Bis-8-hydroxyquinoline and bis-8-hydroxyquinaldine N-substituted amines: A single methyl group structural difference between the two heterocycles, which modulates the antiproliferative effects

Article abstract of DOI:10.1002/jhet.304

(Chemical Equation Presented) The synthesis of a series of bis-8-hydroxyquinoline- and bis-8-hydroxyquinaldine-substituted N-benzyl or thiophenyl amines and their corresponding bis-8-hydroxyquinoline is reported. In vitro growth inhibitory effects of both series have been evaluated. It has been observed that analogs from the bis-8-hydroxyquinoline series exert nanomolar range activity, whereas the antiproliferative activity of the corresponding analogs from the bis-8-hydroxyquinaldine series was found to be drastically lower. Molecular docking and chemical-physical properties account for these observed growth inhibitory differences between the two series of analogs, which differ only by the presence of a methyl group at the 2 position of the heterocyclic ring.

Full text of DOI:10.1002/jhet.304

May 2010
Bis-8-hydroxyquinoline and Bis-8-hydroxyquinaldine
N-Substituted Amines: A Single Methyl Group Structural
Difference between the Two Heterocycles, Which Modulates the
Antiproliferative Effects
719
a
Sebastien Madonna, Aline Marcowycz, Delphine Lamoral-Theys,
b
c
´
Gwendoline Van Goietsenoven,b Jean Dessolin,d Christine Pirker,e
f
Sabine Spiegl-Kreinecker, Cesar-Alain Biraboneye, Walter Berger,
a
e
´
Robert Kiss,b and Jean-Louis Krausa*
a
´
Laboratoire de Chimie Biomoleculaire, CNRS, IBDML-UMR-6216, Campus de Luminy
Case 907, 13288 Marseilles cedex 09, France
b
´
´
Laboratoire de Toxicologie, Toxicologie et Chimie Physique Appliquee, Universite Libre de
Bruxelles, Campus de la Plaine, Boulevard du Triomphe, Bruxelles 1050, Belgique
c
´
´
Laboratoire de Chimie Analytique, Toxicologie et Chimie Physique Appliquee, Universite Libre
de Bruxelles, Campus de la Plaine, Boulevard du Triomphe, Bruxelles 1050, Belgique
d
´
Institut Europeen de Chimie et Biologie (IECB), CNRS UMR 5248 Chimie et Biologie des
Membranes et des Nano-objets (CBMN) 2, rue Robert Escarpit, Pessac Cedex 33607, France
eDepartment of Medicine I, Institute of Cancer Research, Medical University Vienna, Vienna
fDepartment of Neurosurgery, Wagner Jauregg Hospital, Linz, Austria
*E-mail: kraus@univmed.fr
Received July 29, 2009
DOI 10.1002/jhet.304
Published online 6 May 2010 in Wiley InterScience (www.interscience.wiley.com).
The synthesis of a series of bis-8-hydroxyquinoline- and bis-8-hydroxyquinaldine-substituted N-benzyl
or thiophenyl amines and their corresponding bis-8-hydroxyquinoline is reported. In vitro growth inhibi-
tory effects of both series have been evaluated. It has been observed that analogs from the bis-8-hydrox-
yquinoline series exert nanomolar range activity, whereas the antiproliferative activity of the
corresponding analogs from the bis-8-hydroxyquinaldine series was found to be drastically lower. Mo-
lecular docking and chemical–physical properties account for these observed growth inhibitory differen-
ces between the two series of analogs, which differ only by the presence of a methyl group at the 2
position of the heterocyclic ring.
J. Heterocyclic Chem., 47, 719 (2010).
We have reported preliminary results on the antitumor
activity of two analogs JLK1486 and JLK1472, which
belong to the family of bis-8-hydroxyquinoline-substi-
tuted benzylamines [5]. From this work, we discover
that a single methyl subtituent at the position 2 of the
quinoline ring lead to what is called quinaldine series
drastically that diminish the antiproliferative effect of
the resulting compounds. For this purpose, we synthe-
sized a new series of bis-8-hydroxyquinaldine N-substi-
tuted analogs, and we studied their anticancer activities
in comparison with that of the corresponding bis-8-
INTRODUCTION
Hydroxyquinoline is a privileged structural moiety
observed in many biologically active natural products; it
is used as the source for many drugs diversely pre-
scribed among a wide range of pathologies, including
neurodegenerative [1], parasitic amoebic dysentery [2],
and herpes viral diseases [3]. More specifically, 8-
hydroxyquinoline (8-HQ) moiety has been mostly used
for its capacity to strongly chelate metal ions, particu-
larly Cuþþ and Znþþ [4].
