Concise syntheses of 7-anilino-indoline-N-benzenesulfonamides as antimitotic and vascular disrupting agents

Article abstract of DOI:10.1016/j.bmc.2014.06.042

Described herein is the development of a novel series of 7-anilino-indoline-N-benzenesulfonamides, derived from ABT751 (1), as potent anticancer agents. Amongst the synthesized series, compounds 6, 12, 13, and 14 have shown comparable to better anticancer activity on comparing with compound 1. 7-(4-Cyanophenylamino)-1-(4-methoxybenzenesulfonyl)indoline (13) was found to be the most potent one with up to 6 fold better activity against KB, HT29, and MKN45 cancer cell lines with IC₅₀ values of 49.7, 149, and 92 nM, respectively. Compound 13 was also found inhibiting multidrug resistant cancer cell lines, blocking cell cycle at G2/M phase, and inhibiting tubulin polymerization. Capillary disruption assay results revealed that compound 13 was able to disrupt formed capillaries in a concentration-dependent manner without affecting cell viability.

Full text of DOI:10.1016/j.bmc.2014.06.042

Accepted Manuscript
Concise Syntheses of 7-Anilino-indoline-N-benzenesulfonamides as Antimito-
ic and Vascular Disrupting Agents
Samir Mehndiratta, Yi-Fang Chiang, Mei-Jung Lai, Hsueh-Yun Lee, Mei-
Chuan Chen, Ching-Chuan Kuo, Chi-Yen Chang, Jang-Yang Chang, Jing-Ping
Liou
PII:
S0968-0896(14)00488-X
http://dx.doi.org/10.1016/j.bmc.2014.06.042
BMC 11679
DOI:
Reference:
Bioorganic & Medicinal Chemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
19 May 2014
18 June 2014
19 June 2014
Please cite this article as: Mehndiratta, S., Chiang, Y-F., Lai, M-J., Lee, H-Y., Chen, M-C., Kuo, C-C., Chang, C-
Y., Chang, J-Y., Liou, J-P., Concise Syntheses of 7-Anilino-indoline-N-benzenesulfonamides as Antimitoic and
Vascular Disrupting Agents, Bioorganic & Medicinal Chemistry (2014), doi: http://dx.doi.org/10.1016/j.bmc.
2014.06.042
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Graphical Abstract
Concise Syntheses of 7-Anilino-indoline-N-
benzenesulfonamides as Antimitoic and
Vascular Disrupting Agents.
Leave this area blank for abstract info.
Samir Mehndiratta, Yi-Fang Chiang, Mei-Jung Lai,
Hsueh-Yun Lee, Mei-Chuan Chen, Ching-Chuan Kuo, Chi-Yen Chang,
Jang-Yang Chang*, Jing-Ping Liou*
a School of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wuxing Street, Taipei 11031, Taiwan.
b National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan.
c School of Pharmacy, National Defense Medical Center, 161 Minchuan East Road, Section 6, Taipei 114, Taiwan.
d
Division of Hematology and Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National
Cheng Kung University, Tainan, Taiwan.
e Mackay Memorial Hospital, Taipei 10449, Taiwan.
f Ph.D Program for the Clinical Drug Discovery from Botanical Herbs, College of Pharmacy, Taipei Medical University
O
H
N
O
O
S
OCH3
N
N
S
S
O
O
NH
O
NH
OCH3
N
NH
OCH3
Rigidifying Ring
OH
CN
OH

Bioorganic & Medicinal Chemistry
journal homepage: www.els evier.com
Concise Syntheses of 7-Anilino-indoline-N-benzenesulfonamides as Antimitoic and
Vascular Disrupting Agents.
Samir Mehndiratta,a Yi-Fang Chiang,a,e Mei-Jung Lai,a Hsueh-Yun Lee,a Mei-Chuan Chen,f Ching-Chuan
Kuo,b Chi-Yen Chang,b Jang-Yang Chang,b,d∗Jing-Ping Lioua,c∗
a School of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wuxing Street, Taipei 11031, Taiwan.
b National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan.
c School of Pharmacy, National Defense Medical Center, 161 Minchuan East Road, Section 6, Taipei 114, Taiwan.
d
Division of Hematology and Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng
Kung University, Tainan, Taiwan.
e Mackay Memorial Hospital, Taipei 10449, Taiwan.
f Ph.D Program for the Clinical Drug Discovery from Botanical Herbs, College of Pharmacy, Taipei Medical University, 250 Wuxing Street, Taipei 11031,
Taiwan.
ARTICLE INFO
ABSTRACT
Article history:
Received
Described herein is the development of a novel series of 7-anilino-indoline-N-
benzenesulfonamides, derived from ABT751 (1), as potent anticancer agents. Amongst the
synthesized series, compounds 6, 12, 13, and 14 have shown comparable to better anticancer
Received in revised form
Accepted
activity
on
comparing
with
compound
1.
7-(4-Cyanophenylamino)-1-(4-
Available online
methoxybenzenesulfonyl)indoline (13) was found to be the most potent one with up to 6 fold
better activity against KB, HT29, and MKN45 cancer cell lines with IC50 values of 49.7, 149,
and 92 nM, respectively. Compound 13 was also found inhibiting multidrug resistant cancer
cell lines, blocking cell cycle at G2/M phase, and inhibiting tubulin polymerization. Capillary
disruption assay results revealed that compound 13 was able to disrupt formed capillaries in a
concentration-dependent manner without affecting cell viability.
