Synthesis of 4-aryl-6-indolylpyridine-3-carbonitriles and evaluation of their antiproliferative activity

Article abstract of DOI:10.1016/j.tetlet.2013.12.081

A novel class of 6-indolypyridine-3-carbonitrile derivatives were synthesized and evaluated for antiproliferative activities to establish structure-activity relationship. The synthesis was carried out through one-pot multicomponent reaction of 3-acetylindole, aromatic aldehydes, ethyl cyanoacetate, and ammonium acetate in the presence of piperidine as a catalyst, using a microwave irradiation method or a traditional thermal method. This was followed by chlorination for compounds 13a-e and subsequent nucleophilic substitution of the chlorine group by ethylenediamine at C₂ position of the pyridine ring. The antiproliferative activity of these new nicotinonitriles was evaluated against human ovarian adenocarcinoma (SK-OV-3), breast adenocarcinoma (MCF-7), and cervix adenocarcinoma (HeLa) cells. Among all compounds, 2-((2-aminoethyl)amino)-4-aryl-6-indolylnicotinonitriles series (15a, 15b, 15d, and 15e) exhibited higher antiproliferative activity on the three cancer cell lines with IC₅₀ values of 4.1-13.4 μM.

Full text of DOI:10.1016/j.tetlet.2013.12.081

Tetrahedron Letters 55 (2014) 1154–1158
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of 4-aryl-6-indolylpyridine-3-carbonitriles and evaluation
of their antiproliferative activity
Naglaa Salem El-Sayed a,b, Amir Nasrolahi Shirazi b,c, Magda Goda El-Meligy a, Ahmed Kamel El-Ziaty d,
David Rowley b, Jiadong Sun b, Zenat Adeeb Nagib a, , Keykavous Parang b,c,
⇑
⇑
a Cellulose and Paper Department, National Research Center, Dokki, Cairo 12622, Egypt
b Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, 7 Greenhouse Road, Kingston, RI 02881, United States
c School of Pharmacy, Chapman University, Orange, CA 92866, United States
d Chemistry Department, Faculty of Science Ain Shams University, Abbassia, Cairo 11566, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel class of 6-indolypyridine-3-carbonitrile derivatives were synthesized and evaluated for antiprolif-
erative activities to establish structure–activity relationship. The synthesis was carried out through one-
pot multicomponent reaction of 3-acetylindole, aromatic aldehydes, ethyl cyanoacetate, and ammonium
acetate in the presence of piperidine as a catalyst, using a microwave irradiation method or a traditional
thermal method. This was followed by chlorination for compounds 13a–e and subsequent nucleophilic
substitution of the chlorine group by ethylenediamine at C2 position of the pyridine ring. The antiprolifer-
ative activity of these new nicotinonitriles was evaluated against human ovarian adenocarcinoma
(SK-OV-3), breast adenocarcinoma (MCF-7), and cervix adenocarcinoma (HeLa) cells. Among all com-
pounds, 2-((2-aminoethyl)amino)-4-aryl-6-indolylnicotinonitriles series (15a, 15b, 15d, and 15e) exhib-
Received 20 November 2013
Revised 20 December 2013
Accepted 23 December 2013
Available online 3 January 2014
Keywords:
Antiproliferative agents
Acetyl indole
Indolyl carbonitriles
Microwave-assisted synthesis
Multicomponent reactions
ited higher antiproliferative activity on the three cancer cell lines with IC50 values of 4.1–13.4 lM.
Ó 2014 Elsevier Ltd. All rights reserved.
3-Substitued indolyl moiety is a basic constituent in numerous
proteins, the neurotransmitter serotonin, and mammalian hor-
mone melatonin as well as a large number of marketed available
pharmaceutical drugs. For instance, indomethacin (1), naratriptan
(2), tegaserod (3), ondansetron (4), zafirlukast (5), sunitinib (6),
sertinole (7), and panobinostat (8) (Fig. 1) contain 3-substituted in-
dole scaffold in their chemical structures.1
Additionally, several marine indole alkaloids have been isolated
and evaluated for their anticancer, antiviral, and antiinflammatory
activities. Meridianins A-E (9) were isolated from tunicate Aplidium
Meridianm.2,3 Bisindolyl alkaloids spaced by five or six membered
heterocyclic moieties, such as piperazinone (Hamacanthin B, 10),
quinone (Asterriquinone, 11), or imidazole (Nortopsentins A-C, 12)
(Fig. 1) have exhibited modest to high anticancer activities against
a wide range of human cell lines at micromolar concentrations.4–6
Additionally, nicotinonitrile skeletons especially those with
amino substituent at C2 and/or 4,6-diaryl-substitutent have
demonstrated broad range of biological activities, such as antibac-
terial,7,8 antifungal,9 antituberculosis,10 antiviral,11 antipyretic,
analgesic, and antiinflammatory12–14 effects.
antiproliferative agents for the treatment of a number of human
cancer cell lines.19–21
The application of one-pot multicomponent reactions (MCRs)
and microwave-assisted have been demonstrated to offer smooth
reaction conditions and higher overall yield when compared to
classical synthesis methodologies.22–28 Bis(30-indolyl)pyridine and
indol-3-yl pyrazolopyridine derivatives have been previously syn-
thesized through MCR and/or microwave assisted reactions29a,29b
according to the previously reported procedure.29c
In continuation of our efforts to synthesize and evaluate new in-
dole derivatives as antiproliferative agents,30 we designed novel
indole-3-cyanopyridine hybrid structures to determine the substi-
tuent effects at C2 and C4 on the cytotoxic potency of this scaffold.
Although other heterocyclic indolyl derivatives have been previ-
ously synthesized,29 to the best of our knowledge this is the first
microwave-assisted synthesis of hybrid indole and 3-cyano-4-aryl-
substituted pyridine compounds and evaluation of their antiprolif-
erative activities.
Considering the advantages of MCRs approach and microwave
irradiation, 3-acetyl indole reacted with ethyl cyanoacetate and a
series of aromatic aldehydes with an excess of ammonium acetate
under microwave irradiation for 15–20 min affording novel 4-aryl-
6-indolyl-nicotinonitrile-2-one derivatives (13a–e) (Scheme 1). All
compounds were characterized by mass and NMR spectroscopy
(Supplementary material).
Furthermore, they have been used as inhibitors for protein
kinase, topoisomerase,15,16 phosphodiesterase17,18 as well as
⇑
Corresponding authors. Tel.: +1 401 874 4471; fax: +1 401 874 5787.
E-mail address: kparang@uri.edu (K. Parang).
0040-4039/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.12.081

