Green synthesis of 2-amino-3-cyanopyridines via a cooperative vinylogous anomeric-based oxidation and their antiproliferative effects on liver, breast, and prostate cancer studies

Article abstract of DOI:10.1080/00397911.2021.1878537

2-Amino-3-cyanopyridine derivatives were synthesized in an ultrasonic bath and one pot four-component reactions with high yields, in a short time, without solvent and catalyst, and anticancer activity studies on MCF7, DU145, and HepG2 cell lines were inve

Full text of DOI:10.1080/00397911.2021.1878537

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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Green synthesis of 2-amino-3-cyanopyridines via a
cooperative vinylogous anomeric-based oxidation
and their antiproliferative effects on liver, breast,
and prostate cancer studies
Mehmet Erşatır & Metin Yıldırım
To cite this article: Mehmet Erşatır & Metin Yıldırım (2021) Green synthesis of 2-amino-3-
cyanopyridines via a cooperative vinylogous anomeric-based oxidation and their antiproliferative
effects on liver, breast, and prostate cancer studies, Synthetic Communications, 51:8, 1252-1265,
DOI: 10.1080/00397911.2021.1878537
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2021, VOL. 51, NO. 8, 1252–1265
https://doi.org/10.1080/00397911.2021.1878537
Green synthesis of 2-amino-3-cyanopyridines via a
cooperative vinylogous anomeric-based oxidation and their
antiproliferative effects on liver, breast, and prostate
cancer studies
Mehmet Ers¸atıra
and Metin Yıldırımb
b
aDepartment of Chemistry, Arts and Science Faculty, Cukurova University, Adana, Turkey; Department
of Pharmacy Services, Vocational School of Health Services, Tarsus University, Mersin, Turkey
ABSTRACT
ARTICLE HISTORY
Received 2 November 2020
2-Amino-3-cyanopyridine derivatives were synthesized in an ultra-
sonic bath and one pot four-component reactions with high yields,
in a short time, without solvent and catalyst, and anticancer activity
studies on MCF7, DU145, and HepG2 cell lines were investigated. 18
compounds were synthesized in 4–25 min time interval and 85–99%
yield. Among these compounds, the IC50 values in 7a, 6a, and 3a
on MCF7 breast cancer cell line was found to be 1.80, 1.95, and
2.50 mM, respectively, while the values in the HepG2 liver cancer cell
line were 7.71, 7.90, and 8.05 mM, respectively. In studies conducted
in the DU145 prostate cancer cell line, IC50 values of compounds
1b, 2b, and 8b were found to be 9.90, 10.10, and 15.30 mM, respect-
ively.
KEYWORDS
Aminocyanopyridine;
ultrasonic irradiation; multi-
component reaction;
heterocycles; anticancer
activity; prostate cancer;
breast cancer; liver cancer
GRAPHICAL ABSTRACT
Introduction
Cancer is the second of the diseases that cause death worldwide. 16% deaths are related
to cancer. Most common seen cancer types are prostate, colorectal, liver, lung, and
CONTACT Mehmet Ers¸atı r
University 01030, Adana, Turkey.
mersatir@cu.edu.tr
Department of Chemistry, Arts and Science Faculty, Cukurova
Supplemental data for this article can be accessed on the publisher’s website.
ß 2021 Taylor & Francis Group, LLC

