (ALT), biomarkers of
toxicity. Mice were sacrificed on day 75 after daily oral administration of 3. Blood was
collected from heart by using syringe containing heparin to prevent clotting. Plasma was
separated immediately to prevent hemolysis by centrifugation at 10,000 x g for 5 minutes. The
enzymatic activities of AST and ALT were determined using a commercially available kit
12

(Pointe Scientific, Inc, Canton, MI, USA), according to manufacturer’s instructions. To evaluate
the toxicity of 3 upon chronic administration, ALT and AST enzyme activities were evaluated in
the plasma of control and treated mice, and results are depicted in Figure 3. No significant
difference in the activities of ALT and AST was observed between control and treated mice
suggesting that 3 is relatively safe for long-term use.
Figure 3: Effect of compound 3 on the biochemical markers of toxicity. After 75 days of daily
administration of 3 (5 mg/kg) by oral gavage, mice were sacrificed and plasma was separated
from the blood of control and treated mice and evaluated for ALT and AST enzymatic activities.
In summary, a number of neural protective quinoline molecules were synthesized and
evaluated in cells and enzyme assays. Compound 3 and its C6-hydroxyl analog 10 were the
most potent molecules and they inhibit GSK-3β selectively in nanomolar concentrations.
Compound 3 distributed mainly to the brain and pancreases in mice after administration of 5
mg/Kg daily by oral route over 75 days and showed no apparent toxicity through the
examination of locomotors activity and liver transaminases. Hence, the molecule appears to be
safe for long-term study in AD mouse model. The synthetic procedure leading to this class of
13

neural protective compound is general and further structural optimization is possible for future
drug discovery and development.
Acknowledgement
Research reported in this presentation was supported by the National Institute of General
Medical Sciences of the National Institutes of Health under Award Number P20GM103418 and
Johnson Cancer Center, Kansas State University (D.H.H.) and R01 grant CA129038 awarded by
the National Cancer Institute, NIH (S.K.S.). The content is solely the responsibility of the
authors and does not necessarily represent the official views of the National Institutes of Health.
RE and JN were supported by The Council of Higher Education of Turkey and Summer
Undergraduate Research Opportunity Program of Kansas State University, respectively. We
thank Keshar Prasain for obtaining initial PKC data of compound 1.
Supplementary data
Supplementary data (synthetic procedure, chemical analysis data, enzyme assays, cell
assays, in vivo toxicity study, and quantification of tested compound in various tissues)
associated with this article can be found, in the online version, at http://dx.doi.org
References and notes
1. Mangialasche, F.; Solomon, A.; Winblad, B.; Mecocci, P.; Kivipelto, M. Lancet Neurol.
2010, 9, 702.
2. Palmer, A. M. Trends in Pharmacol. Sci. 2011, 32, 141.
14

3. Salomone, S.; Caraci, F.; Leggio, G. M.; Fedotova, J.; Drago, F. Br. J. Clin. Pharmacol.
2012, 73, 504.
4. Chu J.; Li, J. –G.; Pratico, D. Plos One 2013, 8, e70991, 8 pages.
5. Pierce, A.; Podlutskaya, N.; Halloran, J. J.; Hussong, S. A.; Lin, P. –Y.; Burbank, R.; Hart, M.
J.; Galvan, V. J. Neurochem. 2013, 124, 880.
6. Ozcelik, S.; Fraser, G.; Castets, P.; Schaeffer, V.; Skachokova, Z.; Breu, K.; Clavaguera, F.;
Sinnreich, M.; Kappos, L.; Goedert, M.; Tolnay, M.; Winkler, D. T. Plos One 2013, 8,
e62459, 7 pages.
7. Ma, Q. –L.; Zuo, X.; Yang, F.; Ubeda, O.; Gant, D. J.; Alaverdyan, M.; Teng, E.; Hu, S.;
Chen, P. –P.; Maiti, P.; Teter, B.; Cole, G. M.; Frautschy, S. A. J. Biol. Chem. 2013, 288,
4056.
8. Herculano, B.; Tamura, M.; Ohba, A.; Shimatani, M.; Kutsuna, N.; Hisatsune, T. J. Alz. Dis.
2013, 33, 983.
9. Lilja, A. M.; Luo, Y.; Yu, Q. –S.; Rojdner, J.; Li, Y.; Marini, A. M.; Marutle, A.; Nordberg,
A.; Greig, N. H. Plos One 2013, 8, e54887, 10 pages.
10. Guo, C.; Wang, T.; Zheng, W.; Shan, Z. –Y.; Teng, W. –P.; Wang, Z. –Y. Neurobiol. Aging
2013, 34, 562.
11. Zhao, L.; Wang, J. –L.; Liu, R.; Li, X. –X.; Li, J. –F.; Zhang, L. Molecules 2013, 18, 9949.
12. Zeng, Y.; Wang, Y. –J.; Zhou, X. –F.; Yueqin, Z. Front. Neurol. 2014, 5, 69.
13. Pokhrel, L.; Maezawa, I.; Nguyen, T. D. T.; Chang, K. –O.; Jin, L. –W.; Hua, D. H. J. Med.
Chem. 2012, 55, 8969.
14. Hong, H. S.; Rana, S.; Barrigan, L.; Shi, A.; Jin, L. –W.; Hua, D. H. J. Neurochem. 2009,
108, 1097.
15

