Diastereoselective synthesis of 3,3-disubstituted 3-nitro-4-chromanone derivatives as potential antitumor agents

Article abstract of DOI:10.1039/c8ob02761g

We report an efficient and highly diastereoselective protocol for the rapid construction of 3-nitro substituted 4-chromanones by an intramolecular Michael-type cyclization of α-nitro aryl ketones bearing unsaturated ester units. A catalytic amount of KOtB

Full text of DOI:10.1039/c8ob02761g

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Diastereoselective synthesis of 3,3-disubstituted
3-nitro-4-chromanone derivatives as potential
antitumor agents†
Cite this: Org. Biomol. Chem., 2019,
17, 1062
Received 6th November 2018,
Accepted 26th December 2018
Huiqing Chen,‡a Jia Xie,‡b Dong Xing, ‡a Jinping Wang,a Jie Tang,a Zhengfang Yi,b
a
Fei Xia, a Wen-Wei Qiu*a and Fan Yang
*
DOI: 10.1039/c8ob02761g
rsc.li/obc
We report an efficient and highly diastereoselective protocol for nones. However, among a large number of methods for the
the rapid construction of 3-nitro substituted 4-chromanones by an construction of 4-chromanone skeletons,3 such as intra-
intramolecular Michael-type cyclization of α-nitro aryl ketones molecular Stetter reaction,4 intramolecular conjugated
bearing unsaturated ester units. A catalytic amount of KOtBu was addition,5 Mitsunobu reaction,6 tandem cyclization7 and many
found to be crucial for the high diastereoselective control of this others,8 methods for the synthesis of 3-nitro-substituted
transformation. With this protocol, a series of 3,3-disubstituted 4-chromanones have not been extensively investigated.9–11 The
3-nitro-4-chromanones were synthesized in good to excellent known methods to introduce the 3-nitro substituent include
yields with high diastereoselectivities and showed moderate to the direction nitration of unsubstituted 4-chromanones, which
good in vitro antitumor activities, representing promising antitu- generally requires harsh reaction conditions and shows a
mor hits for further drug discovery.
narrow substrate scope,9 and intramolecular conjugated
addition of phenol to nitro-substituted enones, in which the
starting material is hard to prepare and the substrate scope is
also narrow.10 Towards these ends, the development of an
efficient method for the preparation of new types of 3-nitro-
substituted 4-chromanones is highly sought after and will
greatly benefit the discovery of new 4-chromanone-based bio-
logically active lead compounds.
By a simple retrosynthetic analysis, we envisioned that an
intramolecular Michael-type cyclization of compound B from
its α-nitro substituted ketone unit to the α,β-unsaturated ester
group would allow an efficient way to construct 3-nitro substi-
4-Chromanones constitute the framework of a large number of
natural products and biologically active molecules, which have
attracted significant attention due to their broad biological
effects such as antibiotic,1a anti-inflammatory,1b anti-HIV,1c
anti-mutagenesis1d and especially antitumor activities (Fig. 1,
A, B and C).1e–g Among a number of pharmacological studies
with 4-chromanone based compounds, Bauvois and coworkers
reported that derivatives of 3-nitro-4-chromanones (Fig. 1, D)
dose-dependently inhibited human AML U937 cells,2a and
Arimondo and coworkers also discovered that a similar struc-
tural motif (Fig. 1, E) exhibited potent antiproliferative activity
against L 1210 murine leukemia cells and human colon cancer
HT29 cells.2b In these studies, it was found that the 3-nitro
substituent on the 4-chromanone skeleton is crucial for their
antitumor activities. Inspired by these interesting discoveries
and related studies,2 we perform the synthesis and pharmaco-
logical evaluation of new types of 3-nitro-substituted 4-chroma-
aShanghai Engineering Research Center of Molecular Therapeutics and New Drug
Development, School of Chemistry and Molecular Engineering,
East China Normal University, Shanghai, 200062, China.
E-mail: wwqiu@chem.ecnu.edu.cn, fyang@chem.ecnu.edu.cn
bShanghai key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and
School of Life Sciences, East China Normal University, Shanghai, 200241, China
†Electronic supplementary information (ESI) available: Information regarding
materials and methods, characterization data of compounds from this study.
