Synthesis and biological evaluation of novel bivalent β-carbolines as potential antitumor agents

Article abstract of DOI:10.1039/c4md00098f

A series of novel bivalent β-carbolines with a spacer of three to ten methylene units between the 3-carboxyl oxygens was synthesized and evaluated as antitumor agents. The results demonstrated that most compounds displayed good and selective cytotoxic activities against 769-P and KB cell lines. Acute toxicities and antitumor efficacies of the selected compounds in mice were also evaluated. Compound 22 exhibited potent antitumor activity against Lewis lung cancer in mice with a tumor inhibition rate of 64.2%. Preliminary structure-activity relationship analysis indicated that (1) the length of the spacer affected cytotoxic activities in vitro and six methylene units were more favorable; (2) the introduction of substituents into position-1 of the β-carboline ring might be detrimental to antitumor potency in vivo models.

Full text of DOI:10.1039/c4md00098f

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Synthesis and biological evaluation of novel
bivalent b-carbolines as potential antitumor
agents†
Cite this: Med. Chem. Commun., 2014,
5, 953
Qifeng Wu,b Zhushuang Bai,a Qin Ma,c Wenxi Fan,c Liang Guo,c Guoxian Zhang,a
a
a
a
a
*
*
Liqin Qiu, Huijuan Yu, Guang Shao and Rihui Cao
A series of novel bivalent b-carbolines with a spacer of three to ten methylene units between the 3-carboxyl
oxygens was synthesized and evaluated as antitumor agents. The results demonstrated that most
compounds displayed good and selective cytotoxic activities against 769-P and KB cell lines. Acute
toxicities and antitumor efficacies of the selected compounds in mice were also evaluated. Compound
22 exhibited potent antitumor activity against Lewis lung cancer in mice with a tumor inhibition rate of
64.2%. Preliminary structure–activity relationship analysis indicated that (1) the length of the spacer
affected cytotoxic activities in vitro and six methylene units were more favorable; (2) the introduction of
substituents into position-1 of the b-carboline ring might be detrimental to antitumor potency in vivo
models.
Received 5th March 2014
Accepted 3rd May 2014
DOI: 10.1039/c4md00098f
www.rsc.org/medchemcomm
Previous investigations28 demonstrated that dimerization of
various intercalating agents by an appropriate spacer could lead
Introduction
to a dramatic increase in the DNA binding affinity. Therefore,
bivalent b-carbolines were expected to exhibit more potent
antitumor efficacies than monomers. Recently, several bivalent
b-carbolines were synthesized and evaluated as anti-Alz-
heimer's29 and antitumor30 agents (Fig. 1) and bivalent b-car-
bolines were proved to exhibit more potent anti-Alzheimer
potencies than monomers. However, to the best of our knowl-
edge, no large, systematic study has been undertaken to
examine the structure–activity relationship of bivalent b-car-
bolines as antitumor agents. We recently began such a study
The b-carboline nucleus is common to many natural and
synthetic products associated with
a wide spectrum of
biochemical and pharmaceutical functions.1 Recently, there
have been intense research efforts in the design and develop-
ment of b-carbolines as a new class of antitumor agents.2–9
These compounds were found to exert antitumor effects
through multiple mechanisms of action including intercalation
into DNA10 inhibiting Topo I and II (topoisomerase 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 and biological
evaluation of a large series of b-carbolines as a new class of
antitumor agents.17–27 Structure–activity relationship analysis of
these compounds indicated that (i) the introduction of appro-
priate substituents into position-1 and 9 of the b-carboline
nucleus played a vital role in determining their antitumor
effects; (ii) the butyl and 3-phenylpropyl substituents in posi-
tion 9 of the b-carboline nucleus were the optimal pharmaco-
phoric groups giving rise to signicant antitumor agents.
aSchool of Chemistry and Chemical Engineering, Sun Yat-sen University, 135 Xin Gang
West Road, Guangzhou 510275, P R China. E-mail: caorihui@mail.sysu.edu.cn; shaog
@mail.sysu.edu.cn
bSchool of Life Science, Sun Yat-sen University, 135 Xin Gang West Road, Guangzhou
510275, P R China
cXinjiang Huashidan Pharmaceutical Co. Ltd., 175 He Nan East Road, Urumqi 830011,
P R China,
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c4md00098f
Fig. 1 The chemical structure of the representative reported and
newly synthesized bivalent b-carbolines.