Keywords:
ABT751
Vascular-disrupting agents
Antimitotic
CA-4
1. Introduction
is under clinical phase II trials,4 most advanced MEK inhibitor 27
(Glaxosmithkline), is currently under phase III trials for the
Chaotic proliferation of malignant tumor cells is hallmark of
cancer cells which distinguish them from normal cells. Cell cycle
inhibitors with capability of halting irrepressible tumor growth
are promising therapeutic agents for cancer treatment.1 ABT751
(1), colchicine (2), combretastatin A-4 (3), combretastatin A-4P
(4) and AVE-8062 (5) are some examples of cell cycle inhibitors
(Figure 1). These compounds not only inhibit the dynamics of
tubulin polymerization but also serve as structural scaffolds for
discovery of novel potent lead molecules.2 It is anticipated that
diverse biological activities are often associated with compounds
sharing a common structural feature found in history of drug
discovery and development. It is also well documented that
treatment of BRAF V600E positive melanoma patients.
Compounds 28 and 29, another MEK inhibitors developed by
Array BioPharma/AstraZeneca and Pfizer respectively are
currently under phase II studies as single agents for the treatment
of a variety of tumor types (Figure 2).5 It is also been reported
that rigidifying the ring may increase the activity of the
antimitotic compounds by locking them in a preferable geometry.
6-8
Initially, an indoline core was used to investigate the effect of
rigidifying ABT751 (1) and we observed that rigidifying 1
improves the activity, as reported in our previous work.9,10 To
closely relate with 1, we replaced indoline with 6-aza indole but
in this series of compounds C7 anilino substitution was found
detrimental to activity.11 Considering importance of biaryl amino
group in syntheses of various drug molecules and to have a better
insight of SAR of rigidified 1 series, we decided to keep biaryl
amino part same as that of 1 to search for more potent
compounds. All of these observations and previous substantial
endeavors initiated quest for the development of a series of 7-
anilino-indoline-N-benzenesulfonamides. It is noteworthy to
mention that this paper is first to explore the 7-anilino-indoline
compounds containing sulfonamides possess
a variety of
biological activities such as antibacterial (19), carbonic
anhydrase inhibitory (20), diuretics (21), antithyroid (22), and
anti-diabetic (23).3 Biaryl amine is another common feature, we
observed, amongst various drugs including: ABT751 (1),
Torasemide (25), VEGFR inhibitor AG019358 (26),
GSK1120212 (27), AZD6244/Selumetinib (28), and PD325901
(—29—). C—ompound 26, developed by Pfizer for ophthalmology use
∗ Corresponding author. Tel.: +886-6-700-0123 ext. 65100; e-mail: jychang@nhri.org.tw
∗ Corresponding author. Tel.: +886-2-2736-1661 ext 6130; e-mail: jpl@tmu.edu.tw

based biaryl amines for the development of potent anticancer
compounds.
Figure 2. Diagram of compounds with common structural features yet
different biological activities
In addition, profound use of organometallic chemistry in
medicinal
chemistry for
scaffold
construction
and
This study not only strengthens SAR of our previous work but
also helps to understand functional diversity of these reactions as
both electron donating and electron withdrawing groups were
well tolerated complying with previous reports.16,17 Figure 3
represents the diagrammatic representation of our work.
functionalization has already been established.12-15 Although the
uses of various Pd-catalyzed reactions are widely explored,
Cu(OAc)2 reactions are more practical, inexpensive, useful over a
broad range of substrates in organic synthesis, and reactionary is
easily available.16 Aromatic C-N bond formation is the key step
for synthesis of series of compounds 6-15. Designed finals were
2. Chemistry
achieved by
a series of reactions including sulfonamide
Scheme 1 illustrates the synthesis of designed 7-anilino-
indoline-N-benzenesulfonamides (6-15). Reaction of 5-bromo-7-
nitroindoline with 4-methoxybenzenesulfonyl chloride achieved
the preparation of 5-bromo-1-(4-methoxybenzenesulfonyl)-7-
nitroindoline (16) in yield of 89%, which was subsequently
reduced to provide the corresponding amine 17 in yield of 93%.
The treatment of 17 with tributyltin hydride (Bu3SnH) and 2,2′-
azobis(2-methylpropionitrile) (AIBN) initiates a free radical
cascade leading to debrominated compound 18 in yield of 94%.
The starting material 18 was reacted with various substituted
boronic acids via modified Chan-Lam type N-arylation17,18 using
Cu(OAc)2 to afford compounds 6-14. Compound 14 was treated
with 1M LiOH (aq) in dioxane at 40 oC, yielding compound 15 in
yield of 96%.
formation, Fe/NH4Cl reduction, Bu3SnH/AIBN mediated
dehalogenation, and finally Cu(OAc)2 mediated N-arylation.
These reactions are extensively used in the field of medicinal
chemistry; therefore, increased diversity of our designed
structures is expected.
O
H
N
S
OCH
3
H CO
3
O
NHCOCH
O
3
N
NH
H CO
3
CH O
3
OCH
3
OH
1: ABT751
2: Colchicine
O
3
1
H CO
3
H
O
N
S
OCH
3
N
A
S
4
O
H CO
3
O
NH
5
B
OCH
N
NH
3
Ring rigidification
OCH
3
R
OCH
3
3: Combretastatin A-4 (CA4), R = OH
4: Combretastatin A-4P (CA4P), R = OPO Na
5: AVE-8062, R = NH-serine
OH
OH
3
2
ABT751 (1)
6
Modified functional group
Figure 1. Potent antimitotic agents.
