Optimization of substituted cinnamic acyl sulfonamide derivatives as tubulin polymerization inhibitors with anticancer activity

Article abstract of DOI:10.1016/j.bmcl.2018.10.037

A new series of novel cinnamic acyl sulfonamide derivatives were designed and synthesized and evaluated their anti-tubulin polymerization activities and anticancer activities. One of these compounds, compound 5a with a benzdioxan group, was observed to be an excellent tubulin inhibitor (IC₅₀ = 0.88 μM) and display the best antiproliferative activity against MCF-7 with an IC₅₀ value of 0.17 μg/mL. Docking simulation was performed to insert compound 5a into the crystal structure of tubulin at colchicine binding site to determine the probable binding model. 3D-QSAR model was also built to provide more pharmacophore understanding that could be used to design new agents with more potent anti-tubulin polymerization activity.

Full text of DOI:10.1016/j.bmcl.2018.10.037

Accepted Manuscript
Optimization of Substituted Cinnamic Acyl Sulfonamide Derivatives as Tubulin
Polymerization Inhibitors with Anticancer Activity
Yin Luo, Yang Zhou, Yanhua Song, Guo Chen, Yu-Xiang Wang, Ye Tian, Wei-
Wei Fan, Yu-Shun Yang, Tao Cheng, Hai-Liang Zhu
PII:
S0960-894X(18)30840-0
https://doi.org/10.1016/j.bmcl.2018.10.037
BMCL 26096
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
9 August 2018
8 October 2018
24 October 2018
Please cite this article as: Luo, Y., Zhou, Y., Song, Y., Chen, G., Wang, Y-X., Tian, Y., Fan, W-W., Yang, Y-S.,
Cheng, T., Zhu, H-L., Optimization of Substituted Cinnamic Acyl Sulfonamide Derivatives as Tubulin
Polymerization Inhibitors with Anticancer Activity, Bioorganic & Medicinal Chemistry Letters (2018), doi: https://
doi.org/10.1016/j.bmcl.2018.10.037
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Optimization of Substituted Cinnamic Acyl Sulfonamide Derivatives
as Tubulin Polymerization Inhibitors with Anticancer Activity
Yin Luoa,†,*, Yang Zhoub, †, Yanhua Songc, Guo Chend,, Yu-Xiang Wange, Ye Tiane,
Wei-Wei Fane, Yu-Shun Yange, Tao Chengf, Hai-Liang Zhue,*
aDepartment of neurosurgery, Changhai Hospital, Second Military Medical University,
Shanghai 200433, People’s Republic of China
bCixi Institute of BioMedical Engineering, Ningbo Institute of Industrial Technology, CAS,
Ningbo 315201, People’s Republic of China
cTianjin 4th Centre Hospital, Tianjin 300140, People’s Republic of China
dDepartment of Radiation Oncology, Emory University School of Medicine and Winship
Cancer Institute of Emory University, Atlanta, GA 30322, USA
eState Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093,
People’s Republic of China
fPharmaron Ningbo Co., Ltd., Ningbo 315366, People’s Republic of China
†These three authors contributed equally to this paper.
1

Keywords:
Cinnamic acid
Sulfonamide
Antiproliferative activity
Molecular docking
Anti-tubulin polymerization
A new series of novel cinnamic acyl sulfonamide derivatives were designed and
synthesized and evaluated their anti-tubulin polymerization activities and anticancer
activities. One of these compounds, compound 5a with a benzdioxan group, was
observed to be an excellent tubulin inhibitor (IC50 = 0.88 µM) and display the best
antiproliferative activity against MCF-7 with an IC50 value of 0.17 μg/mL. Docking
simulation was performed to insert compound 5a into the crystal structure of tubulin
at colchicine binding site to determine the probable binding model. 3D-QSAR model
was also built to provide more pharmacophore understanding that could be used to
design new agents with more potent anti-tubulin polymerization activity.
HER-2: human epidermal growth factor receptor 2
Hsp90:heat shock protein 90
SAR:structure-activity relationship
DMAP:4-dimethyaminopyridine
EDCI:1-[3-(dimethyamino)-propyl]-3- ethylcarbodiimide hydrochloride
ELISA:enzyme linked immunosorbent assay
2