N. S. El-Sayed et al. / Tetrahedron Letters 55 (2014) 1154–1158
1155
O
N
Cl
HN
O
N
N
NH
O
H
N
N
O
O
O
N
H
O
N
O
S
HN
HN
O
S
O O
N
O
OH
N
H
N
H
N
2
5
3
1
4
Naratriptan (AmergeTM
GalaxoSmithKline
)
O
Tegasserod (ZelmactTM
Novartis
)
Zafirlukast (AccolateTM
)
IndomethacinTM
Ondansetron (ZofranTM
)
AstraZeneca
GalaxoSmithkline
H2N
N
Cl
O
N
N
N
H
R1
NH
A
B
C
D
E
R1 = OH; R2 = R3 = R4 = H
R1 = OH; R2 = R4 = H; R3 = Br
R1 = R3 = R4 = H; R2 = Br
R1 = R2 = R4 = H; R3 = Br
R1 = OH; R2 = R3 = H; R4 = Br
R2
R3
O
HN
N
H
O
F
N
N
F
N
N
NHOH
6
7
NH
H
N
H
8
R4
Sertinol (CompazineTM
Lundbbeck
)
Panobinostat
Novartis
O
Sunitinib (SutentTM
Sugen/Pfizer
)
9
Meridianins A-E
Br
R1
O
HO
O
A
B
C
D
R
1 = R2 = Br
HN
R
1 = Br; R2 = H
1 = H; R2 = Br
HN
N
NH
N
HN
R
N
N
R1 = R2 = H
O
HN
OH
11
Asterriquinone
10
Hamacanthin B
12
R2
Br
Nortopsentins A-D
N
H
Figure 1. Common biologically active 3-substituted indolyl derivatives.
Ar
CN
O
Ar
CN
a
N
H
O
CH3COO-NH4
+
+
+
+
O
H
O
N
OEt
13a-e
N
H
H
Ar
a
b
c
d
e
2-C4H3S (2-thiophenyl)
4-CH3OC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
Scheme 1. Synthesis of indolylnicotinonitriles (13a–e). Reagents and conditions: (a) piperidine (1 mL), ethylene glycol (1 mL), MW irradiation (W 250 and T 150 °C).
Table 1
Ethylene glycol and piperidine were used as a solvent and a cat-
Comparative synthesis of 2-oxo-1,2-dihydropyridine-3-carbonitrile derivatives (13a–
e) by microwave irradiation and thermal heating
alyst, respectively, during the microwave reaction at a power of
250 W and 150 °C for a given time. The reactions were successful
in achieving the benefits of both utilizing microwave irradiation
and the one-pot MCRs. Compared to the traditional thermal meth-
Ar
CN
od, the reaction time was shortened from hours to minutes with
N
H
O
improvement in both the target product purity and overall product
yield (77–87%) in case of microwave method. The results for each
entry are summarized in (Table 1).
N
H
13a-e
The mechanism of one pot syntheses of nicotinonitrile deriva-
tives is known to be through the formation of a,b-unsaturated ke-
Product
Ar
Time
Yieldc (%)
MWa Thb
mp (°C)
MWa (min)
Thb (h)
tones intermediate via the Claisen–Schimdt reaction between
active methylene containing ketones and aromatic aldehydes using
catalytic amount of strong bases like sodium hydroxide, triethyl-
amine, or piperidine (10%). This reaction is followed by condensa-
tion with nitrile containing active methylene compounds (e.g.,
ethyl cyanoacetate or malononitrile) through the Michael addition
reaction in the presence of ammonium acetate, cyclization, and
aromatization to afford the corresponding 4-aryl-2-oxo-1H-pyri-
dine-3-carbonitrile derivatives31 (Scheme 2).
13a
13b
13c
13d
13e
2-C4H3S
4-OCH3C6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
20
20
15
17
17
17
18
10
15
14
77
79
87
82
83
44
45
56
63
61
>300
>300
>300
>300
>300
a
b
c
The reaction was carried out by microwave irradiation at 250 W and 150 °C.
The reaction was carried out by thermal heating at 150 °C in oil bath.
Isolated yields.
Results in Table 1 showed that, the electronic effect and the
nature of the substituent on the aromatic aldehyde ring played a
critical effect in terms of reaction time and product yield under
similar reaction conditions. When aromatic aldehydes bearing a
strong electron withdrawing group (e.g., 4-fluorine, 4-chloro, 4-
bromo) in para positions were used, the yield of the products
was increased in a shorter reaction time compared to those carry-
ing electron donating groups (e.g., 4-methoxy group) in para posi-
tion under a similar reaction condition.
Moreover, the reaction of compounds 13a–e with phosphoryl
chloride for 18–24 h afforded the corresponding 2-chloropyridine
derivatives (14a–e) after thermal heating at 80 °C as shown in