O
N
S
O
NH
OCH
3
O
S
N
O
S
H
N
2
OCH
3
N
S
N
H
R
O
N
NH
NH
2
Figure 3. Diagrammatic representation of our work
F
O
Sulfathiazole (19)
N
N
H
N
H
N
H
H C
3
OH
NH
N
2
H C
3
N
S
Scheme 1. Synthetic route to 7-anilino-indoline-N-
benzenesulfonamides (6-15):
CH
3
SO
2
ABT751 (1)
Biaryl amine +Sulfonamide
O
N
N
AG019358 (26)
F
I
Acetazolamide (20)
Br
Br
Br
O
N
HN
b
a
CH
O
3
O
H
N
N
N
N
N
N
H
Cl
SO2
SO2
NH2
NO2
O
Biaryl Sulfon-
amine -amide
derivatives derivatives
NO2
H
N
2
CH
3
S
O
COOH
O
5-Bromo-7-nitroindoline
2
H C
3
N
H
OCH3
OCH3
Furosemide (21)
GSK1120212 (27)
17
16
H
N
HO
O
O
NH
NH
O
N
Cl
2
H
N
H N
2
S
N
c
d
Biaryl amine +Sulfonamide
O
2
N
SO2
N
H C
3
F
Br
NH
SO2
NH2
Sulfaguanidine (22)
N
R
CH
3
AZD6244 (28)
O
O
H
N
OCH3
OCH
S
3
OCH3
HO
HO
O
N
O
F
H
N
18
6: R = 4-OH
7: R = 4-H
11: R = 3,4-di-F
12: R = 4-NO2
13: R = 4-CN
NH
CH
3
R
H
H
N
N
N
8: R = 4-OCH3
9: R = 4-Cl
10: R = 4-F
S
O
CH
3
F
I
2
14: R = 4-COOCH3
15: R = 4-COOH
10
O
O
F
R= -NO (23)
2
e
-
CN (24)
PD325901 (29)
Torasemide (25)
Reagents and conditions: (a) 4-methoxybenzenesulfonyl chloride, pyridine,
95-100 oC, 89%; (b) Fe, NH4Cl, IPA/H2O, reflux, 93%; (c) Bu3SnH, AIBN,

dry toluene, reflux, 94%; (d) Cu(OAc)2, myristic acid, 2,6-lutidine, various
substituted boronic acids, toluene, rt, 41-83% ; (e) 1M LiOH (aq), dioxane, 40
oC, 96%.
to 11 and overall 1.5- to 2.5-fold increases in activity compared
to 1. Compound 12 was found to be most active against KB cells
followed by MKN45 and least active against HT29 cells with
IC50 values of 101, 107, and 191 nM, respectively. Compound 13
possessing a cyano substitution, exhibited greater potency in
activity against KB (IC50 = 49.7 nM), HT29 (IC50 = 149 nM), and
MKN45 (IC50 = 92 nM) cell lines compared to 1, with IC50 values
of 251, 338, and 166 nM, respectively. Compound 13 showed
activity against KB cells in two digit nanomolar range and also
showed better performance than compound 12 in anti-
proliferative activity in the three cell lines mentioned above..
This indicated that cyano group is well tolerated and is a
favorable substitution. Compound 14 also showed two digit
nanomolar activity against KB cells (IC50 = 93.5 nM) with up to
3 fold increase in activity compared to 1, against KB cell lines
though it was found to be less potent against HT29 and MKN45
cells. Compound 15 showed a marked decrease in activity as
compared to its precursor 14. Trend followed by these
compounds in their activities against cervical carcinoma KB cell
lines suggested that after rigidifying the structure and
maintaining biaryl amine moiety electron withdrawing groups are
more favored than electron donating and order of tolerance of
these groups is -CN (IC50 = 49.7 nM) > -COOCH3 (IC50 = 93.5
3. Results and discussion
3.1 In vitro cell growth inhibitory activity
With the aim to explore the effect of biaryl amino moiety and
of rigidifying 1 on the cancer cell inhibitory ability In vitro cell
growth inhibitory activity was evaluated.22 All synthetic
compounds (6-15) along with reference compound (1) were
evaluated for their anti-proliferative activities against three
human cancer cell lines, cervical carcinoma KB cells, colorectal
carcinoma HT29 cells, and stomach carcinoma MKN45 cells
(Table 1).
Table 1. Antiproliferative activity of compounds 6-15 and
reference compound 1.
Cell type (IC50 nM SDa)
Compd
KB
HT29
MKN45
493 85
187 102
487 170
463 56
563 298
726 239
6
239 55
511 60
343 184
803 295
658 194
588 27
968 66
nM) > -NO2 (IC50 = 101 nM) > -OH (IC50 = 239 nM) > 1 (IC50
=
251.3 nM)11. To improve our understanding of the efficacy
against drug-resistant cell lines, compounds 12 and 13 were
evaluated for anti-proliferative activity against a variety of
resistant lines as shown in Table 2. Despite the high level of
expression of drug-resistant efflux protein (MDR/P-gp or MRP)
in KB-Vin 10, KB-S15, and KB-7D cells, compounds 12 and 13
showed almost similar cytotoxic efficacy between parental cells
and these resistant cell lines.