Oxygen-bearing heterocycles especially 1,3-benzodioxole and 1,4-benzodioxan
have been observed to display potent anticancer activity as tubulin [1, 2], human
epidermal growth factor receptor 2 (HER-2) [3], topoisomerase II [4], heat shock
protein 90 (Hsp90) inhibitors [5] and 5-HT1A receptor Agonist [6, 7]. Sulfonamides
have reported to display broad biological activity as carbonic anhydrase [8], tubulin
[9-11], matrix metalloproteinase [12], gelatinase A [13], HIV-1 protease [14],
potassium ion channel [15], alkaline phosphatase inhibitor [16] and so on. Recently
the main research field about sulfonamides is to evaluate their anticancer activities. In
a previous paper, we have reported the potent in vitro anticancer activities of a series
of cinnamic acyl sulfonamides (Fig. 1) [17]. Besides, our group also reported another
series of compounds containing sulfonamide scaffold with tubulin polymerization
activities as anticancer agents[10]. These findings encouraged us to continuously
design new sulfonamides bearing oxygen-bearing heterocycles as anticancer agents.
Tubulin, the major component of microtubule and cytoskeleton, has become the
most important molecular target for cancer chemotherapeutic agents. A number of
sulfonamide derivatives have been identified as inhibitors of tubulin polymerization.
Yoshino et al screened out compound E7010 (Fig. 1) which was demonstrated to be
an outstanding tubulin inhibitor with IC50 values of 0.06-0.8 µg/mL against cancer
cell lines [18]. Based on the result, they modified the chemical structure of E7010 and
discovered ER-34410 (Fig. 1) which displayed much better anticancer activity than
E7010 [19]. After that, Owa et al reported another series of novel anticancer
sulfonamides with E7070 as a lead compound [20]. These compounds were
demonstrated to bind to the colchicine binding site on β-tubulin reversibly [19]. While
there are no anticancer agents that bind to the colchicine site of tubulin in clinic, the
above mentioned sulfonamide derivatives are currently in clinical trials [21].
3

Figure 1. Chemical structures of compound 1, E7010 and ER-34410.
In this paper, we have prepared a series of novel sulfonamide derivatives, which
arised from the structure-activity relationship (SAR) study, explored their
antiproliferative and anti-tubulin activities, investigated the inhibitor-protein
interaction by docking study and built a 3D-QSAR model to provide more
pharmacophore understanding. All the results mentioned above demonstrated that the
synthesized sulfonamide derivatives could be a new class of potent anti-tubulin agents
with anticancer activity.
The general synthetic route for the novel cinnamic acyl sulfonamide derivatives
5a-7e is depicted in Scheme 1 as reported by our group [17]. 3,
4-Dihydroxybenzaldehyde, substituted alkanes and benzenesulfonamides were
commercially available. Compounds 2-4 were prepared by substitution reaction of 3,
4-dihydroxybenzaldehyde and dichloromethane (1, 3-dichloroethane or 1,
4-dichloropropane). The cinnamic acids 5-7 were obtained from the reaction of
compounds 2-4 and malonic acid. In a similar manner with previous paper [17],
cinnamic acids 5-7 and sulfonamides a-e were added together with
4-dimethyaminopyridine
(DMAP)
and
1-[3-(dimethyamino)-propyl]-3-
ethylcarbodiimide hydrochloride (EDCI) as catalyst to get the target compounds
5a-7e. The related experimental details were summarized in Supporting Information.
1
Based on the results of H NMR spectroscopy and X-ray determination, the
configuration of sulfonamides was determined. The crystal structure of compound 5b
(CCDC number: 1559627) and 6c (CCDC number: 1559632) are shown in Figure 2.
Crystallographical and experimental data of compounds 5b and 6c were summarized
in Table 3 of Supplementary Material.
4