CCDC 1873098. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c8ob02761g
Fig. 1 Representative structures of antitumor 4-chromanones and
‡These authors contributed equally to this work.
3-nitro-4-chromanones.
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Table 1 Optimization of conditionsa
tuted 4-chromanones with
a
quaternary stereocenter
(Scheme 1). Substrate
B can be easily prepared from
2-hydroxyl-benzaldehyde, nitroalkane and alkynyl esters.
Although this method seems easy to realize and quite straight-
forward, however, as the methylene group of the α-nitro ketone
unit is very reactive, the desired Michael-type cyclization may
proceed very fast, making the diastereoselectivity control a
difficult task. Nonetheless, the rich chemistry on metal and/or
organo-catalyzed transformations based on α-nitro carbonyl
compounds would allow us to realize a good diastereoselective
control of this transformation by choosing
catalyst.12
a suitable
Catalyst
Entry (10 mol%) Solvent
Temperature Yield of
(°C)
Initially, the designed substrate 1a was synthesized from
α-hydroxy-benzaldehyde, ethyl propiolate and nitroethane via a
three-step sequence with a good yield.13 With this substrate in
hand, different conditions for the designed Michael-type cycli-
zation were tested. While 1a did not undergo the desired cycli-
zation in the absence of a base catalyst (Table 1, entry 1), the
reaction occurred smoothly in the presence of organic base
catalysts such as Et3N, pyridine, DMAP and DBU, providing the
desired cyclization product 2a in high yields but with low
diastereoselectivity (Table 1, entries 2–5). Different inorganic
bases could catalyse this transformation with high efficiency
and greatly improved diastereoselectivity, and the highest dr
was observed when KOtBu was used (Table 1, entries 6–12). By
choosing KOtBu as the catalyst, different solvents were tested
(Table 1, entries 13–20). While nonpolar solvents such as
toluene, 1,4-dioxane, and Et2O gave similar dr to that of
CH2Cl2 and protic solvents such as MeOH gave very poor dr,
the use of THF as the solvent gave a further improved dr
(Table 1, entry 16). The reaction was then conducted under
different temperatures (Table 1, entries 21–24). It was found
that lowering the temperature was beneficial for the diastereo-
selectivity, and the highest dr was observed when this reaction
was conducted at −40 °C while the yield still remained excel-
lent (Table 1, entry 24). Finally, while the efficiency of this
reaction remained unaffected by the amount of the catalyst,
the use of 10 mol% of KOtBu was most optimal for the dr.14
With the optimized reaction conditions in hand, the sub-
strate scope was then investigated (Table 2). For most α-nitro
2a b (%) drc
1
2
3
4
5
6
7
8
—
Et3N
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
1,4-Dioxane
Et2O
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
−10
−20
−30
−40
<5
89
80
89
91
92
92
93
94
94
93
93
70
>95
84
>95
83
75
75
72
91
91
93
>95
—
1 : 1
Pyridine
DMAP
DBU
Cs2CO3
K2CO3
KOH
2.2 : 1
1.2 : 1
2.1 : 1
8.3 : 1
8.7 : 1
8.6 : 1
9.0 : 1
7.4 : 1
7.7 : 1
6 : 1
9.4 : 1
9.7 : 1
10.5 : 1
12.3 : 1
11.3 : 1
9.4 : 1
10.8 : 1
1.9 : 1
14 : 1
9
KOtBu
NaOtBu
NaOEt
NaOMe
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
THF
EtOAc
Acetone
DMSO
MeOH
THF
THF
THF
14.5 : 1
16.2 : 1
20 : 1
THF
a Reaction conditions: 1a (1 mmol), catalyst (10 mol%), solvent (5 mL).
