Design, synthesis, anticancer activity and docking studies of theophylline containing 1,2,3-triazoles with variant amide derivatives

Article abstract of DOI:10.1039/c6md00479b

A new series of theophylline analogues containing 1,2,3-triazoles with different amide groups (22-41) has been designed and synthesized, and their biological activities have been evaluated as potential anticancer agents. The anticancer activities of the synthesized compounds were studied in four cancer cell lines viz. lung (A549), colon (HT-29), breast (MCF-7) and melanoma (A375). Furthermore, these compounds were screened for computational ADME and Lipinski's analysis followed by molecular docking and binding energy calculations against the various therapeutic targets involved in cell proliferation. The in vitro results demonstrate that compounds 22, 27, 36 and 40 have pivotal anticancer activity. Among these, compounds 22 and 27 have significant cytotoxic activity in all three cell lines; the in silico docking studies also reveal that compounds 22, 27 and 36 have good dock scores, binding affinities and binding energies towards human epidermal growth factor receptor 2. This is the first report to demonstrate theophylline hybrids containing 1,2,3-triazoles as potential anticancer agents.

Full text of DOI:10.1039/c6md00479b

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RESEARCH ARTICLE
Design, synthesis, anticancer activity and docking studies of
theophylline containing 1,2,3-triazoles with variant amide
†
WReceived 00th January 20xx,
Accepted 00th January 20xx
derivatives
a
a
a
Radhakrishnam Raju Ruddarraju, Adharvana Chari Murugulla,* Ravindar Kotla, Muni Chandra
b
b
a
c
DOI: 10.1039/x0xx00000x
Babu Tirumalasetty, Rajendra Wudayagiri, Shobha Donthabakthuni, Ravichandar Maroju
www.rsc.org/
A new series of theophylline containing 1,2,3-triazoles with different amide analogues (22–41) has been
designed, synthesized and their biological activities were evaluated as potential anticancer agents. The
synthesized compounds was subjected for anticancer activity in four cancer cell lines viz. Lung (A549), Colon
(HT-29), Breast (MCF-7) and Melanoma (A375). Further these compounds were screened for computational
ADMET and Lipinski analysis followed by molecular docking and binding energy calculations against various
therapeutic targets involved in cell proliferation. The in vitro results demonstrate that compounds 22, 27, 36
and 40 have pivotal anticancer activity. Among them, compounds 22 and 27 have significant cytotoxic
activity in all three cell lines and the in silico docking studies also reveal that compounds 22, 27 and 36 have
good dock score, binding affinity and binding energies towards human epidermal growth factor receptor 2.
This is the first report to demonstrate the theophylline containing 1,2,3-triazole hybrids as potential
anticancer agents.
Introduction
serious side effects and problems. Thus, these limitations are
compelling we search for novel anticancer agents with diverse
The Cancer is considered as the second most lethal disease
chemical structure and herein it is reported that the synthesis and
biological evolution of theophylline containing 1,2,3-triazoles with
different amide derivatives as potential anticancer agents.
1
responsible for 21% of annual deaths globally. Approximately, 7.6
million people die of cancer every year worldwide which is
expected to reach up to 13 million in 2030. As per a report
Analogues of naturally occurring purine bases are valuable tools in
defining chemical interactions involved in a specific biological
response. Structural alternations of xanthine have resulted in
several potent biological systems e.g. theophylline also known as
2
published in The Lancet, total deaths due to cancer were 0.55
million in 2010 in India. In the developing and under developed
countries lung, breast, colon and melanoma cancers are most
common ones. Lung and breast cancers among men and women
are more prevalent in developed countries. Overall, 16.8% of
people in the United States diagnosed with lung cancer survive five
1
,3-dimethylxanthine, is a proven bronchodilator drug used in
therapy for respiratory diseases such as asthma or chronic
10–12
pulmonary obstructive disease (COPD).
