Iodine catalyzed simple and efficient synthesis of antiproliferative 2-pyridones

Article abstract of DOI:10.1016/j.bmcl.2016.03.071

A simple and efficient method for the selective synthesis of 2-pyrdones from 4H-pyrans using iodine as catalyst and ethanol as solvent was developed. The present method is equally effective for both aromatic and hetero aromatic ring containing 4H-pyrans.

Full text of DOI:10.1016/j.bmcl.2016.03.071

Accepted Manuscript
Iodine catalyzed simple and efficient synthesis of antiproliferative 2-pyridones
Komuraiah Buduma, Srinivas Chinde, Niranjana Kumar Arigari, Paramjit
Grover, K.V.N.S. Srinivas, J. Kotesh Kumar
PII:
S0960-894X(16)30303-1
DOI:
http://dx.doi.org/10.1016/j.bmcl.2016.03.071
BMCL 23714
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
6 October 2015
25 February 2016
17 March 2016
Please cite this article as: Buduma, K., Chinde, S., Arigari, N.K., Grover, P., Srinivas, K.V.N.S., Kotesh Kumar, J.,
Iodine catalyzed simple and efficient synthesis of antiproliferative 2-pyridones, Bioorganic & Medicinal Chemistry
Letters (2016), doi: http://dx.doi.org/10.1016/j.bmcl.2016.03.071
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Iodine catalyzed simple and efficient synthesis of
antiproliferative 2-pyridones
Komuraiah Budumaa, Srinivas Chindeb, Niranjana Kumar Arigaria and Paramjit
Groverb, Srinivas KVNSa* and Kotesh Kumar Ja*
aNatural Product Chemistry, CSIR-Central Institute of Medicinal and Aromatic Plants- Research
Centre, Boduppal, Hyderabad-500092, India
bToxicology Unit, Biology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad-
500007, India.
Corresponding
authors
Tel.:
+91-040-27211131;
fax:
+91-040-27202602;
e-mail:
koteshkumarj@yahoo.com; kvnssrinivas@yahoo.co.in
Abstract
A simple and efficient method for the selective synthesis of 2-pyrdones from 4H-pyrans
using iodine as catalyst and ethanol as solvent was developed. The present method is equally
effective for both aromatic and hetero aromatic ring containing 4H-pyrans. The compatibility
with various functional groups, mild reaction conditions, high yields and application of
inexpensive, readily and easily available iodine as catalyst and formation of 2-pyridones as
major products are the advantages of the present procedure. In vitro antiproliferative activity of
the final synthesized compounds was evaluated with four different Human cancer cell lines
(Lung adenocarcinoma-A549, Hepatocarcinoma-HepG2, Breast carcinoma-MCF-7 and
Ovarian carcinoma-SKOV3) and Normal human lung fibroblast cell line (MRC-5).
Compounds 2b showed better inhibition against MCF-7, HepG2 and A549 cell lines (IC50
8.00±0.11, 11.93±0.01 and 15.85±0.04 µM respectively) as compared with doxorubicin and
also 2e showed moderate inhibition against MCF-7, HepG2 (IC50 9.32±0.21 and 20.22±0.01
µM respectively cell lines respectively) as compared with doxorubicin. As many clinically
used antiproliferative agents induce apoptosis in cancer cells hence, the 2-pyridone analogues
were also tested for their ability to induce apoptosis in MCF-7 cells using the caspases-3 and -9
assays.