NMM: N-methylmorpholine; DMP: Dess–Martin periodinane; DMAP:
4-dimethylaminopyridine; DBU: 1,8-diazabicyclo[5,4,0]undec-7-ene.
b Isolated yield after column chromatography; “<5%” means that the
corresponding product was not observed by 1H NMR analysis of the
crude mixture. c Determined by 1H NMR of the crude mixture.
acetophenones, regardless of their substitution pattern and 8-MeO substituted products (Table 2, entries 1–10). α-Nitro
the electronic property on the aryl group, the cyclization pro- propiophenone derived from nitropropane also underwent the
ceeded smoothly to provide the corresponding 3-nitro-4-chro- desired cyclization with excellent yield and good dr (Table 2,
manones in good yields. However, decreased diastereo- entry 11). Substrates bearing different ester groups including
selectivities were generally observed for substrates bearing sub- n-butyl, phenyl, cyclohexanyl and adamantyl esters were all
stituents on the aryl ring except for those yielding 6-MeO and suitable substrates, yielding the corresponding 4-chromanones
in high to excellent yields with moderate to high dr (Table 2,
entries 12–16). Surprisingly, the relatively bulky adamantyl
ester group gave the corresponding cyclization product with a
much lower dr (Table 2, entry 16). Finally, the relative configur-
ation of the product was determined as (2R*,3R*) by the X-ray
crystallographic analysis of 2f (Fig. 2).15
A possible pathway for this transformation was proposed as
shown in Scheme 2. First, substrate 1a was deprotonated into
its enolate form A, which underwent an intramolecular
Scheme 1 Design of an intramolecular Michael addition strategy for the
construction of 3,3-disubstituted-3-nitro-4-chromanone derivatives.
Michael-type addition to generate a cyclized intermediate fol-
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Table 2 Substrate scopea
gen bonding between the nitro oxygens and the olefinic
protons. In the absence of KOtBu or with weaker bases, the for-
mation of enolate B was incomplete, and both Si and Re-face
attacks from enolate A might happen and lead to low dr of the
cyclized product. The poor dr observed for the substrate
bearing an adamantyl ester group might be caused by the
much bulkier adamantyl that led to a weaker π–π interaction
between the nitro and ester group.
To demonstrate the synthetic potential of this transform-
ation, we explored a gram-scale reaction. This transformation
could be easily scaled up, making it very attractive and con-
venient for further structure modifications. As shown in
eqn (1), the use of 3 g of 1a produced 2.86 g of 2a in 95% yield
while the diastereoselectivity remained excellent. On the other
hand, the 3-nitro-4-chromanone product 2a can be easily
reduced to 3-amino-4-chromanone 3 in a good yield by using
Fe/NH4Cl as the reductants (eqn (2)).17
Entry
2
R1
R2
R3
Yieldb (%)
drc
20 : 1
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Me
Me
Me
Me
Me
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Me
n-Bu
Ph
Cy
Ad
95
92
92
92
92
93
94
93
95
94
92
92
92
92
86
77
6-Me
6-CF3
6-F
6-Cl
6-Br
5-MeO
6-MeO
7-MeO
8-MeO
H
H
H
H
H
13 : 1
10 : 1
10 : 1
11 : 1
11 : 1
13 : 1
17 : 1
13 : 1
>20 : 1
14 : 1
20 : 1
12 : 1
18 : 1
16 : 1
9 : 1
9
10
11
12
13
14
15
16
H
ð1Þ
ð2Þ
a Reaction conditions: 1 (1 mmol), KOtBu (10 mol%), THF (5 mL).
b Isolated yield after column chromatography. c Determined by 1H
NMR of the crude mixture.
The newly synthesized 3-nitro-4-chromanones 2a–p and 3
were evaluated against the growth of various tumor cell lines,
and it was found that they are more sensitive on prostate
cancer DU145 and PC3 cells using the SRB (sulforhodamine B)
assay (Table 3). Cisplatin was used as the positive control. The
results showed that only a part of these compounds possessed
moderate to potent antiproliferative activity. The adamantyl
ester modified 2p showed the most potent antiproliferative
activity with IC50 values of 2.54 and 10.60 μM on DU145 and
PC3 cell lines, respectively, which was slightly more potent
than cisplatin. One of the major hindrances for the druggabil-
Fig. 2 X-ray crystal structure of compound 2f. The thermal ellipsoids
are drawn at 30% probability.