Theophylline derivatives
3
years after the diagnosis while, breast cancer survival rates in the
in 7- and 8-positions have been investigated with respect to their
4
developed world are high, with 80% to 90% of those in England
13–16
17
bronchospasmolytic,
anticancer and circulatory blood system
5,6
and in the United States alive for at least 5 years. On the other
18
activity. In this study, the present research activity has been taken
up in order to expand the pharmacological profile of theophylline,
to reduce the side effects and also identify the possible candidates
for further development.
hand, globally, colon cancer is the third most common type of
7
cancer making up about 10% of all cases. It is less common in
women than men and in developed countries. Melanoma is the
most dangerous type of skin cancer. They are more common in men
Meanwhile, 1,2,3-triazoles have gained enormous interest in
8
than women. Globally, in 2012, it occurred in 2.32 lacks people and
recent years owing to their broad spectrum pharmaceutical and
resulted in 55,000 deaths. For this purpose, chemotherapy is the
19–21
great diverse biological activities, such as anticancer,
antifungal,
Thus, click
9
most commonly used treatment worldwide. But it has several
22–24
25–27
28–30
antibacterial,
antituberculosis
and antivirus.
chemistry has attracted extensive interest in almost all aspects of
drug discovery, such as leading discovery through combinatorial
chemistry, target-templated in vitro chemistry, proteomics and DNA
research by using bio-conjugation reactions. Some of theophylline
and 1,2,3-triazole bioactive molecules are shown (Fig. 1).
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Journal Name
between the alkyne and an appropriate azide. The 1,2,3-triazoles
O
6
R
N7
O
N
N
Cl
O
N
were synthesized by propynyl compounds 19a–19b upon reaction
O
N
1
N
2
5
N
N
8
N
N
S
4 2
with 3-azidopropanoic acid in the presence of CuSO .5H O and
N
4
N9
N
sodium ascrobate in t-BuOH and H O for 16 hours gave 20a–20b
2
O
N3
O
N
1B
N
O
1
A
(85% and 78%) and whereas 2-azido acetic acid in the presence of
phosphodiesterase inhibitor
1C
R= H, Asthma and COPD
R= CH3, CNS Stimulant
Anticancer agent
CuSO .5H O and sodium ascrobate in t-BuOH and H O for 16 hours
4
2
2
O
gave 21a–21b (82% and 77%).
H2N
N
N
Finally, the 1,2,3-triazole acid compounds 20a–20b or 21a–21b
were coupled with different aliphatic cyclic amines or biphenyl
amines by using reagent (1-[Bis(dimethylamino)methylene]-1H-
N
N
H2N
N
Cl
1
,2,3-triazolo[4,5-b]pyridinium-3-oxid hexafluorophosphate) HATU
O
and base N,N-diisopropylethylamine (DIPEA) in dichloromethane to
O
2B
2
A
Cl
CAI) Anticancer
get desired final compounds 22–41 in yield 44–86%.
(
Anticancer activity
Cl
Fig 1. Bioactive theophylline and 1,2,3-triazole moieties.
Based on the biological significance, it has been envisaged the
integration of theophylline and 1,2,3-triazole pharmacophore units
with amide linkage in one molecular platform to generate a new
theophylline containing 1,2,3-triazoles with variant amide analogue
hybrids frame work with anticancer activity. In addition, structure-
activity relationship (SAR) studies, molecular docking, risk of toxicity
screening and ADME properties were evaluated.
Results and discussion
Chemistry
The commercially available different aryl halide compounds
Scheme 1 Synthesis of biphenyl amine compounds 5,7,12 and 15.
4
,6,9,11 and 13 were treated with boronic acids or boronate esters
,8 and 14 by using the base potassium phosphate and catalyst dioxane:H O, 100°C, 10-16 h.
Reagents and conditions: (a)
3 4 2 2 2
K PO , Pd(dppf)Cl ·CH Cl , 1,4-
3
2
2 2 2
Pd(dppf)Cl ·CH Cl in 1,4-dioxane and water at 100°C for 10 to 16
hours which gave biphenyl amine compounds 5,7,10,12 and 15 as Biological activity
shown (Scheme 1).
Anticancer activity
The synthesis of theophylline containing 1,2,3-triazoles with
The synthesized compounds were evaluated for their anticancer
activity in four human cancer cell lines: lung (A549), colon (HT-29),
breast (MCF-7) and melanoma (A375) had shown (Table 1 & 2).