2-Pyridone moiety is present in a large number of natural and synthetic bioactive
molecules. 2- Pyridones and their analogues have attracted considerable interest recently
because of their antiproliferative, antiviral and anti-inflammatory properties.1-3 The drugs
Amrinone4 (I) and Milrinone (II) 5 used as cardiotonic agents for the treatment of heart failure
contains 2-pyridone moiety in their structure. Recently, 2-pyridone derivative (III) has been
identified as a specific non nucleoside reverse transcriptase inhibitor of human immuno
deficiency virus-1 (HIV-1).6 2-Pyrdiones are important intermediates in some synthetic
approaches for the synthesis of camptothecin family of antitumor agents. 2-Pyridones and their
analogues are targeted compounds in a large number of drug discovery programs related to
cancer and inflammatory disorders such as CDK4 and FGFR inhibitors and p38 inhibitors
7-10
(IV−V)
respectively (Fig 1). Hence, synthesis of 2-pyridones has gained much chemical
and pharmaceutical importance in recent years.
So far, only a few methods have been reported for one-pot synthesis of 2-pyridones by
condensation of three components, an aldehyde, a β-ketoester and cyano acetate or cyano
acetamide under acidic or basic conditions such as HNO2, H2SO4, Piperidine, NH4OAc, ZnO,
SOCl2 etc,.11-14 However, these methods suffers from very low yields with a mixture of 2-
pyridones as minor and 3,4-dihydro-2-pyridones as major products.
Figure1. Pyridin-2-one containing compounds of medicinal interest.

Subsequently, several multistep methods have been reported with somewhat higher
yields to synthesize 2-pyridones. In general, these methods involve synthesis of 4H-pyrans by
condensation of three components using an aldehyde, a β-ketoester and malononitrile in first
step, then conversion of the 4H-pyrans to 2-pyridones in second step. Several reagents have
been reported for the synthesis of 4H-pyrans like Al2O3/KF, metal oxide nano particles, ionic
liquids, solid supported catalysts etc.,15-20 but for the conversion of 4H-pyrans to 2-pyridones,
very few methods were reported under strong acidic conditions like H2SO4, HNO2, and mixture
of HNO2 and H2SO4 with very low yields with 2-pyridones as minor and 3,4-dihydro-2-
pyridones as major or exclusive products. 21-24 However, many of the reported one-pot as well
as multistep methods have significant drawbacks such as expensive and toxic reagents,
incompatibility with other functional groups, long reaction times, strong acidic conditions,
tedious workup procedures and low yields etc. Thus, there is a need for simple, efficient,
economic and eco-friendly procedure to synthesize 2-Pyridones under mild conditions.
As a part of our ongoing work of novel methodologies for the synthesis of bioactive
molecules, we were interested to synthesize 2-pyridone derivatives due to their biological
importance. Recently, iodine has received considerable attention as an inexpensive, readily
available mild and efficient catalyst for various organic reactions such as Suzuki-Miyaura
coupling reaction,25 Michael addition,26-27 protection28 and deprotection29 of acetals, synthesis
of bis-indols,30 β-keto enol ethers,31 chalcones,32 and quinolines33 etc. Here, we report a
simple, efficient and mild method for the synthesis of 2-pyridones selectively from 4-H pyrans
using iodine as catalyst.
It is well known that cancer deaths are more than those caused by AIDS, malaria, and
tuberculosis combined. The drugs like Indomethacin, doxorubicin has created some hope for
the life of cancer patients. However, the chemotherapeutic agents under present use suffer from
various drawbacks. This undoubtedly underscores the need of developing new
chemotherapeutic agents for more effective and economical treatment of cancer.
In this paper, we report a novel methodology for the synthesis of various 2-pyridones
and the resulting analogues were also screened for in vitro antiproliferative activity using four
different human cancer cell lines and Normal human cell line. Because of many clinically used
antiproliferative agents induce apoptosis in cancer cells34, we tested the 2-pyridone analogues
for their ability to induce apoptosis in MCF-7 cells using the caspases-3 and 9 assays.