7
342 43
8
1200 300
1100 500
557 272
412 64
9
10
11
12
13
14
15
1b
101 2.4
49.7 15
93.5 22
846 183
251.3 64.9
191
8
107
1
149 51
678 267
92 34
487 51
3.2 Inhibition of tubulin polymerization and colchicine
binding activity
2377 548
1394 390
To investigate whether these 7-anilino-indoline-N-
benzesulfonamides could interfere with polymerization of
microtubule, tubulin polymerization inhibition activity20,23 and
competitive colchicine binding activity25 of 12, 13, 14, and
reference compounds 2 and 3 were evaluated, (Table 3). The
results of tubulin inhibitory activity indicated that all these
compounds showed better tubulin inhibitory activity as compared
to 2 but lesser than 3. Colchicine binding activity data revealed
that these synthetics showed better affinity for colchicine binding
site than colchicine (64.4%). Amongst these compounds, 13 with
cyano substitution showed the best binding affinity (86.4%)
almost similar to 3 (90.3%). In Figure 4, [3H] colchicine bound
curve showed that compound 13 binds the colchicine-binding site
of tubulin. Double-reciprocal plot revealed that compound 13 is a
competitive inhibitor of colchicine binding to tubulin. As
depicted in Figure 5, 12 and 13 inhibited polymerization of pure
MAP-rich tubulins in a concentration-dependent manner and 13
disrupted tubulin assembly almost completely at 10.0 µM. High
colchicine binding site affinity and tubulin polymerization
inhibition demonstrated that 12, 13 and 14 cause the death of
cancer cells through halting the dynamic of tubulin
polymerization.
338.7 118.5
166 8.5
aSD: standard deviation. All experiments were independently performed at
least three times.
b data from reference 11.
Compound 6 showed comparable potencies for KB cell lines
(IC50 = 239 nM) but found less potent for HT29 and MKN45
cells as compared to 1 (KB cell, IC50 = 251 nM). Compound 7,
with no substitution on phenyl ring, showed comparable
potencies with compound 1 against all cell lines. These results
indicated that the strategy of structural restriction is an acceptable
modification in current study, although –OH substitution is not
the most favored one. This increased fervency to see the group
substitution effect on the anti-proliferative activity of these
compounds. Compound 8 with an electron-donating –OMe
showed overall decrease in activity in all cell lines compared to
1. To examine the effect of electron withdrawing group,
compound 9 with a chloro substitution was synthesized. It
demonstrated slightly better activity than compound 8 but still
1.5- to 4-fold less activity than 1. Although, replacing –Cl with –
F (10) led to increase in activity against KB and HT29 cell lines
compared to 9, it was still less potent than 1. Di-fluoro
substitution of 11, showed increase in activity against KB cell
line compared to 10, but an inexplicable decrease of activity
against HT29 and MKN45 cells. Compound 12 with an NO2
substitution depicted marked improvement in activity compared
3.3 Flow cytometry analysis
The effect of compound 13 on cell cycle progression of KB
cells was examined by flow cytometry (Figure 6). Compound 13
treatments resulted in a concentration-dependent accumulation of
KB cells in the G2/M phase with concomitant losses from G1

and S-phase. In addition, characteristic hypodiploid DNA content
peak (sub-G1), indicated as apoptotic cells, and was also detected
with dose-dependent manner. The value of sub-G1 phase reaches
a peak at 100 nM. These results indicate that compound 13
induced cell cycle arrest in G2/M phase and apoptotic cell death
occurrence.
radiolabeled colchicines at 37 oC, and the amount of [3H]-colchicine bound
was determined by using scintillation proximity assay beads. Each data point,
the mean S.D. Insert panel: double-reciprocal plot showed that compound
13 is a competitive inhibitor of colchicine binding to tubulin.
3.4 In vitro vascular disrupting effect
After the discovery of compound 3 as vasculature disrupting
agent, opened a new era of anti-cancer drug development. Many
antitubulin agents and synthetic flavonoids are classified as small
molecular vascular disrupting agent (VDA).26 Therefore;
compound 13 was further investigated for vascular disrupting
activity based on the following methods.27 The HUVECs were
plated on Matrigel and allowed to form capillary tubes in the
presence of VEGF (20 ng/mL), followed by exposure to different
concentrations of compound 13. Figure 7 revealed that 13 was
able to disrupt formed capillaries in a concentration-dependent
manner without affecting cell viability, and this function is
observed while treating with 100 nM of 13.
Figure 4. [3H]-Colchicine bound curve showed that compound 13 binds the
colchicine-binding site of tubulin. Tubulin was incubated with the
Table 2. Growth inhibition of compounds 12, 13, and reference compounds against drug-resistant cell lines.
IC50 SDa
Resistant
type
Cell lines
KB
vincristineb
0.4 0.1 nM
90.1 7.4 nM
17.6 2.2 nM
1.2 0.4 nM
paclitaxelb
3.3 1.2 nM
16500 707 nM
273 15 nM
7.9 0.5 nM
VP-16b
12
13
Parental
1.1 0.5µM
23 3µM
101 2.4 nM
109.4 4.8 nM
95.4 3.4 nM
115.4 2.4 nM
49.7 15 nM
71.9 2.9 nM
77.3 14.8 nM
71.1 9.6 nM
KB-VIN10
KB-S15
KB-7D
MDR ↑
↑
MDR
3.5 0.3µM
↑
MRP
54 3.5µM
aSD: standard deviation. All experiments were independently performed at least three times.
bData from reference 19.