Interesting results were observed, the highest activity in lung cancer
cells is displayed by compounds 27, 40 and 22 (IC50 = 1.21±0.16,
different aliphatic cyclic amide and biphenyl amide analogues 22–
1 were outlined (Scheme 2). Initially it was started with
commercially available starting material theophylline 16 alkylating
with ethyl 2-bromoacetate and K CO in N,N-dimethylformamide
DMF) at 85°C for 12 hours which gave 17a in yield 84% and on the
4
2
3
(
1
.34±0.14, 1.40±0.09 µM) respectively. The next molecule in this
series is compound 32 also exhibited relatively high activity (IC50
.12±0.26 µM) and compounds 28 and 39 were also found to be
other hand 17b was prepared by using Mitsunobu reaction.
Theophylline 16 reacted with ethyl 2-hydroxypropanoate by using
triphenylphosphine (TPP) and diisopropyl azodicarboxylate (DIAD)
at room temperature that gave 50% yield. The ester compounds
=
2
active (IC50 = 3.54±0.44, 4.20±0.18 µM) compared to all the
remaining compounds which were proved inactive in lung cancer
cells. The utmost activity in colon cancer cells was again displayed
by compound 27 (IC50 = 2.30±0.16 µM) and compounds 36 and 39
1
2 2
7a-17b were hydrolyzed with LiOH.H O in THF and H O at room
temperature for 2 hours to get 18a–18b (91% and 98%). The
propynyl compounds were prepared by acid compounds 18a-18b
coupled with propargyl alcohol by using reagent N,N'-
dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine
(
IC50 = 2.90±0.73, 2.96±0.10 µM) also exhibited good activities. The
next high activity in breast cancer cell lines was demonstrated by
compounds 22 and 27 (IC50 = 2.20±0.32, 2.31±0.41 µM). In this
series, compounds 34 and 36 (IC50 = 2.40±0.17, 2.71±0.44 µM) also
showed good activity compared to compounds 39, 37 and 28.
(
DMAP) at room temperature for 16 hours which gave 19a–19b in
yield 78% and 83%. Lastly, the 1,2,3-triazole ring was constructed
based on Cu(I) catalyzed 1,3-dipolar cycloaddition as the key step
2
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Similarly, the highest activity in melanoma cancer cell lines was
shown by compounds 22 and 35 (IC50 = 2.51±0.58, 2.80±0.29 µM).
These results clearly indicated that compounds 22 and 27 were the
most potent in all investigated cancer cell lines (lung, colon, breast
and melanoma).
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Scheme 2 Synthesis of aliphatic cyclic amide and biphenyl amide compounds 22–31 and 32–41. Reagents and conditions: (a) (i) K
5°C, 12 h (ii) TPP, DIAD, THF, rt, 5 h; (b) LiOH·H O, THF:H O, rt, 2h; (c) DCC, DMAP, DCM, rt, 16 h; (d & e) CuSO ·5H O, sodium ascorbate, t-
BuOH:H O, rt, 16 h; (f, g & h) HATU, DIPEA, DCM, rt, 16 h.
2 3
CO , DMF,
8
2
2
4
2
2
With regard to the amide analogues (22–31), the series of
aliphatic cyclic amides showed massive difference in potency and
selectivity with decrease in cyclic ring size. Here, a slight difference
between two series of compounds 22–25 and 26–30 having methyl
group on α-carbon at position 7 of theophylline ring displayed a
dramatic change in activity. Among them, compounds 22 and 27
showed highest anticancer activity against three cancer cell lines
such as lung, breast, melanoma (IC50 = 1.40±0.09, 2.20±0.32,
bipyridine showed activity in the cell lines i.e. lung (IC50 = 2.12±0.26
µM) and melanoma (IC50 = 2.80±0.29 µM) respectively and inactive
against all the remaining three cell lines. In the similar way, among
the compounds 33 and 36 having 2-phenylpyridine and 34 and 37
having 3-phenylpyridine, the compounds 33 and 37 showed no
activity in all four cancer cell lines where as other compounds 34
and 36 interestingly showed activity in the cancer cell lines like i.e.
breast (IC50 = 2.40±0.17 µM) and colon, breast (IC50 = 2.90±0.73,
2.71±0.44 µM) respectively.
2
2
.51±0.58 µM) and lung, colon, breast (IC50 = 1.21±0.16, 2.30±0.16,
.31±0.41 µM) respectively than other compounds. In comparison,
Some other biphenyl amide analogues synthesized (i.e., 39–41)
were based on the aliphatic cyclic amide scaffold, which had been
shown to display the promising anticancer activity and selectivity of
the amide series. The compound 40 was shown to have slightly
better anticancer activity towards the lung (IC50 = 1.34±0.14 µM) but
loss in activity towards other cell lines i.e., colon, breast and
melanoma displayed as compared to the aliphatic cyclic amide
analogues 22 and 27. Comparing the compounds 39 and 41,
compound 39 having 2-phenylpyridine showed activity in colon (IC50
= 2.96±0.10 µM) whereas other compound 41 showed no activity in
all four cancer cell lines as compared to the compounds 39 and 40.
According to this data, it is found that compounds which have
aliphatic cyclic amide analogues showed higher anticancer activity in
all three cancer cell lines than biphenyl amide analogues.
compound 22 in which the cyclohexyl ring is replaced with
cyclopentyl and cyclobutyl rings forming compounds 23 and 24
respectively displayed loss in activity against four cancer cell lines. In
the similar way, compounds 26, 28 and 29 having cyclohexyl,
cyclobutyl and cyclopropyl rings displayed loss in activity against
four cancer cell lines as compared with compound 27. Here,
anticancer activity for the cyclic amides 22–24 and 27–29 clearly
showed decreasing trend with decrease in ring size as displayed loss
in activity. While the other cyclic amides like morpholine analogues
in 25 and 30 and ethyl piperazine derivative in 31 showed no
improvement in the potency or selectivity.
In the next upcoming compounds, substituting the aliphatic cyclic
amide moiety with biphenyl amide structures, such as those found
in 32–38, typically resulted in less anticancer activity as compared
with cyclic amide analogues. While some of the biphenyl series (32–
In conclusion, it has been designed, synthesized and evaluated
theophylline containing 1,2,3-triazoles with different amide
analogues systematically with variations like, having electron
donating group such as methyl group on α-carbon atom at position
7 of theophylline ring, substitutions such as cyclic rings and
biphenyls and also established a structure activity relationship.
Although, the role of methyl is still not clear, substitution of cyclic
rings and biphenyl rings seems to be important for their activity
against cancer cell lines.
3
8) still displaying good inhibition activity and showing values
comparable to some of the better amide analogues which could not
be explained significantly. Compounds 32, 34, 35 and 36 showed
higher anticancer activities than other compounds 33, 37 and 38. A
vital comparison between two series of compounds 32–34 and 35–
3
7 having α-carbon at position 7 of theophylline ring displayed a
change in activity. Comparing the compounds 32 and 35 having 2,3-
4
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From a medicinal chemistry perspective, each functional group
provides specific properties and behaviours that allow drug
molecules to exert their desired pharmacodynamic and
pharmacokinetic effects. Any given molecule may play a significant
role in the overall water/lipid solubility, electronic effect, steric
effect and ability to interact with specific biological targets.
drug likeness. Drug score associate with drug likeness, clogP,
molecular weight and toxicity risks as a total value may be used to
judge the overall potential to qualify it as a drug. The toxicity
screening of all compounds (22–41) showed that no risk of
mutagenic, tumorigenic, irritant and reproductive toxicity (refer
Table 3 in supplementary material).
Theoretical evolution of ADME properties
Molecular docking studies
The Bioavailability of amide analogues (22–41) was accessed
through ADME (Adsorption, Distribution, Metabolism and Excretion)
using MOE QSAR (Molecular Operating Environment Quantitative
structure–activity relationship) models descriptor module. In order
to explore drug-like properties of compounds (22–41), the
lipophilicity, expressed as the octanol/water partition coefficient
and here it is called logP(o/w), as well as other theoretical
calculations such as molecular size, TPSA, the number of hydrogen
bond acceptors and donors, and the number of rotatable bonds
were calculated (refer Table 4 in supplementary material).
In order to better understanding, it has been observed that the
structures-activity relationships and molecular docking study of the
compounds (22–41) with the various therapeutically targets of
cancer showed that human epidermal growth factor receptor 2
have shown significant dock score, binding energy and binding
affinity with all the compounds. Whereas majority of the
compounds have shown moderate score with another targets i.e.,
EGFR, VEGFR2 and Aromatase.
From the results of docking, binding affinity and binding energy
calculations against HER2 compounds 22, 27 and 36 have shown
highest dock scores. Compound 22 has shown two H-bonds with
active site amino acids with -15.42, -25.43 and 10.29 of dock score,
binding energy and binding affinity respectively. The docking results
revealed that amino acids Thr862 and Asp863 located in the binding
pocket of protein played an important roles. The C=O group of
oxygen atom act as H-bond acceptors and its oxygen atom has
formed between two H-bonds one with OH of Thr862 (bond length
Conclusion
In the present work, an efficient, clean and convenient synthesis of
novel theophylline containing 1,2,3-triazoles with different amide
analogues has been designed. The procedure offers several
advantages including simple reaction conditions as well as simple
experimental and product isolation procedures. Here in a series of
novel twenty compounds were synthesized and characterized with
good yields. This work focused on anticancer activity of chemically
diverse theophylline containing 1,2,3-triazoles by synthesizing
analogues 22, 27, 36 and 40 significantly exhibiting inhibitory
activity against the three cancer cell lines viz., lung (A549), colon
2
.49 Å) and another with N of Asp863 (bond length 2.82 Å)
respectively. In the similar way, compound 27 has shown two H-
bonds with the dock score, binding energy and binding affinity of -
1
5.23, -9.673 and 10.95 respectively. The hydrogen atom of amine
group has formed one H-bond with oxygen atom of Asp863 by
donating an electron pair with bond length of 1.55 Å. The nitrogen
atom of theophylline ring has formed one H-bond with OH of
Ser783 by accepting an electron pair with bond length of 2.71 Å.
Compound 36 has formed four H-bonds with the active site amino
acid residues with the dock score, binding energy and binding
(HT-29), breast (MCF-7) and melanoma (A375). Although, the
docking results correlate with the IC50 data, and allowed to analyze
the importance of specific interactions for describing the binding
energy and binding affinity of different amide derivatives. The
results obtained also showed that structural modification of
theophylline can yield products with different pharmacological
actions from those commonly associated with theophylline
analogues such as asthma, COPD and adenosine receptor
antagonism. Therefore, this class of compounds could be a good
starting point to develop a new lead in the treatment of anticancer
studies. To demonstrate the utility of this chemistry, several
biologically important molecules were synthesized and will require
further studies to design more specific and efficient molecules.
th
affinity of -16.71, -25.52 and 14.10 respectively. The 6 position-OH
of theophylline act as H-bond acceptor and its oxygen atom has
formed two H-bonds one with OH of Ser783 and another one with
OH of Thr798 with 2.66 and 2.76 Å, respectively. The oxygen atom
of C=O group has one H-bond with OH of Thr862 by accepting an
electron pair with bond length of 2.86 Å. In biphenyl ring, the
nitrogen atom has formed one H-bond with NE of Arg849 by
accepting an electron pair with bond length of 2.89 Å. Based on the
characterization of protein-ligand interactions, it is evidenced that
theophylline, 1,2,3-triazole and amide analogues played a key role
in forming H-bond interactions in both in vitro and in silico studies.
The docking calculation of all the compounds (22–41) was also
depicted in (refer Table 5 in supplementary material).
Acknowledgment
Authors are thankful to Dr. V. Koteswara Rao, Postdoctoral
Research Associate, University of Kansas, USA, for providing MOE
software.
Toxicity risk assessment screening
The toxic properties such as irritant, mutagenic, tumorigenic and
reproductive effects were screened for the amide analogues (22–
4
1) using Molinsperation and Osiris server. The server is inbuilt with
list of about 5300 distinct substructure fragments created by 15,000
commercially available fragments with reported drug score and
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Table 1 Anticancer activity (IC ) of aliphatic cyclic amide analogues (22–31)
5
0
Compound
R
1
R
2
No.
