Zn/MCM-41-catalyzed unsymmetrical Hantzsch reaction and the evaluation of optical properties and anti-cancer activities of the polyhydroquinoline products

Article abstract of DOI:10.1007/s00706-020-02549-x

Abstract: The three-component Hantzsch condensation of various aryl aldehydes, dimedone, and methyl 3-aminocrotonate was investigated in the presence of MCM-41-supported ZnNO₃. The polyhydroquinoline products which were obtained under mild cond

Full text of DOI:10.1007/s00706-020-02549-x

Monatshefte für Chemie - Chemical Monthly
https://doi.org/10.1007/s00706-020-02549-x
ORIGINAL PAPER
Zn/MCM‑41‑catalyzed unsymmetrical Hantzsch reaction
and the evaluation of optical properties and anti‑cancer activities
of the polyhydroquinoline products
Elaheh Farajzadeh Oskuie1 · Sajjad Azizi1,2 · Zarrin Ghasemi1 · Mahtab Pirouzmand3 · Behnaz Nikzad Kojanag3 ·
Jafar Soleymani4
Received: 5 November 2019 / Accepted: 7 January 2020
© Springer-Verlag GmbH Austria, part of Springer Nature 2020
Abstract
The three-component Hantzsch condensation of various aryl aldehydes, dimedone, and methyl 3-aminocrotonate was inves-
tigated in the presence of MCM-41-supported ZnNO3. The polyhydroquinoline products which were obtained under mild
conditions and very easy workup were evaluated for anti-cancer activities against MCF-7, SK-BR-3, and HT-29 of breast and
colon cancer cells. The fuorescence emission of some products was also studied and their optical parameters were reported.
Graphic abstract
Keywords Hexahydroquinolines · Hantzsch reaction · Heterocycles · Fluorescence spectroscopy · Multicomponent
reactions · Anti-cancer activity
Introduction
Hexahydroquinoline-5-ones are the modifed structures
based on both quinolines and 1,4-dihydropyridines
Electronic supplementary material The online version of this
(DHPs), with many medicinal and biological properties
[1, 2]. They have been shown to possess antimicrobial [3],
anti-infammatory [4], and neuroprotective [5] activities.
Figure 1 shows the structure of some members of these
compounds as potent anti-cancers (1–3) [6–8], antioxidant
(4) [9], and calcium channel modulator agents (5) [10].
The catalytic-modifed Hantzsch reaction between aro-
matic aldehydes, 1,3-cyclohexanediones, β-ketoesters, and
ammonium acetate is the known one-pot method for the
synthesis of these heterocycles [11]. Development of sev-
eral synthetic methodologies to achieve various diversities
article (https://doi.org/10.1007/s00706-020-02549-x) contains
supplementary material, which is available to authorized users.
* Zarrin Ghasemi
z.ghasemi@tabrizu.ac.ir
1
Department of Organic Chemistry and Biochemistry, Faculty
of Chemistry, University of Tabriz, Tabriz 5166614766, Iran
2
Drug Applied Research Center, Tabriz University of Medical
Sciences, Tabriz, Iran
3
Department of Inorganic Chemistry, Faculty of Chemistry,
University of Tabriz, Tabriz 5166614766, Iran
4
Pharmaceutical Analysis Research Center, Tabriz University
of Medical Sciences, Tabriz, Iran
Vol.:(0123456789)
1 3

E. F. Oskuie et al.
Fig. 1 Some hexahydroquin-
oline-5-one derivatives with
potent biological activities
of hexahydroquinoline-5-one derivatives exhibits the
growing interests on these compounds [12–17]. Using
inexpensive and available reagents as well as structural
variability have also increased the attractiveness of their
synthesis [18, 19]. Among the reported catalytic condi-
tions, application of heterogeneous and reusable cata-
lysts has been extensively concerned for multicomponent
reactions [20, 21]. The mesoporous materials such as
MCM-41 (Mobil Composition of Matter) with high sur-
face capacity and nano-sized pores have been widely uti-
lized as proper support for many metal cations [22–25].