1156
N. S. El-Sayed et al. / Tetrahedron Letters 55 (2014) 1154–1158
Ar
Step 1
Step 2
H
O
Ar
H
Base
O
O
+
N
H
N
H
Ar
Ar
H
H
H
CN
H
H
CN
O
O
Michael addition
Cyclization
+
N
OEt
-H
-H2O
O
N
H
EtO
N
H
N
H
H
H
H
Ar
N
Ar
Ar
H
H
CN
CN
OH
CN
Aromatization
N
H
N
H
O
O
N
H
N
H
N
H
Scheme 2. Mechanistic illustration for the formation of 2-oxo-1,2-dihydropyridine-3-carbonitrile system.
Scheme 3. 2-Chloropyridine derivatives (14a–e) were used as
precursors for nucleophilic substitution reaction with ethylenedia-
mine under a reflux condition in ethanol to afford the correspond-
ing 2-aminoethylenamino 6-indolylnicotinonitrile derivatives
(15a–e), The chemical structures of these novel compounds 14a–
e and 15a–e were elucidated by IR, mass, and NMR spectroscopy
(see Supplementary material).
The antiproliferative activities of all synthesized compounds in
a panel of cancer cell lines including human ovarian adenocarci-
noma (SK-OV-3), breast adenocarcinoma (MCF-7), and cervix ade-
have an ethylene-1,2-diamine moiety attached to the substituted
pyridine ring. Changing the substation at C2 from oxo (compounds
13a–e) to ethylene-1,2-diamine (compounds 15a–e) showed that,
an ethylene-1,2-diamine moiety plays a significant role in elevat-
ing the anti-proliferative activity. However, among indolyl nicoti-
nonitrile derivatives (15a–e), compound 15c with p-fluorophenyl
substituent at C4 did not show similar potency when compared
with the other compounds in this series, suggesting that the pres-
ence of a strong electron withdrawing fluorine group is not pro-
ductive. On the other hand, the presence of a heterocyclic ring as
in compound 15a or an electron donating group like p-methoxy
group as in compound 15b resulted in higher antiproliferative
activity. Thus, electronic effect of the substituent of the phenyl
group substituent appears to have a direct effect on antiprolifera-
tive activity.
Based on the results from the preliminary screening, com-
pounds 15a, 15b, 15d, and 15e were selected for further IC50 eval-
uation. IC50 is the concentration that causes 50% inhibition of
cancer cell growth. The IC50 values of 15a, 15b, 15d, and 15e deriv-
atives were tested in HeLa, SK-OV-3, and MCF-7 cells (Table 2). As
it is shown in the IC50 graphs (Fig. S1, Supplementary material), all
these four derivatives showed high potency in the inhibition of the
proliferation of different cancer cells. The IC50 values of compounds
nocarcinoma (HeLa) cells were evaluated. All compounds (50
were tested for their anticancer potency after 72 h incubation.
DMSO (3%) and doxorubicin (Dox 10 M) were used as negative
lM)
l
and positive controls for the assay, respectively.
As it is shown in Figure 2, compounds 13a, 13c, 13d, 13e, 14a,
14c, and 14d did not show any significant antiproliferative activity
against HeLa, SK-OV-3, and MCF-7 cells. Among all derivatives,
compounds 13b, 14b, and 15a–e showed modest to high antiprolif-
erative potency. However, compounds 15b, 15d, and 15e showed
comparable potency with that of Dox in HeLa cells and significantly
higher potency in SK-OV-3 and MCF-7 cells versus Dox. For exam-
ple, compounds 15b, 15d, and 15e inhibited the proliferation of
HeLa, SK-OV-3, and MCF-7 cells by 62–67%, 85–88%, and 84–87%.
Interestingly, these three compounds inhibited the cell prolifera-
tion of SK-OV-3 and MCF-7 cells with higher potency compared
to that of HeLa cells, indicating that their activity was cell-specific.
All synthesized compounds have a common scaffold of conju-
gated substituted 6-indolyl pyridine ring. Compounds 15a–e also
15a, 15b, 15d, and 15e were in the range of 4.1–13.4
lM, 6.5–
8.1 M, 5.9–7.1 M, and 5.8–8.8 M, respectively, in HeLa, SK-
l
l
l
OV-3, and MCF-7 cells. Compounds 15a and 15e showed slightly
lower IC50 values in MCF-7 and SK-OV-3 cells compared to the
other compounds. The partition coefficient (LogP) of all the synthe-
sized compounds was calculated by using ChemDraw 10.0 (Sup-
plementary information, Table S1). The data revealed that the
compounds 15a–e with moderate LogP values of 3.23–4.19
showed significantly higher antiproliferative activity compared to
other compounds possibly because of higher cellular uptake of
these compounds).32 Compounds 13a–e with low LogP values
(2.43–3.28) did not show high antiproliferative activity, while
compounds 14a–e with high lipophilicity (LogP = 4.82–5.77)
showed moderate activity. These data indicate that there is a cor-
relation between the partition coefficient and antiproliferative
activity of these compounds, and an optimal LogP is required for
generating maximum activity.
Ar
Ar
CN
O
CN
Cl
a
N
H
N
14a-e
Ar
N
H
N
H
13a-e
Ar
CN
a
2-C4H3S
b
c
d
e
4-CH3OC6H4
4-FC6H4
NH2
N
N
H
b
4-ClC6H4
4-BrC6H4
15a-e
N
H
In conclusion, we have demonstrated a facile and efficient
method for the preparation of a new series of 6-indolypyridine-
3-carbonitrile derivatives via the one-pot MCR with the
Scheme 3. Reagents and conditions: (a) POCl3, reflux, 80 °C for 18–24 h; (b)
ethylenediamine, ethanol, reflux, 36–48 h.