Table 3 IC50 values of 3-nitro-4-chromanones against the growth of
prostate cancer cell lines
IC50 a (μM)
Scheme 2 Proposed
mechanism
and
explanation
of
the
stereochemistry.
Entry
Compound no.
DU145
PC3
HAF
1
2
3
5
13
15
16
18
Xb
2b
2c
2e
2m
2o
2p
Cisplatin
>50
>50
>50
22.14
>50
>50
32.93
10.60
11.04
>200
>200
>200
>200
>200
>200
160.90
41.13
45.50
22.89
39.26
21.08
20.91
2.54
lowed by proton transformation to give 4-chromanone 2a.
While the exact reason for the high dr of this reaction is
unclear, it was possible that a catalytic amount of KOtBu
under lower temperature may accelerate the kinetically favored
formation of enolate B,16 and the favored conformation of the
product may come from a Si-face attack owing to a π–π inter-
action between the nitro and ester carbonyl group and hydro-
3.13
From the SRB assay after 96 h of treatment. a IC50 data are an average
of at least 3 independent experiments, variation 10%. b X = com-
pounds 2a, 2d, 2f–2l, 2n and 3.
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ity of candidate compounds is their toxicity to normal cells.
Thus, it is important to test the cytotoxicity on normal cells in
antitumor drug discovery. Compounds 2a–p and 3 were
chosen for the selectivity test on a normal human fibroblast
(HAF) cell line using the SRB assay. The selectivity indexes (SI)
were calculated by dividing the IC50 values in HAF by the IC50
values in the prostate cancer cell lines. The results disclosed
that these 3-nitro-4-chromanones were less toxic on human
fibroblasts in comparison with the tumor cells. The most
active compound 2p (SI = 15.2 and 63.3) showed 15.2 and 63.3
times higher selectivity towards cancer cells than towards
human fibroblasts, which were more than 4-fold better than
those of cisplatin (SI = 3.7 and 13.1).
In summary, an efficient and highly diastereoselective
KOtBu-catalyzed intramolecular Michael-type cyclization of
α-nitro aryl ketones bearing unsaturated ester units was
reported. With this method, a series of 3,3-disubstituted
3-nitro 4-chromanones bearing a tertiary stereocenter were
synthesized in high to excellent yields with good to high
diastereoselectivities. KOtBu plays a crucial role both in accel-
erating the reaction rate and in improving the diastereo-
selectivities of this transformation. Some of the newly syn-
thesized 3-nitro-4-chromanones displayed promising in vitro
antiproliferative activity and good selectivity indexes (SI)
between normal cells and cancer cells, and could be used as
promising antitumor hits for further development. Further
studies on structure modification and biological evaluation are
currently ongoing.
2013, 23, 4102; (g) H. I. C. Lowe, N. J. Toyang, C. T. Watson,
K. N. Ayeah and J. Bryant, Cancer Cell Int., 2017, 17,
38.
2 (a) S. Bouchet, M. Piedfer, S. Susin, D. Dauzonne and
B. Bauvois, AIMS Mol. Sci., 2016, 3, 368; (b) A. Ceccaldi,
A. Rajavelu, C. Champion, C. Rampon, R. Jurkowska,
G. Jankevicius, C. Sénamaud-Beaufort, L. Ponger, N. Gagey,
H. D. Ali, J. Tost, S. Vriz, S. Ros, D. Dauzonne, A. Jeltsch,
D. Guianvarc’h and P. B. Arimondo, ChemBioChem, 2011,
12, 1337; (c) D. Dauzonne, B. Folléas, L. Martinez and
G. G. Chabot, Eur. J. Med. Chem., 1997, 32, 71;
(d) G. Kellermann, F. Dingli, V. Masson, D. Dauzonne,
E. S. Bendirdjian, M.-P. T. Fichou, D. Loew and
S. Bombard, FEBS Lett., 2017, 591, 863.
3 For selected leading reviews, see: (a) G. P. Ellis, Chemistry of
Heterocyclic Compounds: Chromenes, Chromanones, and
Chromones, Wiley-Interscience, New York, 2008, vol. 31;
(b) A. E. Nibbs and K. A. Scheidt, Eur. J. Org. Chem., 2012,
449; (c) S. Emami and Z. Ghanbarimasir, Eur. J. Med.