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and have reported the synthesis and antitumor evaluation of weeks) weighing 18–22 g were housed in rooms where the
bivalent b-carbolines with a spacer of three to ten methylene temperature was approximately 24 Æ 2 ꢀC, with a relative
units between the indole nitrogens31 (Fig. 1). We report now the humidity of 60–70%, and in a 12 h light–dark cycle. The sterile
synthesis, in vitro evaluation, in vivo efficacies and preliminary food and water were provided according to institutional
structure–activity relationship for the new bivalent b-carbolines guidelines. All animals were provided by the Xinjiang Medicine
with a spacer of three to ten methylene units between the 3- University Medical Laboratory Animal Center. All animal
carboxyl oxygens.
procedures were approved by the Animal Ethical Committee of
the Xinjiang Medicine University. Prior to each experiment,
mice were fasted overnight and allowed free access to water.
Various doses of the bivalent b-carbolines ranging from 10–
1500 mmol kgÀ1 dissolved in 0.5% carboxymethyl cellulose
sodium (CMC-Na) salt solution were given via intraperitoneal
(i.p.) injection to different groups of healthy C57BL/6 mice, and
each group contained 10 mice (5 males and 5 females). Aer the
administration of the compounds, mice were observed contin-
uously for the rst 2 h for any gross behavioral changes and
deaths, then intermittently for the next 24 h and occasionally
thereaer for 14 days, and for the onset of any delayed effects.
All animals were sacriced on the 14th day aer drug admin-
istration and checked macroscopically for possible damage to
the heart, liver and kidneys. Mice dying immediately following
drug administration were also examined for any possible organ
damage. LD50 values were calculated graphically as described.33
Chemistry
The synthetic route to the newly designed bivalent b-carbolines
14–44 is outlined in Scheme 1. Monovalent b-carboline-3-
carboxylic acids 1–13 were synthesized according to our previ-
ously published methods.17,18,21 The symmetrical bivalent b-
carbolines 14–44 were prepared by reaction of the correspond-
ing dibromoalkane with monovalent b-carboline-3-carboxylic
acids 1–13 in anhydrous DMF in 55–94% yield.32 The chemical
structures of all the newly synthesized compounds were char-
acterized by MS, HRMS, H NMR and 13C NMR.
1
Experimental section
Cytotoxicity in vitro
Cytotoxicity assays in vitro were carried out using 96 microtitre
plate cultures and MTT staining according to the procedures Assay of antitumor activity
described by Cao et al.23 Briey, cells were grown in RPMI-1640
Antitumor activity against CT-26 colon cancer and Lewis lung
medium containing 10% (v/v) fetal calf serum and 100 mM
penicillin and 100 mM streptomycin. Cultures were propagated
at 37 C in a humidied atmosphere containing 5% CO2. The
cells were exposed to different concentrations of the drug, and
kept for incubation for 48 h. DMSO was used as the solution for
drugs. The nal concentration of DMSO in the growth medium
was 2% (v/v) or lower, concentrations without effect on cell
replication. In all of these experiments, three replicate wells
were used to determine each point.
cancer in mice was evaluated as described by Cao et al.23 with a
slight modication. Briey, CT-26 colon cancer and Lewis lung
cancer cell lines were provided by the Shanghai Institute of
Pharmaceutical Industry. Tumor cells of CT-26 colon cancer
and Lewis lung cancer were inoculated into mice. Aer 7 days,
tumors were taken out and cells were harvested. Viable tumor
cells (2 Â 106 cells per mouse) were inoculated into the armpit
of mice by subcutaneous injection. Each compound was injec-
ted intraperitoneally (i.p.) to different groups of mice (each
group containing 10 female mice) 24 h aer the inoculation at a
dosage of about one h of the LD50 value once a day for 7
consecutive days. Cyclophosphamide (CTX) at 114.9 mmol kgÀ1
was used as a positive control and vehicle as the negative
control. The weights of animals were recorded every 3 days. All
animals were sacriced on the 21st day aer tumor inoculation
and the tumors were excised and weighed. The inhibition rate
was calculated as follows:
ꢀ
Assay of acute toxicities
Acute toxicity assay was performed according to the method
described by Cao et al.23 Briey, healthy C57BL/6 mice (9–12
(C À T)/C Â 100
where T is the average tumor weight of the treated group and C
is the average tumor weight of the negative control group.
