Synthesis, biological evaluation, and structure-activity relationships of new tubulin polymerization inhibitors based on 5-amino-1,2,4-triazole scaffold

Article abstract of DOI:10.1016/j.bmcl.2021.127880

Based on our previous research, thirty new 5-amino-1H-1,2,4-triazoles possessing 3,4,5-trimethoxyphenyl moiety were synthesized, and evaluated for antiproliferative activities. Among them, compounds IIa, IIIh, and IIIm demonstrated significant antiproliferative activities against a panel of tumor cell lines, and the promising compound IIIm dose-dependently caused G2/M phase arrest in HeLa cells. Furthermore, analogue IIa exhibited the most potent tubulin polymerization inhibitory activity with an IC₅₀ value of 9.4 μM, and molecular modeling studies revealed that IIa formed stable interactions in the colchicine-binding site of tubulin, suggesting that 5-amino-1H-1,2,4-triazole scaffold has potential for further investigation to develop novel tubulin polymerization inhibitors with anticancer activity.

Full text of DOI:10.1016/j.bmcl.2021.127880

Bioorg. Med. Chem. Lett. 38 (2021) 127880
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis, biological evaluation, and structure-activity relationships of new
tubulin polymerization inhibitors based on 5-amino-1,2,4-triazole scaffold
a
a
a
Fang Yang , Lin Chen , Jin-Mei Lai , Xie-Er Jian, Dong-Xin Lv, Li-Li Yuan, Yu-Xia Liu,
Feng-Ting Liang, Xiao-Lan Zheng, Xiong-Li Li, Li-Yuan Wei, Wen-Wei You, Pei-Liang Zhao
*
Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Science, Southern Medical University, Guangzhou 510515, PR China
A R T I C L E I N F O
A B S T R A C T
Keywords:
Based on our previous research, thirty new 5-amino-1H-1,2,4-triazoles possessing 3,4,5-trimethoxyphenyl moi-
ety were synthesized, and evaluated for antiproliferative activities. Among them, compounds IIa, IIIh, and IIIm
demonstrated significant antiproliferative activities against a panel of tumor cell lines, and the promising
compound IIIm dose-dependently caused G2/M phase arrest in HeLa cells. Furthermore, analogue IIa exhibited
5
-Amino-1,2,4-triazoles
Synthesis
Tubulin
Antiproliferative activity
the most potent tubulin polymerization inhibitory activity with an IC50 value of 9.4 M, and molecular modeling
μ
studies revealed that IIa formed stable interactions in the colchicine-binding site of tubulin, suggesting that 5-
amino-1H-1,2,4-triazole scaffold has potential for further investigation to develop novel tubulin polymerization
inhibitors with anticancer activity.
Microtubule system of eukaryotic cells is comprised by
α
/β tubulin
reported to possess notable antiproliferative activities. In our ongoing
effort to discover novel 1,2,4-triazole derivatives as tubulin inhib-
heterodimers and is a crucial element in various essential cellular pro-
cesses, such as maintenance of cellular structure, organization of intra-
itors,2
1–26
we found two series of 3-alkylsulfanyl-1,2,4-triazole ana-
logues, exemplified by compounds 5–7 (Fig. 1), which exhibited potent
1
–3
cellular architecture, intracellular transport and cell division.
Due to
2
4–26
These
critical roles in the above-mentioned cellular functions, microtubule has
been a highly attractive therapeutic target for cancer treatment, and
numerous of structurally diverse microtubule-targeting agents have
antiproliferative activities toward a panel of cancer cell lines.
results triggered us to start a pharmacophore exploration and optimi-
zation effort around the 1,2,4-triazole core. Although a great deal of
been investigated.4
–7
1,2,4-triazole derivatives have been reported, only a few N-aroyl-5-
amino-1,2,4-triazoles were investigated.1
9,20,27
Hence the objectives of
Combretastatin A-4 (CA-4, Fig. 1) and its derivatives are well-known
tubulin inhibitors targeting colchicine-binding site which is located at
this work aimed to design and synthesis of various substituents including
acetamides, aryl ketones and benzyl groups at the N-1 position of the
1,2,4-triazole core to develop novel potent antiproliferative agents with
general formulas I–III. All target compounds were evaluated for their
antiproliferative activities, and some promising analogues were further
screened for inhibition of tubulin polymerization.
the interface of
α/β tubulin heterodimers. Compared with other sites,
targeting the colchicine-binding site might provide a promising superi-
ority for reducing multidrug resistance effects, and hence, these tubulin
inhibitors continue to receive substantial attention in recent deca-
8
–12
des.
Extensive studies strongly demonstrated that 3,4,5-trimethoxy-
1
3
phenyl fragment of CA-4 analogues is indispensable, and replacement
of the cis-double bond with a heterocyclic ring has become a well-
documented approach to retain or improve their remarkable
Synthesis of the target 5-amino-3-(3,4,5-trimethoxyphenyl)-1,2,4-
triazoles I–III was described in Scheme 1. The key intermediate 3-
(3,4,5-trimethoxyphenyl)-1H-1,2,4-triazol-5-amine 11 was accom-
plished using a four-step procedure from 3,4,5-trimethoxybenzoic acid
according to reported procedure.20 While required intermediates chloro
acetamides were prepared via a biphasic acylation of appropriate aniline
with chloroacetyl chloride in the presence of triethylamine and
dichloromethane with excellent yields, using our recently reported
activities.1
4–18
Recently, a number of conformationally restricted CA-4 analogues
through incorporating the cis-double bond into a heterocyclic ring sys-
tem have been extensively investigated. Among them, several 1,2,4-tri-
azole derivatives,1
9,20
with general structures 2–4 listed in Fig. 1, were
*
Corresponding author.
E-mail address: plzhao@smu.edu.cn (P.-L. Zhao).
a
These authors contributed equally to this work.
https://doi.org/10.1016/j.bmcl.2021.127880
Received 17 November 2020; Received in revised form 6 February 2021; Accepted 10 February 2021
Available online 24 February 2021
0
960-894X/© 2021 Elsevier Ltd. All rights reserved.

