Straightforward multicomponent synthesis of pyrano[2,3-d]pyrimidine-2,4,7-triones in β-cyclodextrin cavity and evaluation of their anticancer activity

Article abstract of DOI:10.1007/s13738-019-01633-2

Abstract: In the present study, we have developed an efficient and green method for the synthesis of pyrano[2,3-d]pyrimidine-2,4,7-triones employing β-cyclodextrin as a catalyst in aqueous media from substituted aldehydes, barbituric acid and meldrum acid

Full text of DOI:10.1007/s13738-019-01633-2

Journal of the Iranian Chemical Society
https://doi.org/10.1007/s13738-019-01633-2
ORIGINAL PAPER
Straightforward multicomponent synthesis of pyrano[2,3-d]
pyrimidine-2,4,7-triones in β-cyclodextrin cavity and evaluation
of their anticancer activity
Manisha R. Bhosle1 · Pooja Andil1 · Diksha Wahul1 · Giribala M. Bondle1 · Aniket Sarkate2 · Shailee V. Tiwari3
Received: 18 December 2017 / Accepted: 9 February 2019
© Iranian Chemical Society 2019
Abstract
In the present study, we have developed an efficient and green method for the synthesis of pyrano[2,3-d]pyrimidine-2,4,7-
triones employing β-cyclodextrin as a catalyst in aqueous media from substituted aldehydes, barbituric acid and meldrum
acid. The reactions were performed under mild conditions to afford biologically active target molecules in excellent yields.
All the synthesized compounds are evaluated for their in vitro anticancer activity against HePG-2 (Human liver cancer cell
line) and MCF-7 (Human breast cancer cell line). Among them 4c, 4j, 4k, 4l and 4m were active and potent anticancer agents.
Graphical abstract
Keywords Anticancer activity · β-Cyclodextrin · Multicomponent reaction · Pyrano[2,3-d]pyrimidine-2,4,7-triones
Introduction
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s13738-019-01633-2) contains
supplementary material, which is available to authorized users.
Cancer being the second foremost cause of death worldwide,
a number of experiments have been going on to develop
compounds having minor or no side effects. The explora-
tion of privileged structures in drug discovery is a rapidly
emerging theme in medicinal chemistry [1–3]. Pyrano[2,3-
d]pyrimidine-2,4,7-triones are such active molecules hav-
ing pyrimidinone as immensely important pharmacophore,
owing to their potent antitumor activity [4, 5] in the treat-
ment of B16 melanoma and P388 leukemia [6]. The pyrano-
fused pyrimidines have emerged as promising scaffolds
because of their broad spectrum of biological activities,
* Manisha R. Bhosle
d.manisha11@gmail.com
1
Department of Chemistry, Dr. Babasaheb Ambedkar
Marathwada University, Aurangabad, MS 431004, India
2
Department of Chemical Technology, Dr. Babasaheb
Ambedkar Marathwada University, Aurangabad, MS 431004,
India
3
Department of Pharmaceutical Chemistry, Durgamata
Institute of Pharmacy, Dharmapuri, Parbhani-431401,
MS 431001, India
Vol.:(0123456789)
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Journal of the Iranian Chemical Society
such as antimicrobial [7–9], antiplatelet [10], antifungal
[11], as well as anticonvulsant [12] activities. Compounds
which having a uracil moiety in the skeleton of an organic
molecule are distinguished themselves as heterocycles of
profound chemical and biological significance [13–16]. Bar-
bituric acid or 6-hydroxy uracil is a heterocyclic compound
that possesses anti-neoplastic [17], antiviral [18], antibiotic
[19], and anti-inflammatory [20] activities. Many synthetic
drugs of barbituric acid motif-based derivatives and chemo-
therapeutic agents are well known (Fig. 1) [12–23].
General procedure for the synthesis of pyrano[2,3 d]
pyrimidine‑2,4,7‑triones (4a‑r)
A mixture of substituted benzaldehydes (1a–r) (4 mmol),
meldrum acid (2) (4 mmol), barbituric acid (4 mmol) and
β-cyclodextrin (20 mol%) in water (15 ml) was subjected
to ultrasonication at 65 °C. Progress of the reaction was
monitored by thin-layer chromatography. After 60 min,
reaction mixture was cooled to room temperature, filtered
and washed with hot water. Obtained solid was crystallized
by ethanol:DMF.