C
V
2010 HeteroCorporation

720
S. Madonna, A. Marcowycz, D. Lamoral-Theys, G. Van Goietsenoven, J. Dessolin, C. Pirker,
S. Spiegl-Kreinecker, C.-A. Biraboneye, W. Berger, R. Kiss, and J.-L. Kraus
Vol 47
Scheme 1. Reagents and conditions: (i) HCHO, 37% HCl in H2O, HCl (gas), r.t., overnight, 80%; (ii) corresponding primary amine K2CO3,
CH3CN, r.t., overnight.
hydroxyquinoline N-substituted series. Molecular dock-
ing techniques and physicochemical studies were carried
out to account for the observed differences in antitumor
activity between the two families of 8-HQ and 8-
hydroxyquinaldine (8-HQD) analogs.
activity than bis-8-hydroxyquinaldine derivatives.
Indeed, in contrast to these bis-8-hydroxyquinoline
derivatives for some of which antiproliferative effect
could be observed in two digit nM range, the corre-
sponding bis-8-hydroxyquinaldine analogs (3b, 4b, 5b)
displayed antitumor effects higher than 5 lM, and thus,
revealing themselves 100–1000-fold weaker antiprolifer-
ative compounds when compared with 8-HQ derivatives.
In addition, it must also be highlighted that the large
variations observed in terms of antitumor activity for
various bis-8-hydroxyquinoline derivative series on a
given cancer cell line, say for example the BxPC3 pan-
creas cancer and the VM-47 melanoma cell lines.
CHEMISTRY
Starting from 8-HQ (1a) or 8-HQD (1b), commer-
cially available compounds, the corresponding 5-chloro-
methyl derivatives (2a and 2b) were obtained in good
yields by direct reaction with 37% formaldehyde in
strong acidic conditions [6,7]. The solid compounds
were directly collected by simple filtration and used
without purification. The next step consisted in an addi-
tion on 2a and 2b of an excess of selected N-substituted
primary amines that preferentially led to the formation
of the desired bis-8-hydroxyquinoline or bis-8-hydroxy-
quinaldine benzyl or thiophenyl amines (Scheme 1).
Under these experimental conditions, the desired bis-8-
hydroxyquinoline and quinaldine derivatives (3a, 3b, 4a,
4b, 5a, 5b) were obtained with moderate yields (40–
50%), whereas mono-8-hydroxyquinoline or mono-8-
hydroxyquinaldine by-products were only present as
traces. The desired compounds were purified by column
chromatography and fully identified by conventional
spectral and centesimal analysis.
These data prompted us to envisage preliminary struc-
ture–activity relationship analysis. Compounds (2a) and
(2b), which are mono-8-hydroxyquinoline analogs and
which include a chloromethyl moiety at the position 4
of the 8-HQ or 8-HQD nucleus, are found totally inac-
tive in comparison with the N-substituted benzyl or thio-
phenylamine derivatives, a feature that reveals that the
presence of a N-substituted amine moiety is essential for
anticancer activity and also confirm that bis-8-hydroxy-
quinoline analogs are more potent antiproliferative com-
pounds than the corresponding mono-8-hydroxyquino-
line analog [5]. These observations led us, therefore, to
try to understand why bis-8-hydroxyquinoline and bis-8-
hydroxyquinaldine derivatives display such marked dif-
ferences in terms of antiproliferative effect. Such obser-
vation that bis-8-hydroxyquinoline analogs are more
potent bioactive molecules than their corresponding
mono-8-hyroxy analog has been reported in the case of
neurodegenerative diseases [12]. We have, thus, consid-
ered the possible electronic effects induced by the elec-
tron pair of the amine group in the 8-HQ or quinaldine
system in terms of chemical reactivity, and the possible
physical–chemical properties differences between the
two scaffolds mainly in terms of nucleophilicity,
RESULTS AND DISCUSSION
Compounds from the bis-8-hydroxyquinoline and bis-
8-hydroxyquinaldine series were evaluated for their anti-
proliferative effect on a panel of 15 cancer cell lines [8–
11].
The data in Table 1 clearly show that bis-8-hydroxy-
quinoline derivatives display higher in vitro antitumor
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2010
Bis-8-hydroxyquinoline and Bis-8-hydroxyquinaldine N-Substituted Amines
Antiproliferative Effects
721
Table 1
Determination of the IC50 (nM) in vitro growth inhibitory in 5 carcinoma, 5 glioma, and 5 melanoma.