F. Yang et al.
Bioorganic & Medicinal Chemistry Letters 38 (2021) 127880
Fig. 1. Structures of selected tubulin inhibitors, including CA-4, and 1,2,4-triazole-based compounds 2–7.
Scheme 1. Regents and conditions: (a) conc. H
2
SO
4
, ethanol, reflux; (b) NH
2
NH
2
·H
2
O, ethanol, reflux; (c) S-methylisothiourea sulfate; (d) 5% NaOH, 36 h, reflux; (e)
3
CO , DMF, r.t.; (g) chloroacetyl chloride, Et N, CH Cl , r.t.; (h) K CO ,
substituted benzyl chloride, K
2
CO
3
, DMF, r.t.; (f) substituted phenacyl bromides, K
2
3
3
2
2
2
◦
DMF, 80 C.
methodology.22 Subsequently, the 5-amino-3-(3,4,5-trimethoxyphenyl)-
,2,4-triazole derivatives Ia–g and IIa–i were acquired through a
nucleophilic substitution reaction of appropriate benzyl chloride and
phenacyl bromide, with the key intermediate 11, using solid K CO as a
example, the growth inhibition values of compounds Ia, Ie, Ig, IIa, IIi,
IIIh, IIIm ranged from 51 to 95% on the three tested cell lines. Espe-
cially, derivative IIIm demonstrated the most powerful cell growth in-
hibition activity against a broad-spectrum of tumor cell types with GI
values of 95, 93, 93, 93, and 70% on HeLa, MCF-7, A549, Panc-1, and
PC-3, respectively.
1
2
3
base in anhydrous N,N-dimethylformamide at room temperature.
◦
Meanwhile, increase of the temperature to 80 C, the reaction of triazole
1
1
6
1 with diverse N-substituted 2-chloroacetamides provided desired
,2,4-triazoles IIIa–n in moderate to good isolated yields ranging from
5% to 85%. The chemical structures of the final compounds were fully
According to the above data, some promising compounds were then
selected for further evaluation for their antiproliferative activities to-
ward MCF-7, HeLa, Panc-1, and K562 cell lines. As summarized in
Table 2, IIIm exhibited the most promising antiproliferative activities on
1
13
characterized by H NMR, C NMR and HRMS spectroscopic tech-
niques, and the spectral data agree with the proposed structures.
The newly prepared compounds Ia–g, IIa–i, and IIIa–n were evalu-
ated for their in vitro antiproliferative activities at single concentration
K562 and HeLa cell lines with IC50 values of 9.23 and 18.94
μM,
respectively. It was interesting to note that compounds I–III with
electron-donating groups always exerted more potent cytotoxic activity
than the corresponding derivatives having electron withdrawing group
(Ia vs. Ie, Ia vs. Ig, IIa vs. IIi, IIIh vs. IIIn, IIIm vs. IIIn). Moreover,
acetamide derivatives IIIh, IIIm having bulky groups (n-propyl and t-
butyl), displayed much higher antiproliferative activities than the cor-
responding derivatives with small substituents.
of 100
tissues, including MCF-7 (huma mammary adenocarcinoma cells), HeLa
human cervical cancer cells), A549 (human lung adenocarcinoma
μM toward five human cancer cell lines taken from different
(
cells), PC-3 (human prostate cancer cell lines), and Panc-1 (human
pancreatic carcinoma cell line) through MTT screening assay. The re-
sults for each compound were reported as the percent growth of treated
cells compared to untreated control cells. Unfortunately, as shown in
Table 1, nearly all of the 5-amino-1,2,4-triazole derivatives were inef-
fective toward A549 and PC-3 with growth inhibition (GI) percent lower
than 50%. Interestingly, most compounds displayed substantial anti-
proliferative activities against MCF-7, HeLa, and Panc-1 cell lines. For
To explore the mode of action of these compounds on cancer cells,
effect of compound IIIm on cell division in HeLa cell line was investi-
gated by determining distribution of the cells in different phases of the
cell cycle using flow cytometric technique. In this study, HeLa cells were
treated with compound IIIm at indicated concentrations (10, 20, 40
μM). As depicted in Fig. 2, cell cycle analysis suggested that the
2