In this context development of green alternative multi-
component reactions (MCRs) has attracted much attention
as these reactions produced important biological scaffolds
[24] and various designer as well as marketed drugs in an
environment-friendly pathway. Water is the greenest solvent
among all and accordingly it has been widely used as the
reaction medium for straightforward organic transformations
as well as in MCRs [25].
Synthesized compounds characterized by IR, 1H NMR
and are in good agreement with those reported in the lit-
erature [27, 28].
Experimental procedure for MTT assays
However, few reports have appeared in the literature on
the synthesis of pyrano[2,3-d]pyrimidine-2,4,7-triones [27,
28] and no reports are available on its biological screening.
With this background and as part of our ongoing program
toward the development of greener chemical approaches
for the synthesis of biologically relevant intermediates and
heterocyclic moieties [29–31], herein, we wish to report a
straightforward, efficient, clean, and high-yielding MCR
protocol for the one-pot facile synthesis of biologically rel-
evant diverse and densely functionalized 5-aryl-5,6-dihydro-
1H-pyrano[2,3-d]pyrimidine-2,4,7-triones heterocyclic scaf-
folds and their anticancer activity.
The stock solutions of test compounds were prepared in
DMSO. After 24 h incubation, different concentrations (2,
4, 6, 8 µM) of compounds, made by serial dilution in culture
medium, were added in 48 h incubation. The final concentra-
tion of DMSO was 0.01% in each well. A separate well con-
taining 0.01% DMSO only was run as DMSO control, which
was found inactive under applied conditions. The cell growth
was determined using MTT (3-(4,5-dimethylthiazol-2-yl))-
2,5-diphenyl tetrazolium bromide (Sigma) reduction assay,
which is based on ability of viable cells to reduce a soluble
yellow tetrazolium salt to blue farmazan crystal [32, 33].
Briefly, after 48 h of treatments, 10µl of MTT dye, prepared
in phosphate-buffered saline (PBS) was added to all wells.
The plates were then incubated for 4 h at 37 °C. Superna-
tant from each well was carefully removed, formazan crystals
were dissolved in 100 µL of DMSO and absorbance at 540 nm
wavelength was recorded and each concentration was tested
in threefold. The IC50 values were determined as concentra-
tion of compounds that inhibited cancer cell growth by 50%.
Experimental
General: all the chemicals used were of laboratory grade.
Melting points of all the synthesized compounds were
determined in open capillary tubes and are uncorrected.
1H NMR spectra were recorded with a Bruker Avance 400
spectrometer operating at 400 MHz using DMSO solvent
and tetramethylsilane (TMS) as the internal standard and
chemical shift in δ ppm Mass spectra were recorded on a
Sciex, Model; API 3000 LC–MS/MS Instrument. The purity
of each compound was checked by TLC using silica-gel,
60F254 aluminum sheets as adsorbent and visualization was
accomplished by iodine/ultraviolet light.
Spectral analysis
5,6-dihydro-5-phenyl-1H-pyrano[2,3-d]
pyrimidine-2,4,7(3H)-trione (4a)
FTIR (ATR υ cm-1) characteristic absorptions: 3207 (N–H
stretching), 3083 (Ar–H stretching), 2844 (C–H stretching),
Fig. 1 Representative bio-
logically active molecules that
posses pyrimidinone and uracil
structural motif
O
O
HN
N
O
NH2
NH
NH
N
O
N
H
O
R
O
N
H
O
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Journal of the Iranian Chemical Society
1184 (C–O–C stretching), 1690(C=O stretching); 1H-NMR
(400 MHz, DMSO-d6, δ ppm): 3.29–3.37 (dd, 1H, –CH2),
3.55–3.65 (dd, 1H, –CH2), 4.9–5.1 (t, 1H, J = 7.2 Hz,
CH), 7.52–7.59 (d, 2H, J=8 Hz, Ar-H), 8.02–8.09 (d, 2H,
J=8 Hz, Ar-H), 8.24 (s, 1H, Ar–H), 11.26 (s, 1H, –NH) and
11.41 (s, 1H, –NH).
hydroxyl groups outside. These macrocycles act as host
molecules and form stable complexes with hydrophobic
compounds. Thus, we performed model reaction using
20 mol% β-CD in water at room temperature the prod-
uct was obtained in moderate yield (71%). The reaction
was found to be sluggish at room temperature; however,
by increasing the temperature to 60 °C, the correspond-
ing product (4a) was obtained in 89% yield within 5 h
(Scheme 1). No product formation was detected in the
absence of cyclodextrin, which clearly demonstrates the
catalytic role of cyclodextrin. This result indicates that
catalyst plays a critical role in this reaction.
