Synthesis and biological evaluation of novel pyrazolo[3,4-b]pyridines as cis-restricted combretastatin A-4 analogues

Article abstract of DOI:10.1016/j.bmcl.2020.127025

Twenty-six novel pyrazolo[3,4-b]pyridine-bridged analogues of combretastatin A-4 possessing 3,4,5-trimethoxylphenyl groups, were synthesized and evaluated for their antiproliferative and tubulin polymerization inhibitory activities. Preliminary biological evaluation demonstrated that some of the target compounds displayed significant antiproliferative effect against four different cell lines including MCF-7, MDA-MB-231, HeLa and Kyse150. The most active analogue 6n was found to induce HeLa cells arrest in the G2/M phase in a dose-dependent manner. Molecular modeling studies indicated that derivative 6n most likely occupies the colchicine site of tubulin. The initial results suggest that the 3,4,5-trimethoxyphenyl substituted pyrazolo[3,4-b]pyridine could serve as a promising scaffold for development of potent tubulin inhibitors as anticancer agents.

Full text of DOI:10.1016/j.bmcl.2020.127025

Journal Pre-proofs
Synthesis and biological evaluation of novel pyrazolo[3,4-b]pyridines as cis-
restricted combretastatin A-4 analogues
Xie-Er Jian, Fang Yang, Cui-Shan Jiang, Wen-Wei You, Pei-Liang Zhao
PII:
S0960-894X(20)30095-0
DOI:
https://doi.org/10.1016/j.bmcl.2020.127025
BMCL 127025
Reference:
Bioorganic & Medicinal Chemistry Letters
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Received Date:
Revised Date:
Accepted Date:
29 December 2019
6 February 2020
9 February 2020
Please cite this article as: Jian, X-E., Yang, F., Jiang, C-S., You, W-W., Zhao, P-L., Synthesis and biological
evaluation of novel pyrazolo[3,4-b]pyridines as cis-restricted combretastatin A-4 analogues, Bioorganic &
Medicinal Chemistry Letters (2020), doi: https://doi.org/10.1016/j.bmcl.2020.127025
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Synthesis and biological evaluation of novel pyrazolo[3,4-b]pyridines as
cis-restricted combretastatin A-4 analogues
Xie-Er Jian#, Fang Yang#, Cui-Shan, Jiang, Wen-Wei, You, Pei-Liang, Zhao*
Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical
Science, Southern Medical University, Guangzhou 510515, P.R.China
ABSTRACT: Twenty-six novel pyrazolo[3,4-b]pyridine-bridged analogues of combretastatin A-4
possessing 3,4,5-trimethoxylphenyl groups, were synthesized and evaluated for their
antiproliferative and tubulin polymerization inhibitory activities. Preliminary biological evaluation
demonstrated that some of the target compounds displayed significant antiproliferative
effect against four different cell lines including MCF-7, MDA-MB-231, HeLa and Kyse150. The
most active analogue 6n was found to induce HeLa cells arrest in the G2/M phase in a
dose-dependent manner. Molecular modeling studies indicated that derivative 6n most likely
occupies the colchicine site of tubulin. The initial results suggest that the 3,4,5-trimethoxyphenyl
substituted pyrazolo[3,4-b]pyridine could serve as a promising scaffold for development of potent
tubulin inhibitors as anticancer agents.
Keywords: Pyrazolo[3,4-b]pyridine; Synthesis; Tubulin polymerization; Antiproliferative activity.
——————————
Corresponding author.E-mail: plzhao@smu.edu.cn (P.-L.Zhao)
# These authors contributed equally to this work.
1

