5-Amino-2-Aroylquinolines as highly potent tubulin polymerization inhibitors

Article abstract of DOI:10.1021/jm900685y

A series of aroylquinoline derivatives were synthesized and evaluated for anticancer activity. 5-Amino6-methoxy-2-aroylquinoline 15 showed more potent antiproliferative activity (IC₅₀ values ranging from 0.2 to 0.4 nM) as compared to la (combretastatin A-4) (IC₅₀ = 1-9-835 nM) against various human cancer cell lines and a MDR-resistant cancer cell line. Compound 15 (IC₅₀ = 1-6 μM) exhibited more potent inhibition of tubulin polymerization than la (IC₅₀ = 2.1 μM) and showed strong binding property to the colchicine binding site of microtubules.

Full text of DOI:10.1021/jm900685y

J. Med. Chem. 2010, 53, 2309–2313 2309
DOI: 10.1021/jm900685y
5-Amino-2-Aroylquinolines as Highly Potent Tubulin Polymerization Inhibitors
Chih-Ying Nien,† Yun-Ching Chen,‡ Ching-Chuan Kuo,‡ Hsing-Pang Hsieh,§ Chi-Yen Chang,‡
Jian-Sung Wu,§ Su-Ying Wu,§ Jing-Ping Liou,*,† and Jang-Yang Chang*,‡,
†College of Pharmacy, Taipei Medical University, Taipei 110, Taiwan, Republic of China, ‡National Institute of Cancer Research, National
Health Research Institutes, Tainan 704, Taiwan, Republic of China, §Division of Biotechnology and Pharmaceutical Research, National Health
Research Institutes, Miaoli 350, Taiwan, Republic of China, and Division of Hematology/Oncology, Department of Internal Medicine, National
Cheng Kung University Hospital, Tainan 704, Taiwan, Republic of China
Received May 21, 2009
A series of aroylquinoline derivatives were synthesized and evaluated for anticancer activity. 5-Amino-
6-methoxy-2-aroylquinoline 15 showed more potent antiproliferative activity (IC50 values ranging from
0.2 to 0.4 nM) as compared to 1a (combretastatin A-4) (IC50 = 1.9-835 nM) against various human
cancer cell lines and a MDR-resistant cancer cell line. Compound 15 (IC50 = 1.6 μM) exhibited more
potent inhibition of tubulin polymerization than 1a (IC50 = 2.1 μM) and showed strong binding
property to the colchicine binding site of microtubules.
Introduction
Microtubules are dynamic structures that play a crucial role
in cellular division and are recognized as an important target
for anticancer therapy.1A number of naturally occurring
compounds, such as paclitaxel, epothilone A, vinblastine,
dolastatin 10, 1a (combretastatin A-4), and 3 (colchicine),
exhibit their anticancer properties by interfering with the
dynamics of tubulin polymerization and depolymerization,
resulting in mitotic arrest. Recent reports show that drugs
binding to the colchicine domain are undergoing intensive
investigationas vascular-disrupting agentsfor cancer therapy.
For example, clinical candidates of the microtubule inhibitor,
combretastatin A-4P (1b, Zybrestat) and AVE-8062 (2b,
Ombrabulin), act as a vascular disrupting agent (VDAa) that
rapidly depolymerize microtubules of newly formed vascula-
tures and subsequently shut down the blood supply to
tumors.2 In addition, the sulfonamide-containing small mo-
Figure 1
lecule compound, 4 (ABT-751), demonstrated efficacious
antimitotic activity by inhibition of tubulin polymerization
and is currently undergoing clinical trials.3 (Figure 1)
seem to play an important role in their bioactivity. Here we
report our attempt to explore the quinoline core coupled with
the 3,4,5-trimethoxybenzoyl group as tubulin polymerization
inhibitors. The structure-activity relationship studies of ser-
ies of aroylquinoline regioisomers led to the discovery of
5-amino-2-aroylquinolines as novel highly potent inhibitors
of tubulin polymerization. (Figure 2)
The current available clinically used chemotherapeutic
microtubule inhibitors have high toxicity, and their potential
is limited by the development of multidrug resistance (MDR).