15. Maezawa, I.; Hong, H. S.; Wu, H. C.; Battina, S. K.; Rana, S.; Iwamoto, T.; Radke, G. A.;
Pettersson, E.; Martin, G. M.; Hua, D. H.; Jin, L. –W. J. Neurochem. 2006, 98, 57.
16. Flaherty, D. B.; Soria, J. P.; Tomasiewicz, H. G.; Wood, J. G. J. Neurosci. Res. 2000, 62,
463.
17. Spittaels, K.; Van Den Haute, C.; Van Dorpe, J.; Geerts, H.; Mercken, M.; Bruynseels, K.
Lasrado, R.; Vandezande, K.; Laenen, I.; Van Lint, J.; Vandenheede, J.; Moechars, D.; Loos,
R.; Van Leuven, F. J. Biol. Chem. 2000, 275, 41340.
18. Eldar-Finkelman, H.; Martinez, A. Front. Mol. Neurosci. 2011, 4, 1.
19. Small, S. A.; Duff, K. Neuron 2008, 60, 534.
20. Phukan, S.; Babu, V. S.; Kannoji, A.; Hariharan, R.; Balaji, V. N. British J. Pharm. 2010,
160, 1.
21. Shi, A.; Nguyen, T. A.; Battina, S. K.; Rana, S.; Takemoto, D. J.; Chiang, P. K.; Hua, D. H.
Bioorg. & Med. Chem. Lett. 2008, 18, 3364.
22. Pokhrel, L.; Kim, Y.; Nguyen, T. D. T.; Prior, A. M.; Lu, J.; Chang, K. –O.; Hua, D. H.
Bioorg. & Med. Chem. Lett. 2012, 22, 3480.
23. Schmidt, L. H. Antimicrob. Agents Chemother. 1983, 24, 615.
24. Campbell, K. N.; Sommers, A. H.; Kerwin, J. F.; Campbell, B. K. J. Am. Chem. Soc. 1946,
68, 1556.
25. Each experiment was performed in triplicate and standard deviation was calculated.
26. Wilkinson, S. E.; Parker, P. J.; Nixon, J. S. Biochem. J. 1993, 294, 335.
27. Yamasaki, T.; Takahashi, A.; Pan, J.; Yamaguchi, N.; Yokoyama, K. K. J. Biol. Chem. 2009,
284, 8567.
16

28. Bertrand, J. A.; Thieffine, S.; Vulpetti, A.; Cristiani, C.; Valsasina, B.; Knapp, S.; Kalisz, H.
M.; Flocco, M. J. Mol. Biol. 2003 333, 393.
29. Shishido, S. N.; Prasain, K.; Beck, A.; Nguyen, T. D. T.; Hua, D. H.; Nguyen, T. A. Plos
One 2013, 8, e67174; 13 pages.
17

Graphical abstract
Syntheses, Neural Protective Activities, and Inhibition of Glycogen Synthase-
3β of Substituted Quinolines
Jianyu Lu, Izumi Maezawa,
Sahani Weerasekara,
Me
O
Me
R1
O
Me
N
R1
Me
O
Me
N
Ramazan Erenler, Tuyen D.
T. Nguyen, James Nguyen,
Luxi Z. Swisher, Jun Li,
Lee-Way Jin, Alok Ranjan,
Sanjay K. Srivastava, and
Duy H. Hua. Department of
Chemistry, Kansas State
University, Manhattan, KS
66506 U.S.A.
N
O
O
R2
HN
NH2
HN
HN
NH2
OH
Me
N
O
R1 = F
R1 = H
R1 = CF3; R2 = Me
R1 = CF3; R2 = H
R1 = F ; R2 = Me
R1 = H ; R2 = Me
Me
HN
OH
18