Design, synthesis and biological evaluation of novel chiral oxazino-indoles as potential and selective neuroprotective agents against Aβ25–35-induced neuronal damage

Article abstract of DOI:10.1016/j.bmcl.2016.05.061

A series of chiral oxazino-indoles have been synthesized via a key intermolecular oxa-Pictet–Spengler reaction. These compounds exhibited significant and selective neuroprotective effects against Aβ_25–35-induced neuronal damage. This is the first report of evaluating the influence of chiral diversity of oxazino-indoles on their neuroprotective activities, with the structure–activity relationship been analyzed. The highly active compounds 3f, 3g, 4g, 4h, and 6b all performed over 90% cell protection, providing a new direction for the development of neuroprotective agents against Alzheimer's disease.

Full text of DOI:10.1016/j.bmcl.2016.05.061

Bioorganic & Medicinal Chemistry Letters xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design, synthesis and biological evaluation of novel chiral
oxazino-indoles as potential and selective neuroprotective agents
against Ab25–35-induced neuronal damage
b,
Jing Chen a,y, Ling-Xue Tao b,y, Wei Xiao c,y, Sha-Sha Ji d, Jian-Rong Wang a, Xu-Wen Li a, , Hai-Yan Zhang
⇑
⇑
,
Yue-Wei Guo a,
⇑
a State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zi Road, Zhangjiang Hi-Tech Park, Shanghai 201203,
PR China
b CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, PR China
c Jiangsu Kanion Pharmaceutical Co. Ltd, Lianyungang 222001, PR China
d School of Biological Science and Technology, Weifang Medical University, 7166 Bao Tong West Street, Weifang, Shandong 261053, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of chiral oxazino-indoles have been synthesized via a key intermolecular oxa-Pictet–Spengler
reaction. These compounds exhibited significant and selective neuroprotective effects against Ab25–35
Received 4 March 2016
Revised 9 May 2016
Accepted 21 May 2016
Available online xxxx
-
induced neuronal damage. This is the first report of evaluating the influence of chiral diversity of oxa-
zino-indoles on their neuroprotective activities, with the structure–activity relationship been analyzed.
The highly active compounds 3f, 3g, 4g, 4h, and 6b all performed over 90% cell protection, providing a
new direction for the development of neuroprotective agents against Alzheimer’s disease.
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Oxazino-indoles
Oxa-Pictet–Spengler reaction
Neuroprotective agent
Alzheimer’s disease
SAR
Alzheimer’s disease (AD) is one of the most common dementia
occurring in elderly people. The pathogenesis of AD is still
unknown, while multiple hypotheses1–3 have been proposed based
on a series of evidence. Among them, the amyloid cascade hypoth-
esis2 is the prevailing one, which suggested that the production
and the accumulation of aggregates of b-amyloid peptide (Ab)
may be a key process. According to this hypothesis, Ab was pro-
duced by proteolytic cleavage of the amyloid precursor protein
(APP)4–6, and based on such evidence, various anti-Ab strategies
including lowering the production of the peptide, preventing the
formation of Ab aggregates, and increasing the rate of Ab clearance
from the brain have been pursued.7–10 Although many neuropro-
tective compounds with various structure features have been
reported, the progress of the new and effective drug discovery in
this field is still slow and the novel specific bioactive compounds
investigation are urgently merited.11–15
Indole-containing compounds are pharmacologically attractive
due to their inherently biological activities and physicochemical
properties.16–18 In this superfamily, N-fused indoles19,20, especially
those incorporated with oxazino (Fig. 1), have drawn considerable
attention due to the rigid skeleton and concurrently varied biolog-
ical activities. 3,4-Dihydro-1H-[1,4]oxazino[4,3-a]indoles, a series
representative N-fused bicyclic indoles, was firstly investigated
by Humber and coworkers as the antidepressant reagents.21 Due
to their promising biological activities and pharmaceutical privi-
leged scaffolds, a large number of synthetic methods22,23 have been
developed to construct such skeleton. In 2010, Xiao24 described a
general approach to oxazino[4,3-a]indole skeleton by applying
vinyl sulphonium salts as the reactants. Later on, Gharpure25 firstly
developed stereoselective method for the synthesis of oxazino[4,3-
a]indoles, employing an oxa-Pictet–Spengler reaction.26,27 Inspired
by the previous works and in order to screen the bioactive small
molecules for drug discovery, we envisaged the possibility of
developing
a simple and effective way to synthesize chiral
oxazino[4,3-a]indoles by employing an intermolecular oxa-Pictet–
Spengler reaction. With regard to the stereochemistry-based
activity relationship, we speculated that the chiral methyl group
of the starting material could induce the new chiral center and
⇑
Corresponding authors.