Microtubules, are critical components of the eukaryotic cell cytoskeleton that maintain cell
shape and play a significant role in cellular events such as supporting the process of mitosis and cell
morphology and movement. 1-3 The aforementioned functions have made microtubules become an
4-6
attractive target for development of clinically effective anticancer drugs.
A great deal of
7-10
microtubule-targeting agents with diverse scaffolds have been investigated.
Among them,
combretastatin A-4 (CA-4, Fig.1), one of the most active tubulin polymerization inhibitors, exerts
outstanding antitumor activity with potencies in the low nanomolar on a wide variety of human
cancer cells in vitro and in vivo, but isomerization of the cis isomer in CA-4 to the less active trans
isomer and poor solubility have greatly hindered its clinical application. 11, 12
Structure-activity relationship (SAR) studies indicated that the common features of these
analogues consist of 3,4,5-trimethoxy substituents on the A ring and the cis-orientation of the
aromatic A- and B-rings. Hence, incorporating the cis-olefin bridge of CA-4 into a heterocyclic ring
to restrict the configuration has become a well-verified strategy to design potent CA-4 analogues.
13-16
For example, pyrazole analogue 2 was recently shown to effectively inhibit tubulin
polymerization and to display strong cytotoxicity of the colon-26 adenocarcinoma cell line with an
IC50 of 8.4 nM. 17 In addition, pyridine-bridged analogue 3 potently inhibited cancer cell survival
18
and growth.
More recently, 3,5-substitutedpyrazolo[3,4-b]pyridine fused analogue 4 was also
reported to possess excellent antiproliferative activities. 19
In our previous efforts to search for novel tubulin inhibitors as anticancer agents, a series of
CA-4 analogs with a locked cis-type bridge were designed and synthesized that showed remarkable
20-24
anticancer activities.
In this study, as shown in Fig. 1, we designed a class of novel
1,3-diarylpyrazolo[3,4-b]pyridine 5a-f and 6a-t as cis-restricted CA-4 analogues, by retaining the
3,4,5-trimethoxybenzene as A ring and incorporating the cis-olefin bridge into a fused-ring
pyrazolo[3,4-b]pyridine. Herein we reported the synthesis, preliminary biological evaluation
including antiproliferative, tubulin polymerization and cell cycle analysis, and molecular modeling
2

was also performed to explore the possible binding mode of target compounds.
N
NH
O
Bridge
O
O
O
A
O
N
O
OH
O
B
O
O
O
R
NH2
O
O
3
2
1 CA-4 (R =OH)
R
O
O
O
O
N
O
N
O
N
O
N
N
O
N
N
N
O
N
R
H
5a-f
6a-t
4
New designed compounds
Fig. 1. Structures of selected tubulin inhibitors (1–4) with potent antiproliferative activity and our newly designed
compounds (5a–f, 6a–t).
The general synthetic route for designed pyrazolo[3,4-b]pyridine derivatives 5a–f and 6a–t
was illustrated in Scheme 1. The key intermediate 3-iodo-1H-pyrazolo[3,4-b]pyridine 8 was
prepared via iodination reaction of 1H-pyrazolo[3,4-b]pyridine 7 with N-iodosuccinimide (NIS) in
the presence of potassium carbonate (K2CO3) as a base. Subsequently, intermediate 8 was treated
with commercially available arylboronic acids using cupric acetate monohydrate as a catalyst, to
give N-aryl pyrazolo[3,4-b]pyridines 9 which reacted with (3,4,5-trimethoxyphenyl)boronic acid,
Pd2(dba)3, xantphos, and K3PO4 in a mixed solution of DMSO/H2O under N2 atmosphere, and
provided 3-(3,4,5-trimethoxyphenyl) pyrazolo[3,4-b]pyridines 5a–f in yields ranging from 75 to
85%. Finally, in a similar manner, N-(3,4,5-trimethoxyphenyl) pyrazolo[3,4-b]pyridines 6a–t were
generated from two step Suzuki coupling reactions, starting from the intermediate 8 with the
appropriate arylboronic acids and (3,4,5-trimethoxyphenyl)boronic acid, respectively. The
1
structures of the designed pyrazolo[3,4-b]pyridine derivatives 5a–f and 6a–t were identified by H
NMR, 13C NMR, and HRMS spectroscopic techniques and the results were shown in the
supplementary section.
3