Results and discussion
Cytotoxicity in vitro
The cytotoxic potencies of all the newly synthesized bivalent b-
carbolines against a panel of human tumor cell lines were
investigated and compared with the monovalent b-carbolines 3
and 8 and the reference drug cisplatin. Our previous investiga-
tion indicated that BGC823, A375, 769-P, KB and SK-OV-3 tumor
Scheme 1 Synthesis of the bivalent b-carbolines 14–44.
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cells were more sensitive to b-carbolines than other tumor cells, showed that compound 22 with a spacer of six methylene units
so these tumor cells are selected and evaluated in the present exhibited moderate to strong cytotoxic activities with IC50 values
investigation. The results are summarized in Table 1.
of 43.2, 18.2 and 15.6 mM against BGC823, A375 and KB cell
As shown in Table 1, compound 14 displayed a broad spec- lines, while compounds 23–25 with a spacer of eight to ten
trum of cytotoxic activities with an IC50 value of lower than methylene units displayed a weaker cytotoxic effect against
20 mM against four tumor cell lines, while compounds 17, 19, tumor cell lines tested. Similarly, compounds 15, 17, 26, 30, 33,
22, 23, 29, 30, 37 and 43 show signicant and selective cyto- 34, 37 and 39 with a spacer of six methylene units showed good
toxicities with an IC50 value of lower than 20 mM against one or and selective cytotoxic effects against tumor cell lines, while
two tumor cell lines. Interestingly, most compounds showed other compounds had weaker cytotoxic activities. These results
selective cytotoxic activities against renal carcinoma (769-P) and suggested that the length of the spacer might affect cytotoxic
epidermoid carcinoma of the nasopharynx (KB).
activities and six methylene units might be more favorable.
We examined the inuence of the spacer length of bivalent b-
Next, we examined the inuence of the substituents in
carbolines on cytotoxic activities. The data collected in Table 1 position-1 and 9 of the b-carboline ring on cytotoxic potencies.
Table 1 Cytotoxic activity of bivalent b-carbolines in vitro
IC50 (mM) Æ SDa
Compounds
R1
R9
n
BGC823b
A375
769-P
KB
SK-OV-3
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
H
H
H
CH3
CH3
CH3
H
H
H
CH3
CH3
H
H
H
H
CH3
CH3
CH3
C2H5
C2H5
C2H5
C4H9
C4H9
C4H9
C4H9
C4H9
C4H9
C4H9
C4H9
C4H9
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
(3-Cl)PhCH2
(3-Cl)PhCH2
Ph(CH2)3
Ph(CH2)3
Ph(CH2)3
Ph(CH2)3
Ph(CH2)3
C2H5
3
6
10
6
8
9
4
5
6
8
9
10
6
7
10
4
6
8
5
6
6
9
3
6
7
6
9
6
6
6
6
19.5 Æ 2.23
>200
>200
>200
>200
16.6 Æ 3.36
82.6 Æ 12.4
125 Æ 16.8
32.9 Æ 4.25
86.3 Æ 14.2
>200
>200
>200
18.2 Æ 3.28
146 Æ 22.6
89.6 Æ 12.6
>200
>200
>200
42.0 Æ 4.86
7.90 Æ 0.56
>200
16.3 Æ 2.08
28.3 Æ 6.32
42.9 Æ 5.42
43.1 Æ 6.64
21.7 Æ 3.41
10.3 Æ 0.84
42.6 Æ 10.6
32.9 Æ 5.42
112 Æ 14.2
210 Æ 36.4
115 Æ 16.8
89.2 Æ 14.6
60.5 Æ 7.15
95.9 Æ 12.5
114 Æ 12.7
45.4 Æ 5.27
46.8 Æ 5.42
68.6 Æ 8.61
72.4 Æ 10.6
64.7 Æ 9.53
21.9 Æ 2.87
145 Æ 20.8
95.6 Æ 16.3
29.4 Æ 4.54
43.5 Æ 6.54
21.8 Æ 4.21
108 Æ 16.8
65.9 Æ 8.64
95.5 Æ 8.94
10.9 Æ 0.98
118 Æ 20.5
42.7 Æ 4.87
56.8 Æ 6.12
33.6 Æ 4.03
18.4 Æ 4.12
165 Æ 30.2
198 Æ 32.1
16.5 Æ 2.32
>200
56.9 Æ 11.3
89.0 Æ 18.9
53.9 Æ 12.5
15.6 Æ 1.36
19.8 Æ 2.48
26.4 Æ 2.87
45.2 Æ 5.86
54.6 Æ 8.24
>200
21.0 Æ 4.85
>200
>200
>200