E-mail addresses: xwli@simm.ac.cn (X.-W. Li), hzhang@simm.ac.cn (H.-Y.
Zhang), ywguo@simm.ac.cn (Y.-W. Guo).
y
Authors contributed equally to this work.
http://dx.doi.org/10.1016/j.bmcl.2016.05.061
0960-894X/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Chen, J.; et al. Bioorg. Med. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.bmcl.2016.05.061

2
J. Chen et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
R2
H
N
O
R1
R1
N
Efficient access to
chiral N-fused bicyclic
skeleton
(CH2)3NHCH3
O
N
N
O
OH
N
∗
R2
antidepressant
Me
5-HT4 receptor antagonist
R1
R2
Me
9
R1
10
8
R3
Biological evaluation
for neuroprotective
effect
1 O
2
7
R2
5 N
4
Me
O
6
3
N
O
R3
R4
N
O
H
Oxazino[4,3-a]indole skeleton
with chiral diversity
treatment of atrial arrhythmia
and CNS disorders
antitumor
Scheme 1. Efficient access to neuroprotective chiral oxazino[4,3-a]indoles.
Figure 1. Oxazino incorporated indoles in bioactive molecules.
O
R
R
(S)
R
CHO
(S) O
influence the physicochemical property and biological activity of
the indole derivatives (Scheme 1). Aromatic aldehydes were
applied in the reaction, since the additional aryl group could
N
N
N
N
H
(R) O
BF3•Et2O
CH2Cl2
NaH, DMF
OH
(S)
(S)
(S)
1
2
b
3
4
probably increase the molecular rigidity and have
p–p stacking
to the enzyme, which usually play important role for the biological
activities. In addition, aromatic aldehydes were easier to be intro-
duced than the aliphatic ones for an industrial applicable sake.
Herein, we report the construction of chiral oxazino[4,3-a]indoles
via a simple synthetic access, their neuroprotective bioassays,
and the structure–activity relationship (SAR) study.
R=
a
f
c
d
e
O
A novel synthetic route to prepare 3,4-dihydro-1H-[1,4]oxazino
[4,3-a]indoles was developed. As shown in Scheme 2, 3-methyl-
1H-indole (1) was deprotonated by sodium hydride (NaH) in dry
DMF, followed by a nucleophilic addition to (S)-epoxypropane,
affording (S)-1-(3-methyl-1H-indol-1-yl) propan-2-ol (2), which
then underwent an intermolecular oxa-Pictet–Spengler reaction
to afford the desired compounds 3 and 4 by reacting with various
aldehydes in dichloromethane with the Lewis acid BF3ꢀEt2O as a
catalyst. In fact, the chiral methyl group was designed to direct
the unique configuration of the newly generated chiral center of
the R group in 3 or 4. However, the selectivity was unsatisfactory,
and the two diastereomers were generated with almost the same
ratio. Compared to the excellent diastereoselectivity achieved in
the intramolecular oxa-Pictet–Spengler reaction [25], the poor
selectivity in our reaction are probably attributed to the lack of
an CH2CO2Et group as a stereoselective directing group, of which
the ester might be easier to occupy the pseudo-equatorial orienta-
tion in the transition state than the aromatic groups in our case, in
order to avoid 1,3-diaxial interaction with R4 group (Scheme 1).
Fortunately, the diastereomers 3 and 4 were easy to be purified
via column chromatography, leading to the configuration diversity
of the molecule for further biological evaluation. The configura-
tions of 3e and 4e were further confirmed by X-ray diffraction as
shown in Fig. 228 to be (1R, 3S) and (1S, 3S), respectively, by which
the configurations of their analogs were determined accordingly.