O
O
O
I
b
c
N
N
N
N
N
R
N
R
I
5a-f
9
a
N
N
R
N
N
N
N
H
H
N
N
R
7
8
N
e
d
N
N
O
N
H
O
O
6a-t
10
Scheme 1. Synthesis of the target compounds 5–6. Reagents and conditions: (a) DMF, K2CO3, NIS, rt, 8h; (b)
o
substituted benzyl chloride, K2CO3, DMF; or arylboronic acids, Cu(OAc)2, Et3N, THF, 80 C, 24h; (c) DMF,
H2O, (3,4,5-trimethoxyphenyl)boronic acid, Pd2(dba)3, xantphos, K3PO4, 80 oC, 8-12h; (d) DMF, H2O,
arylboronic acids, Pd2(dba)3, xantphos, K3PO4, rt, 8-12h; (e) THF, (3,4,5-trimethoxyphenyl)boronic acid,
Cu(OAc)2, Et3N, O2, 80 oC, 24h.
All of the synthesized target compounds 5a–f and 6a–t were evaluated for their
antiproliferative activities against a panel of four different human cancer cell lines, including
MCF-7 (human mammary adenocarcinoma cells), MDA-MB-231 (human breast cancer cells),
HeLa (human cervical cancer cells), and Kyse150 (human esophageal squamous cells) in vitro
through standard MTT assay. Due to its nanomolar activity to a variety of cancer cells, CA-4 was
used as a positive control in this study. The results of the designed compounds and the reference
were shown in Table 1. The IC50 value symbolizes the concentration causing 50% inhibition of
cancer cell growth.
4

Table 1 Antiproliferative activities of designed compounds 5a–f, 6a–t against human cancer
cell lines in vitro.
R
O
O
N
O
N
N
O
N
O
N
N
O
R
5a-f
6a-t
In vitro cytotoxicity (IC50±SD, µM)a
Comp.
R
MCF-7
>100
MDA-MB-231
61.52±3.07
>100
HeLa
92.73±3.29
>100
Kyse150
>100
5a
5b
5c
5d
5e
5f
4-FC6H4CH2
4-CH3C6H4CH2
4-ClC6H4
>100
>100
>100
>100
>100
>100
3,4-(CH3O)2C6H3
4-CH3CO2C6H4
4-NH2NHCOC6H4
4-FC6H4
>100
>100
>100
>100
>100
>100
>100
>100
65.23±1.75
76.66±2.59
>100
>100
29.66±0.57
51.39±4.29
>100
>100
6a
6b
6c
6d
6e
6f
56.38±3.89
>100
41.12±1.73
>100
4-CH3C6H4
4-ClC6H4
97.63±1.55
96.82±5.77
>100
84.33±4.13
28.65±0.69
>100
>100
>100
3,4-(CH3O)2C6H3
4-CH3CO2C6H4
4-NH2NHCOC6H4
3,4-Cl2C6H3
22.66±0.31
>100
>100
>100
>100
50.95±1.16
>100
21.92±1.08
>100
>100
6g
6h
6i
>100
>100
4-CNC6H4
45.87±1.70
>100
82.53±1.37
69.86±2.46
>100
72.55±4.94
91.79±4.77
>100
85.88±1.26
74.33±3.87
>100
5-F,2-CH3OC6H3
2-CH3OC6H4
2-CF3OC6H4
6j
>100
6k
6l
>100
60.46±4.91
86.66±0.70
46.98±0.78
27.04±6.42
37.28±0.45
>100
78.85±3.32
85.04±5.28
58.33±2.40
18.08±1.48
23.50±2.97
>100
>100
3-CH3OC6H4
4-F,2-CH3OC6H3
3-HO,4-CH3OC6H3
4-CH3O,3-NO2C6H3
4-CH3OC6H4
4-NO2C6H4
86.92±2.04
87.64±1.86
27.22±2.31
28.45±3.49
>100
>100
6m
6n
6o
6p
6q
6r
87.35±0.96
62.82±2.52
>100
>100
>100
>100
84.52±1.94
33.39±1.21
>100
3-NH2,4-CH3OC6H3
O
>100
>100
58.11±2.36
6s
6t
80.11±1.99
79.65±1.36
38.86±1.71
58.85±6.56
O
O
N
>100
>100
>100
>100
CA4
0.041±0.013
0.017±0.07
0.003±0.001
0.60±0.01
a
IC50 was tested after 48h of drug exposure. Each experiment was carried out at least three times. SD represents
standard deviation.
5