Scheme 1. General synthesis of cinnamic acid sulfonamide derivatives (5a-7e).
Reagents and conditions: (I) K2CO3，acetone，reflux，29 h; (II)piperidine, pyridine,
80-90 ºC, 24 h; (III) substituted benzenesulfonamides, CH2Cl2, EDCI, DMAP,
overnight
Figure 2. Crystal structure of compounds 5b and 6c.
The synthesized sulfonamides were screened for their antiproliferative activities
toward MCF-7 human breast cancer cells. The results are summarized in Table 1 with
colchicine as control. The data showed that some of the tested compounds displayed
significant antiproliferative activity toward MCF-7 cell lines. Compound 5a (IC50 =
0.17 μg/ml), which had benzdioxan group on A ring and no substituent on B benzene
ring, was even more potent than colchicine (IC50 = 0.33 μg/ml). Compared with 5a,
compounds 5b-7e didn’t exhibit significant antiproliferative activity, indicating that
substituents on B benzene ring had a deleterious decreasing effect on activity.
In particular, a methyl replacement of para-position of B benzene ring, represented by
5

5b (IC50 = 48.95 μg/ml), leaded to weaker activity. Other compounds (5c, 5d and 5e)
(IC50 = 74.05 μg/mL, 47.27 μg/mL and 89.01 μg/mL) with substituted para-halogen
exhibited approximately antiproliferative activities with the same order of magnitude.
From the data presented in Table 1, it could conclude that in the case of same
substituents on B ring, change of oxygen-bearing heterocycle on A ring could also
affect the antiproliferative activities of the compounds. The sulfonamide derivatives
containing 1, 3-benzodioxole scaffold (5a–5e) displayed better antiproliferative
activities whereas the derivatives containing 1, 4-benzodioxan and 1,
5-benzodioxepine groups, in general, displayed relatively weaker activities. Overall,
the results indicated that the structure of heterocycles and aromaticity of benzene ring
could influence antiproliferative activity of these synthesized compounds.
Table 1. Antiproliferative activities and anti-tubulin activities of 5a-7e against MCF-7
cells.
MCF-7 IC50a (μg/ml) ITP IC50b (μM)
n
R
Compd
1
1
1
1
1
2
2
2
2
2
3
3
3
3
3
H
CH3
F
Cl
Br
H
CH3
F
Cl
Br
H
0.17
48.95
74.05
47.27
89.01
2.16
>100
52.13
51.31
>100
53.87
>100
>100
>100
>100
0.33
0.88
40.85
76.90
94.72
51.59
5.47
93.33
27.46
87.92
>100
49.01
>100
>100
>100
>100
1.36
5a
5b
5c
5d
5e
6a
6b
6c
6d
6e
7a
7b
7c
7d
7e
CH3
F
Cl
Br
Colchicine
a
IC50 was determined by the concentration of compounds required for 50% inhibition of cell
growth (MCF-7). Cells were treated with compounds for 48 h, and cytotoxicity was determined by
b
MTT assay.
IC50 values were determined by in vitro tubulin polymerization assay and
represented the concentration of compounds for 50% inhibition of the maximum tubulin
polymerization levels.
6

To examine whether the compounds interact with tubulin and inhibit tubulin
polymerization in vitro, we performed the tubulin polymerization assay. As shown in
Table 1, compounds 5a which was most potent in antiproliferative assay also showed
best tubulin polymerization inhibition activity (IC50 = 0.88 µM). Besides, the tubulin
polymerization inhibition activities of other compounds were also relative to
antiproliferative activity. The calculated Pearson Product-Moment Correlation
Coefficient of the values was 0.831, which indicated a strong positive correlation
between the two sets of data. This result indicated the antiproliferative activity was
probably produced by direct interaction of tubulin with the compound. Overall，5a
could be a promising lead for the further development of novel tubulin inhibitor.
In order to explore probable interaction model of inhibitors with target protein,
molecular docking was performed to simulate a binding model derived from tubulin
crystal structure (PDB ID: 1SA0). All docking runs were applied CDOCKER protocol
of Discovery Studio 3.1. The 2D and 3D binding model of compound 5a and tubulin
was depicted in Figure 3. In this model, compound 5a was docked into the colchicine
binding site of tubulin with binding free energy of -35.24 KJ mol-1, One hydrogen
bond was observed (CYS241: S-H…O: 2.4 Å, Angel: 147.8). Also other residues
shown in Figure 3 interacted with compound 5a through Van der Waals force. These
residues influenced the accessibility of the hydrophobic pocket and their size could be
important in controlling tubulin selectivity. Overall, these results suggested that
compound 5a could be well inserted into tubulin, similar with colchicine.
7