In order to obtain the chiral diversity of our designed products
for bioassay, the syntheses of compounds 6a, 6b, 7a and 7b were
carried out by using the similar approach as that of 3 and 4, while
(R)-epoxypropane as one of the reactants instead of (S)-epoxypro-
pane, to investigate the effect of absolute configuration on the neu-
roprotective activity. Meanwhile, the de-3-methyl indole
derivatives were also prepared by reacting with 2-bromoethanol,
followed by oxa-Pictet–Spengler reaction to obtain compounds
9a and 9b as shown in Scheme 3.
O
O
O
O
j
i
k
g
h
O
O
S
CF3
l
F
m
Cl
n
o
p
Scheme 2. Synthesis of 3,4-dihydro-1H-[1,4]oxazino[4,3-a]indoles comprising
various phenyl rings by a key intermolecular oxa-Pictet–Spengler reaction.
Figure 2. Crystal structure of 3e and 4e.
to methylation reaction in the presence of formaldehyde and
NaBH3CN to produce intermediate 11, which was then converted
to compound 12 by reacting with (S)-epoxypropane in the pres-
ence of NaH in DMF. Finally, the oxazine ring was constructed by
oxa-Pictet–Spengler reaction with the same conditions as pre-
sented above to get the target compounds 13a–13c. All these syn-
thesized products were characterized by extensive spectroscopic
analyses of MS, 1H and 13C NMR.
With all the target compounds in hand, their neuroprotective
properties were assessed aiming at discovering bioactive agents
to prevent Ab25–35-induced neuronal damage in SH-SY5Y neurob-
lastoma cell lines. All the synthesized compounds were tested for
With the aim to improve the water solubility of these com-
pounds and investigate the substitution variety of the indole moi-
ety, commercially available compound 5-methoxytryptamine (10)
was utilized as the starting material to prepare the tryptamine
derivatives as shown in Scheme 4. Compound 10 was subjected
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J. Chen et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
3
O
(Z)
R
(Z)
R
R
CHO
(R)
(S) O
N
(R)
(R) O
N
N
N
H
BF3•Et2O
CH2Cl2
OH
(R)
NaH, DMF
(R)
1
5
7a
6a
, R= phenyl
, R= phenyl
7b, R= 4-flourophenyl
6b, R= 4-flourophenyl
OH
(Z)
R
Br
R
CHO
N
N
N
O
BF3•Et2O
CH2Cl2
OH
NaH, DMF
H
1
8
9a
, R= 4-methoxyphenyl
9b, R= 4-flourophenyl
Scheme 3. Synthesis of (3R)-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indoles and de-methyl indole derivatives.
NH2•HCl
N
O
MeO
MeO
(S)
HCHO
NaBH3CN
MeO
NaH, DMF
N
H
N
H
10
12
11
N
N
MeO
R
CHO
(Z)
(S)
R
13a
, R= phenyl
13b, R= 4-flourophenyl
N
BF3•Et2O
CH2Cl2
N
O
OH
13c, R= 4-methoxyphenyl
(S)
Scheme 4. Synthesis of compounds 13a–13c.
the biological activity at the concentration of 10
l
M and the results
have been introduced on the C-1 position to obtain compounds
3o–p and 4o–p. Unfortunately, no neuroprotective effect has been
observed for the above compounds.
are summarized in Table 1. Interestingly, Compounds 3a and 4a, a
pair of diastereomers differing at C-1 position, displayed the highly
variant biological results. 3a, with (1R)-configuration, was inactive
whereas 4a, with (1S)-configuration, exhibited significant neuro-
protection with cell viability recovered to 87.1% of control as com-
pared with Ab-alone group (62.1%). This surprising result
stimulated our interest for further SAR studies in the following
aspects: (i) The influence of the stereochemistry; (ii) The impor-
tance of the methyl substitution at the 3,10-position; (iii) The
effect of substitution at the benzene ring. Compared to 4a, com-
pounds 3b–e, and 4b–e bearing mono-methyl substitution at
o-, m-, p-position, respectively, or no substitution (for 3e and 4e),
did not perform any protecting activity. Compounds 3f–h and
4f–h with bulkier alkyl substitution at para-position of benzene
ring were synthesized and evaluated. Compounds 3f–h, 4g–h
showed 93.0%, 108.4%, 84.5%, 96.2%, 92.1% cell viability, respec-
tively, similar as that of the positive control epigallocatechin gal-
late (EGCG) (98.6%). This series of compounds presented
significant activity except for compound 4f, which indicated that
the size of the substituent at the para-position might be important
for the biological activity. The different electronic features (elec-
tron-withdrawing or electron-donating) of the benzene ring were
further investigated. Among compounds 3i–k and 4i–k, bearing
electron-donating groups on the benzene ring, only o-methoxysub-
stitution with (S)-configuration at C-1 position (4j) displayed 77.7%
cell viability. Furthermore, compounds 3l–n, 4l–n with electron-
withdrawing groups on the benzene ring were synthesized and
evaluated, while only para-chloro substituted derivative 3n with
the (R)-configuration at C-1 position displayed 74.4% cell viability,
while its diastereoisomer 4n with (S)-configuration was not active.