Compounds 5a–f possess 3,4,5-trimethoxyphenyl at the 3-position of the
pyrazolo[3,4-b]pyridine ring, whereas their analogues 6a–t were substituted by
3,4,5-trimethoxyphenyl on the 1-position of the core. This feature allowed us to explore the effect
of the location of 3,4,5-trimethoxyphenyl group on antiproliferative activities. As illustrated in
Table 1, it is obviously to find that derivatives 6a–t with 3,4,5-trimethoxyphenyl at position-1
showed more potent antiproliferative activities than the analogues 5a–f possessing corresponding
group at position-3 (for example, 5a vs. 6a, 5c vs. 6c, 5d vs. 6d), indicating that the
3,4,5-trimethoxyphenyl at position-3 was beneficial for antiproliferative activity. Among the series
of 6a–t, in agreement with CA-4, analogue 6n with (3-hydroxy, 4-methoxy)phenyl group exhibited
potent growth inhibitory activity against all the four tumor cell lines. On the contrary,
electron-withdrawing groups such as fluorine (6a), chlorine (6c), carbomethoxy (6e), and cyano
(6h) at the 4-position of the phenyl moiety, displayed much decreased antiproliferative activity,
compared to derivative 6n, while the compound 6t with a 2-methoxypyridine substitution of
(3-hydroxy, 4-methoxy)phenyl moiety, completely lost its inhibitory activity. These results again
highlighted the importance of the (3-hydroxy, 4-methoxy)phenyl group in maintaining inhibitory
potency against tumor cells.
Generally, significantly arresting cells in the G2/M phase is a typical feature of tubulin
polymerization inhibitors. Hence, cell cycle analysis was carried out on HeLa cells for the highly
active derivative 6n to explore whether the antiproliferative activity was related to arrest the cell
cycle. In this study, HeLa cells was treated with 9, 18, 36 μM concentrations of compound 6n for
24h by flow cytometry. As depicted in Fig. 2, with the increasing concentration, HeLa cells
accumulated continuously in the G2/M phase, from 26.93% (9 μM) to 34.87% (18 μM) and then to
48.13% (36 μM) after 24h of treatment, which compared with 13.92% of the G2/M phase for
untreated cells. These data suggested that compound 6n arrested the cell cycle at the G2/M phase in
a concentration-dependent manner.
6

A
B
C
D
Fig. 2. Effect of compound 6n on cell cycle in HeLa cells. Flow cytometry analysis of HeLa cells stained
with propidium iodide and treated with 6n for 24h. (A) Control; (B) 6n, 9 μM; (C) 6n, 18 μM; (D) 6n, 36 μM.
To elucidate whether the newly pyrazolo[3,4-b]pyridines could inhibit tubulin polymerization
in vitro, five representative analogues were selected to evaluate for their inhibitory activities at 10
μM concentration, meanwhile CA-4 was used as a positive control. As presented in Table 2, some
extent correlation with respect to antitubulin and antiproliferative activity was observed. Compound
6n, one of the most active antiproliferative compounds in this series, also exhibited much higher
antitubulin activity with 31% inhibition at a concentration of 10 μM, which indicated that this
analogue most likely targeted at tubulin.
7