86.4 Æ 15.6
>200
>200
116 Æ 18.8
123 Æ 18.7
>200
>200
>200
43.2 Æ 6.42
68.9 Æ 10.8
>200
124 Æ 20.4
>200
168 Æ 28.6
>200
>200
>200
>200
>200
43.6 Æ 3.64
164 Æ 26.5
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
140 Æ 16.8
159 Æ 25.6
168 Æ 21.4
125 Æ 14.0
36.7 Æ 4.21
20.8 Æ 1.64
71.5 Æ 9.82
>200
>200
>200
>200
15.7 Æ 1.45
162 Æ 30.2
42.4 Æ 6.27
112 Æ 16.8
46.9 Æ 6.54
71.2 Æ 8.21
72.4 Æ 8.46
56.4 Æ 6.68
78.9 Æ 10.2
>200
50.7 Æ 8.24
89.2 Æ 10.2
218 Æ 30.4
20.7 Æ 1.64
>200
27.8 Æ 3.66
>200
>200
125 Æ 20.6
>200
>200
>200
>200
>200
>200
14.4 Æ 3.18
143 Æ 20.1
>200
>200
>200
132 Æ 18.6
40.4 Æ 4.83
134 Æ 18.7
79.6 Æ 8.52
67.6 Æ 7.64
8.90 Æ 1.32
19.0 Æ 2.32
>200
>200
8.50 Æ 0.64
H
CH3
CH3
>200
73.4 Æ 9.82
>200
>200
(4-OCH3)-Ph
(4-OCH3)-Ph
3,4,5-Tri(OCH3)-Ph
3,4,5-Tri(OCH3)-Ph
3
Ph(CH2)3
C2H5
Ph(CH2)3
>200
47.4 Æ 6.42
>200
67.7 Æ 8.20
86.4 Æ 7.86
32.0 Æ 2.87
>200
>200
4.20 Æ 0.36
8
Cisplatin
a
Cytotoxicity as IC50 for each cell line is the concentration of compound which reduced by 50% the optical density of treated cells with respect to
untreated cells using the MTT assay. The data represent mean values Æ SD of at least three independent experiments. Values >200 mM indicate less
b
than 50% growth inhibition at >200 mM. Cell lines include gastric carcinoma (BGC823), malignant melanoma (A375), renal carcinoma (769-P),
epidermoid carcinoma of the nasopharynx (KB) and ovarian carcinoma (SK-OV-3).
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Table 1 shows that compound 22 displayed signicant and gave compound 22 which also exhibited lower acute toxicity
selective cytotoxic effects against most tumor cell lines. Intro- with a LD50 value of 161.8 mmol kgÀ1. In addition, monovalent
duction of a methyl group into position-1 of compound 22 led to b-carboline-3-carboxylic acids 3 and 8 exhibited weaker acute
compound 26, which exhibited weaker cytotoxic activities. toxicity with LD50 values of 1119.4 and 1090.9 mmol kgÀ1
,
Similarly, compounds 33 and 39 having a methyl group in respectively. These results suggested that the introduction of
position-1 exhibited weaker cytotoxic potencies than substituents into position-1 of the b-carboline nucleus might
compounds 30 and 37. In comparison with compound 37, play an important role in determining acute toxicity.
compounds 42 and 44 bearing an additional 4-methoxyphenyl
and 3,4,5-trimethoxyphenyl group in position-1 of the b-carbo-
line ring, respectively, were almost inactive against all tumor
Four bivalent b-carbolines were selected for in vivo evaluation
cell lines at a concentration of 100 mM. In addition, the
compounds 22, 30, 34 and 37 bearing an n-butyl (22), benzyl
compared with monovalent b-carboline-3-carboxylic acids 3 and
(30), 3-chlorobenzyl (34), and 3-phenylpropyl (37) and having
the same spacer of six methylene units showed good cytotoxic
previous investigation demonstrated that mice bearing CT-26
activities with the tendency of 3-phenylpropyl > 3-chlorobenzyl >
benzyl > n-butyl group. These results indicated that (1) the
introduction of substituents into position-1 of the b-carboline
ring might be detrimental to cytotoxic effects of this class of
compounds; (2) the 3-phenylpropyl substituent in position-9 of
the b-carboline nucleus is the suitable group giving rise to
potent cytotoxic agents.