Initial attempt of one pot synthesis of 2-pyridones by condensation of an aldehyde, a β-keto
ester and malononitrile with either molecular Iodine (I2) or metal iodides like HgI, NaI, CuI
and KI was not successful. Then two step method was devised in which first 4H-pyrans were
prepared by condensation of an aldehyde, malononitrile and ethylacetoacetate as per the
35-36
reported methods
but with slight modifications. In the second step, different 2-pyridones
were synthesized selectively from the 4H-pyrans under reflux conditions in the presence of
iodine as catalyst and ethanol as a solvent (Scheme).
Scheme: Iodine catalyzed simple and efficient synthesis of 2-pyridones.
.
The reaction proceeded via iodination at benzylic positon of 4H-pyran in the presence
of iodine at 80 oC to form intermediate I, which further underwent formation of oxonium ion II
by leaving iodide ion and shifting of the double bond. Further rearrangement took place by

instantaneous opening of pyran to give pyridonium ion III and finally removal of hydrogen
iodide (HI) resulted 2-pyridone (Fig. 2).
Figure 2: Plausible mechanism for 2-pyridines formation.
The method was also optimized with respect to different catalysts, solvents and catalyst
load etc. It was observed that molecular iodine and ethanol are the most effective catalyst and
solvent in terms of yields and reaction times than other catalyst sources such as HgI, NaI, CuI
and KI (Table 1) and solvents such as toluene, DCM, dichloroethane, CHCl3, acetone,
methanol, ethanol, CH3CN, THF, propane-2-ol, ethanol+water, etc (Table 2, entry 4). When
catalyst load increased from 2.5 to 10 mol %, yields were steadily increased and thereafter no
significant change was observed from 10 to 20 mol %. But, further increase in catalyst load,

led to significant decrease in the yields of the final product. This may be due to the coagulation
of I2.
Table 1: Catalysts screened for the synthesis of pyridin-2-onea
Entry Lewis acid
Solvent
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
Time
10 hrs
12 hrs
24 hrs
8 hrs
5 hrs
5 hrs
5 hrs
5 hrs
5 hrs
5 hrs
5 hrs
5 hrs
Yieldb (%)
1
KI 10 mol%
NaI 10 mol%
HgI 10 mol%
CuI 10 mol%
I2 2.5 mol%
I2 5 mol%
30
20
15
35
40
60
95
95
95
70
50
40
2
3
4
5
6
7
I2 10 mol%
I2 15 mol%
I2 20 mol%
I2 25 mol%
I2 30 mol%
I2 40 mol%
8
9
10
11
12
aethyl-6-amino-5-cyano-2-methyl-4-(3,4,5-trimethoxyphenyl)-4H-pyran-3-
carboxylate (1k) (3.521 mmol), was refluxed at 800C in 5 ml EtOH for
stipulated time in the presence of specific amount of catalyst.
bIsolated yield of pure product.
The above methodology was tolerant to a wide variety of electron releasing as well as
electron withdrawing 4H-pyrans to give the corresponding products (2a-m) in excellent yields
selectively. The reaction with ethyl-6-amino-5-cyano-4-(4-fluorophenyl)-2-methyl-4H-pyran-
3-carboxylate, ethyl-6-amino-5-cyano-4-(4-bromophenyl)-2-methyl-4H-pyran-3-carboxylate
and
ethyl-6-amino-5-cyano-2-methyl-4-(3,4,5-trimethoxyphenyl)-4H-pyran-3-carboxylate
maintained high yield and gave the corresponding products 2f, 2g and 2k in 91, 93 and 95 %
yields respectively. Also, the reaction with other 4H-pyrans viz., 1a, 1b, 1c, 1d, 1e, 1h, 1i, 1j,
1l and 1m with iodine gave corresponding products 2a, 2b, 2c, 2d, 2e, 2h, 2i, 2j, 2l and 2m in
90, 85, 75, 87, 89, 73, 68, 70, 74 and 72 % yields respectively (Scheme).

