7-Aroyl-aminoindoline-1-sulfonamides as a novel class of potent antitubulin agents

Article abstract of DOI:10.1021/jm061076u

A novel series of 7-aroyl-aminoindoline-1-benzenesulfonamides showed excellent activity as inhibitors of tubulin polymerization through binding with the colchicine binding site of microtubules. Compound 15 and 16 display IC ₅₀ values of 1.1 and

Full text of DOI:10.1021/jm061076u

6656
J. Med. Chem. 2006, 49, 6656-6659
7-Aroyl-aminoindoline-1-sulfonamides as a Novel
Class of Potent Antitubulin Agents
Jang-Yang Chang,†,‡ Hsing-Pang Hsieh,§ Chi-Yen Chang,†
Kuo-Shun Hsu,† Yi-Fang Chiang,| Chi-Ming Chen,|
Ching-Chuan Kuo,† and Jing-Ping Liou*,|
Institute of Cancer Research, National Health Research Institutes,
Taipei, Taiwan, Republic of China, DiVison of Hematology/
Oncology, Department of Internal Medicine, Tri-SerVice General
Hospital, National Defense Medical Center, Taipei, Taiwan,
Republic of China, DiVision of Biotechnology and Pharmaceutical
Research, National Health Research Institutes, Miaoli County,
Taiwan, Republic of China, and College of Pharmacy, Taipei
Medical UniVersity, Taipei, Taiwan, Republic of China
ReceiVed September 12, 2006
Abstract: A novel series of 7-aroyl-aminoindoline-1-benzenesulfona-
mides showed excellent activity as inhibitors of tubulin polymerization
through binding with the colchicine binding site of microtubules.
Compound 15 and 16 display IC50 values of 1.1 and 1.2 µM,
respectively. Compound 15 inhibited the human cancer cell growth of
KB, MKN45, H460, HT29, and TSGH, as well as one human-resistant
cancer line of KB-vin 10, with an IC50 of 9.6, 8.8, 9.4, 8.6, 10.8, and
8.9 nM, respectively.
Figure 1.
Microtubules are dynamic structures that play a crucial role
in cellular division and are recognized as an important target
for anticancer therapy.1 A number of naturally occurring
compounds, such as paclitaxel, epothilone A, vinblastine,
combretastatin A-4, dolastatin 10, and colchicine, all exhibit
their anticancer properties by interfering with the dynamics of
tubulin polymerization and depolymerization, resulting in mitotic
arrest. Recent research reported that drugs with binding to the
colchicines domain are undergoing intensive investigation as
vascular-discrupting agents for cancer therapy.2 For example,
some antitubulin clinical candidates, 3, 4, and 5, act as vascular-
discrupting agents, rapidly depolymerizing microtubules of
newly formed vasculatures to shut down the blood supply to
tumors.3
Because the antitubulin chemotherapy drugs have problems
with toxicity and drug resistance, scientists have been actively
exploring new antitubulin agents. A variety of synthetic small
molecules have been reported as inhibitors of tubulin polym-
erization, which complete the colchicine-binding site to tubulin.4
Structurally, they involve various heteroaromatic cores, for
instance including the indole, benzothiophene,5 benzofuran,6
imidazole,7 thiazole,8 and oxadiazoline9 moieties. A number of
indole-based compounds, for example 2-aroylindoles,10 3-aroylin-
doles,11 3-aroyl-2-phenylindoles,6 3-arylthioindoles-2-carboxyl-
ate,12 and indolyl-3- glyoxamides,13 have shown strong anti-
proliferative and antitubulin activity, and some of them are being
developed. (Figure 1).
Figure 2.
Compounds 6 and 7 are now undergoing human clinical trial
against various tumor types.16,17 To our knowledge, there have
been no reports on the inhibition of tubulin polymerization by
indoline-sulfonamides. Therefore, here we describe the structure-
activity relationships of a series of 7-aroylaminoindoline-1-
sulfonamides as novel, highly potent inhibitors of tubulin
polymerization. (Figure 2).
Indoline-sulfonamides 8-27 were synthesized as shown in
Scheme 1. The preparation involved a straightforward reaction
sequence with high yields (overall 48-56% in three or four
steps). The commercially available 5-bromo-7-nitroindoline (28)
was reacted with the 4-methoxybenzenesulfonyl chloride in
pyridine to afford the 5-bromo-1-(4-methoxybenzenesulfonyl)-
7-nitroindoline (29). The reduction of the 7-nitro group in 29
with Fe/NH4Cl in isopropanol gave the corresponding 30,
7-amino-5-bromo-1-(4-methoxybenzenesulfonyl)indoline, which
was converted to the 7-amino-1-(4-methoxybenzenesulfonyl)-
indoline (8) by a free radical-mediated debromination in the
presence of AIBN and Bu3SnH. Compound 30 or 8 was further
reacted in pyridine with the corresponding electrophiles, such
as aroyl chloride, heteroaroyl chloride, ArSO2Cl, ArO(CO)Cl,
ArN(CH3)(CO)Cl, benzyl chloride, acetic anhydride, and piv-
aloyl chloride, to afford the desired 7-aminoindoline-1-sulfona-
mides (9-14, 16-25, and 27, respectively). 7-Isonicotinoyl-
substituted indolines, 15 and 26, were obtained by treatment of
The sulfonamide-containing compounds, such as N-pyridinyl
sulfonamide 614 and styryl-pyridine N-oxide sulfonamide 7,15
demonstrated effective inhibition of tubulin polymerization and
were found to be potent antimitotic agents, respectively.
* To whom correspondence should be addressed. Phone: 886-2-2736-
1661 ext. 6130. Fax: 866-2-27369558. E-mail: jpl@tmu.edu.tw.
† Institute of Cancer Research, National Health Research Institutes.
‡ National Defense Medical Center.
§ Division of Biotechnology and Pharmaceutical Research, National
Health Research Institutes.
| College of Pharmacy, Taipei Medical University.
10.1021/jm061076u CCC: $33.50 © 2006 American Chemical Society
Published on Web 10/20/2006