At last, compounds 3o–p and 4o–p with heteroaromatic ring
instead of benzene ring on C-1 position did not show any neuro-
protective activity. In addition, thiophene and chromone featured
In order to further evaluate the influence of the stereochem-
istry on the neuroprotective activity, compounds 6 and 7 with
(R)-configuration at C-3 position were synthesized (Scheme 3)
by using the same procedure as that of 3 and 4, while with
(R)-epoxypropane as the reagent to introduce the diversity of
the stereochemistry. All the four compounds 6a, 6b, 7a and 7b
were biologically evaluated. In the bioassay, 6a and 7a did not
exhibit neuroprotective activity. Interestingly, compound 6b
displayed remarkable activity with cell viability remained as
90.6% of control, while its diastereoisomer 7b was inactive. It is
worth to note that among all the isomers (3m, 4m, 6b and 7b),
only 6b was active, indicating the impact of absolute configura-
tion was essential on the neuroprotective activity of such
structure. In addition, compounds 9a and 9b, with methyl group
removed at C-3 position, was proved to be inactive. Finally,
5-methoxytryptamine was utilized as the starting material to
design and synthesize compounds 13a–c characterized by an
8-methoxyl substitution and an N,N-dimethylethanamine at
C-10 position, with the aim to improve their neuroprotective
activity and water solubility as a drug candidate. Unfortunately,
all the three compounds were inactive, despite the improving
of the water solubility.
All the target compounds were also subjected to bioassays of
H2O2 induced damage and oxygen glucose deprivation (OGD)
induced injury in SH-SY5Y, with no effect observed, suggesting that
such compounds are selectively neuroprotective against the
Ab25–35-induced neuronal cell damage. We also examined the
effects of the most active compounds 3f, 3g, 6b, 4g and 4h on cell
viability and cell proliferation under Ab-free condition by using
MTT and sulforhodamine B (SRB) assay, respectively. The results
showed that none of the above compounds have the influence on
the cell proliferation.
by their influence on a wide range of pharmacological properties29
,
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4
J. Chen et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
Table 1
The neuroprotective of compounds 3 and 4 against Ab25–35-induced neurotoxicity in SH-SY5Y cells
Compd
R
Cell viabilitya (%)
Compd
R
Cell viability (%)
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
6ac
6bc
3,5-Dimethylphenyl
4-Methylphenyl
3-Methylphenyl
2-Methylphenyl
Phenyl
4-Ethylphenyl
4-Isobutylphenyl
4-tBu-phenyl
3-Methoxyphenyl
2-Methoxyphenyl
3,4,5-trimethoxyphenyl
4-Trifluoromethylphenyl
4-Fluorophenyl
4-Chlorophenyl
2-Thiophene
N.A.b
N.A.
N.A.
N.A.
N.A.
93.0
108.4
84.5
N.A.
N.A.
N.A.
N.A.
N.A.
74.4
N.A.
N.A.
N.A
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
7ac
7bc
EGCG
3,5-Dimethylphenyl
4-Methylphenyl
3-Methylphenyl
2-Methylphenyl
Phenyl
4-Ethylphenyl
4-Isobutylphenyl
4-tBu-phenyl
3-Methoxyphenyl
2-Methoxyphenyl
3,4,5-Trimethoxyphenyl
4-Trifluoromethylphenyl
4-Fluorophenyl
4-Chlorophenyl
2-Thiophene
87.1
N.A.
N.A.
N.A.
N.A.
N.A.
96.2
92.1
N.A.
77.7
N.A.
N.A.
N.A.
N.A.
N.A.
N.A.
N.A.
N.A.