Results and discussion
Chemistry
Recently, growing awareness about environmental safety and
global warming has attracted worldwide concern towards
use of renewable sources and reduction of waste. This has
shifted paradigm towards the use of eco-friendly and green
protocols in organic synthesis [34, 35]. A catalyst derived
from biomass and green solvent increases the greenness of
a process. Cyclodextrins are those produced from starch by
means of enzymatic conversion. They catalyse reactions by
supramolecular catalysis through non-covalent bonding,
forming reversible host–guest complexes just like enzymes
[36–40]. Among the cyclodextrins β-cyclodextrin is useful
both from an economic and environmental point of view,
apart from being non toxic, metabolically safe and readily
recoverable and reusable. In this work, we report the use of
β-cyclodextrin as a catalyst in the synthesis of 5-aryl-5,6-di-
hydro-1H-pyrano[2,3-d]pyrimidine-2,4,7-triones (4a-r) in
aqueous medium (Scheme 1).
US irradiation offers an alternative energy source which
is ordinarily accomplished by heating [41–44]. Ultrasound-
assisted reactions proceed by acoustic cavitation phenom-
enon, that is, the formation, growth, and collapse of bubbles
in the liquid medium. During the collapse of a cavity, high
local temperatures and pressures arise which lead to increase
in the rate of reactions [45–48]. Considering the synthetic
utility of ultrasonication, we performed the model reaction
using β-CD under ultrasonication, it was observed that the
corresponding product was obtained in 96% yield within 1 h
at 65 °C. Here ultrasonication reduces the reaction time from
5 h to 1 h. Therefore all the reactions were carried under
ultrasonication.
The three most common cyclodextrins are α, β and
γ-species having 6, 7 and 8 sugar molecules, respectively,
in the ring system. Efforts were made to carry out the cyclo-
condensation using α, β and γ-species in water under ultra-
sound irradiation. Based on screening results in Table 1,
β-CD is the best catalyst among others. Low conversions
were observed with either α- or γ-cyclodextrin because of
the size of cavities. Cavity of α-CD might be too small
to hold three reagents and the cavity of γ-CD was too big
compared to β-CD. This observation is in a good agree-
ment with the known fact that β-CD has usually one order
of magnitude higher affinity for the benzene derivatives as
compared to α- and γ-CD [49–52]. No product formation
was detected in the absence of cyclodextrin under ultra-
sonication, which clearly demonstrates the catalytic role of
cyclodextrin. Therefore, β-CD was preferred as a catalyst
for this reaction.
To find out the best experimental conditions for the
preparation of 5-aryl-5,6-dihydro-1H-pyrano[2,3-d]pyrimi-
dine-2,4,7-triones, a model reaction, involving the 3-compo-
nent annulation between benzaldehyde (1a), meldrum acid
(2a) and barbituric acid (3) was selected.
In this study, a model reaction was conducted by sequen-
tial addition of aldehyde, meldrum acid and barbituric
acid at room temperature in the absence of β-CD to obtain
the corresponding 5-aryl-5,6-dihydro-1H-pyrano[2,3-d]
pyrimidine-2,4,7-triones (4a) in aqueous medium. It was
observed that there was no product formation even after
heating for longer time. Cyclodextrin can boost solubility
in water and reduce toxicity by complexation. Cyclodex-
trins contain hydrophobic cavities inside and hydrophilic
Scheme 1 Synthesis of 5-aryl-
5,6-dihydro-1H-pyrano[2,3-d]
pyrimidine-2,4,7-triones (4a-r)
R
O
O
O
O
β-CD/H2O
HN
O
H
HN
60-65 0C
))))
O
N
H
(3)
O
O
O
O
N
H
O
O
R
(1a-r)
(2)
(4a-r)
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Journal of the Iranian Chemical Society
Table 1 Formation of
Entry
Catalyst
Time (h)
Concentration (mol%)
Yield (%)
pyrano[2,3 d]pyrimidine-2,4,7-
triones (4a) using different
catalysts in aqueous medium
1
2
3
4
Water
15
9
1
–
20
No condensation
45
72, 89, 96 and 96
39
α-Cyclodextrin
β-Cyclodextrin
γ-Cyclodextrin
10, 15, 20, 25
20
5
aReaction conditions: benzaldehyde (1a) (3 mmol), barbituric acid (2) (3 mmol), meldrum acid (3)
(3 mmol), water, at 65 °C
bIsolated yield
Table 2 Optimization of solvents for synthesis of pyrano[2,3 d]
pyrimidine-2,4,7-triones (4a)
β-CD, i.e., 10, 15, 20 and 25 mol%, and gave the product
in 72, 89, 96 and 96% yield, respectively (Table 1). Thus,
it is clear that reaction rate was positively influenced by
increasing catalyst concentration up to 20 mol% and then
became static on further increasing the catalyst concen-
tration. It means that the presence of 20 mol% of β-CD
was sufficient for catalyzing the reaction effectively in the
forward direction.