Carcinoma
Nꢀ A549 BxPC3 LoVo MCF7 PC3
Glioma
Melanoma
HS683 T98G U373 U138 GL19 VM-21 VM-48 VM-47 SKMEL-28 B16F10
3a
4a
5a
8
9
4299
79
10
10
34
38
35
nd
nd
66
71
44
10
181
35
99
72
88
44
96
49
46
44
1241
2143
3451
81
47
79
nd
nd
nd
1584
98
97
146
1726
nd
>10 lM
>10 lM
4826
nd
92
76
86
nd
nd
nd
27
89
nd
40
5565
7954
85
7209
8695
1757
nd
3b >10 lM
4b 9713
5b >10 lM
9605 >10 lM nd
8787 >10 lM nd
nd >10 lM
nd >10 lM
nd
nd
nd
nd
nd
nd
nd
nd
>10 lM nd >10 lM >10 lM nd >10 lM nd >10 lM
Compound in vitro antiproliferative effect has been performed in 5 carcinoma, 5 glioma, and 5 melanoma cell lines. The cancer cells have been
cultured in the presence of the drugs for 3 days. The IC50 values were determined by means of the MTT colorimetric assay as detailed previously
[6,8]. The values reported in this table are means obtained on six distinct values. The standard errors are not reported for the sake of clarity,
because they are <5% as compared with the mean values.
IC50 are expressed in nM unless in lM when specified in the table.
Cell lines: A549, human alveolar epithelial; BxPC3, pancreatic cancer; LoVo, colon cancer; MCF7, breast cancer; PC3, humanprozstate cancer;
HS683, human glioma; T98G, human glioblastoma; U373, human glioblastoma-astrocytoma epithelial; U318, human glioma; GL19, glioblastoma
multiform; VM-21 and VM-47 are mutant melanoma; SKMEL-28 and B16F10 are human melanoma.
nd: not determined.
basicity, and hydrophobicity. There is a conceptual rela-
tionship between nucleophilicity and basicity. Both
properties are involved in the formation of a new bond
by donation of an electron pair to an electrophilic spe-
cies. Basicity in the Brønsted sense involves formation
of a bond to hydrogen, while generally nucleophilicity
refers to the effect of a Lewis base on the rate of nucle-
ophilic substitution reaction. The relative nucleophilic-
ities may differ from reaction to reaction, and several
parameters have significant influence on nucleophilic-
ities. From literature reports [13], it can be seen that the
presence of a methyl group in 8-HQD makes the nitro-
gen donor more basic in comparison with 8-HQ (Fig.
1).
consequently, the observed anticancer activities. The
calculated clogP values determined for analogs 3a
(quinoline series) and 3b (quinaldine series) were,
respectively, 6.16 and 7.64 (calculated from ACD Labs/
LogP dB 3.5 and ChemSketch 3.5). As expected, 8-
HQD derivatives were slightly more hydrophobic than
their corresponding analogs from the bis-8-hydroxyqui-
noline series, but these rather small differences in hydro-
phobicity cannot account alone for the observed drastic
differences in antiproliferative effect.
As steric effects of substituted quinolines on lithium
coordination geometry have been reported [14], we next
examined the possible influence of steric hindrance
induced by the methyl group at position 2 of the quino-
line heterocycle. For this purpose, compounds 3a and
3b were selected as representative compounds for mini-
mal energy conformational search. Minimal energy con-
formations for both analogs were generated and super-
imposed after a Monte Carlo Conformational Search
(Macromodel version 6.5 was used for molecular
mechanics calculations) [15].
Considering the possible biological mode of action of
the compounds under study in which the proton of the
hydroxyl group in the ground state could be involved in
their antitumor mechanism(s) of action, the observed
differences in pKa values (Fig. 1) could account for the
observed differences in antiproliferative effects. Differ-
ences in the pKA values between the two systems could
induce variations in the electronic driving force from
the exocyclic nitrogen lone pair electron to the hydroxy
group through the aromatic ring. Electronic effects
induced by the presence of the methyl substituent at the
2 position of the quinoline ring influence the acidity of
the OH proton and consequently, the conjugation
between the nitrogen atom lone pair electron from the
benzylamine moiety and the phenol group through the
aromatic system.