98.6
3-Chromone
Phenyl
4-Fluorophenyl
3-Chromone
Phenyl
4-Fluorophenyl
90.6.
a
The neuroprotective effect of these compounds on Ab25–35-induced neurotoxicity in SH-SY5Y cells. The cell viability in control was taken as 100%, and the average value of
cell viability under Ab25–35 exposure was 62.1 2.2%. The positive control is epigallocatechin gallate (EGCG).
b
N.A. means not active.
With R-configuration at 3-position.
c
The scaffold of N-fused indoles has attracted intensive attention
due to its frequently existence in natural products and pharmaceu-
tical agents. In this study, we effectively constructed bicyclic chiral
oxazino[4,3-a]-indoles by the application of intermolecular oxa-
Pictet–Spengler reaction. More than 40 derivatives have been syn-
thesized and evaluated for their neuroprotective effect against
Ab25–35-induced neuronal cell damage. The results clearly indi-
cated that five compounds, namely 3f, 3g, 4g, 4h, and 6b, exhibited
robust neuroprotective effects against Ab-induced neurotoxicity.
Furthermore, the results of SRB assay indicate that the beneficial
pharmacological profiles of above active compounds are attributed
to their ability on battling Ab-associated neurotoxicity rather than
promoting the cell proliferation. The preliminary SAR analysis sug-
gested that bulky alkyl substitution of the para-position of the ben-
zene ring plays a crucial role in the neuroprotection. In addition,
the influence of stereochemistry on the bioactivity varied by differ-
ent substitutions at the core structure. For instance, among the
compounds with 3,5-dimethyl group (3a and 4a) and 2-methoxyl
group (3j and 4j), those with (1S, 3S)-configuration (4a and 4j)
exhibited strong neuroprotective effect, whereas the ones with
(1R, 3S)-configuration (3a and 3j) were inactive. Similar result
was also observed on the 4-fluorophenyl substituted compounds
(3m, 4m, 6b and 7b), of which only 6b with (1S, 3R)-configuration
showed significant neuroprotective activity. It is worth to mention
that the strong activities of 1,3-trans-isomers 4a and 4j and the
1,3-cis-isomer 6b, suggesting that the trans-configuration com-
bined with the nucleophilic substitution at C-1 for 4a and 4j,
whereas the cis-configuration combined with the electrophilic sub-
stitution at C-1 for 6b, were probably important for the activities.
In conclusion, the above described interesting chemical and bio-
logical results provided a fascinating clue for the discovery of more
potent N-fused indole derivatives with neuroprotective activities.
More-in-depth investigation should be conducted towards the
most bioactive compounds, such as 3f, 3g, 4g, 4h, and 6b, including
chemical modification, molecular action mechanism, and in vivo
biological study.
the Natural Science Foundation of China (Nos. 81520108028,
81273430, 41306130, 41476063, 81522045), NSFC Shangdong
Joint Fund for Marine Science Research Centers (Grant No.
U1406402), SCTSM Project (No. 14431901100 and 15431901000),
the SKLDR/SIMM Projects (SIMM1203ZZ-03 and 1501ZZ-03). T.K.
thanks the Hungarian National Research Foundation (OTKA
K105871) for financial support and the National Information
Infrastructure Development Institute (NIIFI 10038) for computer
time. X.W. Li thanks to the financial support of ‘Youth Innovation
Promotion Association’ (No. 2016258) from Chinese Academy of
Sciences and ‘Young Talent Supporting Project’ from China Associ-
ation for Science and Technology.
References and notes
1. Scarpini, E.; Scheltens, P.; Feldman, H. Lancet. Neurol. 2003, 2, 539.
2. Hardy, J. A.; Higgins, G. A. Science 1992, 256, 184.
3. Hardy, J.; Allsop, D. Trends Pharmacol. Sci. 1991, 12, 383.
4. Selkoe, D. J. Physiol. Rev. 2001, 81, 741.
5. Selkoe, D. J. Trends Cell Biol. 1998, 8, 447.
6. Goate, A.; Chartier-Harlin, M. C.; Mullan, M.; Brown, J.; Crawford, F.; Fidani, L.;
Giuffra, L.; Haynes, A.; Irving, N.; James, L. Nature 1991, 349, 704.