Figure 3. Binding model of compound 5a with tubulin (PDB: 1SA0). a) 2D
structure of the binding model (H-bonds are displayed as dashed lines.) The purple
circles showed the amino acids which participate in hydrogen bonding, electrostatic or
polar interactions and the green circles show the amino acids which participate in the
van der Waals interactions b) 3D structure of the binding model.
Based on previous and current results, in order to provide more statistically
correlation between structure and activity and acquire more potent inhibitors, we
developed a 3D-QSAR model of the cinnamic acyl sulfonamide derivatives.
Twenty-five compounds randomly selected from the previous paper [14] and ten
compounds 5a-6d and 7a from this paper which exhibited anti-tubulin activity with
IC50 less than 100 µM were selected as the mimic objects. The whole process was
initiated by a 3D-QSAR protocol of Discovery Studio 3.1. The data combined the
predicted pIC50 values and experimental pIC50 values were listed in Table 2.
Table 2. Experimental and predicted inhibitory activities of compounds by 3D-QSAR
models
Experimental pIC50
Predicted pIC50
Residual error
-0.00793
0.00324
0.00318
0.00108
0.14146
-0.01766
0.01695
0.13147
0.03705
-0.25358
0.01237
0.00734
-0.10531
0.01081
0.20067
0.00199
0.03936
5aa
5b
6.05551
4.38881
4.11407
4.02365
4.28819
5.26201
4.03012
4.56225
4.05601
4.30971
5.34679
4.39794
5.61979
5.24413
5.27572
5.05061
5.03152
6.53081
4.38557
4.11089
4.02257
4.14673
4.29668
4.01317
4.43078
4.01896
3.82286
5.33442
4.39059
5.72511
5.23332
5.07505
5.04861
4.99216
5c
5d
5e
6a
6b
6c
6d
7a
10ab
10b
10c
10e
11a
11c
11d
8

11e
12b
12c
12d
12e
13b
13d
14d
14e
15a
15b
15c
15e
16a
16b
16c
16d
16e
5.16749
3.86328
5.42022
4.25964
4.27572
3.83565
4.28400
4.85387
4.46852
4.30103
3.82102
5.20066
3.78781
4.13077
3.9914
5.17213
3.88493
5.46658
4.32116
4.25123
3.82084
4.20282
4.77873
4.42690
4.51751
4.12619
4.87134
3.73222
4.30604
4.01146
4.18798
4.15459
3.92235
-0.00463
-0.02165
-0.04636
-0.06151
0.02448
0.01481
0.08118
0.07513
0.04162
-0.21647
-0.30517
0.32931
0.05558
-0.17526
-0.02006
-0.02683
-0.04667
-0.04944
4.16115
4.10791
3.87290
b
a Bold fonts represented compounds from this paper. No bold fonts represented
compounds from previous paper.
In this model, we selected (E)-N-(methylsulfonyl)but-2-enamide (Fig. 4a) as
substructure to build alignment conformation before QSAR analysis, then applied
CDOCKER protocol to explore each molecule with lowest energy before alignment
conformation. Then the process of QSAR analysis was conducted following previous
protocol [22], the initial set of compounds has been randomly divided into training set
and test set in QSAR protocol. Predicted pIC50 values and residual errors of all
compounds were calculated by this QSAR model had been summarized in Table 2.
The fitting curve of the observed pIC50 vs. the predicted data was shown in Figure 4b.
As shown, the correlation coefficient r2 between observed and predicted activity of
training set was found to be 0.990, while that of test set was found to be 0.893, which
proved this QSAR model was acceptable.
9