Therefore, there has been great interest in identifying novel
microtubule inhibitors that overcome various modes of resis-
tance and exhibited improved pharmacology profiles.4 The
quinolines is a pharmacologically active class of heterocyclic
compounds.5 Analysis of thesemicrotubule inhibitors, suchas
1a, 2a, 3, and 4, indicates that the 3,4,5-trimethoxyphenyl/
3,4,5-trimethoxybenzoyl and para-methoxyphenyl groups
Results and Discussion
Chemistry. The general method for the synthesis of aroyl-
quinolines 5-11, 14, and 16-17 is depicted in the Scheme 1.
The preparation of 2-, 3-, 4-, 5-, 6-, 7-, and 8-aroylquinolines
(5-11) involved a concise two-step reaction sequence, with
an overall yield of 57-72%. Grignard reaction of 3,4,5-
trimethoxyphenylmagnesium bromide with various com-
mercially available quinoline-carboxaldehydes (18-24) fol-
lowed by pyridinium dichromate (PDC) oxidation afforded
the desired aroylquinolines 5-11. The 6-aroylquinoline 14,
*To whom correspondence should be addressed. For J. P. Liou:
phone, 886-2-2736-1661 ext 6130; fax, 866-2-27369558; E-mail, jpl@
tmu.edu.tw. For J. Y. Chang: phone, 886-6-700-0123 ext. 65100; fax,
886-6-208-3427; E-mail, jychang@nhri.org.tw.
a Abbreviations: MDR, multidrug-resistant; VDA, vascular disrupt-
ing agent; PDC, pyridinium dichromate; m-CPBA, meta-chloroperben-
zoic acid; SeO2, selenium dioxide; POCl3, phosphorus oxychloride.
r
2010 American Chemical Society
Published on Web 02/11/2010
pubs.acs.org/jmc

2310 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 5
Nien et al.
Figure 2
Scheme 1a
aReagents and conditions: (a) (i) 3,4,5-trimethoxyphenylmagnesium bromide, 0-25 °C; (ii) pyridinium dichromate (PDC), CH2Cl2, molecular sieves,
rt; (b) (i) m-CPBA, CH2Cl2, (ii) POCl3, CH2Cl2, reflux, (iii) sodium methoxide, CH3OH, reflux; (c) m-CPBA, CH2Cl2; (d) CH3I, CH2Cl2.
Scheme 2a
aReagents and conditions: (a) 65% HNO3, H2SO4, 0-25 °C; (b) SeO2, 1,4-dioxane, reflux; (c) (i) 3,4,5-trimethoxyphenylmagnesium bromide,
0-25 °C, (ii) pyridinium dichromate (PDC), CH2Cl2, molecular sieves, rt, (d) sodium sulfide nonahydrate, NaOH, ethanol, H2O, reflux.
with a methoxy group at the C2-position, was synthesized in
51% yield by treatment of 9 with m-chloroperbenzoic acid
(m-CPBA) in CH2Cl2 at room temperature, followed by a
phosphorus oxychloride heating at reflux and sodium meth-
oxide addition. The N1-substituted quaternary salt deriva-
tives 16 and 17 were prepared in 95% and 91% yield from 9
by reaction with m-CPBA and CH3I, respectively. The 6-
methoxy-2-aroylquinolines 12 and 15 were prepared starting
from the 6-methoxyquinaldine (25) as shown in the Scheme 2.
The C2-methyl group of 25 was converted into the aldehyde
followed by the treatment with Grignard reagent derived from
3,4,5-trimethoxyphenylmagnesium bromide and pyridinium
dichromate (PDC)-mediated oxidation togivethe 6-methoxy-
2-aroylquinoline 12. Compound 15, with an additional amino
group at the 5-position of the quinoline ring in 12, was
synthesized from the key intermediate 26. Compound 25
was treated with the HNO3/H2SO4-mediated nitration, giving
the 2-methyl-6-methoxy-5-nitroquinoline (26) in 75% yield.