Chem., 2015, 93, 539; (d) N. X. Wang, Y. L. Xing and
Y. J. Wang, Curr. Org. Chem., 2013, 17, 1555.
4 For selected examples, see: (a) D. Enders, K. Breuer and
J. Runsink, Helv. Chim. Acta, 1996, 79, 1899; (b) J. R. de
Alaniz and T. Rovis, J. Am. Chem. Soc., 2005, 127, 6284;
(c) A. Aupoix and G. Vo-Thanh, Synlett, 2009, 1915;
(d) Z. Q. Rong, Y. Li, G. Q. Yang and S. L. You, Synlett, 2011,
1033.
5 For selected examples, see: (a) T. Ishikawa, Y. Oku,
T. Tanaka and T. Kumamoto, Tetrahedron Lett., 1999, 40,
3777; (b) L. G. Meng, H. F. Liu, J. L. Wei, S. N. Gong and
Conflicts of interest
S.
Xue,
Tetrahedron
Lett.,
2010,
51,
1748;
(c) S. V. N. Vuppalapati, L. Xia, N. Edayadulla and Y. R. Lee,
Synthesis, 2014, 46, 465.
The authors declare no conflicts of interest.
6 Y. Noda and M. Watanabe, Helv. Chim. Acta, 2002, 85, 3473.
7 For selected examples, see: (a) M. M. Biddle, M. Lin and
K. A. Scheidt, J. Am. Chem. Soc., 2007, 129, 3830;
(b) J. M. He, J. Y. Zheng, J. Liu, X. G. She and X. F. Pan, Org.
Lett., 2006, 8, 4637; (c) H. F. Wang, H. F. Cui, Z. Chai, P. Li,
C. W. Zheng, Y. Q. Yang and G. Zhao, Chem. – Eur. J., 2009,
15, 13299; (d) H. F. Cui, P. Li, Z. Chai, C. W. Zheng, G. Zhao
and S. Z. Zhu, J. Org. Chem., 2009, 74, 1400.
8 For selected examples, see: (a) X. Y. Ren, C. F. Han,
X. Q. Feng and H. F. Du, Synlett, 2017, 28, 2421;
(b) D. B. Zhao, B. Beiring and F. Glorius, Angew. Chem., Int.
Ed., 2013, 52, 8454; (c) T. Izumi and K. Suenaga,
J. Heterocycl. Chem., 1997, 34, 1535; (d) S. T. Saengchantara
and T. W. Wallace, Tetrahedron, 1990, 46, 6553;
(e) Z. H. Zhang, C. F. Pan and Z. Y. Wang, Chem. Commun.,
2007, 4686.
9 (a) Z. Q. Zhang, T. Chen and F. M. Zhang, Org. Lett., 2017,
19, 1124; (b) M. Ji, J. X. Hu, T. J. Fu, W. Y. Hua and
H. W. Hu, J. Chem. Crystallogr., 2000, 30, 99;
(c) D. R. Buckle, C. S. V. Houge-Frydrych, I. L. Pinto,
D. G. Smith and J. M. Tedder, J. Chem. Soc., Perkin Trans. 1,
1991, 63; (d) P. E. Brown, R. A. Lewis and M. A. Waring,
J. Chem. Soc., Perkin Trans. 1, 1990, 2979.
Acknowledgements
Financial support from the National Natural Science
Foundation of China (21772043) is greatly acknowledged.