F. Yang et al.
Bioorganic & Medicinal Chemistry Letters 38 (2021) 127880
Table 1
Single concentration growth inhibition of compounds Ia–g, IIa–i, and IIIa–n toward five human tumor
cell lines.
a
Comp.
R
Growth inhibition percent % at 100
μ
M IC50( M)
μ
MCF-7
HeLa
A549
PC-3
Panc-1
Ia
4-CH
4-F
3
55
34
33
49
52
43
55
73
53
30
48
27
/
76
28
33
55
58
28
73
76
70
27
31
9
34
42
24
38
13
30
6
39
41
35
48
21
/a
36
31
35
37
28
18
26
38
/
53
7
Ib
Ic
2-F
5
Id
4-Cl
39
53
6
Ie
4-NO
3-CN
2
If
Ig
3.5-(CF
3
O)
2
71
57
17
/
IIa
IIb
IIc
IId
IIe
IIf
4-CH
4-CH
3-CH
3,4-F
4-F
3
3
3
O
21
/
O
20
14
13
26
12
15
35
/
2
52
/
4-CI
4-Br
H
38
41
42
66
35
39
30
32
12
41
18
75
49
20
29
45
95
30
6
IIg
IIh
IIi
27
30
59
/
6
4
3-Br
4-CH
3-CH
4-CH
19
31
6
51
5
IIIa
IIIb
IIIc
IIId
IIIe
IIIf
IIIg
IIIh
IIIi
IIIj
IIIk
IIIl
IIIm
IIIn
3
3
O
34
50
21
31
12
23
70
34
32
14
8
17
9
/
3
O
33
25
40
42
50
61
50
/
/
2-F, 4-CH
4-CH CH
3.4-(CH O)
3
12
27
22
34
37
16
29
7
22
/
2
3
3
2
14
10
91
32
32
/
3-CH
4-CH
3
2
CH
CH
2 3
2.4.6-(CH
3.4-(CH
4-N(CH
4-CH(CH
3 3
)
3 2
)
3
)
2
35
37
70
14
3
)
2
/
22
93
12
4-C(CH
4-CI
3
)
3
93
37
93
22
a
/
: not detectable under the employed experimental conditions.
Table 2
inhibitory effects on tubulin polymerization at 10 M concentration to
μ
In vitro antiproliferative evaluation of representative compounds toward four
examine whether these analogues could potentially interact with
tubulin, and the typical microtubule depolymerization agent CA-4 was
employed as a positive reference. The results showed that most tested
compounds exhibited potent inhibitory activity (Table 3). Particularly,
compounds IIa and IIIm with greatest antiproliferative efficacy, also
significantly inhibited tubulin polymerization by 52 and 48%, respec-
tively. Notably, it was found in Fig. 3, analogue IIa inhibited tubulin
polymerization in a similar way to CA-4, and demonstrated potent
cancer cell lines.
a
Compd.
IC50
(
μ
M)
MCF-7
HeLa
Panc-1
K562
Ia
73.76 ± 3.35
82.10 ± 4.21
>100
46.90 ± 1.33
57.19 ± 2.31
53.14 ± 3.24
52.17 ± 3.66
54.04 ± 0.83
58.24 ± 4.75
56.12 ± 2.72
18.94 ± 1.98
4.7 ± 0.2
61.52 ± 3.80
>100
17.1 ± 0.63
>100
Ie
Ig
73.01 ± 1.02
59.82 ± 5.95
>100
31.53 ± 1.06
65.99 ± 4.12
33.04 ± 2.17
>100
IIa
40.64 ± 0.72
53.02 ± 4.11
68.41 ± 2.19
44.71 ± 1.68
35.56 ± 0.23
170 ± 7.0
IIb
antitubulin activities with an IC50 value of 9.4 M. These results indi-
μ
IIi
79.61 ± 3.92
20.03 ± 5.04
35.15 ± 6.50
cated that the mechanism of IIa was consistent with previously reported
CA-4, suggesting that compound IIa is a novel tubulin polymerization
inhibitor.
IIIh
IIIm
CA-4(nM)
41.1 ± 0.97
9.23 ± 1.81
610 ± 20
b
ND
Molecular modeling studies were performed to further confirm the
capability of the promising compound IIa for binding to the colchicine-
binding site in tubulin. Binding pose shown in Fig. 4 indicates that IIa
a
IC50 is the concentration of compound required to decrease cellular growth
by 50% and data are indicated as the mean ± SD from three independent
experiments.
b
binds to the β-tubulin subunit, at its interface with α-tubulin, similar to
that of colchicine and CA-4. Oxygen atom of carbonyl moiety in IIa
ND: not determined.
forms a powerful hydrogen bonding with amine group of Val181 (1.9 Å)
percentage of cell in G2/M phase reached from 14.45% to 28.74% after
of
tween the free amine of 1,2,4-triazole nucleus and thiol group of Met259
3.5 Å) of β-subunit. In addition, nitrogen atom of N-4 position in tri-
α
-subunit. Meanwhile, there is a hydrogen bonding interaction be-
treatment of 48 h. Hence, the significant increase revealed that IIIm
2
induced a significant cell cycle arrest at the G /M phase in a
(
concentration-dependent manner, compared to untreated cells.
azole ring also establishes a weak hydrogen bonding with Lys352 (3.6 Å)
Six representative compounds were further evaluated for in vitro
of β-subunit.
3

