Synthesis and biological evaluation of piperazine group-linked bivalent β-carbolines as potential antitumor agents

Article abstract of DOI:10.1039/c5md00312a

A series of novel bivalent β-carbolines with a piperazine group spacer between 3-methylene units were synthesized and evaluated as antitumor agents. The results demonstrated that compounds 7e and 7g exhibited the most potent cytotoxic activities against ten tumor cell lines. Structure-activity relationships analysis indicated that (1) the substituents in positions 1 and 9 of the β-carboline ring played a significant role in modulating the antitumor activity; (2) the introduction of alkyl groups into position-9 of the β-carboline nucleus enhanced their cytotoxic potencies and the butyl substituent was the optimal group. Investigation of the preliminary mechanism of action demonstrated that compound 7g showed obvious anti-angiogenic activity in the in vivo CAM assay, and the potency was similar to that of CA4P (200 μM).

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CONCISE ARTICLE
Synthesis and biological evaluation of piperazine
group-linked bivalent β-carbolines as potential
antitumor agents†
Cite this: DOI: 10.1039/c5md00312a
Rongqin Sun,a Rui Liu,a Chi Zhou,a Zhenghua Ren,b Liang Guo,c Qin Ma,c
c
a
a
a
a
*
*
Wenxi Fan, Liqin Qiu, Huijuan Yu, Guang Shao and Rihui Cao
A series of novel bivalent β-carbolines with a piperazine group spacer between 3-methylene units were
synthesized and evaluated as antitumor agents. The results demonstrated that compounds 7e and 7g
exhibited the most potent cytotoxic activities against ten tumor cell lines. Structure–activity relationships
analysis indicated that (1) the substituents in positions 1 and 9 of the β-carboline ring played a significant role
in modulating the antitumor activity; (2) the introduction of alkyl groups into position-9 of the β-carboline
nucleus enhanced their cytotoxic potencies and the butyl substituent was the optimal group. Investigation
of the preliminary mechanism of action demonstrated that compound 7g showed obvious anti-angiogenic
activity in the in vivo CAM assay, and the potency was similar to that of CA4P (200 μM).
Received 25th July 2015,
Accepted 21st October 2015
DOI: 10.1039/c5md00312a
www.rsc.org/medchemcomm
3 and 9 of the β-carboline nucleus played a vital role in deter-
mining their antitumor potencies; (iii) the n-butyl and
Introduction
β-Carboline alkaloids are a large group of natural and syn-
thetic indole alkaloids with a tricyclic pyridoij3,4-b]indole ring
system, and possess a broad spectrum of biochemical effects
and pharmaceutical functions.1 Recently, many researchers
have done much to design and synthesize many novel
β-carbolines as a new class of antitumor agents.2–9 These
compounds were discovered to exhibit their antitumor activi-
ties through multiple mechanisms, which include intercala-
tion into DNA10 and inhibition of Topo I and II (topoisomer-
3-phenylpropyl substituents in position-9 of the β-carboline
nucleus were the optimal pharmacophoric groups giving rise
to significant antitumor agents.
Previous investigations29 suggested that dimerization of
various intercalating agents by an appropriate spacer could
lead to a marked increase in the DNA binding affinity. There-
fore, bivalent β-carbolines were expected to exhibit more
potent antitumor efficacies than monomers. Recently, several
bivalent β-carbolines were synthesized and evaluated as anti-
Alzheimer's30 and antitumor31 agents (Fig. 1), and were
proved to exhibit higher anti-Alzheimer potencies than mono-
mers. However, to the best of our knowledge, no extensive,
systematic study has been undertaken to examine the struc-
ture–activity relationships of bivalent β-carbolines as anti-
tumor agents. We recently began such a study and have
reported the synthesis, in vitro evaluation, in vivo efficacies
and structure–activity relationships of new bivalent
β-carbolines linked at the N-9 and C-3 position with a spacer
of three to ten methylene units, respectively.32–34 (Fig. 1).
However, the bivalent β-carbolines mentioned above have
limited utility in cancer therapy because of their poor
solubility.
ase
I
and II),11 CDK (cyclin-dependent kinase),12 MK-2
(mitogen activated protein kinase-activated protein kinase
2),13 kinesin-like protein Eg5,14 IKK (I-Kappa-B kinase)15 and
PLK (polo-like kinase).16
Our group previously reported the synthesis of a large
quantity of β-carbolines as a new class of antitumor agents
and the evaluation of their antitumor activities in vitro and
in vivo.17–28 Structure–activity relationships analysis of these
compounds indicated that (i) the common β-carboline moiety
was very important for their potent antitumor activities; (ii)