Table 2 Tubulin polymerization inhibitory activities of representative selected compounds
Tubulin polymerization
Comp.
R
% inhibition a
6a
6d
6m
6n
6o
4-FC6H4
3,4-(CH3O)2C6H3
4-F,2-CH3OC6H3
3-HO,4-CH3OC6H3
4-CH3O,3-NO2C6H3
CA-4
18
14
20
31
16
80
a Compounds were tested at a final concentration of 10 μM.
In order to investigate the binding features for this series of compounds, the representative
derivative 6n was chosed to perform the molecular docking study on the colchicine binding site of
tubulin. As shown in Fig. 3, 6n occupied the colchicine binding site at the interface of α/β-tubulin,
as expected, and the binding modes were quite similar with that of CA-4 in the co-crystallized
tubulin structure (PDB: 5lyj). 1H-pyrazolo[3,4-b]pyridine framework of the compound 6n was
placed deeply in the β subunit of the tubulin, while the oxygen of trimethoxyphenyl formed a strong
hydrogen bonding with βCys241 (2.1Å). In addition, the hydroxyl of the analogue 6n established
two H-bonds with βAsn258 (2.5 Å) and βMet259 (2.6 Å), respectively. These molecular docking
results suggested that compound 6n efficiently bound to the colchicine site of tubulin, which may
be responsible for its tubulin polymerization inhibitory activities.
Fig. 3. Proposed binding model of compound 6n (yellow) overlapping with CA-4 (magenta) in the colchicine
binding site of tubulin. Subunits α and β of the tubulin heterodimer are shown as green and blue cartoon
respectively. Potential hydrogen bonding interactions are indicated as black dashed lines. The main interacting
residues are shown and labeled, including Cys241 (2.1Å), Asn258 (2.5Å) and Met259 (2.6Å). Final figure for
docking pose was generated by PyMOL.
8

In conclusion, a series of novel 3,4,5-trimethoxyphenyl substituted pyrazolo[3,4-b]pyridine as
cis restricted combretastatin A-4 analogues were designed and synthesized via a two-step Suzuki
coupling reaction. Biological assays revealed that the most active derivative 6n exhibited potent
antiproliferative activities against four different cell lines including MCF-7, MDA-MB-231, HeLa
and Kyse150. Furthermore, compound 6n was shown to effectively arrest HeLa cells in the G2/M
phase by flow cytometric analysis and inhibit tubulin polymerization. In addition, molecular
docking study demonstrated that 6n most likely occupied the colchicine binding site at the interface
of α/β-tubulin, employing quite similar binding modes with that of CA-4. These observations
indicated that 3,4,5-trimethoxyphenyl substituted pyrazolo[3,4-b]pyridine might be a promising
scaffold for the development of novel tubulin inhibitors as anticancer drugs.
Acknowledgments
This work was supported by the Natural Science Foundation of Guangdong Province, China
(Grant No. 2018B030311067), and the Science and Technology Program of Guangzhou City, China
(Grant No. 201707010198).
A. Supplementary data
Supplementary data associated with this article can be found, inthe online version, at
https://doi.org/10.1016/j.bmcl.2020.xx.xxx.
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Synthesis and biological evaluationof novel pyrazolo[3,4-b]pyridines as
11

cis-restricted combretastatin A-4 analogues
Xie-Er Jian #, Fang Yang #, Cui-Shan, Jiang, Wen-Wei, You, Pei-Liang, Zhao*
Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Science,
Southern Medical University, Guangzhou 510515, P.R.China
N
NH
O
O
O
N
Cell cycle arrest
N
O
OH
O
O
NH2
O
O
3
2
O
N
N
O
O
O
OH
O
O
6n
O
OH
O
1 (CA-4)
Molecular modeling
Declaration of interests
 The authors declare that they have no known competing financialinterestsor personal relationships that could
have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered as
potential competing interests:
12

13