We have already reported the use of ZnNO3-incorporated
MCM-41 as an efcient catalyst for Biginelli reaction at
solvent-free conditions [26]. Zn2+ is a potential Lewis
acid to activate organic reactants to promote many trans-
formations [27, 28]. In this work, we report the three-
component reactions between various aromatic aldehydes,
methyl 3-aminocrotonate and dimedone in the presence of
ZnNO3-impregnated MCM-41 at room temperature. We
found that our dihydropyridine products show emission
properties which have not been already reported. The opti-
cal parameters and fuorescence spectra of some synthetic
products are herein reported. The anti-cancer activities of
the products were then evaluated against MCF-7, SK-BR-
3, and HT-29 of breast and colon cancer cells for which
the results are presented.
Results and discussion
The modifed three-component Hantzsch reaction between
aromatic aldehydes, dimedone, and methyl 3-aminocroto-
nate in the presence of Zn(NO3)2/MCM-41 (prepared by
impregnation method [26]) in ethanol at room temperature,
aforded the dihydropyridine products 6a–6o in good to
excellent yields (Table 1). Using not-impregnated MCM-
41, aqueous media or solvent-free conditions resulted in
the complex mixtures or poor yields. Among the used
aldehydes, 3- and 4-fuorobenzaldehyde, salicylaldehyde,
4-hydroxybenzaldehyde, and also 3-indolecarbaldehyde
showed the least reactivity (entries 4–7 and 13). Although
a variety of aromatic aldehydes with electron-withdrawing
or -donating substituents and also heterocyclic aldehydes
underwent this conversion efciently, utilizing 3-benzyl-
oxy-2-formyl-4H-pyran-4-one (7) [29, 30] gave only the
Knoevenagel product resulted from the condensation of
aldehyde and dimedone with no participation of aminocro-
tonate ester. By adding ammonium acetate to this mixture,
acridine-based product 8 was obtained (Scheme 1). Fur-
thermore, we examined the efciency of the used catalyst
for the condensation of methyl acetoacetate (instead of
dimedone), methyl 3-aminocrotonate and 5-methylfurfural
that gave the symmetrical product 9 in 97% yield within
2 h (Scheme 1).
1 3

Zn/MCM-41-catalyzed unsymmetrical Hantzsch reaction and the evaluation of optical properties…
Table 1 Zn/MCM-41-catalyzed synthesis of methyl 4-aryl-5-oxo-hexahydroquinoline-3-carboxylates 6a–o
Entry
Ar
Product
Yield/%
Reaction
time/h
1
2
3
4
5
6
7
8
4-ClC6H4
3-BrC6H4
2-BrC6H4
4-FC6H4
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
86
89
93
74
75
77
77
87
92
82
85
85
76
87
96
2
2
2
5
5
10
10
2
2
7
5
5
10
6
1
3-FC6H4
4-HOC6H4
2-HOC6H4
3-O2NC6H4
2-O2NC6H4
3,4-(OMe)2C6H3
4-MeOC6H4
5-Methylfuran-2-yl
Indole-3-yl
4-Me2NC6H4
4-MeC6H4
9
10
11
12
13
14
15
Scheme 1
The proposed mechanism can involve the activation of
aldehyde and diketone components for Knoevenagel con-
densation by coordination of their carbonyl groups with
zinc cation (Fig. 2). The Michael attack of enamine to the
resulted intermediate I and then tautomerization of the
adduct gives species II, which under catalytic intramolecu-
lar cyclization and then elimination of H2O is converted to
the desired products 6a–6o.