The 5-nitroquinoline 26 was subject to a four-step reaction
sequence, which involved the selenium dioxide-mediated C2-
oxidation, Grignard reaction of 3,4,5-trimethoxyphenylmag-
nesium bromide, PDC-mediated oxidation, and Na2S-medi-
ated reduction, afforded the desired compound 15 (24% yield
from 25). The 8-methoxy-4-aroylquinoline 13 was obtained in
17% yield from commercially available o-anisidine (30)
through a four-step synthesis. Treatment of 30 with methyl
vinyl ketone in AcOH in the presence of ferric chloride and
zinc chloride gave the 4-methylquinoline 31, which on oxida-
tion with selenium dioxide in p-xylene, followed by Grignard
reaction with 3,4,5-trimethoxyphenylmagnesium bromide and
PDC oxidation afforded the desired compound 13 (Scheme 3).
Biological Evaluation. A. In Vitro Cell Growth Inhibitory
Activity. The synthesized aroylquinolines 5-17 were evalu-
ated for antiproliferative activities against oral epidermoid
carcinoma KB cells, non-small-cell lung carcinoma H460
cells, colorectal carcinoma HT29 cells, and stomach carcino-
ma MKN45 cells, as well as the MDR-positive cancer cell line,
KB-vin10 cells, that overexpressed P-gp 170/MDR (Table 1).
First, we evaluated the position effect of aroyl group (3,4,5-
trimethoxybenzoyl) in the quinoline system. The regioisomers

Brief Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 5 2311
Table 1. IC50 Values (nM ( SDa) of Compounds 5-17, and Reference Compounds (3 and 1a)
cell type
(IC50 nM ( SDa)
compd
KB
H460
HT29
MKN45
KB-vin10
5
173.6 ( 33.1
1800 ( 100
3500 ( 700
2900 ( 400
24 ( 6.1
180 ( 25.5
1600 ( 380
3800 ( 520
3800 ( 620
36 ( 5.5
148 ( 17
1000 ( 210
2300 ( 480
2800 ( 310
24.6 ( 3
>10000
4500 ( 1100
77 ( 5.7
162.5 ( 28.7
205.5 ( 4.9
0.4 ( 0.2
872 ( 86.2
>10000
245.5 ( 32.7
562 ( 42
920 ( 90
1200 ( 150
16.3 ( 4.5
>10000
117.3 ( 23.7
1100 ( 220
2200 ( 600
2300 ( 400
21.5 ( 7.7
>10000
6
7
8
9
10
11
12
13
14
15
16
17
3
>10000
>10000
8100 ( 700
27.2 ( 9.8
155 ( 15.1
300.6 ( 64.4
0.3 ( 0.1
5000 ( 920
61.5 ( 20.5
193 ( 35.3
256.5 ( 34.6
0.4 ( 0.3
3200 ( 700
150 ( 31.2
147 ( 25.4
138.5 ( 54.4
0.3 ( 0.2
6000 ( 800
21.5 ( 0.6
165.2 ( 33
202.3 ( 26.2
0.2 ( 0.1
829.5 ( 171.5
>10000
1100 ( 150
>10000
617.3 ( 85
>10000
764 ( 111.1
>10000
12 ( 1.2
2.4 ( 0.2
20.1 ( 3
2.6 ( 0.3
13.2 ( 2.3
835 ( 54
12.4 ( 2
4.9 ( 0.2
128 ( 8
1.9 ( 0.4
1a
a SD: standard deviation. All experiments were independently performed at least three times.
Scheme 3a
gave 6-methoxy-2-aroylquinoline 12 and 8-methoxy-4-ar-
oylquinoline 13, respectively, with increases in cell growth
inhibition ability as compared to the parental compound.