Table 2. Solvent screened with 10 mol% of catalysta
Entry
1
2
3
4
5
6
7
8
9
10
11
Solvent
CHCl3
Toluene
MeOH
EtOH
THF
Acetonitrile
Propane-2-ol
DCM
EtOH+Water
Acetone
Substrate
1i
Product
Time
4hrs
Yieldb (%)
2i
2i
2i
2i
2i
2i
2i
2i
2i
2i
2i
65
60
85
95
75
45
50
50
80
75
40
1i
1i
1i
1i
1i
1i
1i
1i
1i
4 hrs
4 hrs
2 hrs
5 hrs
5 hrs
5 hrs
4 hrs
6 hrs
4 hrs
6 hrs
Dichloroethane 1i
aethyl-6-amino-5-cyano-2-methyl-4-(3,4,5-trimethoxyphenyl)-4H-pyran-3-carbox- ylate (1k) (3.521 mmol),
was heated at 80 0C in 5 mL solvent for stipulated time in the presence of 10 mol % I2.
bIsolated yield of the pure product.
Antiproliferative activity of the synthesized 2-Pyridones were evaluated in in vitro
mode using 3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay37 on
the human cancer cell lines and as well as normal cell line i.e., Human lung adenocarcinoma
cell line (A549), Human hematoma (HepG2), Human breast adenocarcinoma (MCF-7), Human
Ovarian carcinoma cell line (SKOV3) and Normal human lung fibroblast cell line (MRC-5).
The assay is based on the reduction of MTT by the mitochondrial dehydrogenase of viable
cells into purple formazan crystals which gets dissolved in DMSO and read at 570 nm. The
results of in vitro cytotoxic activity were expressed as the IC50 (µM) and doxorubicin was used
as positive control. As shown in Table 3, most of the compounds were moderately active but,
compound 2b showed better inhibition against MCF-7, HepG2 and A549 cell lines (IC50
8.00±0.11, 11.93±0.01 and 15.85±0.04 µM respectively) as compared with doxorubicin and
also 2e showed better inhibition against MCF-7, HepG2 cell lines (IC50 9.32±0.21 and
20.22±0.01 µM respectively) as compared with doxorubicin. Compounds 2b, 2f, 2e and 2k
showed better inhibition against HepG2 cell line (IC50 2b: 11.93±0.01; 2f: 18.55±0.01; 2e:
20.22±0.01 and 2k: 20.92±0.02 µM) as compared with doxorubicin. Keeping in view the
above fact, the cell viability of these test compounds was also determined in normal human
lung cell line (MRC-5). All the tested compounds were considered non-cytotoxic since the IC50
values were >100 µM against the normal cell line.

Table 3: Antiproliferative activity of compound 2a-2m.
Antiproliferative activity (IC50 in µM)
Compound
A549
>100
HepG2
38.45±0.10 21.96±0.01
8.00±0.11
25.12±0.04 51.51±0.01 36.07±0.04
MCF-7
SKOV3
>100
>100
>100
>100
>100
>100
>100
>100
MRC-5
220.37±0.09
438.36±0.034
192.14±0.144
2228.21±0.025
1220.37±0.09
148.931±0.085
309.68±0.064
228.68±0.206
2a
2b
2c
2d
2e
2f
2g
2h
2i
15.85±0.04 11.93±0.01
>100
>100
21.72±0.11 81.95±0.04
20.22±0.01
9.32±0.21
22.94±0.01
65.50±0.03 31.75±0.01
15.40±0.05 18.55±0.01
>100
25.00±0.11 34.07±0.01 25.38±0.04
>100
57.35±0.01
76.01±0.21 406.86±0.106
17.52±0.04
74.05±0.05 33.44±0.11 97.31±0.11 205.28±0.035
2j
2k
2l
2m
Doxo
20.10±0.06
23.37±0.02
27.33±0.04
>100
>100
>100
252.81±0.112
191.96±0.068
195.67±0.075
20.92±0.02 18.12±0.04
>100 33.98±0.24
24.03±0.01 32.32±0.01 31.38±0.04
0.23±0.01 3.39±0.11
1.94±0.01 25.04±0.01 89.68±0.064
The activity of caspases- 3 and 9 was determined according to reported method38 in the
active compound 2b to confirm its antiproliferative active before generating more toxicological
data in animals and also we need to carry out mechanistic studies to detect the main target of
these 2-pyridones. Caspases (cysteine aspartase enzyme), a group of intracellular proteases, are
responsible for the induction of apoptosis. Among all the caspases, caspase-3 is one of the
effective caspases that is activated by initiator caspases (caspase-8 and 9) by proteolytic
cleavage39. Synthesis of a large number of analogues and their evaluation in different type of
cell lines is required to understand these intriguing observations, which may pave the way to
compounds with highly selective toxicity profiles. The induction of apoptosis by the potent
compound 2b was investigated using the MCF-7 cell line in both time-dependent and dose-
dependent manner in the proportion of cells undergoing apoptosis by activation of caspases-3
and 9 with the maximum occurring after 48 h of treatment. Considering this fact, it was
interesting to understand the association of cytotoxicity with that of apoptosis by the compound
2b. In the present study, the MCF-7 cells were treated with 2b compound (8 and 12 µM) along
with the positive control doxorubicin at different concentrations and observed for the activation
of caspase-3, and 9. The results showed 2 to 3 fold increase in both caspase-3 and 9 activities
when compared to untreated control cells indicating that they have the capacity to induce