Letters
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 23 6657
Scheme 1a
Table 2. Inhibition of Tubulin Polymerization and Colchicine Binding
by Compounds 10, 11, 15, 16, 17, 23, 24, Colchicine, and CA4
colchicine bindingb (% ( SD)
tubulina
cmpd
10
11
15
16
17
23
24
IC50 ( SD (µM)
1µM inhibitor
5µM inhibitor
1.5 ( 0.2
1.9 ( 0.3
1.1 ( 0.1
1.2 ( 0.1
1.7 ( 0.3
> 5
1.9 ( 0.2
3.3 ( 0.3
1.2 ( 0.3
65 ( 1
62 ( 2
78 ( 0.5
74 ( 1
75 ( 2
-
93 ( 2
91 ( 3
96 ( 2
95 ( 1
94 ( 1
-
57 ( 3
86 ( 4
colchicine
CA4
81 ( 0.2
97 ( 2
a Reagents and conditions: (a) 4-methoxyphenylsulfonyl chloride, py-
ridine, 85%; (b) Fe, NH4Cl, isopropanol, 89%; (c) AIBN, Bu3SnH, toluene,
reflux, 90%; (d) aroyl chloride, heteroaroyl chloride, ArSO2Cl, ArO(CO)Cl,
ArN(CH3)(CO)Cl, benzyl chloride, acetyl chloride, or pivoyl chloride,
pyridine, 75-90%; (e) isonicotinoyl chloride hydrochloride, Cs2CO3,
CH3CN, reflux, 80-82%.
a Inhibition of tubulin polymerization.18 b Inhibition of [3H]colchicine
binding.18,19 Tubulin was at 1 µM; [3H]colchicine was at 5 µM.
in the 7-aminoindoline-core demonstrating substantial antipro-
liferative activity, aroyl-substituted 7-aminoindoline-sulfona-
mides, compounds 10-14, were further synthesized and evalu-
ated for the activity. The para -fluoro, nitro, and cyano-benzoyl
compounds 10, 11, and 12, respectively, showed strong cellular
growth inhibitory activities with IC50 values of 45-105 nM
against KB and MKN45 lines, apparently more potent than that
of compound 9 and 13 with a benzoyl and 4-methoxybenzoyl
substitutions, respectively. Compound 14 with a 4-(methoxy-
carbonyl)benzoyl substitution on the 7-aminoindoline ring also
displayed a moderate cytotoxicity. This finding revealed that
the inductive effect on the benzoyl substitution of the 7-amino-
indoline-1-sulfonamides plays an important role for activity,
which compounds with electron-withdrawing properties on the
7-aroylaminoindoline systems, is beneficial for potency. The
substantial activity of 7-aroyl substitution in the aminoindoline-
1-sulfonamides sparked us to investigate the effect of the 7-het-
eroaroyl substitutions. Compound 15 with an isonicotinoyl sub-
stitution, compound 16 with a 2-furoyl group, and compound
17 with a 2-thienoyl group on the 7-aminoindoline ring exhibit
highly potent antiproliferative activities against human cancer
cell lines. Notably, compounds 15 and 16 showed IC50 values
of 8-11 nM in all six human cancer lines and are more potent
than colchicine.
Table 1. IC50 Values (nM ( SDa) of Indoline-1-sulfonamides (8-27)
and Colchicines
cell type (IC50 nM ( SDa)
cmpd
KB
2800 ( 600 1200 ( 80
297 ( 15 250 ( 18 257 ( 28 192 ( 32 201 ( 35 180 ( 23
MKN45
H460
HT29
TSGH KB-vin10
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
93 ( 10
102 ( 15
105 ( 18
45 ( 2
95 ( 13 55 ( 7 100 ( 21 85 ( 12
95 ( 7 122 ( 9 65 ( 8 116 ( 11 95 ( 14
89 ( 12
2600 ( 510 1600 ( 150
376 ( 17 312 ( 14
9.6 ( 1
9.6 ( 4
47 ( 9
8.8 ( 5
10.7 ( 4
31 ( 2
9.4 ( 2 8.6 ( 3 10.8 ( 1 8.9 ( 3
9.8 ( 2 9.5 ( 7 11.1 ( 4 9.2 ( 2
49 ( 7 37 ( 4
54 ( 6
43 ( 3
650 ( 21 562 ( 35
1100 ( 150 933 ( 78
1200 ( 60 890 ( 24
>10 000
>10 000
>10 000
89 ( 7
>10 000
>10 000
>10 000 >10 000 >10 000 >10 000 >10 000
61 ( 6
359 ( 20 289 ( 38
75 ( 9 51 ( 11 103 ( 13 90 ( 9
91 ( 8
89 ( 10
86 ( 3
78 ( 2
15 ( 3
colchb 13.3 ( 4
117 ( 8
In an effort to further understand the substitution effect of
the 7-aminoindoline ring, 7-alkylcarbonyl group, compounds
24 and 25 with an acetyl and pivaloyl moiety, respectively, were
prepared. Compound 24, with an acetyl group, displays sub-
stantial cytotoxicity, with IC50 values of 51-103 nM against