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breast cancers. According to American Cancer Society, for 2020, estimated numbers of
new cases of breast cancer, liver cancer and prostate cancer are 279,100, 42,860, and
191,930, respectively.[1]
Pyridine moiety is important because it is in the active center of many pharmaceut-
ical drugs, as well as in the structure of natural compounds and important starting
materials used in the synthesis of some important heterocyclic compounds.
The biological activity studies of the compounds containing the structure of 2-amino-
3-cyanopyridine are limited. However, despite a small number of biological studies,
these compounds are included in the literature where they show a wide range of bio-
logical activities such as antitumor,[2] antifungal, HIV-1 integrase inhibitory activity,[3]
IKK-Serine-Threonine protein kinase inhibitory activity,[4] A2A adenosine receptor
antagonists.[5]
There are many studies in the literature on the synthesis of 2-amino-3-cyanopyridine
derivatives. In these studies, besides catalysts such as ytterbium perfluorooctanoate [Yb
[8]
[9]
(PFO)3],[6] Cu2O,[7] HBF4, and Fe3PO4, cellulose sulfuric acid[10] and liquid–liquid
phase transfer catalysts[11] were also used. In addition, there are studies using nano-
sized catalysts[7,9,12–17] in recent studies. Studies have also been done on solvent systems
using PEG-200,[18] PEG-400[19] and ionic liquids.[20,21] The use of solvent and heavy
metal-containing catalysts, long-lasting reactions, low yields, need for separation, and
purification processes in these studies indicate the need for more moderate synthesis
conditions for the synthesis of 2-amino-3-cyanopyridine derivatives.
Multicomponent reactions have a very important role in the development and
advancement of organic synthesis and medicinal chemistry. The main advantage of
these reactions is that there is no need for separation and purification methods, thus
reducing time and cost and not creating waste products.
In our previous studies, the 2-amino-3-cyano groups on the selenophene ring showed
very good anticancer activity on breast cancer and prostate cancer cell lines.[22,23] In
this study, 2-amino-3-cyanopyridine derivatives were synthesized in an ultrasonic bath
without catalysts and solvents in a short time with high yields, and the anticancer activ-
ities of these compounds were tested on three different cancer lines.
Results and discussion
Chemistry
In this study, 2-amino-3-cyanopyridine derivatives were synthesized in a short time and
with high yields in an ultrasonic bath without using solvents and catalysts in a single
pot multicomponent reaction. Figure 1 shows the synthetic route for the synthesis of
aminocyanopyridines.
In this study, 2-amino-3-cyanopyridine compounds were synthesized with high yields
in an one pot multicomponent method in an ultrasound bath without using solvents
and catalysts. In the studies in the literature, it is seen that aminocyanopyridine com-
pounds are synthesized with the use of solvents, catalysts, and long-lasting reactions at
different temperatures. The superiority of this study in the literature is shown in
Table 1.

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M. ERŞATIR AND M. YILDIRIM
Figure 1. Ultrasound-assisted synthesis of 2-amino-3-cyano-4,6-diphenylpyridine derivatives in solv-
ent-free and catalyst-free environment.
2-Amino-3-cyano-4,6-diphenylpyridine derivatives were synthesized by reacting p-
substituted benzaldehyde derivatives with malononitrile, ammonium acetate, and 20-
aminoacetophenone or acetophenone in a solvent-free and catalyst-free environment
in an ultrasonic bath with one-pot multicomponent reaction. At the end of the reac-
tion, the products were synthesized for 4–25 min and yields of 85–99% (Table 2).
In this study, products with high yields were obtained without using chemicals and
consumables at the end of simple separation and purification processes.
Table 2 shows that, in the presence of electron donating groups on benzaldehyde (1a,
3a, 15a, and 17a), reaction yields are lower and reaction times are longer than the pres-
ence of electron withdrawing groups (5a, 7a, 9a, 11a, and 13a). While the reaction time
is in the range of 18–25 min in the presence of electron-donating groups (Table 2,
entries 1, 3, 15, and 17), it is between 5 and 14 minutes in the presence of electron-
withdrawing groups (Table 2, entries 5, 7, 9, 11, and 13).
When we compare the yield and reaction times in the reactions using acetophenone and
20-aminoacetophenone; in the reactions with 20-aminoacetophenone the time was shorter
but the yields were higher in the presence of other groups except the ꢀ CH3, ꢀOCH3,
ꢀCF3, andꢀ NO2 groups (Table 2, Entries 2, 4, 6, 8, and 10).
All new compounds were individually characterized and their structures identified by
1
FT-IR, H NMR, and 13C NMR.
A cooperative vinylogous anomeric-based oxidation mechanism is proposed as a
rational mechanism for the synthesis of 2-amino-3-cyanopyridine derivatives without
solvent and catalyst in a single pot multicomponent reaction using p-substituted benzal-
dehyde, acetophenone, and/or 20-aminoacetophenone, malononitrile, and ammonium
acetate.[25,26] At first, the carbonyl group of aldehyde is activated by the acidic group of
ammonium acetate. Malononitrile reacts with the carbonyl group of aldehyde by remov-
ing one molecule of H2O. Then, this intermediate product, respectively, acts as a
Michael acceptor, followed by intramolecular cyclocondensation reactions and finally
giving the final desired product through a cooperative vinylogous anomeric-based oxi-
dation reaction (Scheme 1).[27,28]
Antiproliferative activity
The anticancer activity of compounds 1aꢀ9a and 1bꢀ9b was determined against to
MCF-7 (Breast cancer) cell line via using xCELLigence system. Then, the promising