We also noticed the emission properties of our syn-
thesized dihydropyridines. We recorded the UV–Vis and
1 3

E. F. Oskuie et al.
Fig. 2 The proposed mechanism
for the generation of products
6a–6o
Table 2 IC50 values for cell lines/μM
Product
MCF 7
SK BR 3
HT 29
HEK 293
6a
200
100
30
40
35
35
145
100
100
120
80
130
130
95
135
100
130
45
1350
990
795
1236
980
710
1450
998
700
1100
854
1019
1211
878
6b
6c
6d
45
6e
100
100
70
100
17
50
100
40
45
60
40
125
100
2.4 0.12
6f
6g
6h
125
30
Fig. 3 The fuorescence spectra of some chosen products in dilute
(1.0×10−5 M) ethanol solutions
6i
65
6j
100
100
50
100
100
100
130
120
100
140
120
0.49
6k
fluorescence spectra of some chosen products as dilute
(1.0 × 10−5 M) solutions in ethanol, to access their opti-
cal parameters. Figure 3 shows the emission spectra of the
selected derivatives, which reveals that the emission wave-
lengths of the compounds, λem, are close to each other and in
the visible area. As seen, product 6c containing 2-bromophe-
nyl group at the 4th position of the molecule showed higher
emission quantum yield.
6l
6m
45
6n
120
125
150
115
1.29 0.16
6o
1334
1452
1322
1.30
8
9
Doxorubicin
1 3

Zn/MCM-41-catalyzed unsymmetrical Hantzsch reaction and the evaluation of optical properties…
Fig. 4 Graphical presentation
of the cytotoxic activity of the
1,4-dihydropyridines
the presence of ZnNO3-incorporated MCM-41 mesoporous
Biological studies
bed. We then studied the UV–Vis and fuorescence spectra
of some chosen products in dilute (1.0×10−5 M) solutions in
ethanol and calculated their optical parameters. By consider-
ing the inherent biological properties of dihydropyridines,
we have also evaluated the in vitro cytotoxicity of our prod-
ucts against three diferent cancer cell lines: human breast
adenocarcinoma (MCF 7), human breast cancer (SK BR-3),
and human colon adenocarcinoma (HT 29) using the MTT
assay. Some of the synthesized hexahydroquinolines show
considerable activities.
The prepared 1,4-dihydropyridine (DHPs) 6a–6o were tested
for in vitro cytotoxicity analyses against three diferent cancer
cell lines: human breast adenocarcinoma (MCF 7), human
breast cancer (SK BR-3), and human colon adenocarcinoma
(HT 29) using the MTT assay [31, 32]. Doxorubicin, a well-
known anti-cancer agent, was used as the positive control in
our study. The antiproliferative efcacy records are presented
as IC50 values which describe the concentration of the product
that reduces cell proliferation at 50% (Table 2). The IC50 val-
ues for cell lines were determined after at least three individ-
ual experiments. Cell survival was ascertained by MTT assay
as explained in “Cell cytotoxicity assay by MTT”. All of the
synthetic compounds (6a–6o, 8, 9) were investigated for cyto-
toxicity efects and some of them showed interesting results.
The results proved the considerable activity of derivatives 6c
and 6i against all of the three cell lines. The compounds 6a
and 6b exhibited promising activities against SK BR-3 cell
line, while compound 6g against HT 29 cell line. It has been
also observed that the products containing 4-chlorophenyl
(6a), 3- or 2-bromophenyl (6b and 6c), and 2-nitrophenyl (6i)
substituents at the 4th position of the 1,4-dihydropyridines
showed relatively good activity, but those with 3-fuorophe-
nyl (6e), 4-hydroxyphenyl (6f), and 4-methoxyphenyl (6k)
groups, as well as the symmetric compounds 8 and 9, were
completely inactive. In addition, the attendance of a heterocy-
clic moiety (such as 6l and 6m) enhanced the cytotoxic prop-
erties against MCF-7 and SK BR-3 cell lines. The cytotoxic
activities of all the 1,4-dihydropyridines have been graphically
exhibited in Fig. 4. The efects of the synthetic compounds
on normal cells (HEK 293) were also investigated. As could
be seen in Table 2, the desired compounds have low activity.