cell lines, but a further increase in the bulkiness of substituent
pivaloyl group in 25 resulted in a slight decrease in potency,
thus revealing that the steric effect of the substitutions on the
7-aminoindoline ring influences cytotoxic activities. The bromo
group at the C-5 position of 1-(4-methoxybenezenesulfonyl)-
indolines 15 and 16, gave 26 and 27, respectively, with a 3-4-
fold magnitude decreased cell growth inhibition as compared
to that of the parent compounds.
To examine whether our indoline-1-sulfonamides were the
tubulin inhibitors through the colchicines-binding domain, we
selected compounds 10, 11, 15, 16, 17, 23, 24, and references
compounds (colchicine and combretastatin A-4) to evaluate for
their antitubulin activities and determine their ability to compete
for colchicine-binding sites (Table 2).
a SD: standard deviation; all experiments were independently performed
at least three times. b colch ) colchicine.
8 and 30 with isonicotinoyl chloride hydrochloride in the
presence of Cs2CO3 in anhydrous CH3CN.
The synthesized indoline-sulfonamides 8-27 were evaluated
for their cytotoxic activities against five types of human cancer
cell lines, oral epidermoid carcinoma KB cells, colorectal
carcinoma HT29 cells, non-small cell lung carcinoma H460
cells, and two stomach carcinoma TSGH, MKN45 cells, as well
as one type of MDR-positive cell line: KB-VIN10 cells,
overexpressed P-gp 170/MDR (Table 1).
We first evaluated the effect of the 7-amino group substitution
on the indoline ring in the 1-(4-methoxybenzenesulfonyl)-indo-
line series for cytotoxic activity. Compounds 9, 18, 21, 22, and
23 with an amide, sulfonamide, carbamate, urea, and alkyl func-
tionalities, respectively, on the 7-indoline were evaluated for
their cell growth inhibitory activity. The SAR information indi-
cates that amide 9, with a benzoyl substitution on the 7-amino-
indoline, showed the most potent activity, changing to 7-sulfon-
amide group (compound 18), which resulted in moderate activity
with 606 nM values of mean IC50 (KB and MKN-45), while
changing to carbamate, urea, or alkyl functionalities decreased
the activity drastically, even weaker than the unsubstituted 7-ami-
noindoline (8). On the basis of this result, of the benzoyl group
The results demonstrated that the drug cytotoxicity correlated
with the inhibition of tubulin polymerization and colchicine-
binding activities. As shown in Table 2, 10, 11, 15, 16, 17, and
24 were effective in inhibiting tubulin assembly, with IC50 values
of 1.5, 1.9, 1.1, 1.2, 1.7, and 1.9 µM, respectively, which were
comparable or superior to the colchicine and combretastatin A-4

6658 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 23
Letters
(IC50 ) 3.3 and 1.2 µM, respectively). In the [3H] colchicine-
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bonyl-aminoindoline-1-sulfonamides (15-17), 7-aroylcarbonyl-
aminoindoline-1-sulfonamides (10 and 11), and 7-alkylcarbonyl-
aminoindoline-1-sulfonamides (24) were strongly bound to the
colchicines binding site on the microtubules.
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Acknowledgment. This research was supported by National
Science Council of the Republic of China (Grant No. NSC 95-
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Supporting Information Available: Spectral data of com-
pounds 8-27, 29, and 30 and experimental procedures for synthesis
and biological evaluations. This material is available free of charge
via the Internet at http://pubs.acs.org.
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