Evaluation of antitumor activity
against CT-26 colon cancer and Lewis lung cancer in mice and
8 and the reference drug cyclophosphamide (CTX). Our
colon cancer and Lewis lung cancer were more susceptible to b-
carbolines than other animal models, therefore these animal
models are selected and evaluated in the present investigation.
The tumor inhibition rates of all investigated bivalent b-carbo-
lines are summarized in Table 2. As shown in Table 2, Lewis
lung cancer was more susceptible to all tested compounds than
CT-26 colon cancer. Compounds 22 and 37 exhibited more
potent antitumor activities against Lewis lung cancer in mice
than their monovalent b-carboline-3-carboxylic acids 3 and 8.
Preliminary assessment of acute toxicity
The LD50 values of the selected bivalent b-carbolines in mice
aer administration by the i.p. route are summarized in Table
2. All the tested bivalent b-carbolines resulted in acute toxic
manifestations. Animals showed a decrease in locomotive
activity aer the administration of various bivalent b-carbo-
lines. Death occurred mostly in the high dosage group within 4–
8 hours aer injection. All surviving animals returned to normal
on the next day. Autopsy of the animals that died in the course
of experiment and the necropsy ndings in surviving animals at
the end of the experimental period (14 days) revealed no
obvious changes in any organs.
Particularly, compound 22 was found to be the most potent
antitumor agent with the tumor inhibition rate of 64.2% against
Lewis lung cancer in mice. Compound 37 having a 3-phenyl-
propyl group in position-9 of the b-carboline ring displayed
good antitumor effects with the tumor inhibition rate of 53.5%
against Lewis lung cancer in mice at a dose of 26.9 mmol kgÀ1
,
while compound 42 with an additional 4-methoxyphenyl group
appended to position-1 displayed lower antitumor effects.
Although compound 14 had signicant cytotoxic activities
against tumor cell lines, it displayed weaker antitumor poten-
cies with tumor inhibition rates of 23.6 and 28.1% against CT-
26 colon cancer and Lewis lung cancer in mice, respectively.
These results suggested that the introduction of substituents
into position-1 of the b-carboline ring might be detrimental to
antitumor potency.
Of all investigated bivalent b-carbolines, compound 42 with
a 4-methoxyphenyl group appended to position-1 displayed
remarkable acute toxicity with a LD50 value of 55.8 mmol kgÀ1
,
while compound 37 having no substituent in position-1 of the b-
carboline ring demonstrated weaker acute toxicities with a LD50
value of 134.7 mmol kgÀ1. Replacement of the 3-phenylpropyl
group in postion-9 of compound 37 with a butyl substituent
Conclusions
In conclusion, we have synthesized a series of novel bivalent b-
carbolines with a spacer of three to ten methylene units between
the 3-carboxyl oxygens. Most compounds exhibited good and
selective cytotoxic activities against 769-P and KB cell lines.
Antitumor evaluation of the selected bivalent b-carbolines in
animal models indicated that Lewis lung cancer was more
susceptible to all tested compounds than CT-26 colon cancer,
and compounds 22 and 37 bearing a butyl and 3-phenylpropyl
group in position-9 of the b-carboline nucleus, respectively,
exhibited potent antitumor potencies with the tumor inhibition
rate of over 50% against Lewis lung cancer in mice. Preliminary
structure–activity relationship information revealed that (1) the
length of the spacer affected cytotoxic activities in vitro and six
methylene units were more favorable; (2) the introduction of
substituents into position-1 of the b-carboline ring might be
Table 2 Acute toxic effects of bivalent b-carbolines in mice and
antitumor activities of these compounds against CT-26 colon cancer
and Lewis lung cancer in mice
Tumor inhibition rate (%)
LD50
Dosage
Lewis lung
cancer
Compounds (mmol kgÀ1
)
(mmol kgÀ1
)
CT-26
14
22
37
42
3
384.6
161.8
134.7
55.8
1119.4
1090.9
76.9
32.3
26.9
23.6
33.8
28.3
15.1
18.7
20.3
87.6
28.1
64.2
53.5
24.6
45.4
40.3
88.1
11.1
223.8
212.1
114.9
8
CTX
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This work was supported by the MEGA-Project (2009ZX09102-
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National Natural Science Foundation of China (21342010) and
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