Experimental
All the reagents were purchased from commercial suppliers
and used without further purifcation. The progress of the
reactions was monitored using thin-layer chromatography
(TLC) performed on Merck Silica Gel 60 F254 plates. Melt-
ing points were measured on an Electrothermal MEL-TEMP
apparatus (model 1202D). FT-IR spectra were obtained with
a Bruker Tensor 27 spectrometer. 1H and 13C NMR spectra
were recorded with a Bruker Spectrospin Avance 400 spec-
trometer operating at 400 and 100 MHz, respectively; chemi-
cal shifts are given in parts per million (ppm, δ) relative to
solvent peaks as internal standards (CDCl3: 7.26 ppm (1H),
76 ppm (13C); DMSO-d6: 2.50 ppm (1H), 39.5 ppm (13C)).
Elemental analyses were measured by Vario EL III appara-
tus (Elementar Co.), their results agreed favorably with the
calculated values. UV–Vis spectra were recorded on an Ana-
lytic Jena Specorel 250 spectrometer. Fluorescence emission
spectra were acquired on a Jasco FP-750 spectrofuorim-
eter. For biological studies, 3-(4,5-dimethylthiazol-2-yl)-
2,5-diphenyltetrazolium bromide (MTT) and phosphate
bufer solution (PBS) were purchased from Sigma-Aldrich
Co. Fetal bovine serum (FBS), penicillin–streptomycin,
trypsin–EDTA (25%) and Roswell Park Memorial Institute
1640 growth medium (RPMI) were purchased from Gibco
BRL Life Technologies (USA). All cancer cells includ-
ing breast (MCF 7 and SK BR 3) and colon (HT 29) were
Conclusion
As a result, we have reported the synthesis of some hexahyd-
roquinoline-5-one derivatives by three-component reactions
of aryl aldehydes, dimedone, and methyl 3-aminocrotonate in
1 3

E. F. Oskuie et al.
provided from the standard cell banks of the National Cell
Bank of Iran (NCBI) (Tehran, Iran). All cancer cells were
cultured in a sterilized fask with RPMI media supported by
10% FBS and 1% penicillin–streptomycin.
NMR (400 MHz, DMSO-d6): δ =0.77 (s, 3H, dimedone-
CH3), 0.99 (s, 3H, dimedone-CH3), 1.94 (d, J=16.1 Hz, 1H,
CH2), 2.14 (d, J=16.1 Hz, 1H, CH2), 2.26 (s, 3H, Py-CH3),
2.29 (d, J = 17.6 Hz, 1H, CH2), 2.41 (d, J = 17.0 Hz, 1H,
CH2), 3.50 (s, 3H, OCH3), 5.13 (s, 1H, CH), 6.87–6.90
(m, 2H, Ar–H), 6.95–6.99 (m, 1H, Ar–H), 7.24 (d, J=8.0,
1H, Ar–H), 7.52 (d, J=7.9, 1H, Ar–H), 9.16 (s, 1H, N–H),
10.67 (s, 1H, N–H) ppm; 13C NMR (100 MHz, DMSO-d6):
δ=18.1, 18.2, 26.6, 27.2, 29.2, 32.1, 39.4, 50.4, 50.6, 103.6,
109.8, 111.2, 118.0, 119.6, 120.3, 121.2, 122.5, 122.6,
125.7, 136.2, 144.0, 149.0, 167.7, 194.4 ppm.
General procedure for the synthesis of methyl
4‑aryl‑1,4,5,6,7,8‑hexahydro‑2,7,7‑trimethyl‑5‑oxoquino‑
line‑3‑carboxylates 6a–6o The mixture of the dimedone
(1 mmol), aromatic aldehydes (1 mmol), methyl 3-amino-
crotonate (1 mmol), and 0.02 g catalyst (Zn(NO3)2/MCM-
41/calcinated/wet impregnated [26]) in 4 cm3 ethanol was
stirred at room temperature for the specifc time (Table 1).