Table 3. Inhibition of tubulin polymerization and colchicine binding inhibition by compounds 12-14 and reference compounds.
colchicine bindingb
tubulina
(% SD)
Compd
IC50 SD (µM)
1 µM
44.0
5 µM
69.3
12
13
14
2
3.7
3.2
4.7
5.4
2.5
83.6
41.4
34.5
80.6
86.4
66.9
64.4
90.3
3
aInhibition of tubulin polymerization.20
bInhibition of [3H]-colchicine binding. Tubulin was at 1 µM; [3H]-colchicine was at 5 µM.21

Cyanophenylamino)-1-(4-methoxybenzenesulfonyl)indoline (13)
showed that an electron withdrawing group is favored for the
improvement of biological activity of this series of compounds.
These biaryl amine based sulfonamides obtained by the approach
of ring constraining increased the activity of the compounds with
electron withdrawing substitution and could act as a template for
further development of potent anticancer compounds.
Figure 6. The concentration effect of compound 13 on cell cycle progress of
KB cells. Cells were treated with different concentrations of compound 13 for
24 hours and analyzed for propidium iodide-stained DNA content by flow
cytometry.
Figure 5. Effect of compounds 12 and 13 on in vitro tubulin polymerization.
MAP-rich tubulins were incubated at 37 °C in the absence [dimethyl
sulfoxide (DMSO) control] or presence of drugs (colchicine or serial
concentrations of compounds 12 and 13). The absorbance at 350 nm was
measured every 30 sec for 30 min and is presented as the increased
polymerized microtubule.
4. Conclusion
A series of 7-anilino-indoline-N-benzenesulfonamides were
developed and evaluated for a set of biological activities. The
biological results indicated that total of four compounds (6, 12,
13, and 14 possessing -OH, -NO2, -CN, and -OAc, respectively)
showed better activity against KB and HT29 cell lines as
compared to Compounds 13 and 14 showed marked activity
against KB cell lines with IC50 values of 49.7 nM and 93.5 nM as
compared to parent compound 1 (IC50 = 251 nM. Compound 13
inhibited KB, HT29, and MKN45 cells with IC50 values of 49,
149, and 92 nM, respectively. 12 and 13 exhibited almost same
potency in both, parental as well as multidrug resistant cell lines.
These results revealed that these compounds are equipotent even
against MDR cells. In addition to anti-proliferative activity, 12,
13, and 14 exhibited higher tubulin polymerization inhibitory
activity compared to colchicine. Colchicine binding activity
results were also consistent with that of tubulin polymerization
inhibitory activity. All of these three compounds showed better
affinity for colchicine binding site than colchicine at both 1 µM
and 5 µM concentrations. Compound 13 exhibited the highest
affinity (86.4 %) amongst the other analogs of the series, binding
competitively to colchicine binding site of tubulin and disrupting
tubulin assembly almost completely at 10.0 µM. 7-(4-
Figure 7. Investigation of the vascular disrupting activity of compound 13.
HUVECs were plated on Matrigel and allowed to form capillary tubes in the
presence of VEGF (20 ng/mL) followed by exposure to different
concentrations of compound 13. Cultures were photographed, and the number

o
1
of capillary tube networks was determined by counting under a microscope
(original magnification of 100×). Data reflect the mean number of capillary
tube networks to vehicle control group (DMSO) S.D. from three separate
experiments.
116.2-117.5 C. H NMR (500 MHz, CDCl3) δ 7.54 (d, J = 8.5
Hz, 2H), 6.91 (t, J = 8.0 Hz, 1H), 6.84 (d, J = 9.0 Hz, 2H), 6.59
(d, J = 8.0 Hz, 1H), 6.42 (d, J = 7.5 Hz, 1H), 4.70 (br, 1H), 3.96
(t, J = 7.5 Hz, 2H), 3.83 (s, 3H), 2.16 (t, J = 7.5 Hz, 2H).
5.1.2. Syntheses of compounds 6-15.
5. Experimental
5.1. Chemistry
5.1.2.1. 7-(4-Hydroxyphenylamino)-1-(4-methoxybenzene-
sulfonyl)indoline (6)
To a flame-dried 100 mL pear shaped flask was added 4-
hydroxyphenylboronic acid (0.14 g, 1.02 mmol), 20 mol% of
solid Cu(OAc)2 (0.03 g, 0.16 mmol), crystalline myristic acid
(0.08 g, 0.33 mmol) and dry toluene (5 mL). The resulting
suspension was stirred for 10 min and 2,6-lutidine (0.20 mL, 1.73
mmol) was added by syringe. After 30 min, 18 (0.20 g, 0.66
mmol) was added and stirred vigorously at ambient temperature
for 24 h. The reaction mixture was filtered and washed by
CH2Cl2 and EtOAc. The organic layers were dried over MgSO4,
concentrated and purified by flash column chromatography
(EtOAc: n-hexane = 1: 3) to afford 6 (0.18 g, 68 %) as a rufous
solid, yield 68%; mp 150.4-151.9 °C. 1H-NMR (500 MHz,
CDCl3) δ 7.53 (d, J = 9.0 Hz, 2H), 7.34 (dd, J = 2.5, 10 Hz, 1H),
7.23-7.28 (m, 1H), 7.15 (t, J = 7.5, 1H), 7.03 (d, J = 7.5 Hz, 1H),
6.88 (d, J = 8.5 Hz, 3H), 6.79 (br, 1H), 6.68 (dd, J = 2.0, 10.0 Hz,
1H), 6.54-6.60 (m, 2H), 4.08 (t, J = 7.5 Hz, 2H), 3.85 (s, 3H),
2.53 (t, J = 7.5 Hz, 2H). 13C-NMR (75 MHz, CDCl3) δ 188.2,
163.8, 158.4, 142.5, 141.9, 139.0, 134.9, 133.6, 133.3, 130.4,
130.0, 139.9, 127.2, 122.9, 120.4, 114.6, 56.1, 53.1, 29.7. MS
(EI) m/z: 396 (M+, 5.34%), 223 (100%). HRMS (EI) for
C21H20N2O4S (M+): calcd, 396.4596; found, 396.1145.