Figure 4. (a) E)-N-(methylsulfonyl)but-2-enamide as substructure for QSAR analysis.
(b) The fitting curve of the observed pIC50 vs. the predicted pIC50
The aligned molecules with the iso-surfaces from the 3D-QSAR model on van der
Waals grids (Fig. 5b) and electrostatic potential grids (Fig. 5a) were shown. As
described in previous paper, electrostatic map indicated red contours around regions
where high electron density (negative charge) was expected to increase activity, and
blue contours represent areas where low electron density (partial positive charge) was
expected to increase activity [22]. Steric map derived from van der Waals analysis
indicates areas where steric bulk was predicted to increase (green) or decrease (yellow)
activity [22].
Figure 5. (a) 3D-QSAR model coefficients on electrostatic potential grids. Blue
represents positive coefficients; red represents negative coefficients. (b) 3D-QSAR
10

model coefficients on van der Waals grids. Green represents positive coefficients;
yellow represents negative coefficients
According to the maps in Figure 5, it suggested that the compounds with negative
charged and small groups on B benzene ring showed better activity, indicating that no
substituent or small negative charged group on B ring might be better choice than
other substituents. Whereas, oxygen-bearing heterocycle group on A ring was
surrounded by yellow grids ring, which suggested that the molecule size on A ring
would benefit activity promotion, however, for the electron density it seemed that the
electronegativity didn’t influence the activity obviously.
In this paper, a series of cinnamic acyl sulfonamides (5a-7a) had been synthesized
and evaluated their biological activities as novel tubulin polymerization inhibitors.
These compounds exhibited potent tubulin polymerization inhibition activities and
antiproliferative activities against MCF-7 human breast cancer cell line. Compound
5a showed the most potent antiproliferative activity with IC50 value of 0.17 μg/ml
against MCF-7 and anti-tubulin polymerization activity with IC50 of 0.88 μM.
Molecular simulation was performed to predict probable inhibitor-tubulin protein
interaction model. Besides, through 3D-QSAR study, the model was built to provide
more pharmacophore understanding that could be used to design other novel agents.
Overall, the information provided by this work might be helpful for the design and
synthesis of tubulin polymerization inhibitors with better activities.
The main work on the synthesis of target compounds, evaluation of their biological
activities, data analysis, and manuscript preparation were performed by Yin Luo and
Yang Zhou. Yanhua Song and Guo Chen contributed to manuscript revision.
Yu-Xiang Wang, Ye Tian and Wei-Wei Fan contributed to the synthesis. Yu-Shun
Yang and Tao Cheng contributed to the 3D QSAR and molecular docking. Hai-Liang
Zhu and Yin Luo are the corresponding authors.
The content of the manuscript is original and has not been submitted for publication
11

elsewhere. There is no conflict of interest in the manuscript.
Acknowledgement
This work was supported by China Postdoctoral Science Foundation Funds
(2014M551563), International Postdoctoral Exchange Fellowship Program (20130023)
and National Natural Science Foundation of China (81701164).
References:
[1] M. Lorion, V. Agouridas, A. Couture, E. Deniau, P. Grandclaudon, Synthesis and
cytotoxic evaluation of cis-locked and constrained analogues of combretastatin and
combretastatin A4, Tetrahedron Letters, 51 (2010) 5146-5149.
[2] Y.-J. Qin, Y.-j. Li, A.-Q. Jiang, M.-R. Yang, Q.-Z. Zhu, H. Dong, H.-L. Zhu,
Design, synthesis and biological evaluation of novel pyrazoline-containing derivatives
as potential tubulin assembling inhibitors, European Journal of Medicinal Chemistry,
94 (2015) 447-457.
[3] H.-H. Wang, K.-M. Qiu, H.-E. Cui, Y.-S. Yang, L. Yin, M. Xing, X.-Y. Qiu, L.-F.
Bai, H.-L. Zhu, Synthesis, molecular docking and evaluation of thiazolyl-pyrazoline
derivatives containing benzodioxole as potential anticancer agents, Bioorganic &
Medicinal Chemistry, 21 (2013) 448-455.
[4] R. Mitra, S. Das, S.V. Shinde, S. Sinha, K. Somasundaram, A.G. Samuelson,
Anticancer Activity of Hydrogen-Bond-Stabilized Half-Sandwich RuII Complexes
with Heterocycles, Chemistry – A European Journal, 18 (2012) 12278-12291.
[5] S.-H. Kim, A. Bajji, R. Tangallapally, B. Markovitz, R. Trovato, M. Shenderovich,
V. Baichwal, P. Bartel, D. Cimbora, R. McKinnon, R. Robinson, D. Papac, D.
Wettstein,
R.
Carlson,
K.M.
Yager,
Discovery
of
(2S)-1-[4-(2-{6-Amino-8-[(6-bromo-1,3-benzodioxol-5-yl)sulfanyl]-9H-purin-9-yl}et
hyl)piperidin-1-yl]-2-hydroxypropan-1-one (MPC-3100), a Purine-Based Hsp90
Inhibitor, Journal of Medicinal Chemistry, 55 (2012) 7480-7501.
[6] W. Quaglia, A. Piergentili, F. Del Bello, Y. Farande, M. Giannella, M. Pigini, G.
Rafaiani, A. Carrieri, C. Amantini, R. Lucciarini, G. Santoni, E. Poggesi, A. Leonardi,
12