At the end of the reaction (controlled by TLC), the obtained
solid was fltered, washed with ethanol for several times and
then poured into a stirred chloroform–methanol solution (2:1
v/v, 6 cm3). Filtration of the mixture allowed the separation
of unsolved catalyst. Concentration of the fltrate with rotary
evaporator resulted in the solid product which was washed
twice with diethyl ether (2×5 cm3) to give the pure products
6a–6o (6g, 6l, 6m, and 8 are new compounds).
9‑(5‑Benzyloxy‑4‑oxo‑4H‑pyran‑2‑yl)‑3,4,6,7‑tet‑
rahydro‑3,3,6,6‑tetramethylacridine‑1,8‑dione (8,
C29H31NO5) According to the general procedure, using dime-
done (2 mmol), aldehyde 7 (1 mmol), ammonium acetate
(1 mmol), and 0.02 g Zn(NO3)2/MCM-41/calcinated (WI)
in 4 cm3 ethanol and stirring the mixture at room tempera-
ture for 4 h, the compound 8 was obtained as a white solid.
Yield 425 mg (90%); m.p.: 194–196 °C; FT-IR (KBr):
1
v̄ = 3440, 3083, 2957, 1739, 1642, 1547, 1262 cm−1; H
Methyl 4‑(2‑hydroxyphenyl)‑1,4,5,6,7,8‑hexahydro‑2,7,7‑tri‑
methyl‑5‑oxoquinoline‑3‑carboxylate (6g, C20H23NO4) White
solid; yield 262 mg (77%); m.p.: 232–234 °C; FT-IR (KBr):
NMR (400 MHz, CDCl3): δ=1.08 (s, 6H, dimedone-CH3),
1.14 (s, 6H, dimedone-CH3), 2.26–2.42 (m, 8H, CH2),
5.02 (s, 2H, CH2OPh), 5.30 (d, J= 1.1 Hz, 1H, CH), 6.23
(d, J = 1.4 Hz, 1H, pyrone-H3), 7.31–7.39 (m, 6H, Ph-H,
pyrone-H6), 11.93 (s, 1H, NH) ppm; 13C NMR (100 MHz,
CDCl3): δ=25.8, 28.4, 30.4, 31.7, 45.1, 45.6, 70.7, 111.5,
112.2, 126.8, 127.3, 127.6, 134.6, 139.7, 145.7, 163.3,
173.4, 188.9, 189.3 ppm.
1
v̄ = 3436, 3018, 2959, 1737, 1644, 1524, 1216 cm−1; H
NMR (400 MHz, DMSO-d6): δ =0.78 (s, 3H, dimedone-
CH3), 1.00 (s, 3H, dimedone-CH3), 2.07 (d, J=16.4 Hz, 1H,
CH2), 2.27 (d, J=16.4 Hz, 1H, CH2), 2.29 (d, J=17.1 Hz,
1H, CH2), 2.34 (s, 3H, Py-CH3), 2.42 (d, J=17.0 Hz, 1H,
CH2), 3.45 (s, 3H, OCH3), 4.94 (s, 1H, CH), 6.67–6.72 (m,
2H, Ar–H), 6.89 (dd, J=8.3, 1.5 Hz 1H, Ar–H), 6.92–6.97
(m, 1H, Ar–H), 9.38 (s, 1H, N–H), 9.42 (s, 1H, O–H) ppm;
13C NMR (100 MHz, DMSO-d6): δ=18.1, 18.2, 26.3, 28.7,
30.0, 32.1, 39.4, 49.6, 50.8, 103.6, 109.3, 116.9, 117.0, 119.7,
127.1, 128.4, 133.8, 145.2, 152.2, 153.2, 167.3, 196.9 ppm.