After calculations, both lowest energy conformations
for 3a (132.8 kcal/mol) and 3b (134.5 kcal/mol) were
Next, we considered the differences in terms of
hydrophobicity between the two scaffolds as a possible
parameter which could influence cell permeation and
Figure 1. pKa values: 8-hydroxyquinoline [pKA1 ¼ 5.13 (NH4þ/NH2),
pKA2
¼
9.89 (OH/Oꢁ)] and 8-hydroxyquinaldine [pKA1
¼
5.67
(NH4þ/NH2), pKA2 ¼ 9.97 (OH/Oꢁ)].
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

722
S. Madonna, A. Marcowycz, D. Lamoral-Theys, G. Van Goietsenoven, J. Dessolin, C. Pirker,
S. Spiegl-Kreinecker, C.-A. Biraboneye, W. Berger, R. Kiss, and J.-L. Kraus
Vol 47
in the 2-methyl group only. The steric effect of a methyl
group at the 2 position of the heterocycle and the differ-
ence in clogP values appeared to be too weak to
account for the observed drastic antiproliferative differ-
ences between both series of analogs. Investigations on
the mechanism of action and on the possible biological
targets of those are underway.
EXPERIMENTAL
Compounds 2a and 3a have been already reported [5]. Start-
ing quinaldin-8-ol intermediate 2b has been synthesized as
follows:
5-(Chloromethyl)-2-methylquinolin-8-ol hydrochloride
(2b). A mixture of 7.3 g (0.045 mol) of quinaldin-8-ol
(Aldrich), 8 mL of concentrated hydrochloric acid, and 8 mL
(0.05 mol) of 37% formaldehyde was treated with hydrogen
chloride gas for 90 min. The yellow solid was collected on a
filter and dried to give 8.5 g of compound (70% yield) mp
Figure 2. Superimposition of compounds 3a (green) and 3b (yel-
low)—best conformations obtained through a Monte Carlo conforma-
tional search. [Color figure can be viewed in the online issue, which is
available at www.interscience.wiley.com.]
1
280ꢀC NMR (250 MHz, DMSO): 9.14 (d, 1H, J ¼ 8.75 Hz),
8.05 (d, 1H, J ¼ 8.75 Hz), 7.83 (d, 1H, J ¼ 8 Hz), 7.56 (d,
1H, J ¼ 8 Hz), 5.233 (s, 2H), 2.5 (s, 3H). Anal. Calcd. for
C11H11NOCl2: C, 54.09; H, 4.51; N, 5.73. Found: C, 54.19; H,
4.45; N, 5.81.
identical. They exhibit an energetic difference inferior
to 2 kcal/mol between the two analogs, which could not
account for the drastic drop in biological activity of the
methylated compounds. Further, superimposition of the
successively obtained conformations within a 3 kcal/mol
span (from the lowest representative conformation)
between these analogs revealed no differences between
both analogs, which displayed similar poses with a simi-
lar energy difference in favor of the quinoline scaffold
(Fig. 2).
General procedure for the reaction of 5-chloromethyl 8-
hydroxyquinaldine (2a) and (2b) with primary amines for
the synthesis of analogs 4a, 5a, 3b, 4b, and 5b. All of these
reactions were carried out under a nitrogen atmosphere. To a
solution of 5-chloromethyl quinolin-8-ol dihydrochloride (2a)
or 5-chloromethylquinaldin-8-ol dihydrochloride (2b) (1.3
mmol) at 50ꢀC in ethyl acetate (10 mL) was added appropriate
primary amines (3.91 mmol). Stirring is maintained overnight.
Then, the solution is cooled down to 0ꢀC and filtrated; the fil-
ter cake is washed with cold ethyl acetate (5 mL). The filtrate
is concentrated in vaccuo, diluted in diethyl ether (5 mL), and
centrifuged. The ethereal phase is removed, and the obtained
solid is washed two more time by centrifugation with diethyl
ether at 0ꢀC to give the desired products.
From these results, steric effects induced by the pres-
ence of a methyl group at the position 2 appear to be
too weak to entirely abolish the anticancer activity of all
the 8-HQD analogs irrespective of the cancer cell lines
(carcinoma, glioma, or melanoma) used in the assay.