Structure−Activity Relationships in 1,4-Benzodioxan-Related Compounds. 9. From
1,4-Benzodioxane to 1,4-Dioxane Ring as a Promising Template of Novel
α1D-Adrenoreceptor Antagonists, 5-HT1A Full Agonists, and Cytotoxic Agents,
Journal of Medicinal Chemistry, 51 (2008) 6359-6370.
[7] A. Bonifazi, A. Piergentili, F. Del Bello, Y. Farande, M. Giannella, M. Pigini, C.
Amantini, M. Nabissi, V. Farfariello, G. Santoni, E. Poggesi, A. Leonardi, S. Menegon,
W. Quaglia, Structure–Activity Relationships in 1,4-Benzodioxan-Related
Compounds. 11. Reversed Enantioselectivity of 1,4-Dioxane Derivatives in
α1-Adrenergic and 5-HT1A Receptor Binding Sites Recognition, Journal of
Medicinal Chemistry, 56 (2013) 584-588.
[8] V. Menchise, G. De Simone, V. Alterio, A. Di Fiore, C. Pedone, A. Scozzafava,
C.T. Supuran, Carbonic Anhydrase Inhibitors:ꢀ Stacking with Phe131 Determines
Active Site Binding Region of Inhibitors As Exemplified by the X-ray Crystal
Structure of a Membrane-Impermeant Antitumor Sulfonamide Complexed with
Isozyme II, Journal of Medicinal Chemistry, 48 (2005) 5721-5727.
[9] L. Hu, Z.-r. Li, Y. Li, J. Qu, Y.-H. Ling, J.-d. Jiang, D.W. Boykin, Synthesis and
Structure−Activity Relationships of Carbazole Sulfonamides as a Novel Class of
Antimitotic Agents Against Solid Tumors, Journal of Medicinal Chemistry, 49 (2006)
6273-6282.
[10] R.-J. Man, D.-J. Tang, X.-Y. Lu, Y.-T. Duan, X.-X. Tao, M.-R. Yang, L.-L. Wang,
B.-Z. Wang, C. Xu, H.-L. Zhu, Synthesis and biological evaluation of novel indole
derivatives containing sulfonamide scaffold as potential tubulin inhibitor,
MedChemComm, 7 (2016) 1759-1767.
[11] A.M.F. Galal, M.M. Soltan, E.R. Ahmed, A.G. Hanna, Synthesis and biological
evaluation of novel 5-chloro-N-(4-sulfamoylbenzyl) salicylamide derivatives as
tubulin polymerization inhibitors, MedChemComm, 9 (2018) 1511-1528.
[12] G. Pochetti, E. Gavuzzo, C. Campestre, M. Agamennone, P. Tortorella, V.
Consalvi, C. Gallina, O. Hiller, H. Tschesche, P.A. Tucker, F. Mazza, Structural
Insight into the Stereoselective Inhibition of MMP-8 by Enantiomeric Sulfonamide
Phosphonates, Journal of Medicinal Chemistry, 49 (2006) 923-931.
13