the introduction of appropriate substituents into positions 1,
a School of Chemistry and Chemical Engineering, Sun Yat-sen University,
135 Xin Gang West Road, Guangzhou 510275, PR China.
E-mail: caorihui@mail.sysu.edu.cn, shaog@mail.sysu.edu.cn
b School of Life Science, Sun Yat-sen University, 135 Xin Gang West Road,
Guangzhou 510275, PR China
c Xinjiang Huashidan Pharmaceutical Co., Ltd., 175 He Nan East Road,
Urumqi 830011, PR China
To circumvent the solubility problem and find more active
congeners as potential antitumor agents, in this investiga-
tion, we designed and synthesized a series of piperazine
group-linked bivalent β-carbolines as potent antitumor
agents. These compounds were expected to exhibit signifi-
cantly improved antitumor activities due to the improved
water solubility. We report herein the synthesis, in vitro
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c5md00312a
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Fig. 1 Chemical structure of the representative reported and newly
synthesized bivalent β-carbolines.
evaluation, preliminary structure–activity relationships and
mechanism of action of the new bivalent β-carbolines with a
piperazine group spacer between 3-methylene units.
Chemistry
The synthetic route of the bivalent β-carbolines 7a–y is
outlined in Scheme 1. Monovalent β-carbolines 3a–c, 3f, 4b–i,
4w–y, 5a–h, 5v–y, 6a–h and 6v–y were synthesized according
to previously published methods.17–19,21–23 An intermediate
Schiff base was prepared by the condensation of compounds
6a–y with piperazine in anhydrous sym-dichloroethane at 60
°C, followed by reduction with NaBH3CN in anhydrous sym-
dichloroethane at room temperature to afford compounds
7a–y in 21–56% yield. The chemical structures of all the
newly synthesized compounds were characterized by MS,
Scheme 1 Synthesis of the bivalent β-carbolines 7a–y. Reagents and
conditions: (i) acetic acid, R1CHO, reflux, 3 h; (ii) ethanol, SOCl2, reflux,
4 h; (iii) xylene, S, reflux, 8 h; (iv) DMF, NaH, alkyl halogenide, stirred at
RT; (v) THF, LiBH4, stirred at RT; (vi) CH3CN, MnO2, reflux, 2 h; (vii)
sym-dichloroethane, NaBH3CN, stirred at RT.
1
HRMS, H NMR and 13C NMR.
Academy of Sciences. DMSO was used as solvent for drugs.
The final concentration of DMSO in the growth medium was
2% (v/v) or lower, concentrations without an effect on cell
replication. In all of these experiments, three replicate wells
were used to determine each data point.
Experimental section
Cytotoxicity in vitro
In vitro cytotoxicity assays were carried out using 96-
microtiter plate cultures and MTT staining according to the
procedures described by Cao et al.23 Briefly, cells were grown
in RPMI-1640 medium containing 10% (v/v) fetal calf serum,
100 μM penicillin and 100 μM streptomycin. The cultures
were propagated at 37 °C in a humidified atmosphere
containing 5% CO2. Cell lines were obtained from the Shang-
hai Institute of Biochemistry and Cell Biology, Chinese
In vivo CAM assay
The anti-angiogenic activity of the selected compound 7g was
investigated in vivo using the chicken chorioallantoic mem-
brane (CAM) assay. Five day-old fertilized eggs were obtained
from a local hatchery. 5 mL of albumin was aspirated and
the eggs were incubated horizontally to allow the CAM to
detach from the shell. Compound 7g was prepared in 1.2%
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agarose discs at concentrations of 200, 100 and 50 μM per
disc, respectively. Combretastatin A4 phosphate (CA4P) was
used as the reference drug. Discs containing only the vehicle
(DMSO) were used as negative control. A small window open-
ing was made in the shell, and the discs were directly applied
onto the CAM. The square opening was covered with steril-
ized surgical tape and the embryos were incubated for 48 h
at 37 °C. The CAMs were photographed under a dissecting
microscope and the blood vessels in each CAM were counted.
The results are presented as the mean percentage of inhibi-
tion to the control SD (n = 3).
LLC cells were investigated, and cisplatin was used as the ref-
erence drug. In order to enhance the solubility in aqueous
solution, all bivalent β-carbolines were prepared in the form
of a hydrochloride salt before use. As predicted, the hydro-
chloride salt of the novel bivalent β-carbolines linked with a
piperazine group spacer in position-3 showed good water sol-
ubility (more than 1.0 mg ml−1). The results are summarized
in Table 1.
As shown in Table 1, compounds 7b, 7d, 7h, 7j, 7o, 7r, 7s
and 7x displayed significant and selective cytotoxicities with
IC50 values lower than 20 μM against some tumor cell lines.