F. Yang et al.
Bioorganic & Medicinal Chemistry Letters 38 (2021) 127880
Fig. 2. Effect of compound IIIm on cell cycle in HeLa cells. Flow cytometry analysis of HeLa cells stained with propidium iodide and treated with IIIm for 48 h. (A)
Control; (B) IIIm, 10
μM; (C) IIIm, 20
μ
M; (C) IIIm, 40 M.
μ
Table 3
Tubulin polymerization inhibitory activities of representative selected
compounds.
Comp.
Tubulin polymerization
a
b
%
inhibition
IC50( M)
μ
c
Ia
25
52
42
14
48
79
–
IIa
9.4 ± 0.3
IIb
–
IIIh
IIIm
CA-4
–
–
4.22 ± 0.15
a
Compounds were tested at a final concentration of 10
μ
M.
b
IC50 values are presented as mean values of three independent experiments
done in quadruplicates.
Fig. 4. Proposed binding model for IIa in colchicine-site of tubulin (PDB code:
lyj). The backbone of tubulin is illustrated as ribbon representation ( -tubulin,
c
NT: Not test.
5
α
cyan; β-tubulin, green). Hydrogen bonds are shown as dotted black lines.
In summary, based on our previous work, three new classes of 5-
amino-1H-1,2,4-triazoles carrying 3,4,5-trimethoxyphenyl moiety were
synthesized and evaluated for their antiproliferative activities. Com-
pound IIIm displayed highest activity among all new derivatives against
cancer cell growth and also demonstrated a significant inhibition of
tubulin polymerization. Furthermore, IIIm concentration-dependently
induced cell cycle arrest at the G
showed the most potent antitubulin activity with an IC50 value of 9.4
M. Molecular docking studies revealed that IIa is likely to bind to the
2
/M phase in HeLa cells. Notably, IIa
μ
Fig. 3. Effects of IIa on tubulin polymerization in vitro. Tubulin in reaction
◦
buffer was incubated at 37 C in the presence of the control (1% DMSO),
colchicine-binding site in a similar way with typical tubulin polymer-
ization inhibitors. These preliminary results suggested that the novel 5-
amino-1H-1,2,4-triazole scaffold has potential for further investigation
to develop tubulin polymerization inhibitors with anticancer activity.
compound IIa (10
μ
M) and CA-4 (1.5, 6, 10 M). Absorbance at 340 nm was
μ
◦
monitored at 37 C every minute, and polymerizations were followed by an
increase in fluorescence emission at 340 nm over a 20 min period. The exper-
iments were performed three times.
4

F. Yang et al.
Bioorganic & Medicinal Chemistry Letters 38 (2021) 127880
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Appendix A. Supplementary data
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