[13] L. Shi, Q. Wang, H. Wang, H. Zhou, Y. Li, X. Li, Sulphonamide
1,4-dithia-7-azaspiro[4,4]nonane derivatives as gelatinase A inhibitors, Bioorganic &
Medicinal Chemistry, 21 (2013) 7752-7762.
[14] A.K. Ganguly, S.S. Alluri, C.-H. Wang, A. Antropow, A. White, D. Caroccia, D.
Biswas, E. Kang, L.-K. Zhang, S.S. Carroll, C. Burlein, J. Fay, P. Orth, C. Strickland,
Structural optimization of cyclic sulfonamide based novel HIV-1 protease inhibitors to
picomolar affinities guided by X-ray crystallographic analysis, Tetrahedron, 70 (2014)
2894-2904.
[15] R.I. Olsson, I. Jacobson, T. Iliefski, J. Boström, Ö. Davidsson, O. Fjellström, A.
Björe, C. Olsson, J. Sundell, U. Gran, J. Gyll, J. Malmberg, O. Hidestål, H. Emtenäs,
T. Svensson, Z.-Q. Yuan, G. Strandlund, A. Åstrand, E. Lindhardt, G. Linhardt, E.
Forsström, Å. Högberg, F. Persson, B. Andersson, A. Rönnborg, B. Löfberg, Lactam
sulfonamides as potent inhibitors of the Kv1.5 potassium ion channel, Bioorganic &
Medicinal Chemistry Letters, 24 (2014) 1269-1273.
[16] M. al-Rashida, R. Raza, G. Abbas, M.S. Shah, G.E. Kostakis, J. Lecka, J. Sévigny,
M. Muddassar, C. Papatriantafyllopoulou, J. Iqbal, Identification of novel chromone
based sulfonamides as highly potent and selective inhibitors of alkaline phosphatases,
European Journal of Medicinal Chemistry, 66 (2013) 438-449.
[17] Y. Luo, K.-M. Qiu, X. Lu, K. Liu, J. Fu, H.-L. Zhu, Synthesis, biological
evaluation, and molecular modeling of cinnamic acyl sulfonamide derivatives as
novel antitubulin agents, Bioorganic & Medicinal Chemistry, 19 (2011) 4730-4738.
[18] H. Yoshino, N. Ueda, J. Niijima, H. Sugumi, Y. Kotake, N. Koyanagi, K.
Yoshimatsu, M. Asada, T. Watanabe, Novel sulfonamides as potential, systemically
active antitumor agents, Journal of Medicinal Chemistry, 35 (1992) 2496.
[19] K. Yoshimatsu, A. Yamaguchi, H. Yoshino, N. Koyanagi, K. Kitoh, Mechanism
of Action of E7010, an Orally Active Sulfonamide Antitumor Agent: Inhibition of
Mitosis by Binding to the Colchicine Site of Tubulin, Cancer Research, 57 (1997)
3208-3213.
[20] T. Owa, H. Yoshino, T. Okauchi, K. Yoshimatsu, Y. Ozawa, N.H. Sugi, T. Nagasu,
N. Koyanagi, K. Kitoh, Discovery of Novel Antitumor Sulfonamides Targeting G1
14

Phase of the Cell Cycle, Journal of Medicinal Chemistry, 42 (1999) 3789-3799.
[21] C.M. Rudin, A. Mauer, M. Smakal, R. Juergens, S. Spelda, M. Wertheim, A.
Coates, E. McKeegan, P. Ansell, X. Zhou, J. Qian, R. Pradhan, B. Dowell, A.
Krivoshik, G. Gordon, Phase I/II Study of Pemetrexed With or Without ABT-751 in
Advanced or Metastatic Non–Small-Cell Lung Cancer, Journal of Clinical Oncology,
29 (2011) 1075-1082.
[22] Y. Luo, S. Zhang, K.M. Qiu, Z.J. Liu, Y.S. Yang, J. Fu, W.Q. Zhong, H.L. Zhu,
Synthesis, biological evaluation, 3D-QSAR studies of novel aryl-2H-pyrazole
derivatives as telomerase inhibitors, Bioorganic & Medicinal Chemistry Letters, 23
(2013) 1091-1095.
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Compounds of novel cinnamic acyl sulfonamide derivatives as tubulin polymerization
inhibitors were designed, synthesized and evaluated for the inhibitory activity against
tubulin polymerization and cancer cell inhibitory activity. Docking simulation and
3D-QSAR of these compounds were also conducted.
16

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
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15 novel cinnamic acyl sulfonamide derivatives have been synthesized.
Their biological activities were as potential tubulin polymerization inhibitors.
Compound 5a showed the most inhibitory activity against tubulin and cancer
cells.

Crystal structures of compounds 5b and 6c were determined.
17