Compound 7e showed the most potent cytotoxic activity with
IC50 values of 7.62, 8.95, 5.32, 3.02, 8.35, 5.51, 7.62 and 5.15
μM against MCF-7, HepG2, 22RV1, 769-P, A375, SK-OV-3,
BGC-823 and LLC tumor cell lines. Similarly, compound 7g
exhibited potent cytotoxic activities with IC50 values lower
than 20 μM against the ten tumor cell lines. On the other
Result and discussion
Cytotoxicity in vitro
The cytotoxic potencies of all the newly synthesized bivalent
β-carbolines against a panel of human tumor cell lines and
Table 1 Cytotoxic activity of bivalent β-carbolines in vitro
a
IC50 (μM)
Compds R1
R9
MCF-7b HepG2 22RV1 HT-29 769-P A375
SK-OV-3 Eca-109 BGC-823 LLC
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
7o
7p
7q
7r
7s
7t
7u
7v
7w
7x
H
H
H
H
H
CH3
CH3
CH3
Ph
Ph
Ph
Ph
C2H5
82.8
29.2
>100
72.8
7.62
>100
7.16
>100
15.2
65.4
76.3
8.95
>100
9.66
38.1
>100
>100
>100
>100
>100
55.0
52.3
43.9
>100
60.6
5.32
86.3
12.5
40.8
54.3
24.92
>100
>100
>100
47.8
32.8
17.1
36.8
18.3
18.7
>100
11.3
25.2
>100
17.6
64.3
38.2
>100
29.0
3.02
>100
12.74 13.0
45.8
>100
29.6
>100
>100
>100
>100
16.6
>100
>100
61.1
49.9
16.8
>100 46.5
46.0
8.35
>100 31.0
24.4
11.3
>100
26.4
>100
24.7
24.6
>100
14.3
68.6
9.52
>100
85.6
7.62
78.5
10.8
40.8
>100
38.8
13.8
2.36
79.8
15.9
5.15
61.8
7.68
12.0
34.5
14.0
>100
>100
>100
69.0
27.4
40.4
>100
9.68
9.78
36.4
>100
>100
39.0
19.8
>100
9.97
n-C4H9
PhCH2
(4-F)PhCH2
PhIJCH2)3
CH3
8.43
5.51
i-Bu
16.0
51.4
>100
19.8
(3-Cl)PhCH2 43.7
CH3
C2H5
PhCH2
PhIJCH2)3
H
32.4
40.9
9.92
>100 >100
>100 >100
>100 >100
45.7
19.6
>100 >100
>100 >100
37.3
15.5
>100 >100
>100 >100
>100 >100
64.2
36.0
>100 >100
5.23 52.3
57.6
>100
>100
>100
>100
>100
>100
20.6
>100
>100
27.3
>100
>100
>100
>100
>100
68.5
>100
>100
>100
29.0
>100
>100
>100
56.3
(4-OCH3)Ph
(4-OCH3)Ph
(4-OCH3)Ph
(4-OCH3)Ph
(4-OCH3)Ph
3,4-DiIJOCH3)Ph
3,4-DiIJOCH3)Ph
3,4-DiIJOCH3)Ph
3,4-DiIJOCH3)Ph
3,4,5-TriIJOCH3)-Ph
CH3
57.8
24.6
n-C4H9
PhCH2
PhIJCH2)3
C2H5
n-C4H9
PhCH2
PhIJCH2)3
H
25.7
27.6
11.8
24.7
28.8
>100
>100
27.2
>100
>100
42.3
>100
>100
34.3
>100
>100
68.5
>100
>100
19.8
32.7
25.7
14.5
17.0
19.5
11.8
10.0
32.4
6.21
>100
>100
>100
65.6
12.5
>100
3.70
>100
>100
>100
>100
7.26
>100
>100
>100
>100
6.82
>100
>100
>100
>100
13.5
>100
>100
>100
>100
15.6
>100
>100
>100
26.3
18.3
>100
70.6
>100
>100
>100
45.3
26.6
>100
29.4
3,4,5-TriIJOCH3)-Ph CH3
3,4,5-TriIJOCH3)-Ph n-C4H9
3,4,5-TriIJOCH3)-Ph PhIJCH2)3
18.9
7.11
7y
>100
46.6
>100
3.70
>100
>100
>100
14.7
Cisplatin
a
Cytotoxicity, expressed as IC50 for each cell line, is the concentration of compound which reduced the optical density of the treated cells by
50% with respect to the untreated cells using the MTT assay. The data represents mean values SD of at least three independent experiments.
b
Values > 100 μM indicate less than 50% growth inhibition at > 100 μM. Cell lines include breast carcinoma (MCF-7), liver carcinoma
(HepG2), prostate carcinoma (22RV1), colon carcinoma (HT-29), renal carcinoma (769-P), malignant melanoma (A375), ovarian carcinoma (SK-
OV-3), esophageal carcinoma (Eca-109), gastric carcinoma (BGC-823) and Lewis lung carcinoma (LLC).