Nuclear magnetic resonance (1H and 13C NMR) spectra of
final compounds were obtained with Bruker fourier 300 and
Bruker DRX-500 spectrometer, with chemical shift in parts per
million (ppm, δ) downfield from TMS as an internal standard.
High-resolution mass spectra (HRMS) were measured with a
JEOL (JMS-700) electron impact (EI) mass spectrometer. Purity
of the final compounds were determined using an Agilent 1100
series HPLC system using C-18 column (Agilent ZORBAX
Eclipse XDB-C18 5 µm. 4.6 mm × 150 mm) and were found to
be ≥ 95%. Flash column chromatography was done using silica
gel (Merck Kieselgel 60, No. 9385, 230-400 mesh ASTM).
5.1.1. Syntheses of intermediate compound 18 from 16.
5.1.1.1. 5-Bromo-1-(4-methoxybenzenesulfonyl)-7-
nitroindoline (16)
To a solution of 5-bromo-7-nitroindoline (2.0 g, 8.23 mmol),
4-methoxyphenysulfony chloride (8.5 g, 41.15 mmol) in pyridine
(5 mL) and stirred at 95-100 oC under N2 for 10 h. The reaction
mixture was extracted with water (50 mL) and CH2Cl2 (50 mL
×3). The organic layers were dried (MgSO4), filtrated and
evaporated. The crude product was purified by flash column
chromatography (EtOAc: n-hexane = 1: 3) to afford 25 (3.03 g,
89 %) as a yellow solid; mp 148.3-150.1 oC. 1H-NMR (500 MHz,
CDCl3) δ 7.91 (br, 1H), 7.50 (d, J = 1.5 Hz, 1H), 6.95 (d, J = 9.0
Hz, 2H), 4.07 (t, J = 8.0 Hz, 2H), 3.88 (s, 3H,), 2.70 (t, J = 8.0
Hz, 2H).
5.1.2.2. 7-(4-Phenylamino)-1-(4-methoxybenzenesulfonyl) -
indoline (7)
The title compound was obtained in 48% overall yield from
18 in a similar manner as described for the preparation of 6 by
using 4-hydroxyphenylboronic acid; mp 175.3-176.5 oC. 1H
NMR (500 MHz, CDCl3) δ 7.95 (bs, 1H), 7.54 (d, J = 8.9 Hz,
2H), 7.27-7.29 (m, 3H), 7.14 (d, J = 7.7 Hz, 2H), 7.01 (t, J = 7.8
Hz, 1H), 6.94 (t, J = 7.25 Hz, 1H), 6.84 (d, J = 8.9 Hz, 2H), 6.56
(d, J = 7.4 Hz, 1H), 4.01 (t, J = 7.4 Hz, 2H), 3.83 (s, 3H), 2.20 (t,
J = 7.4 Hz, 2H). 13C-NMR (75 MHz, CDCl3) δ 164.0, 144.1,
139.4, 137.6, 131.1, 130.1, 129.6, 129.2, 128.4, 128.0, 121.4,
118.9, 116.6, 116.5, 114.5, 56.0, 53.8, 29.5. MS (EI) m/z: 380.1
(M＋ , 11%), 209.1 (100%). HRMS (EI) C21H20N2O3S (M＋ ):
calcd, 380.1195; found, 380.1189.
5.1.1.2 5-Bromo-1-(4-methoxybenzenesulfonyl)-7-
aminoindoline (17)
A mixture of 16 (1.43 g, 3.46 mmol), Fe powder (0.6 g, 10.4
mmol) and NH4Cl (0.37 g, 6.92 mmol) in isopropanol (72 mL)
and water (18 mL) was heated to reflux for 8 h. After cooling to
room temperature, the reaction mixture was filtered. The filtrate
was extracted with water (100 mL) and EtOAc (100 mL × 3).
The organic layers were dried over MgSO4 and purified by flash
column chromatography (EtOAc: n-hexane = 1: 3) to afford 17
5.1.2.3. 7-(4-Methoxyphenylamino)-1-(4-methoxybenzene-
sulfonyl)indoline (8)
o
1
(1.23 g, 93 %) as a white solid; mp 183.4-184.0 C. H NMR
(500 MHz, CDCl3) δ 7.56 (d, J = 9.0 Hz, 2H), 6.87 (d, J = 9.0
Hz, 2H), 6.74 (d, J = 1.5 Hz, 1H), 6.54 (d, J = 1.0 Hz, 1H), 4.78
(br, 2H), 3.96 (t, J = 7.5 Hz, 2H), 3.85 (s, 3H), 2.15 (t, J = 7.5
Hz, 2H).