Entry
β-Cyclodextrin (mol Solvent
%)
Yield (%)
1
2
3
4
5
20
20
20
20
20
Water
EtOH
MeOH
DMF
Acetonitrile
96
65
67
45
51
We also screened different solvents such as water,
EtOH, MeOH, DMF and acetonitrile with cyclodextrin as
catalyst. Among all these solvents, water was found to play
an effective role in this transformation affording highest
yields due to better solubility of cyclodextrin in water.
(Table 2). Therefore, water was selected as the solvent
system for this transformation.
aReaction conditions: benzaldehyde (1a) (3 mmol), barbituric acid (2)
(3 mmol), meldrum acid (3) (3 mmol) at 65 °C
bIsolated yield
A variety of structurally divergent aldehydes possessing
a wide range of functional groups (Scheme 2) was selected
to understand the scope and generality of the β-CD-
promoted cyclocondensation reaction to form pyrano[2,3-
d]pyrimidine-2,4,7-triones and the results are summarized
To optimize the catalyst, the model reaction was car-
ried out at different concentration of β-CD in water. As
catalyst concentration is a important factor that exclusively
affects the reaction rate and product yield. To study this,
the reaction was performed at different concentrations of
Scheme 2 Synthesis of 5-aryl-
OH
O
Hydrophilic medium
5,6-dihydro-1H-pyrano[2,3-d]
H2O
pyrimidine-2,4,7-triones (4a-r)
O
HO
O
OH
HO
OH H2O
R
O
OH
H2O
HO
O
O
HO
O
O
OH
O
O
O
O
))))) 60-65 0C
H
HN
O
HO
O
OH
H2O
HO
R1
OH
O
N
H
O
O
O
H2O
O
HN
H2O
(4a-r)
HO
OH
O
N
H
O
HO
O
O
OH
O
H2O
OH
O
HO
H2O
HO
O
OH
Hydrophobic cavity
cyclodextrin
β−
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Journal of the Iranian Chemical Society
in Table 3. The results showed that substituted aryl alde-
hydes containing either electron-donating or electron-
withdrawing groups gave the analogous products in good
yields at short reaction times (Table 3). We have also used
aliphatic aldehyde, butaraldehyde and β-CD also afforded
the respective pyrano[2,3-d]pyrimidine-2,4,7-trione (4r)
in good yield.
Table 3 Scope of the substrate
for the synthesis of 5-aryl-
5,6-dihydro-1H-pyrano[2,3-d]
pyrimidine-2,4,7-triones (4a–r)
in aqueous β-CD
Sr.
Melting Point
Aldehydes
Structure
Yield (%)
No.
(ºC)
O
CHO
1
2
96
254-256
HN
O
N
H
O
O
O
CHO
CH3
O
90
92
260-261
291-293
HN
O
N
H
O
OCH3
CHO
OCH3
O
3
4
HN
O
N
H
O
O
Cl
CHO
Cl
O
88
282-284
HN
O
N
H
O
O
O
Cl
CHO
Cl
O
5
6
78
84
268-270
242-244
HN
O
N
H
O
O
Cl
O
CHO
Cl
HN
O
N
H
O
Br
CHO
Br
O
7
84
273-275
HN
O
N
H
O
O
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Journal of the Iranian Chemical Society
Table 3 (continued)
Sr.
Melting Point
Aldehydes
Structure
Yield (%)
No.
(ºC)
OH
CHO
OH
O
8
9
93
83
82
3̴ 00
HN
O
N
H
O
O
O
OH
O
CHO
OH
290-292
HN
O
N
H
O
OH
OCH3
CHO
O
10
280-282
HN
OCH3
OH
O
N
H
O
O
OCH3
OH
CHO
O
11
12
13
14
80
84
90
81
290-291
281-282
268-270
249-251
HN
OH
OCH3
O
N
H
O
O
OCH3
OCH3
CHO
O
HN
OCH3
OCH3
O
N
H
O
O
OCH3
OCH3
H3CO
CHO
O
H3CO
OCH3
OCH3
HN
O
N
H
O
O
NO2
CHO
NO2
O
HN
O
N
H
O
O
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Journal of the Iranian Chemical Society
Table 3 (continued)
Sr.