7. Xie, Q.; Wang, H.; Xia, Z.; Lu, M.; Zhang, W.; Wang, X.; Fu, W.; Tang, Y.; Sheng,
W.; Li, W.; Zhou, W.; Zhu, X.; Qiu, Z.; Chen, H. J. Med. Chem. 2008, 51, 2027.
8. Rizzo, S.; Riviere, C.; Piazzi, L.; Bisi, A.; Gobbi, S.; Bartolini, M.; Andrisano, V.;
Morroni, F.; Tarozzi, A.; Monti, J. P.; Rampa, A. J. Med. Chem. 2008, 51, 2883.
9. Ono, K.; Condron, M. M.; Ho, L.; Wang, J.; Zhao, W.; Pasinetti, G. M.; Teplow, D.
B. J. Biol. Chem. 2008, 283, 32176.
10. Rosini, M.; Andrisano, V.; Bartolini, M.; Bolognesi, M. L.; Hrelia, P.; Minarini, A.;
Tarozzi, A.; Melchiorre, C. J. Med. Chem. 2005, 48, 360.
11. Zhang, X.; Wang, J.; Hong, C.; Luo, W.; Wang, C. Acta Pharm. Sin. B. 2015, 5, 67.
12. Abed, D. A.; Goldstein, M.; Albanyan, H.; Jin, H.; Hu, L. Acta Pharm. Sin. B. 2015,
5, 285.
13. Canto, R. F.; Barbosa, F. A.; Nascimento, V.; De Oliveira, A. S.; Brighente, I. M.;
Braga, A. L. Org. Biomol. Chem. 2014, 12, 3470.
14. Williams, P.; Sorribas, A.; Howes, M. J. Nat. Prod. Rep. 2011, 28, 48.
15. Rosini, M.; Simoni, E.; Bartolini, M.; Cavalli, A.; Ceccarini, L.; Pascu, N.;
McClymont, D. W.; Tarozzi, A.; Bolognesi, M. L.; Minarini, A.; Tumiatti, V.;
Andrisano, V.; Mellor, I. R.; Melchiorre, C. J. Med. Chem. 2008, 51, 4381.
16. Melander, R. J.; Minvielle, M. J.; Melander, C. Tetrahedron 2014, 70, 6363.
17. Humphrey, G. R.; Kuethe, J. T. Chem Rev. 2006, 106, 2875.
18. Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873.
19. Osyanin, V. A.; Klimochkin, Y. N. Chem. Heterocycl. Compd. 2009, 45, 833.
20. Fedouloff, M.; Hossner, F.; Voyle, M.; Ranson, J.; Powles, J.; Riley, G.; Sanger, G.
Bioorg. Med. Chem. 2001, 9, 2119.
Acknowledgments
21. Demerson, C. A.; Santroch, G.; Humber, L. G. J. Med. Chem. 1975, 18, 577.
22. Chiarucci, M.; Mocci, R.; Syntrivanis, L. D.; Cera, G.; Mazzanti, A.; Bandini, M.
Angew. Chem., Int. Ed. 2013, 52, 10850.
This research work was financially supported by the National
Marine ‘‘863” Projects (Nos. 2013AA092902 and 2012AA092105),
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J. Chen et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
5
23. Chiarucci, M.; Matteucci, E.; Cera, G.; Fabrizi, G.; Bandini, M. Chem. Asian J.
2013, 8, 1776.
24. An, J.; Chang, N. J.; Song, L. D.; Jin, Y. Q.; Ma, Y.; Chen, J. R.; Xiao, W. J. Chem.
Commun. 2011, 47, 1869.
25. Gharpure, S. J.; Sathiyanarayanan, A. M. Chem. Commun. 2011, 47, 3625.
26. Larghi, E. L.; Kaufman, T. S.; European, J. Org. Chem. 2011, 5195.
27. Larghi, E. L.; Kaufman, T. S. Synthesis-Stuttgart 2006, 187.
28. Detailed crystallographic data of compounds 3e and 4e have been deposited
with the Cambridge Crystallographic Data Center as supplementary
publication CCDC 1446119 and CCDC 1446120, respectively. These data can
be obtained free of charge from the Cambridge Crystallographic Data Centre at
http://www.ccdc.cam.ac.uk/data_request/cif.
29. Dekermendjian, K.; Kahnberg, P.; Witt, M. R.; Sterner, O.; Nielsen, M.; Liljefors,
T. J. Med. Chem. 1999, 42, 4343.
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