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Table 1. Comparison of our method in the synthesis of 2-amino-3-cyanopyridine compounds with
the studies in the literature.
Entry
1
Reaction conditions
Reference
This work
Catalyst free, solvent free, at room temperature for 4–25 min, in an
ultrasonic bath
[6]
[7]
2
3
Yb(PFO3) (2,5 mol %), ethanol (2 ml), at refluxing temperature for 4 h
Nano-sized Cu2O on melamine-formaldehyde resin (0,072 mol%),
Ethanol:water (1:1), at refluxing temperature for 1–5 h
HBF4 (0,1 g), solvent free, at 100oC, under air or nitrogen atmosphere
for 150 min.
[8]
4
[9]
5
6
7
Fe3O4@TiO2@O2PO2(CH2)NHSO3H (7 mg), solvent free, at 90 ꢁC for 20 min.
Cellulose–SO3H (0,05 mmol), water (5 ml), at 60 ꢁC for 2.5 h
[10]
[11]
R
V
i)NaBH4 in Chlorobenzene, Water, Aliquat 336, reflux
ii) NaBH4 in CH3CN, 18-crown-6, at 80 ꢁC
SrFe12O19 (0.02 g), solvent free, at 100 ꢁC for 8 min
Cu/C nanocatalyst (2,0 mol%), acetonitrile (2,0 mL) at 80 ꢁC for 6 h
Cu@imineZCMNPs (10 mg), solvent free, at 80 ꢁC for 1 h
fFe3O4@SiO2@(CH2)3ImgC(CN)3 (7 mg), solvent free, at 100 ꢁC for 40 min
Fe3O4@SiO2@Si(CH2)3Cl (10 mg), solvent free, at 80 ꢁC for 10–25 min
a-zirconium phosphate (Zr(HPO4)2ꢂH2O) nanocrystals (15 mg), solvent free, at
60 ꢁC for 20–90 min
[12]
[13]
[14]
[15]
[16]
[17]
8
9
10
11
12
13
[18]
[19]
[24]
[21]
14
15
16
17
PEG-200/water, at refluxing temperature for 4 h
PEG-400/water, at 80 ꢁC for 6 h
Trifluoroethanol (TFE), at refluxing temperature for 6 h
Nicotinium methane sulfonate (NMS) (5 mol %), solvent free, at 80 ꢁC
for 100 min
activity shown by tested 6a and 7a encouraged us to measure the anticancer activity of
the other analogues in selected human cancer cell lines such as liver (HepG2) and pros-
tate (DU-145) by using same method. Results was shown in Table 3.
The mean IC50 values for tested 7a are 1.8 0.11, 7.71 0.41 against to MCF-7 and
HepG2, respectively (Table 3 entry 7 and Figure 2). For HepG2, tested 6a, 7a, and 3a
showed better anticancer activity than positive control (Table 3, entries 3, 6, and 7).
Moreover, the anticancer properties of tested 1aꢀ9a was determined to substantiate
the potentiality of these conjugates (1bꢀ9b) as anticancer agents. While conjugates
1bꢀ9b exhibited a lower cytotoxicity than 1aꢀ9a, respectively, on MCF-7 and HepG2
cells, this situation was the opposite in DU-145 cells (Figure 3). Compounds 1b and 2b
showed the closest activity to the positive control in the DU-145 cell line.
All of the compounds 1aꢀ9a showed better antiproliferative effect on the MCF7
breast cancer cell line than the control compound used. On the other hand, 1bꢀ9b
compounds showed cytotoxic effects on the same cell line at IC50 values ranging from
8.13 to 12.26 mM (Table 3, entries 10ꢀ18). This indicates that synthesized aminocyano-
pyridine compounds have a very good antiproliferative effect on the MCF7 cell line.
Similarly, compounds 1aꢀ9a showed better antiproliferative activity on the HepG2 liver
cancer cell line than compounds 1bꢀ9b (IC50 ¼ 7.71 ꢀ 13.20 mM) (Table 3,
entries 1ꢀ9).
Experimental
General
All the reagents were obtained from different commercial sources. Unless noted
otherwise, all of compounds were used as provided without further purification.