Compound 13 showed over an order of magnitude increase
in activity over the parental compound 7, while 12 showed
improved of IC50 values to double digit nanomolar values in
the KB, H460, HT29, and KB-vin10 cell lines. However, the
addition of a methoxy group at the C-2 position in the
6-aroylquinoline system resulted in a decrease in potency as
compared to the parental compound (14 vs 9). In an effort to
increase the 2-aroylquinolines skeleton’s polarity and acti-
vity, the 5-amino-substituted 2-aroylquinoline 15 was synth-
esized. It exhibited a mean IC50 value of 0.32 nM in all five
cancer cell lines, thus displaying stronger cytotoxicity than
1a. Interestingly, 15 with additional amino group showed
approximately >100-fold improvement in the IC50 value
over its analogue 12 (15 vs 12). To further understand the
underlying structure that give raise to the strong potency of
15, molecular modeling studies of 15, 1a, and 2a were carried
out. Compound 15, 1a, and 2a were docked into the colchi-
cine binding site of tubulin (PDB 1SA0) using Gold (version
4.0) in default mode. Results revealed that the hydrogen-
binding seem play an important role in enhancing the
potency of 15. Compound 15 owned two hydrogen-binding
reactions with the colchicine-binding domain, which were
the 5-amino group of quinoline ring interaction with Thr 179
and the 2-carbonyl moiety of quinoline ring interaction with
Leu 255. However, 1a and 2a had one hydrogen-binding
reaction using their 30-hydroxy and 30-amino group of B-ring
interaction with Val 181 and Thr 179, respectively, thus
providing evidence for the potent activity of 15. (Figure 3)
As the 6-aroylquinoline (9) demonstrated the best cyto-
toxicity stronger the other aroylquinolines, for instance,
2-aroylquinoline (5) and 3-aroylquinoline (6), two N1-sub-
stituted derivatives, 16 and 17, were further prepared. Com-
pound 16 with N-oxide group reduced the activity by >10-
fold magnitude compared with 9 (16 vs 9), but substitution
for N1-methyl group (17) resulted in drastic loss of activity
(17 vs 9), thus revealing that the quaternary salts of alkyl-
quinoline and quinoline N-oxide were not preferred.
aReagents and conditions: (a) ferric chloride, zinc chloride, CH3-
COOH, methyl vinyl ketone, 70 °C-reflux; (b) SeO2, p-xylene, reflux;
(c) (i) 3,4,5- trimethoxyphenylmagnesium bromide, 0-25 °C, (ii) pyridinium
dichromate (PDC), CH2Cl2, molecular sieves, rt.
2-, 3-, 4-, 5-, 6-, 7-, and 8-aroylquinolines (5, 6, 7, 8, 9, 10, and
11, respectively) were evaluated for antiproliferative activity
against five human cancer cell lines. The 3,4,5-trimethoxy-
benzoyl group located at the C-2 and C-6 position on
quinoline ring resulted in the most potent activity with
2-aroylquinoline (5) and 6-aroylquinoline (9) showing mean
IC50 values of 172.8 and 24.4 nM against five cancer cell lines,
respectively. Shifting of the aroyl group to the C-3, C-4, C-5,
or C-8 position resulted in weak cytotoxicity at the μM level,
while shifting to the C-7 position, as in 10, resulted in the loss
of cytotoxicity.
The p-methoxy group substitution in the ring-B of cis-
stilbene (1a)6 and in the 3-benzenesulfonamide of pyridine
(4)7 are important for activity. Thus, we studied the effect of
the addition of the methoxy group in aroylquinolines. The
2-, 4-, and 6-aroylquinolines were modified to introduce a
methoxy group at the opposite site of the 30,40,50-trimethox-
ybenzoyl group to afford 6-methoxy-2-(30,40,50-trimethoxy-
benzoyl)quinoline (12), 8-methoxy-4-(30,40,50-trimethoxybe-
nzoyl)quinoline (13), and 2-methoxy-6-(30,40,50-trimethoxy-
benzoyl)quinoline (14), respectively. All three compounds
showed substantial antiproliferative activity against five can-
cer cell lines with mean IC50 values of 67, 164, and 220 nM,
respectively. Introduction of a methoxy group at the C-6 and
C-8 position of 2-aroylquinoline 5 and 4-aroylquinoline 7,
B. Inhibition of Tubulin Polymerization and Colchicine
Binding Activity. To examine whether aroylquinolines were
microtubule inhibitors acting through the colchicine-binding

2312 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 5
Nien et al.
activity against microtubule assembly than 3 and slightly
superior activity than 1. The SAR information revealed that
the aroyl group (30,40,50-trimethoxybenzoyl moiety) located at
the position 2 and 6 on the quinoline ring significantly
contributed more in activity than in position 3-5 and 7-8
(5 and 9 vs 6, 7, 8, 10, and 11). The addition of a methoxy
group at the C-6 or C-8 position of the 2- and 4-aroylquino-
lines (5and7, respectively) increasedpotency in bothseries(12
and 13), but an additional methoxy group at the C-2 position
of 6-aroylquinoline 9 resulted in a decrease in activity(14vs9).