The title compound was obtained in 30% overall yield from
18 in a similar manner as described for the preparation of 6 by
using 4-methoxyphenylboronic acid; mp 146.8-147.8 oC. 1H
NMR (500 MHz, CDCl3) δ 7.66 (bs, 1H), 7.55 (d, J = 8.8 Hz,
2H), 7.13 (d, J = 8.7 Hz, 2H), 7.00 (d, J = 8.1 Hz, 1H), 6.95 (t, J
= 7.7 Hz, 1H), 6.87 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.9 Hz, 2H),
6.48 (d, J = 7.5 Hz, 1H), 4.02 (d, J = 7.40 Hz, 2H), 3.83 (s, 3H),
3.80 (s, 3H), 2.19 (t, J = 7.4 Hz, 2H). 13C-NMR (75 MHz, CDCl3)
δ 164.1, 155.8, 139.8, 139.4, 136.0, 130.3, 129.9, 128.7, 128.3,
115.4, 115.1, 114.6, 56.1, 54.1, 29.7 MS (EI) m/z: 410 (M＋,
17%), 239 (100%). HRMS (EI) for C22H22N2O4S (M＋): calcd,
410.1300; found, 410.1302.
5.1.1.3 1-(4-Methoxybenzensulfonyl)-7-aminoindoline (18)
To the mixture of 17 (2.04 g, 5.32 mmol) and AIBN (0.88 g,
5.32 mmol) was added the Bu3SnH (4.30 mL, 16.0 mmol) and
dry toluene (20 mL) and then heated to reflux under N2 for 18 h.
After cooling to room temperature, the reaction mixture was
evaporated and the residue was extracted with water (100 mL)
and CH2Cl2 (100 mL × 3). The organic layers were dried over
MgSO4 and purified by flash column chromatography (EtOAc: n-
hexane = 1: 3) to get 18 (1.51 g, 93 %) as a white solid; mp
5.1.2.4. 7-(4-Chlorophenylamino)-1-(4-methoxybenzene-
sulfonyl)indoline (9)

The title compound was obtained in 44% overall yield from
18 in a similar manner as described for the preparation of 6 by
(500 MHz, CDCl3) δ 8.42 (br, 1H), 7.45-7.51 (m, 4H), 7.33 (d, J
= 8.0 Hz, 1H), 7.11 (t, J = 7.5 Hz, 1H), 7.05 (d, J = 8.5 Hz, 2H),
6.86 (d, J = 9.0 Hz, 2H), 6.76 (d, J = 7.5 Hz, 1H), 4.00 (t, J = 7.5
Hz, 2H), 3.84 (s, 3H), 2.24 (t, J = 7.5 Hz, 2H). 13C-NMR (75
MHz, CDCl3) δ 164.3, 148.0, 140.0, 134.5, 134.1, 133.6, 130.1,
128.2, 120.5, 119.9, 119.7, 116.2, 114.8, 102.0, 56.2, 53.7, 29.5.
MS (EI) m/z: 405 (M+, 11.7%), 234 (100%). HRMS (EI) for
C22H19N3O3S (M+): calcd, 405.4696; found, 405.1146.
1
using 4-chlorophenylboronic acid; mp 146.9-148.3 °C. H NMR
(500 MHz, CDCl3) δ 7.96 (bs, 1H), 7.52 (d, J = 8.9 Hz, 2H), 7.21
(d, J = 8.7 Hz, 2H), 7.20 (d, J = 8.7 Hz, 1H), 7.05 (d, J = 8.76
Hz, 2H), 7.01 (t, J = 7.9 Hz, 1H), 6.85 (d, J = 8.8 Hz, 2H), 6.59
(d, J = 7.3 Hz, 2H), 4.01 (t, J = 7.4 Hz, 2H), 3.84 (s, 3H), 2.21 (t,
J = 7.4 Hz, 2H). 13C-NMR (75 MHz, CDCl3) δ 164.2, 141.9,
139.7, 137.2, 131.5, 130.2, 129.6, 128.4, 128.1, 125.9, 120.0,
117.2, 116.8, 114.6, 56.1, 53.8, 29.6. MS (EI) m/z: 414.1 (M＋,
8.5%), 208.1 (100%). HRMS (EI) for C21H19ClN2O3S (M＋ ):
calcd, 414.0805; found, 414.0806.
5.1.2.9. 7-(4-Methoxycarbonylphenylamino)-1-(4-methoxy-
benzenesulfonyl)indoline (14)
The title compound was obtained in 83% overall yield from
18 in a similar manner as described for the preparation of 6 by
using 4-methoxycarbonylphenylboronic acid; mp 180.1-181.5
5.1.2.5. 7-(4-Fluorophenylamino)-1-(4-methoxybenzene-
sulfonyl)indoline (10)
1
°C. H NMR (500 MHz, CDCl3) δ 8.35 (br, 1H), 7.92 (d, J = 8.5
The title compound was obtained in 41% overall yield from
18 in a similar manner as described for the preparation of 6 by
Hz, 2H), 7.51 (d, J = 8.5 Hz, 2H), 7.37 (d, J = 8.0 Hz, 1H), 6.85
(d, J = 9.0 Hz, 2H), 6.71 (d, J = 7.0 Hz, 1H), 4.01 (t, J = 7.5 Hz,
2H), 3.88 (s, 3H), 3.84 (s, 3H), 2.23 (t, J = 7.5 Hz, 2H). 13C-NMR
(75 MHz, CDCl3) δ 167.0, 163.7, 147.5, 139.3, 135.0, 132.4,
131.3, 129.7, 127.9, 127.5, 121.2, 118.8, 118.2, 115.4, 114.2,
55.6, 53.2, 51.6, 29.7, 29.0. MS (EI) m/z: 438 (M+, 7.93%), 208
(100%). HRMS (EI) for C23H22N2O5S (M+): calcd, 438.4962;
found, 438.1249.