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hand, compounds 7a, 7c, 7f, 7i–n, 7p–q, 7t–w and 7y
exhibited weak to inactive cytotoxic activities.
We examined the influence of the substituents in
position-9 of the β-carboline ring on cytotoxic potencies.
Table 1 shows that compounds 7a, 7c and 7d having an
ethyl, benzyl and 4-fluorobenzyl group in position-9 of the
β-carboline ring, respectively, displayed weak to inactive cyto-
toxic activities, while compounds 7b and 7e bearing a butyl
and 3-phenylpropyl group in position-9 of the β-carboline
ring, respectively, exhibited good to strong cytotoxic activi-
ties. Significantly, compound 7e exhibited the most potent
cytotoxic activity with IC50 values lower than 10 μM against
eight tumor cell lines. Similarly, compounds 7g, 7o, 7s and
7x having a butyl group in position-9 of the β-carboline ring,
respectively, also exhibited good cytotoxic activities against
all the investigated tumor cell lines, while the other
compounds had weaker cytotoxic activities. These results
suggested that the butyl substituent in position-9 of the
β-carboline ring was the most suitable group giving rise to
potent cytotoxic agents.
Fig. 2 Inhibitory effects of compound 7g on the angiogenesis of CAM.
Next, we examined the influence of the substituents in
position-1 of the β-carboline ring on cytotoxic potencies. The
data collected in Table 1 showed that compound 7e displayed
significant and selective cytotoxic effects with IC50 values
lower than 20 μM against most tumor cell lines. Introduction
of a phenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl and 3,4,5-
trimethoxyphenyl group into position-1 of compound 7e,
respectively, led to compounds 7l, 7q, 7u and 7y, which were
almost inactive against all tumor cell lines at a concentra-
tion of 100 μM. In comparison with compound 7b, com-
pounds 7o, 7s and 7x bearing an additional 4-methoxyphenyl,
3,4-dimethoxyphenyl and 3,4,5-trimethoxyphenyl group in
position-1 of the β-carboline ring, respectively, exhibited sim-
ilar cytotoxic activities against the ten tumor cell lines. In
addition, compounds 7l and 7k having a 3-phenylpropyl and
benzyl group in position-9 of the β-carboline ring exhibited
weaker cytotoxic potencies than compounds 7i and 7j which
bear a methyl and n-butyl group, respectively. Similarly, com-
pounds 7m, 7p, 7q, 7t, 7u, 7v and 7y with a hydrogen atom
or an arylated alkyl group in position-9 of the β-carboline
ring showed weaker cytotoxic activities, while the other com-
pounds had good and selective cytotoxic effects against the
tumor cell lines. These results indicated that the introduction
of an aryl substituent into position-1 of the β-carboline ring
might be detrimental to the cytotoxic effects of this class of
compounds.
Fig. 3 Anti-angiogenic activity of compound 7g.
anti-angiogenic activity of compound 7g was comparable with
that of CA4P in an in vivo CAM assay at the same dose (200 μM).
Conclusions
In conclusion, we have synthesized a series of novel bivalent
β-carbolines with a piperazine group spacer between 3-methy-
lene units, and investigated their cytotoxic potential against
ten tumor cell lines in culture. Some compounds exhibited
good and selective cytotoxic activities against the ten tumor
cell lines. Compounds 7e and 7g exhibited the most potent
cytotoxic activities against the ten tumor cell lines. Prelimi-
nary structure–activity relationships analysis indicated that
the substituents in position-1 and -9 of the β-carboline ring
played a significant role in modulating the antitumor activity.
The introduction of alkyl groups into position-9 of the
β-carboline nucleus provided compounds with greatly
enhanced cytotoxic potencies and the butyl substituent in
position-9 of the β-carboline nucleus was the optimal group,
while the introduction of arylated alkyl groups might be
harmful to antitumor activities. Moreover, the most active
compound 7g was found to show obvious angiogenic inhibi-
tory effects in the CAM assay, and its anti-angiogenic potency
was comparable to that of the reference drug CA4P. Further
Anti-angiogenic activity in vivo
The most active compound 7g was selected to evaluate the
anti-angiogenic activity by the CAM assay. The inhibitory
effects of compound 7g on the angiogenesis of CAM are
shown in Fig. 2. The anti-angiogenic activity of compound 7g
was semiquantitatively analyzed using Graph Pad Prism 5.0
(shown in Fig. 3). The results showed that compound 7g
(p < 0.05) could inhibit the angiogenesis of CAM. The
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investigations to confirm the antitumor efficacy in animal
models and elucidate the pharmacological mechanisms of
this class of compounds are underway in our laboratory, and
the data will be published elsewhere.
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This work was supported by Xinjiang Huashidan Pharmaceu-
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