N. S. El-Sayed et al. / Tetrahedron Letters 55 (2014) 1154–1158
1157
Figure 2. Antiproliferative activity of 13a–e, 14a–e, and 15a–e.
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Table 2
IC50 values of four selected compounds in SK-OV-3, MCF-7, and HeLa cells
Entry
HeLaa
SK-OV-3
MCF-7
15a
15b
15d
15e
Dox
13.4
7.2
6.8
4.7
6.5
5.9
5.8
3.2
4.1
8.1
7.1
8.8
6.8
0.1533a
7.533b
a
The IC50 values of compounds were calculated in
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microwave-assisted irradiation affording high yields, short reac-
tion times, and the easy workup procedure. Among all compounds,
2-((2-aminoethyl)amino)-4-aryl-6-indolylnicotinonitrile
series
(15a, 15b, 15d, and 15e) exhibited higher antiproliferative activity
than Dox against SK-OV-3, MCF-7, and HeLa cells. These data sug-
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template for further structure optimization for generating com-
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Acknowledgments
We thank the financial support from the American Cancer Soci-
ety Grant # RSG-07-290-01-CDD, National Research Cancer (Dokki,
Giza, Egypt), and the Cultural Affairs and Mission Sector, Ministry
of Higher Education, Egypt) for the financial support. We also
thank the National Center for Research Resources, NIH, and Grant
Number 8 P20 GM103430-12 for sponsoring the core facility. The
authors would like to thank Dr. Brenton DeBoef for providing the
microwave facility.
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