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M. ERŞATIR AND M. YILDIRIM
Table 2. Synthesis of 2-amino-3-cyano-4,6-diphenylpyridines with one-pot multicomponent reaction
in an ultrasonic bath without catalyst and solvent.
Entry
1
Compound
Reaction time (min)
20
Yield (%)
88
2
18
89
3
25
86
4
10
92
(continued)

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Table 2. Continued.
Entry
5
Compound
Reaction time (min)
5
Yield (%)
95
6
4
99
7
14
89
8
8
91
9
10
90
(continued)

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M. ERŞATIR AND M. YILDIRIM
Table 2. Continued.
Entry
10
Compound
Reaction time (min)
4
Yield (%)
96
11
12
13
14
6
5
5
7
99
98
99
97
(continued)

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Table 2. Continued.
Entry
15
Compound
Reaction time (min)
20
Yield (%)
85
16
25
86
17
18
88
18
25
87
General preparation of 2-amino-3-cyano-4,6-diphenylpyridine derivatives (1aꢀ9a
and 1bꢀ9b)
The p-substituted benzaldehyde derivative (5 mmol), 20-amino aminoacetophenone or
acetophenone (5 mmol), malononitrile (5 mmol), and ammonium acetate (6 mmol) are
taken and mixed in a flask. The reaction is carried out in an ultrasonic bath at room
temperature. The reaction is controlled by TLC. After the reaction is complete, cold
water is added to the mixture, stirred and this mixture is poured into 30 ml of ice water,
the solid is filtered off, washed with cold water and recrystallized with ethanol. The
product was identified using FT-IR and NMR spectroscopy. Compounds 2a, 3a, 4a, 5a,

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M. ERŞATIR AND M. YILDIRIM
Table 3. In vitro cytotoxic activity results of 2-amino-3-cyano-4,6-diphenylpyridines (1a–9a and
1b–9b) against MCF7, DU145 and HepG2 cell lines.
Entry
Compound
MCF-7 (mM)
DU-145 (mM)
HepG2 (mM)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
1a
2a
3a
4a
5a
6a
7a
8a
9a
1b
2b
3b
4b
5b
6b
7b
8b
9b
5.10 0.31
4.90 0.23
2.50 0.12
3.40 0.19
3.10 0.14
1.95 0.08
1.80 0.11
4.30 0.12
5.02 0.14
11.20 0.56
11.41 0.71
9.03 0.13
10.49 0.29
10.26 0.23
8.53 0.11
8.13 0.16
10.53 0.32
12.26 0.42
5.93 0.14
28.10 1.53
27.30 2.12
29.20 2.3
32.10 1.67
31.30 1.3
33.50 2.9
36.00 2.4
25.30 1.9
26.30 2.2
9.90 0.43
10.10 0.83
18.10 1.1
19.30 0.59
18.50 0.43
20.10 0.67
21.30 1.2
15.30 1.3
16.20 1.1
6.86 0.13
13.20 0.33
11.30 .78
8.05 0.32
9.12 0.41
8.75 0.38
7.90 0.33
7.71 0.41
10.79 0.81
12.60 0.73
24.00 1.1
26.30 1.21
21.20 1.04
22.10 0.93
22.30 1.13
19.10 1.03
18.30 0.99
22.80 0.14
31.00 0.23
8.53 0.43
17
18
Doxorubicin
Figure 2. Most active molecules in studies on MCF7 and HepG2 cell lines.
Figure 3. Most active molecules in studies on DU145 cell line.

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Scheme 1. A plausible mechanistic pathway for the synthesis of 2-amino-4,6 diphenylnicotinonitrile
via a cooperative vinylogous anomeric-based oxidation reaction.