References
1 For selected examples, see: (a) T. Ponnusamya,
M. Alagumuthub and S. Thamaraiselvic, Bioorg. Med.
Chem., 2018, 26, 3438; (b) C. P. Waller, A. E. Thumser,
M. K. Langat, N. R. Crouch and D. A. Mulholland,
Phytochemistry, 2013, 95, 284; (c) L. Liu, S. C. Liu, S. B. Niu,
L. D. Guo, X. L. Chen and Y. S. Che, J. Nat. Prod., 2009, 72,
1482; (d) E. B. de Melo, J. P. A. Martins, T. C. M. Jorge,
M. C. Friozi and M. M. C. Ferreira, Eur. J. Med. Chem.,
2010, 45, 4562; (e) M. Varasi, F. Thaler, A. Abate,
C. Bigogno, R. Boggio, G. Carenzi, T. Cataudella,
R. D. Zuffo, M. C. Fulco, M. G. Rozio, A. Mai, G. Dondio,
S. Minucci and C. Mercurio, J. Med. Chem., 2011, 54, 3051;
(f) B. Kupcewicz, G. B. Czerniak, M. Małecka, P. Paneth,
U. Krajewska and M. Rozalski, Bioorg. Med. Chem. Lett.,
This journal is © The Royal Society of Chemistry 2019
Org. Biomol. Chem., 2019, 17, 1062–1066 | 1065

View Article Online
Communication
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10 (a) C. Paparao and V. Sundaramurthy, Indian J. Chem., Sect.
B: Org. Chem. Incl. Med. Chem., 1986, 25, 212;
(b) C. Paparao, K. Venkateswara and V. Sundaramurthy,
Synthesis, 1981, 236.
11 For other selected examples of the synthesis of the 3-nitro
substituted chromanone skeleton, see: (a) L. Q. Lu, F. Li,
J. An, J. J. Zhang, X. L. An, Q. L. Hua and W. J. Xiao, Angew.
Chem., Int. Ed., 2009, 48, 9542; (b) X. F. Wang, Q. L. Hua,
Y. Cheng, X. L. An, Q. Q. Yang, J. R. Chen and W. J. Xiao,
X. Chen, Z. Tan and P. Li, Synth. Commun., 2014, 44, 3165;
(c) R. S. Fornicola, E. Oblinger and J. Montgomery, J. Org.
Chem., 1998, 63, 3528; (d) K. Bera, N. S. Satam and
I. N. N. Namboothiri, J. Org. Chem., 2016, 81, 5670;
(e) A. Clemenceau, Q. Wang and J. P. Zhu, Chem. – Eur. J.,
2016, 22, 18368; (f) C. B. Ji, Y. L. Liu, X. L. Zhao, Y. L. Guo,
H. Y. Wang and J. Zhou, Org. Biomol. Chem., 2012, 10,
1158; (g) S. Shirakawa, S. J. Terao, R. J. He and K. Maruoka,
Chem. Commun., 2011, 47, 10557.
Angew. Chem., Int. Ed., 2010, 49, 8379; (c) X. F. Wang, 13 For the detailed experimental procedure for the synthesis
L. Peng, J. An, C. Li, Q. Q. Yang, L. Q. Lu, F. L. Gu and of 1a, see the ESI.†
W. J. Xiao, Chem. – Eur. J., 2011, 17, 6484; (d) T. Sato, 14 For details, see the ESI.†
T. Miyazaki and T. Arai, J. Org. Chem., 2015, 80, 10346; 15 CCDC number of 2f: CCDC 1873098.†
(e) M. Y. Li, X. F. Zhao, W. Yang, F. R. Zhong, L. J. Yuan and 16 For the kinetic formation of enolates with strong bases,
Q. Ren, Tetrahedron Lett., 2018, 59, 3511.
12 For selected examples of metal or organo-catalysed trans-
see: (a) H. O. House and B. M. Trost, J. Org. Chem., 1965,
30, 1341; (b) J. d’Angelo, Tetrahedron, 1976, 32, 2979.
formations of α-nitro carbonyl compounds, see: 17 C. Lu, B. Kirsch, C. K. Maurer, J. C. de Jong,
(a) K. Ohmatsu, Y. Hara, Y. Kusano and T. Ooi, Synlett,
A. Braunshausen, A. Steinbach and R. W. Hartmann,
2016, 27, 1047; (b) S. S. Yao, J. D. Liu, Z. Y. Yang, Q. W. Gui,
Eur. J. Med. Chem., 2014, 79, 173.
1066 | Org. Biomol. Chem., 2019, 17, 1062–1066
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