5,50-(4-(Trifluoromethyl)benzylazanediyl)bis(methylene)bis
(2-methylquinolin-8-ol) (3b). This compound was obtained as
colorless solid. (42%), mp ¼ 205ꢀC 1NMR (250 MHz,
CDCl3): 7.64 (d, 2H, J ¼ 7.75 Hz), 7.41–7.39 (m, 2H), 7.22–
7.06 (m, 4H), 6.95–6.8 (m, 4H), 3.61 (s, 4H), 3.44 (s, 2H),
2.61 (s, 6H). MS, m/z (C30H26F3N3O2): calcd. 518, [M þ H]þ;
found 518. Anal. Calcd. for C30H26F3N3O2: C, 69.50; H, 5.02;
CONCLUSIONS
In conclusion, a series of bis-8-hydroxyquinolines N-
benzyl or thiophenyl amines and their corresponding
bis-8-hydroxyquinaldine derivatives have been prepared.
We found that compounds that belong to the bis-8-
hydroxyquinoline series have an in vitro potent antipro-
liferative effect on a large panel of cancer cell lines at
lower nanomolar IC50 values, while their corresponding
8-HQD counterparts display only weak (in the lM
range), if any, antiproliferative effect. Molecular dock-
ing studies and physico-chemical properties suggest that
the presence of a methyl group in position 2 vicinal to
the endocyclic nitrogen atom induces electronic factors
(pKa values) that greatly influence the driving electronic
force all along the aromatic system, including the exo-
cyclic nitrogen. In contrast, Monte Carlo studies reveal
only a small energy difference with less than 2 kcal/mol
having been observed between the two series differing
N, 8.11. Found: C, 69.37; H, 5.04; N, 8.14.
00
´
5,5 -(3,5-Bis(trifluoromethyl)benzylazanediyl)bis(methylene)
diquinoline-8ol (4a). This compound was obtained as a yellow
1
solid. (50%), mp ¼ 193ꢀC NMR (250 MHz, CDCl3): 9.8 (m,
2H), 6.7–8.05 (m, 13H aromatic) 3.6–3.8 (m 6H, CH2). MS,
m/z (C29H21F6N3O2): calcd. MW 558; found 558. Anal. Calcd.
for C29H21F6N3O2: C, 62.48; H, 3.80; N, 7.54. Found: C,
62.10; H, 3.89; N, 7.33.
0
´
5,5 -(3,5-Bis(trifluoromethyl)benzylazanediyl)bis(methylene)
diquinaldine-8-ol (4b). This compound was obtained as brown
solid. (38%), mp ¼ 207ꢀC H1NMR (250 MHz, CDCl3): 8.76–
8.74 (m, 2H), 7.96–7.92 (m, 2H), 7.64 (s, 1H), 7.43–7.38 (m,
4H), 724, (m, 5H) 7.19–7.13 (m, 4H), 7.08–7.05 (m, 2H), 3.89
(br s, 4H), 3.61 (s, 2H). 2,8 (3H). MS, m/z (C31H25F6N3O2):
calcd. 586, [M
þ
H]þ; found 587. Anal. Calcd. for
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2010
Bis-8-hydroxyquinoline and Bis-8-hydroxyquinaldine N-Substituted Amines
Antiproliferative Effects
723
R. A.; Huang, A.; Vaillancourt, V. A.; Clayton, T. L.; Tucker, J. A.;
Wathen, M. W. Antimicrob Agents Chemother 2002, 46, 724.
[4] Ji, H. F.; Zhang, H. Y. Bioorg Med Chem Lett 2005, 15,
21.
C31H25F6N3O2: C, 63.59; H, 4.30; N, 7.18. Found: C, 64.12;
H, 4.26; N, 7.11.
5,50-(Thiophen-2-ylmethylazanediyl)bis(methylene)diquinolin-
8-ol (5a). This compound was obtained as a brown solid.
(48%), mp ¼ 167 (decomp) 1NMR (250 MHz, MeOD): 8.79
(m, 2H), 8.13 (m, 2H), 7.43 (m, 3H), 7.23 (m, 2H), 7.01 (m,
4H), 3.86 (br s, 4H), 3.76 (s, 2H). MS, m/z (C25H21N3O2S):
calcd. 428.1, [M þ H]þ; found 428.1. Anal. Calcd. for
C25H21N3O2S: C, 72.24; H, 9.83; N, 4.95. Found: C, 71.98; H,
9.86; N, 4.93.
[5] Moret, V.; Laras, Y.; Cresteil, T.; Aubert, G.; Ping, D. Q.;
Di, C.; Barthelemy-Requin, M.; Beclin, C.; Peyrot, V.; Allegro, D.;
Rolland, A.; De Angelis, F.; Gatti, E.; Pierre, P.; Pasquini, L.; Pet-
rucci, E.; Testa, U.; Kraus, J. L. Eur J Med Chem 2009, 44, 558.