1
using 4-fluorophenylboronic acid; mp 142.8-144.2 °C. H NMR
(500 MHz, CDCl3) δ 7.81 (bs, 1H), 7.54 (d, J = 8.8 Hz, 2H),
7.09-7.12 (m, 3H), 6.97-7.01 (m, 3H), 6.84 (d, J = 8.8 Hz, 2H),
6.54 (d, J = 7.3 Hz, 1H), 4.01 (d, J = 7.4 Hz, 2H), 3.84 (s, 3H ),
2.20 (t, J = 7.3 Hz, 2H). 13C-NMR (75 MHz, CDCl3) δ 164.1,
160.0, 156.8, 139.5, 139.0, 138.4, 130.6, 130.1, 128.4, 128.1,
121.5, 121.4, 116.4, 116.3, 116.1, 115.4, 114.5, 56.0, 53.8, 29.5.
MS (EI) m/z: 398.1 (M＋, 8%), 227.1 (100%). HRMS (EI) for
C21H19FN2O3S (M＋): calcd, 398.1100; found, 398.1096.
5.1.2.10. 7-(4-Carboxylphenylamino)-1-(4-methoxybenzene-
sulfonyl)indoline (15)
5.1.2.6. 7-(3,4-Difluorophenylamino)-1-(4-methoxybenzene-
sulfonyl)indoline (11)
The 1M LiOH (aq) (0.37 mL) was added into the solution of 14
(0.08 g, 0.18 mmol) in dioxane (5 mL) and the reaction mixture
was heated to 40 oC for 18 h. After cooling to room temperature,
the reaction mixture was neutralized to pH = 7 and extracted with
water (10 mL) and chloroform/IPA (chloroform/IPA = 3/1; 10
mL × 3). The organic layers were dried over MgSO4 and the
residue was recrystallized from methanol to afford 15 (0.07 g,
The title compound was obtained in 70% overall yield from
18 in a similar manner as described for the preparation of 6 by
using 3,4-difluorophenylboronic acid; mp 123.3-124.1 °C. 1H
NMR (500 MHz, CDCl3) δ 7.91 (br, 1H), 7.52 (d, J = 9.0 Hz,
2H), 7.17 (d, J = 8.0 Hz, 1H), 7.01-7.09 (m, 2H), 6.86-6.89 (m,
1H), 6.85 (d, J = 9.0 Hz, 2H), 6.78-6.81 (m, 1H), 6.62 (d, J = 7.0
Hz, 1H), 4.01 (t, J = 7.5 Hz, 2H), 3.84 (s, 3H), 2.21 (t, J = 7.5
Hz, 2H). 13C-NMR (75 MHz, CDCl3) δ 164.4, 140.4, 140.0,
137.5, 131.8, 130.4, 128.7, 128.5, 118.4, 112.1, 117.6, 117.1,
114.9, 108.1, 107.8, 56.1, 54.1, 29.8. MS (EI) m/z: 416 (M+,
14.17%), 245 (100%). HRMS (EI) for C21H18F2N2O3S (M+);
calcd, 416.4410; found, 416.1003.
1
96%) as a white solid; mp 229.6-230.1 °C. H NMR (500 MHz,
CDCl3) δ 7.88 (d, J = 9.0 Hz, 2H), 7.79 (br, 1H), 7.50 (d, J = 9.0
Hz, 2H), 7.34 (d, J = 8.5 Hz, 1H), 7.11 (m, 1H), 7.01 (d, J = 8.5
Hz, 2H), 6.93 (d, J = 9.0 Hz, 2H), 6.75 (d, J = 7.0 Hz, 1H), 4.02
(t, J = 7.5 Hz, 2H), 3.83 (s, 3H), 2.26 (t, J = 7.0 Hz, 2H). 13C-
NMR (75 MHz, DMSO) δ 167.5, 163.8, 147.9, 140.0, 134.4,
133.1, 130.0, 128.1, 128.0, 121.4, 120.1, 119.4, 114.9, 56.2, 53.1,
29.0. MS (EI) m/z: 424 (M+, 7.3%), 208 (100%). HRMS (EI) for
C22H20N2O5S (M+): calcd, 424.4696; found, 424.1095.
5.1.2.7. 7-(4-Nitrophenylamino)-1-(4-methoxybenzene-
sulfonyl)indoline (12)
Acknowledgments
The title compound was obtained in 70% overall yield from
18 in a similar manner as described for the preparation of 6 by
This research were supported by the National Science Council
of the Republic of China (grant no. NSC 100-2628-M-038-001-
MY3, NSC 102-2325-B-038-002)
1
using 4-nitrophenylboronic acid; mp 139.8-140.9 °C. H NMR
(500 MHz, CDCl3) δ 8.65 (br, 1H), 8.12 (d, J = 9.0 Hz, 2H), 7.50
(d, J = 9.0 Hz, 2H), 7.37 (d, J = 8.0 Hz, 1H), 7.15 (dd, J = 7.5,
8.0 Hz, 1H), 7.02 (d, J = 9.0 Hz, 2H), 6.86 (d, J = 9.0 Hz, 2H),
6.81 (d, J = 7.0 Hz, 1H), 4.03 (t, J = 7.5 Hz, 1H), 3.85 (s, 3H),
2.26 (t, J = 7.5 Hz, 2H). 13C-NMR (75 MHz, CDCl3) δ 163.8,
149.7, 139.7, 139.6, 133.5, 133.4, 129.6, 127.7, 126.0, 120.2,
119.8, 114.4, 114.3, 55.7, 52.2, 29.0. MS (EI) m/z: 425 (M+,
20.08%), 254 (100%). HRMS (EI) for C21H19N3O5S (M+): calcd,
425.4577; found, 425.1042
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