Melting Point
(ºC)
Aldehydes
CHO
Structure
Yield (%)
No.
NO2
O
14
15
16
81
249-251
216-218
280-282
HN
NO2
O
N
H
O
O
O
NO2
O
CHO
NO2
75
94
HN
O
N
H
O
N
N
O
HN
CHO
O
N
H
O
O
O
O
17
18
82
75
294-295
243-245
HN
O
CHO
O
N
H
O
O
O
O
HN
CHO
O
N
H
O
aReaction conditions: substituted benzaldehyde (1a–o) (4 mmol), meldrum acid (2) (4 mmol), barbituric
acid (3) (4 mmol), β-cyclodextrin (20 mol%), at 65 °C
bIsolated yield
cMelting points are in good agreement with those reported in the literature [27, 28]
From the close examination of IC50 values, it is observed
that 4c, 4j, 4k, 4l and 4m were active and potent antican-
cer agents among the synthesized derivatives 4a–r. The
Biological activity
In vitro anticancer evaluation of synthesized compounds
(4a–r)
compound 4j was found to be the most potent anticancer
agent against HePG-2 with IC50 value 6.8 µM and 5-FU
showed IC50 value 7.9 µM against HePG-2. This proves that
compound 4j was more active than the standard drug 5-FU
against HePG-2. The compound 4 k bearing para-methoxy
and ortho-hydroxy group on phenyl ring was found to be
second most active anticancer agent against HePG-2 with
IC50 value 8.8 µM. The compound 4 m bearing 3,4,5-tri-
methoxy group on phenyl ring was found to be most active
anticancer agent against MCF-7 with IC50 value 6.6 µM.
All the synthesized pyrano[2,3-d]pyrimidine derivatives
were evaluated for their in vitro anticancer activity against
HePG-2 (Human liver cancer cell line) and MCF-7 (Human
breast cancer cell line) by MTT assay using 5-Flurouracil
as standard drug. The result obtained for in vitro antican-
cer activity is reported in Table 4. The IC50 (µM) value
means concentration required to inhibit 50% of cancer cells
growth.
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Journal of the Iranian Chemical Society
Table 4 In vitro anticancer
activity of synthesized
compounds (4a–r)
Conclusion
Compounds HePG-2 MCF-7
IC50 µM
In summary, we have presented an elegant and simple
methodology for a one-pot multicomponent synthesis of
pyrano[2,3 d]pyrimidine-2,4,7-triones in water under supra-
molecular catalysis. The operational simplicity, mild reac-
tion conditions, short reaction time, high yields (75–96%)
and environmental friendliness are the notable features of
this procedure. Indeed, a wide range of aldehydes was con-
verted to the corresponding pyrano[2,3 d]pyrimidine-2,4,7-
triones using this method. To the best of our knowledge,
this is the first report of anticancer activity of pyrano[2,3 d]
pyrimidine-2,4,7-triones. Compounds 4c, 4j, 4k, 4l and 4m
from the series (4a–r) were active against HePG-2 (Human
liver cancer cell line) and MCF-7 (Human breast cancer cell
line).
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
46.3
35.9
10.6
28.6
32.7
38.1
36.3
8.2
44.9
43.6
23.4
26.2
38.8
42.1
27.5
22.2
34.5
10.9
14.5
20.8
6.6
16.4
6.8
8.8
8.9
17.2
15.6
26.7
30.3
48.8
>50
7.9
33.2
40.1
47.4
49.5
>50
5.4
Acknowledgements The authors are grateful to Professor Ramrao A.
Mane for his invaluable discussions and guidance. The authors are
also thankful to Department of Chemistry, Dr. Babasaheb Ambedkar
Marathwada University, Aurangabad and Central Drug Research Insti-
tute (CDRI), Lucknow for providing necessary facilities and spectral
analysis, respectively.
5-FU
IC50 values are the concentra-
tions in micro-molar needed
to inhibit cell growth by 50%;
5-FU 5-flurouracil used as
standard drug, HePG-2 Human
liver cancer cell line, MCF-7
Human breast cancer cell line
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