[6] Burckhalter, J. H.; Leib, R. J Org Chem 1961, 26, 4078.
[7] Zhao, K.-Q.; Hu, P.; Zhou, Y.-Q.; Xu, H.-B. Molecules
2001, 6, M208.
5,50-(Thiophen-2-ylmethylazanediyl)bis(methylene)diquinal-
dine-8-ol (5b). This compound was obtained as a gray solid.
(36%), mp ¼ 205ꢀC (decomp) 1NMR (250 MHz, MeOD):
9.83 (m, 2H), 6.8–8.05 (m, 8H), 6.74–7.06 (m, 3H thiophenyl
ring), 3.5–3.6 (m 6H), 2.55 (s, 6H). MS, m/z (C27H25N3O2S):
calcd. 455, [MþH]þ; found 55. Anal. Calcd. for
C27H25N3O2S: C, 71.21; H, 5.50; N, 9.23. Found: C, 71.35; H,
5.38; N, 9.19.
[8] Van Quaquebeke, E.; Mahieu, T.; Dumont, P.; Dewelle, J.;
Ribaucour, F.; Simon, G.; Sauvage, S.; Gaussin, J. F.; Tuti, J.; El
Yazidi, M.; Van Vynckt, F.; Mijatovic, T.; Lefranc, F.; Darro, F.;
Kiss, R. J Med Chem 2007, 50, 4122.
[9] Ingrassia, L.; Nshimyumukiza, P.; Dewelle, J.; Lefranc, F.;
Wlodarczak, L.; Thomas, S.; Dielie, G.; Chiron, C.; Zedde, C.; Tisnes,
P.; van Soest, R.; Braekman, J. C.; Darro, F.; Kiss, R. J Med Chem
2006, 49, 1800.
´
[10] Lefranc, F.; Sauvage, S.; Van Goietsenoven, G.; Megalizzi,
V.; Lamoral-Theys, D.; Debeir, O.; Spiegl-Kreinecker, S.; Berger, W.;
Mathieu, V.; Decaestecker, C.; Kiss, R. Mol Cancer Ther 2009, 8,
1739.
Acknowledgments. IBDML-CNRS (Institut de Biologie du
ˆ
Developpement de Marseille Luminy, France) and canceropole
PACA are greatly acknowledged for financial support.
[11] Mathieu, V.; Pirker, C.; Martin de Lassalle, E.; Vernier, M.;
Mijatovic, T.; DeNeve, N.; Gaussin, J. F.; Dehoux, M.; Lefranc, F.;
Berger, W.; Kiss, R. J Cell Mol Med, to appear.
REFERENCES AND NOTES
[12] Deraeve, C.;.Boldron, C.;.Maraval, A.; Mazarguil, H.; Gor-
nitzka, H.; Vendier, L.; Pitie, M.; Meunier, B. Chem A Eur J 2008,
14, 682.
[1] Adlard, P. A.; Cherny, R. A.; Finkelstein, D. I.; Gautier, E.;
Robb, E.; Cortes, M.; Volitakis, I.; Liu, X.; Smith, J. P.; Perez, K.;
Laughton, K.; Li, Q. X.; Charman, S. A.; Nicolazzo, J. A.; Wilkins, S.;
Deleva, K.; Lynch, T.; Kok, G.; Ritchie, C. W.; Tanzi, R. E.; Cappai,
R.; Masters, C. L.; Barnham, K. J.; Bush, A. I. Neuron 2008, 59, 43.
[2] Thompson, P. E.; Reinertson, J. W. Am J Trop Med Hyg
1951, 31, 707.
[13] Garribba, E.; Micera, G.; Sanna, D.; Lodyga-Chruscinska,
E. Inorg Chim Acta 2003, 348, 97.
[14] Rajeswaran, M.; Begley, W.; Olson, L. P.; Huo, S. Polyhe-
dron 2007, 26, 3653.
[15] Saunders, M.; Houk, K. N.; Wu, Y. D.; Still, W. C.; Lipton,
M.; Chang, G.; Guida, W. C. J Am Chem Soc 1990, 112, 1419.
[3] Oien, N. L.; Brideau, R. J.; Hopkins, T. A.; Wieber, J. L.;
Knechtel, M. L.; Shelly, J. A.; Anstadt, R. A.; Wells, P. A.; Poorman,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet