Design, synthesis, in silico and in vitro evaluation of thiophene derivatives: A potent tyrosine phosphatase 1B inhibitor and anticancer activity

Article abstract of DOI:10.1016/j.bmcl.2017.05.047

A series of novel methyl 4-(4-amidoaryl)-3-methoxythiophene-2-carboxylate derivatives were designed against the active site of protein tyrosine phosphatise 1B (PTP1B) enzyme using MOE.2008.10. These molecules are also subjected for in silico toxicity prediction studies and considering their corresponding drug scores, it implied that, the molecules are promising as anticancer agents. The designed compounds were synthesized by using suitable methods and characterized. They were subjected to inhibitory activity against PTP1B and in vitro anticancer activity by MTT assay. Most of the tested compounds showed potent inhibitory activity against PTP1B, among the compounds tested, compound 5b exhibited the highest activity (IC₅₀?=?5.25?μM) and remarkable cytotoxic activity at 0.09?μM of IC₅₀ against the MCF-7 cell line. In addition to this, compound 5c also showed potential anticancer activity at 2.22?μM of IC₅₀ against MCF-7 and 0.72?μM against HepG2 cell lines as well as PTP1B inhibitory activity at IC₅₀ of 6.37?μM.

Full text of DOI:10.1016/j.bmcl.2017.05.047

Accepted Manuscript
Design, synthesis, in-silico and in-vitro evaluation of thiophene derivatives: A
potent tyrosine phosphatase 1B inhibitor and anticancer activity
Kali Charan Gulipalli, Srinu Bodige, Parameshwar Ravula, Srinivas Endoori,
G.R. Vanaja, G. Sureshbabu, J.N. Narendra Sharath Chandra, Nareshvarma
Seelam
PII:
S0960-894X(17)30528-0
DOI:
http://dx.doi.org/10.1016/j.bmcl.2017.05.047
BMCL 24992
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
8 March 2017
6 May 2017
16 May 2017
Please cite this article as: Gulipalli, K.C., Bodige, S., Ravula, P., Endoori, S., Vanaja, G.R., Sureshbabu, G., Narendra
Sharath Chandra, J.N., Seelam, N., Design, synthesis, in-silico and in-vitro evaluation of thiophene derivatives: A
potent tyrosine phosphatase 1B inhibitor and anticancer activity, Bioorganic & Medicinal Chemistry Letters (2017),
doi: http://dx.doi.org/10.1016/j.bmcl.2017.05.047
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Design, synthesis, in-silico and in-vitro evaluation of thiophene derivatives: A
potent tyrosine phosphatase 1B inhibitor and anticancer activity
Kali Charan Gulipallia, Srinu Bodige a, Parameshwar Ravula b, Srinivas Endooria, Vanaja.GRc,
Sureshbabu G c, JN. Narendra Sharath Chandra d, Nareshvarma Seelama*
a Department of Chemistry, KL University, Green fields, Vaddeswaram, Guntur,
522502, India
b Department of Pharmaceutical Chemistry, Gurunanak Institutions Technical Campus, School
of pharmacy, Hyderabad, India
c Department of Animal Biology, University of Hyderabad, Hyderabad,
500046, India
d Department of Pharmaceutical Chemistry, Bharath Institute of Technology- Pharmacy,
Hyderabad, India
* Corresponding author: email: nareshvarma.klu@gmail.com
Tel: +91-7386591580
Abstract
A series of novel methyl 4-(4-amidoaryl)-3-methoxythiophene-2-carboxylate derivatives were
designed against the active site of protein tyrosine phosphatise 1B (PTP1B) enzyme using
MOE.2008.10. These molecules are also subjected for in silico toxicity prediction studies and
considering their corresponding drug scores, it implied that, the molecules are promising as
anticancer agents. The designed compounds were synthesized by using suitable methods and
characterized. They were subjected to inhibitory activity against PTP1B and in vitro anticancer
activity by MTT assay. Most of the tested compounds showed potent inhibitory activity against
PTP1B, among the compounds tested, compound 5b exhibited the highest activity (IC50 = 5.25
µM) and remarkable cytotoxic activity at 0.09 µM of IC50 against the MCF-7 cell line. In
addition to this, compound 5c also showed potential anticancer activity at 2.22 µM of IC50
against MCF-7 and 0.72 µM against HepG2 cell lines as well as PTP1B inhibitory activity at
IC50 of 6.37 µM.
Keywords: synthesis, anticancer, molecular docking, protein tyrosine phosphatase inhibitor
1

Protein tyrosine phosphatase 1B (PTP1B) is an intracellular phosphorylating enzyme, which
controls both insulin and leptin signalling pathway and uses glucose for energy expenditure.
PTP1B plays a prominent role in the regulation of metabolism. Hence, over expression of this
enzyme can lead to various metabolic disorders, including diabetes, obesity, inflammation,
cancer and Alzheimer’s disease.1-5 PTP1B regulates different growth factors such as epidermal
and insulin, and it also controls receptor tyrosine kinase, which further regulates cell growth, cell
proliferation, cell differentiation, cell to cell contact, cell glucose metabolism and cell insulin
regulation.6 Over expression of PTP1B, raises Src specific activity in colon cancer cell,7, 8 and as
such is mainly associated with P185c-erbB protein expression pathway and produces activation
of stat5 induced phosphorylation in breast cancer patients.9 The literature study, suggested the
correlation between PTP1B depletion and breast cancer, inducing diminished oxygen supply to
cells. Further, it can induce necrosis of breast cancer cells followed by hypoxia induced cell
death. PTP1B promotes cell proliferation and metastasis through activating Src and Erk 1/2 in
lung cancer cell. Moreover, PTP1B has recently been reported to function as an oncogene in
breast cancer. Its inhibitors can be potentially used for the treatment of breast cancer. Therefore,
PTP1B forms an important target for the treatment of cancer.10
In recent year, much attention has been paid by the researchers to the chemistry of the
versatile
heterocyclic rings bearing different functionalities to target PTP1B enzyme, namely;
isoxazoles11, tetrazoles12, thiazolidinedione derivatives13, 14, triaryl sulfonamide derivatives15,
pyrroloazepines16, benzotriazoles17 and thiophene derivatives18, 19. Compounds bearing thiophene
nucleus are among the widely explored molecules to target against PTP1B active site to improve
their binding affinity. Recently, Wyeth pharmaceuticals performed structure based optimization
and identified a series of thiophenes that can be used as potent PTP1B inhibitors.20, 21
In present study, substituents were decided on the thiophene ring by virtual screening of
thiophene analogous using chemexper software on java window, correlating physiochemical
properties and bioavailability. It calculates molecular weight, lipophilicity, solubility,
bioavailability, drug score, mutagenicity, tumorigenicity, irritancy and C Log P. The virtual
substituted thiophene analogous with significant drug score computed values along with least
predicted toxicity scores, have been the main variables, facilitating lead optimization.
Furthermore, selected structures were subjected to molecular docking studies using MOE
2

software version 2008.10.22, 23 Docking studies assess the molecules, virtually in the exact
conformation pose in the active site, using exact geometry of the active site structure of the
enzyme. It predicts the binding mode and type of interaction between active site amino acids and
ligand along with their distance and proximity of functional groups involved. Interaction pattern
of ligands was compared to that of interaction pattern of the known drugs binding to the active
site amino acids of the target in order to select the best one for further studies.
In recent years, numbers of report have been documented on thiophene derivatives with
promising anticancer activity.24-26 Inspired by above information; we herein designed a new
series of thiophene analogues as guided by molecular docking studies against human PTP1B
active site. They were synthesized, characterized and subjected to in vitro inhibitory PTP1B
activity. The synthesized compounds were also evaluated for their in vitro cytotoxic activity
against cancer cell lines, such as MCF-7, MDA-MB-231, K562, HepG2, HeLa and HEK293.
Osiris program was used for prediction of the overall toxicity of the initially designed
structures against PTP1B. The prediction strategies rely on a sub-structure search process
determining the frequency of any fragment (constructed and core fragments) within any of
toxicity classes. Virtual structures selected for the study were found to be less toxic as predicted
by Osiris online software. Osiris program also can be used for prediction of C Log P, in turn an
established parameter to measure the hydrophilicity. Compounds show a reasonable probability
of being well absorbed, when they have a C Log P value less than 5.0. It is well established that
80% of the drugs on the market have Log S value around -5.0. From Table 1, it was observed
that all designed structures (5a-o) have showed C Log P near to 5.0 and Log S values near to -5.0
indicating that the selected structures could be tested as drug candidates. The drug score
combination of C Log P, Log S, molecular weight and toxicity risks may be used to judge the
virtual structures for their overall potential to qualify for a drug. A value around 0.2 makes this
structure a promising lead for future development of safe and efficient drug. Predictions of C
Log P, solubility, and drug score for virtual structures selected were given in Table 1 and almost
all the designed ligands showed good drug score values.
3

Table 1. Computationally predicted lipophilicity, solubility, drug score, and toxicity risks of the
synthesized compounds (www.chemexper.com)
Drug
score
0.19
0.16
0.18
0.16
0.43
0.37
0.24
0.20
0.38
0.25
0.13
0.18
0.20
0.28
0.19
Toxicity risks [a]
Compound
C Log P
Log S
5.22
5.64
5.29
5.46
3.49
4.30
5.68
4.69
2.90
4.25
5.92
5.39
4.80
4.24
5.22
-6.16
-6.99
-6.41
-6.71
-4.61
-5.39
-6.86
-6.14
-5.30
-5.39
-6.99
-6.40
-6.18
-5.43
-6.16
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Negative
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
[a] mutagenicity, tumorigenicity, irritancy, reproductive effects
Methyl-4-(4-amidoaryl)-3-methoxythiophene-2-carboxylate
derivatives
selected
from
chemexper studies were docked on the active site of PTP1B. The docking experiments were
performed to virtually screen selected derivatives from virtual toxicity studies and also to know
their affinity level towards the key amino acids of PTP1B enzyme active site with their binding
and interaction mode. In general, scaffold with the aryl ring system showed better interaction as
compared to scaffold containing pyridyl derivatives. Some derivatives selected for this study
interacted with amino acids such Asp 48, Arg 24 and Tyr 46. These amino acids were also found
to interact with known inhibitors.27 Ligand 5b exhibited effective interaction fit with Arg 24 of
46.6 % binding at a distance of 2.70 Å and Tyr 46 of 65.6% binding at 2.62 Å distance through
water, naphthyl ring of the 5b formed stacking interaction with Arg 24 and also showed potent
inhibitory activity against PTP1B (IC50 = 5.25 µM) in their series. Extent of binding of 5c is also
equally good, methoxy group of 5c ligand predicted to form polar bond to Arg 24 of amino acid
residues with 56.1% binding at a distance of 2.71 Å, thiophene carboxylate carbonyl group also
interacted with Arg 24 of 75.3% binding at a distance of 2.48 Å. Data pertaining to the
interaction of thiophene derivatives (5a-o) with amino acids on PTP1B active site was given in
4

Table 2. The two-dimensional and three-dimensional representation of compound 5b and 5c
were showed in Fig. 1 and Fig. 2.
Table 2. Interaction of thiophene derivatives (5a-o) with amino acids on PTP1B active site
Compound
Interaction with amino acids of PTP1B
Asp 48, Arg 24 (surrounded by Gln 262, Phe 182, Tyr 46)
Arg 24, Tyr 46 (surrounded by Asp 48, Phe 182, Gln 262)
Arg 24 (surrounded by Asp 48, Phe 182, Gln 262, Asp 181)
Tyr 46 (surrounded by Asp 181, Phe 182)
Phe 182, Tyr 46, (surrounded by Asp 48, Gln 262)
Tyr 46, (surrounded by Asp 181, Asp 48, Phe 182)
Tyr 46, (surrounded by Arg 47, Asp 181, Phe 182,Asp 48)
Asp 48, Arg 24 (surrounded by Gln 262, Phe 182, Tyr 46)
Arg 24 (surrounded by Asp 48, Phe 182, Gln 262, Tyr 46)
Arg 221, Gln 262 (surrounded by Asp 48, Phe 182)
Asp 48 (surrounded by Phe 182, Tyr4 6, Gln 262)
Asp 48, Arg 221, Tyr 46, Phe 182 (surrounded by Asp 181)
Asp 48, Arg 47, Tyr 46, Arg 221 (surrounded by Phe 182)
Asp 48, Tyr 46, Lys 120 (surrounded by Asp 181, Phe 182)
Asp 48, Arg 221, Tyr 46, Phe 182
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5

Phe
182
A
Tyr
46
Ile
219
Ala
217
Gln
262
Ser
216
O
O
H2O
O
H
N
S
O
Asp
48
Arg
24
B
Fig. 1. (A) Two-dimensional representation of the interacting mode of 5b on PTP1B enzyme.
(B) Three-dimensional structural model of compound 5b (purple) on PTP1B enzyme.
6

A
B
Fig. 2. (A) Two-dimensional representation of the interacting mode of 5c on PTP1B enzyme.
(B) Three-dimensional structural model of compound 5c (purple) on PTP1B enzyme.
According to scheme 1, hydroxyl group of methyl 4-bromo-3-hydroxythiophene-2-
carboxylate (1) was methylated using methyl iodide and sodium hydride as a base to get methyl
4-bromo-3-methoxythiophene-2-carboxylate (2) 28, in 85% yield. The obtained product was
further coupled with 4-nitro phenyl boronic acid under Suzuki coupling conditions29, using
7

tetrakis(triphenylphosphine)palladium and potassium carbonate to obtain methyl 3-methoxy-4-
(4-nitrophenyl)thiophene-2-carboxylate (3). The nitro group of previous step product was
reduced in the presence of zinc and ammonium chloride using ethanol as solvent to yield
corresponding amine (4), the resultant product was made to react with different aryl/ heteroyl
carboxylic acids to get the corresponding amide derivatives (5a-o) using HATU/DIPEA (Table
13
3). The obtained structures were confirmed by 1H NMR, C NMR, elemental and mass spectral
analysis.
Scheme 1. Synthesis of title compounds. Reagents and conditions (a) NaH (1.2 equiv), MeI
(3.0 equiv), THF, 0°C, 16 h (b) 4-nitrophenylboronic acid (1.2 equiv), K2CO3 (3.0 equiv),
8

Pd(PPh3)4 (0.05 equiv), DME, 85 °C (c) Zn (3.0 equiv), NH4Cl (3.0 equiv), EtOH, 85°C, 16 h (d)
R-COOH (1.2 equiv), HATU (1.5 equiv), DIPEA (3.0 equiv), CH2Cl2, R.T.,
Table 3. Protocol for the synthesis of the title compounds (5a-o)
9

10

The synthesized thiophene derivatives (5a-o) were evaluated for inhibitory activity against
PTP 1B30 using p-nitrophenyl phosphate (pNPP) as a substrate and the results are shown in
Table 4. The known PTP1B inhibitor, ursolic acid (IC50 = 4.12 µM), was used as positive
control. Compounds 5b, 5c and 5j were exhibited potent activity against PTP1B with IC50 values
ranging from 5.25 to 7.29 µM, whereas compounds 5a, 5d, 5e, 5i, 5g, 5k, 5l, 5m, 5n and 5o
displayed moderate activity with IC50 values varying from 11.29 to 20.56 µM. The aryl scaffolds
bearing electron withdrawing functional groups, namely, trifluoro methoxy (5c), trifluoro methyl
(5a) exhibited a better inhibition than scaffolds bearing electron withdrawing functional groups
as disubstituents on aryl ring (5d, 5g, and 5k). On the other hand, pyridyl ring bearing scaffolds
with disubstituents (5m and 5n) elicited more inhibitory activity than pyridyl compounds with
mono substitution (5h and 5i). Moreover, trifluoro methyl (5j) showed significant inhibition than
the rest of the pyridyl derivatives (5e, 5h, 5i, 5m and 5n).
Further, the synthesized compounds (5a-o) were tested for in vitro anticancer activity against
MCF-7, MDA-MB-231, K562, HepG2, HeLa and HEK293 cell lines using the MTT
colorimetric assay31, doxorubicin was used as a reference standard. From percentage inhibition,
IC50 values were calculated (µM) and provided in Table 4. The synthesized compounds
displayed potent to moderate cancer growth inhibitory activity. Among the tested compounds, 5b
and 5c showed more potent activity against different cell lines. Compound 5b with naphthyl ring
elicited exceptionally potent activity against MCF-7 cell lines with IC50 value of 0.096 µM. This
activity is better than that obtained IC50 value of doxorubicin (0.41 µM). The naphthyl ring
replaced with trifluoro methyl pyridyl (5j) led to a reduction in antiproliferative activity, but the
potency was still essentially sustained. Compound 5c with trifluoro methoxy group displayed
excellent antiproliferative activity against MCF-7 and HepG2 with IC50 value of 2.22 µM and
0.72 µM respectively. The replacement of trifluoro methoxy (5c) with trifluoro methyl moiety
(5a) led to decrease antiproliferative activity. Introduction of trifluoro methyl on pyridyl (5j)
showed potent cellular activity as compared to pyridyl scaffold with nitrile and trifluoro methoxy
groups (5h and 5i). Anticancer data from compounds (5a-o) showed that the presence of
disubstitutions on aryl ring (5d, 5g and 5k) led to decrease of anticancer activity. The
replacement of the naphthyl ring in 5b to thiophene (5f) led to a decline in anticancer activity.
The compound 5b showed potency with more than fivefold anticancer activity than doxorubicin
11

against the MCF-7 cell line. It also showed the highest inhibitory activity against PTP1B in vitro
assay. Furthermore, trifluoro methoxy compound 5c displayed a seven fold higher potency than
doxorubicin against HepG2 cell line. All the synthesized compounds were tested against non-
cancerous HEK293 cells. It is evident from Table 4 that, none of the compounds exhibited
significant toxic effect on HEK293 cells indicating their selective toxicity towards the cancer cell
and possible safety against normal cells.
The comparison of PTP1B inhibitory and anticancer activities of investigated potent derivatives
led to the interesting findings. The compounds (5b, 5c and 5j) were found to be superior in both
PTP1B inhibitory and anticancer activities. This might be due to the high degree of association
between PTP1B and ErbB2 in their expression in cancer.
The compound 5b solubility and stability was also investigated in various solvents. The
compound 5b was found to be stable, even for an extended period of time up to 96 h at the
different temperature.
Table 4. In vitro anti proliferative activity and inhibitions of PTP1B of synthesized compounds
Compound
PTP1B
Anticancer activity, IC50 (µM)
IC50 (µM)
MCF-7 K562 HepG2 MDA-MB 231 HeLa HEK293
12.28
5.25
6.37
26.24
0.09
2.22
6.13 32.54
10.25 19.52
18.25 0.72
24.56
5.25
7.54
16.54
8.25
> 50
14.21
15.28
28.52
7.25
19.59
8.24
19.26
18.24
16.56
ND
> 50
> 50
ND
24.42
ND
23.52
16.22
12.65
18.26
16.23
14.36
ND
ND
ND
45.25
ND
> 50
ND
> 50
ND
ND
> 50
42.68
> 50
ND
5a
5b
5c
5d
20.56
11.29
24.29
16.32
22.25
12.46
7.29
16.52
14.53
11.22
12.34
14.79
4.12
22.52 35.56
19.20 24.22 10.26
18.56
12.25
5.25
9.54
1.47
22.41
ND
5e
ND
15.28
5f
5g
9.56 13.52
18.25 > 50
5h
5i
ND
22.52
12.54 23.26
9.25 28.24
5j
5k
12.25 14.69 16.52
5l
5m
5.46
10.26
24.61
12.62 9.53
8.25 10.26
9.26 24.62
8.36
10.28
18.26
5n
5o
48.29
Urasolic acid
Doxorubicin
0.41
0.07
5.00
0.60
0.37
ND: Not determined
12

In conclusion, the novel derivatives of methyl 4-(4-amidophenyl)-3-methoxythiophene-2-
carboxylates (5a-o) were designed against PTP1B enzyme active site using MOE.2008.10. They
13
were further synthesized and characterized by 1H NMR, C NMR, elemental and mass spectral
analysis. The synthesized compounds were subjected to inhibitory action against PTP1B and in
vitro antiproliferative activity against selected cancer cell lines, such as MCF-7, MDA-MB-231,
K562, HepG2, HeLa, and HEK293 by MTT assay. Most of the tested compounds showed potent
inhibitory activity for PTP1B with compound 5b exhibited the highest activity (IC50 = 5.25 µM).
Compound 5b also showed potent cytotoxic activity with IC50 value of 0.096 µM against MCF-7
cell line with positive control Doxorubicin.
Acknowledgments
The authors would like to thank the management of AMRI Hyderabad research centre for
giving an opportunity to carry out this research. The authors are also thankful to Dr. A. Sunil
Kumar Reddy for his valuable guidance.
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Graphical Abstract
Design, synthesis, in-silico and in-vitro evaluation of thiophene derivatives: A
potent tyrosine phosphatase 1B inhibitor and anticancer activity
Kali Charan Gulipallia, Srinu Bodige a, Parameshwar Ravula b, Srinivas Endooria, Vanaja.GRc,
Sureshbabu G c, JN. Narendra Sharath Chandra d, Nareshvarma Seelama*
________________________________________________________________________________________________________________
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Highlights:
• A novel series of 3-methoxythiophene-2-carboxylate derivatives have been synthesized.
• The series of compounds were evaluated for their anticancer activity.
• Couple of compounds exhibited significant inhibitory activity against cancer cells.
• Compound 5b showed highest cytotoxic activity against MCF-7 cell line.
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