apoptosis by the activation of caspases in MCF-7 cells (figure 3). Nevertheless, it is
contemplated that a slight structural modification of these active derivatives may yield
prospective anti-proliferative agents.
The main molecular target of these 2-pyridones are inhibitors of DNA gyrase, a type II
DNA topoisomerases. DNA topoisomerases are a class of enzymes that regulate the
topological structure of DNA in living organisms. In eukaryotes type II DNA topoisomerases
are essential for chromosome segregation at the final stage of DNA replication40.
The results were expressed as means of fluorescence intensity ± standard deviation (SD) of two independent
experiments performed in triplicates.
Figure 3: The effect of 2b (A) caspase-3 and (B) caspase-9 activity was tested in the MCF-7
cell line.
In conclusion we have developed an efficient method for the selective synthesis of 2-
pyrdones from 4H-pyrans using iodine as catalyst and ethanol as solvent. The present
procedure is equally effective for both hetero aromatic and aromatic ring contained pyrans and
electron donating as well as electron withdrawing substituents. The compatibility with various
functional groups, mild reaction conditions, high yields and application of inexpensive, readily
available iodine as catalyst and formation of 2-pyridones as major products are the advantages
of the present procedure. All the synthesized compounds were screened for antiproliferative
activity using four different Human cancer cell lines and Normal cell line (human lung
fibroblast -MRC-5). Introducing methyl, cyano and fluoro groups at fourth position on benzene
ring induced antiproliferative activity of 2-pyridones (2b: IC50 8.00±0.11 µM against MCF-7

cell line; 2b: IC50 11.93±0.01 µM against HepG2 cell line; 2b: 15.85±0.04 µM against A549
cell line.; 2e: IC50 9.32±0.21 µM against MCF-7 cell line; IC50 20.22±0.01 µM against HepG2
cell; 2f: IC50 15.40±0.05 µM against A549 cell line IC50 18.55±0.01 µM against HepG2
cell line) when compared with the unsubstituted 2-pyridone (2a). Similarly, substitution of
three methoxy groups at 3,4,5 positions exhibited enhanced activity (2k: IC50 18.12±0.04 µM
against MCF-7 cell line; IC50 20.92±0.02 µM against HepG2 cell) when compared to the mono
methoxy substituted 2-pyridone at fourth position (2c). In the case of introduction of hetero
aromatic ring in place of phenyl ring, it was observed that 2-pyridones with furan ring was
active against MCF-7 cell line (2i: IC50 17.52±0.04 µM) and thiophene ring was active against
A549 cell lines (2j: IC50 20.10±0.06 µM). As the antiproliferative effect results from the
apoptosis inducing ability of these 2-pyridones, as confirmed by the caspases-3 and 9 assays
with the 2b compound. The potent apoptosis inducing power of the selected 2b compound is
pronounced at concentrations as low as 8 µM.
Supplementary data
Supplementary data associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.bmcl.2015.10.15. These data include NMR, MASS spectral data,
materials and methods.
Acknowledgements
Authors thank Director, CSIR-CIMAP, Lucknow, India, for their constant encouragement
and support. Author Komuraiah Buduma thanks CSIR-New Delhi for granting Senior
Research Fellowship.
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Graphical Abstract