Cell cytotoxicity assay by MTT
The MCF 7, SK BR-3, and HT 29 cancer cells were cultured
in Roswell Park Memorial Institute 1640 (RPMI) media sup-
plemented with 10% FBS and 1% penicillin and streptomy-
cin at 37 °C under 5% CO2. The cells were washed with
phosphate bufer solution (PBS) to remove the excess RPMI
and then the cells were treated with trypsin–EDTA solution
and incubated for 5 min at 37 °C under 5% CO2 to separate
the cell from the fask bottom surface. Then the separated
cancer cells were transferred to a tube and centrifuged to
wash out excess trypsin–EDTA. Finally, the separated cells
were resuspended to the fresh RPMI medium. Cell viability
of MCF 7, SK BR-3, and HT 29 cancer cells were tested
by adding 1.0×104 cells per each well of a 96-well texture
plate. Afterwards, the cancer cells were incubated for about
24 h to grow and cover at least 40% of each well. Then
the wells were treated with diferent concentrations of the
1,4-dihydropyridines and incubated for 48 h. Next, the wells
were washed with PBS bufer solution, and subsequently
20 mm3 of MTT (2.5 mg cm−3) reagent and 180 mm3 RPMI
refresh media were added to each well and incubated for
4 h at 37 °C under 5% CO2. Afterwards, the RPMI medium
Methyl 4‑(5‑methylfuran‑2‑yl)‑1,4,5,6,7,8‑hexahydro‑2,7,7‑tri‑
methyl‑5‑oxoquinoline‑3‑carboxylate (6l, C19H23NO4) White
solid; yield 279 mg (85%); m.p.: 184–186 °C; FT-IR (KBr):
v̄=3441, 3087, 2942, 1690, 1619, 1547, 1218 cm−1; 1H NMR
(400 MHz, CDCl3): δ=1.04 (s, 3H, dimedone-CH3), 1.09
(s, 3H, dimedone-CH3), 2.15 (s, 3H, Fur-CH3), 2.21–2.26
(m, 3H, CH2), 2.34 (s, 3H, Py-CH3), 2.37 (d, J=16.8 Hz,
1H, CH2), 3.68 (s, 3H, OCH3), 5.17 (s, 1H, CH), 5.76 (d,
J=1.9 Hz, 1H, Fur-H), 5.84 (d, J=2.9 Hz, 1H, Fur-H), 6.40
(s, 1H, N–H) ppm; 13C NMR (100 MHz, CDCl3): δ=12.7,
18.3, 25.7, 28.6, 29.0, 31.7, 40.1, 49.7, 50.0, 101.9, 104.2,
105.0, 107.8, 143.6, 148.4, 149.1, 155.1, 166.8, 194.5 ppm.
Methyl 4‑(1H‑indole‑3‑yl)‑1,4,5,6,7,8‑hexahydro‑2,7,7‑trime‑
thyl‑5‑oxoquinoline‑3‑carboxylate (6m, C22H24N2O3) Yellow
solid; yield 276 mg (76%); m.p.: 182–184 °C; FT-IR (KBr):
1
v̄ = 3358, 3077, 2941, 1689, 1618, 1494, 1223 cm−1; H
1 3

Zn/MCM-41-catalyzed unsymmetrical Hantzsch reaction and the evaluation of optical properties…
was replaced with 200 mm3 of DMSO and incubated for
0.5 h. Finally, the absorbance of the wells was measured at
570 nm.
14. Kang SR, Lee YR (2013) Synthesis 45:2593
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(2019) ChemistrySelect 4:11701
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SAS, Abdelhamid IA (2019) Anti-Cancer Agents Med Chem
19:875
Acknowledgements This project has been supported by a research
grant of the university of Tabriz (number: 793). We thank research
afairs of University of Tabriz for this grant. The University of Medi-
cal Sciences, Iran, is also gratefully appreciated for biological studies.
17. Khazaei A, Tavasoli M, Jamshidi V, Ghalil FG, Moosavi-Zare AR
(2018) Appl Organomet Chem 32:368
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