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M. ERŞATIR AND M. YILDIRIM
7a, 8a, and 9a are included in the literature[6,19,21,29] and spectroscopic data of these
compounds are included in the Supplementary File.
2-Amino-6-(2-aminophenyl)-4-(p-tolyl)nicotinonitrile (8b)
orange solid; yield 1.291 g (%86); mp (ꢁC): 148ꢀ150; Rf value: 0.47 (hexane/ethylacetate
90ꢀ10 (4.5:0.5, v/v)); ꢀmax (KBr): ¼ 3201 (NH2 stretching), 3036 (CH stretching, aro-
matic), 2988, 2965, 2917 (CꢀH stretching, aliphatic) 2225 (CN stretching, aliphatic),
1586, 1551 (C ¼ C stretching, aromatic), 1219 (CꢀN stretching), 811, 788, 705 (CꢀH
bending, aromatic) cmꢀ1; dH (600 MHz, CDCl3) 8.32 (d, J ¼ 9.0 Hz, 1H, Ar-H), 7.80 (s,
1H, Ar-H), 7.72 (s, 2H, ꢀNH2), 7.34 (d, J ¼ 9.0 Hz, 2H, Ar-H), 7.26 (d, J ¼ 9.0 Hz, 2H,
Ar-H), 7.14 (t, J ¼ 9.0 Hz, 1H, Ar-H), 6.95 (t, J ¼ 9.0 Hz, 1H, Ar-H), 6.65 (d, J ¼ 9.0 Hz,
1H, Ar-H), 6.27 (s, 2H, ꢀNH2), 2.46 (s, 3H, ꢀCH3); dC (150 MHz, CDCl3) 162.67,
159.83, 150.29, 146.43, 134.42, 132.06, 130.95, 130.92, 130.41, 128.49, 123.37, 118.25,
117.23, 115.77, 114.06, 112.91, 81.18, 22.05; Anal. Calcd. for C19H16N4: C, 75.98; H,
5.37; N, 18.65; Found: C, 76.07; H, 5.36; N, 18.62; Exact Mass: 300.14.
Biological assay
Cell culture
MCF-7 (human breast adenocarcinoma), DU-145 (human prostate cancinoma), and
HepG2 (human hepatocellular carcinoma) cell lines were obtained from ATCC and cul-
ꢀꢀ
ꢀ
ꢀ
tured in Dulbecco’s Modıfıed Eagle Medıum (DMEM) suplemented with Fetal Bovıne
Serum (FBS) 10 and 1% penicillin–streptomycin. Cells were incubated at 37 ꢁC in 5%
CO2 incubator. When the cells reached, 70–80% confluency were harvested and used
for cell viability test.
Cell viability assay
All tested compounds were studied for their anticancer activity against to Hep G2, DU-
145, MCF-7 cells by using xCELLigence system. This method based on the assessment
of cell-impedance variations. Briefly, all cancer cells were seeded in a 16-well E-plate.
Each well containing 1 ꢃ 104 cells. Then, the cells were applied different doses of all
tested. The doses were chosen according to previous studies.[22,23] The cell lines were
incubated with all tested and control for 48 h. Doxorubicin used as control compounds.
IC50 (50% maximun inhibitory concentration) values were calculated from dose–res-
ponse curve by using the GNUPLOT package program (http://www.gnuplot. info). Each
experiment was carried out triplicate. The results were showed in Table 2. IC50 values
were expressed as mM.
Conclusion
A total of eighteen 2-amino-3-cyano-4,6-diphenylpyridine derivatives, 11 of which are
new, were synthesized with a green method by multicomponent reaction, effective in
ultrasonic bath, in a short time and with high yields. The antiproliferative effects of
these compounds have been tested in three different cell lines.

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The compounds tested in the MCF7 breast cancer cell line, compounds 1a–9a
(IC50 values 1.80–5.10 mM) showed more active activity than the reference Doxorubicin
(IC50 ¼ 5.93 mM). While the most effective compound in the DU145 prostate cancer
cell line was 1 b (IC50 ¼ 9.90 mM), in the liver cancer cell line, compounds 7a, 6a, and
3a showed a better cytotoxic effect than the reference substance. (IC50¼7.71, 7.90, and
8.05 mM, respectively).
As a conclusion, we successfully designed and synthesized a number of 2-amino-3-
cyano-4,6-diphenylpyridine compounds as new antitumor candidates on MCF7 breast
cancer, DU145 prostate cancer, and HepG2 liver cancer cell lines. However, such an
optimization of the structures of these molecules may be necessary.
Acknowledgements
The authors are greatly thankful to the Scientific and Technical Research Council of Turkey
(TUBITAK) for a scholarship to Mehmet Er¸satır.
Disclosure statement
The authors declare that they have no known competing financial interests or personal relation-
ships that could have appeared to influence the work reported in this article.
ORCID
Mehmet Er¸satır
http://orcid.org/0000-0003-1077-0626
Data availability statement
The authors confirm that the data supporting the findings of this study are available within the
article [and/or] its supplementary materials.
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