A549 (Lung)
HT-29 (Colon)
MCF-7 (Breast)
A375 (Melanoma)
H
H
H
Cyclohexyl
Cyclopentyl
Cyclobutyl
22
23
24
1.40 ± 0.09
4.70±0.14
5.24±0.49
52.3±1.20
15.4±1.29
19.2±2.81
2.20±0.32
12.8±0.33
9.18±0.99
2.51±0.58
60.8±4.61
61.2±3.51
H
Morpholine
Cyclohexyl
25
26
7.24±1.02
34.6±2.49
38.2±3.22
21.4±0.60
18.2±1.81
7.54±1.36
58.2±1.90
3.92±0.59
CH
3
CH3
Cyclopentyl
Cyclobutyl
27
28
1.21±0.16
2.30±0.16
2.31±0.41
63.2±2.30
8.52±0.34
CH
3
3.54±0.44
55.2±2.76
6.33±1.06
CH
CH
CH
3
3
3
Cyclopropyl
Morpholine
29
30
31
10.2±0.68
5.82±0.39
6.82±0.41
0.11±0.19
14.8±0.34
6.2±0.59
16.8±0.85
5.92±0.30
38.2±2.62
0.18±0.5
68.2±2.71
24.8±1.83
62.3±4.30
0.21±0.62
N-Ethylpiperazine
24.2±1.94
0.93±0.82
Combretastatin-A4
All the assays were performed in triplicate, IC50 values were reported as mean± SD
Table 2 Anticancer activity (IC50) of biphenyl amide analogues (32–41)
Compound
R
1
R
4
No.
32
33
34
35
A549 (Lung)
2.12 ± 0.26
4.70±0.35
53.4±2.02
6.33±0.18
HT-29 (Colon)
54.3±2.10
56.8±2.36
17.3±0.43
50.2±0.90
MCF-7 (Breast)
A375 (Melanoma)
3.80±0.31
H
53.8±3.5
H
8.41±0.63
2.40±0.17
62.8±3.27
9.34±0.55
H
3.62±0.34
CH3
2.80±0.29
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CH3
36
37
38
4.90±0.09
2.90±0.73
27.5±2.06
5.82±0.46
2.71±0.44
5.91±0.28
18.4±0.51
58.2±1.58
CH
3
48.2±0.26
6.82±0.12
10.31±0.25
50.4±3.41
CH3
R
1
R
3
No.
39
H
4.20±0.18
2.96±0.10
11.7±0.19
7.23±0.5
5.72±0.54
13.5±0.49
61.4±2.56
48.2±2.86
H
40
41
1.34±0.14
CH3
8.24±0.05
0.11±0.19
10.2±0.31
0.18±0.5
63.4±2.8
Combretastatin-A4
0.93±0.82
0.21±0.62
All the assays were performed in triplicate, IC50 values were reported as mean± SD
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A
B
Fig. 2 Molecular and Lig plot interactions of compound 22 (A) and 41 (B) with tyrosine kinase domain of Human epidermal growth factor
receptor 2 (HER2).
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Graphical Abstract
Design, synthesis, anticancer activity and docking studies of theophylline
containing 1,2,3-triazoles with variant amide derivatives
a
a,
a
Radhakrishnam Raju Ruddarraju, Adharvana Chari Murugulla, * Ravindar Kotla, Muni Chandra Babu
b
b
a
c
Tirumalasetty, Rajendra Wudayagiri, Shobha Donthabakthuni, Ravichandar Maroju
a
Dr.MACS Bio-Pharma Pvt. Ltd, Factory: Plot-79/B&C, Pasamylaram, Patancheru, Medak (Dist)-502307, Telangana, India.
b
Bioinformatics Center, Division of Molecular Biology, Department of Zoology, Sri Venkateswara University, Tirupati-517 502, Andhra Pradesh, India.
Mahatma Gandhi Institute of Technology, Gandipet, Hyderabad-500 075, Telangana, India.
c