In summary, 5-amino-6-methoxy-2-aroylquinoline (15) ex-
hibited a strong activity in inhibiting tubulin polymerization
and tumor cell growth with potential for further investigation
as an anticancer agent.
Experimental Section
General Procedure for the Preparation of 2- and 6-Aroylqui-
nolines (9, 12). 6-(30,40,50-Trimethoxybenzoyl)quinoline (9). A
solution of 3,4,5-trimethoxyphenylmagnesium bromide (10 mL,
1.0 M in THF, prepared in advance) was added slowly to the
corresponding6-quinoline-carboxaldehyde (22) (1.57 g, 10 mmol)
in tetrahydrofuran (10 mL) at 0 °C. The reaction mixture was
warmed to room temperature, and stirring was continued for
another 1 h. A saturated NH4Cl solution was slowly added to
hydrolyze the adduct at 0 °C and extracted with EtOAc (15 mL ꢀ
2) and CH2Cl2 (15 mL ꢀ 2). The combined organic extracts was
dried over MgSO4 and evaporated to give a crude residue, which
Figure 3. Superimposition of 15 (orange), 1a (pink), and 2a (gray)
in colchicine binding site of tubule (PDB 1SA0) using Gold 4.0. Red
dotted lines represent hydrogen bond.
Table 2. Inhibition of Tubulin Polymerization and Colchicine Binding
by Compounds 5, 9, 12, 14, 15, and Reference Compounds (1a and 3)
tubulina
colchicine bindingb
IC50 ( SD (μM)
(% ( SD)
1 μM
inhibitor
5 μM
inhibitor
˚
was dissolved in CH2Cl2 (50 mL). Molecular sieves (4 A, 7.52 g)
compd
and pyridinium dichromate (7.52 g, 20 mmol) were added to the
reaction mixture with stirring at room temperature for 16 h. The
reaction mixture was filtered through a pad of celite. The filtrate
was evaporated to give a residue that was purified by silica gel
flash column chromatography (EtOAc:n-hexane = 2:3) and
recrystallized (CH3OH) to afford the desired compound 9, yield
72%; Rf 0.32, mp 132-134 °C. 1H NMR (500 MHz, CDCl3) δ
3.87 (s, 6H), 3.96 (s, 3H), 7.11 (s, 2H), 7.51 (dd, J = 4.3, 8.2 Hz,
1H), 8.13 (d, J = 8.7 Hz, 1H), 8.22 (d, J = 8.7 Hz, 1H), 8.26-8.27
(m, 2H), 9.03-9.04 (m, 1H). MS (EI) m/z: 323 (Mþ, 100%).
HRMS (EI) for C19H17NO4 (Mþ): calcd, 323.1158; found,
5
>10
9
2.9 ( 0.5
3.5 ( 0.6
>10
51 ( 3
40 ( 3
72 ( 3
68 ( 2
12
14
15
3
1.6 ( 0.2
4.2 ( 0.6
2.1 ( 0.3
90 ( 0.5
97 ( 1
1a
87 ( 1
95 ( 2
aInhibition of tubulin polymerization.8 bInhibition of [3H]colchicine
binding.9 Tubulin was at 1 μM; [3H]colchicine was at 5 μM.
323.1153. Anal. (C19H17NO4 0.5H2O) C, H, N.
3
site, the 2-aroylquinoline (5, 12, and 15), 6-aroylquinoline (9
and 14), and reference compounds (1a and 3) were evaluated for
antitubulin activity and the ability to compete for the colchi-
cine-binding site. (Table 2) Compounds 9, 12, and 15 were
effective in inhibiting microtubule assembly with IC50 values of
2.9, 3.5, and 1.6 μM, respectively. Compound 15 showed more
potent antitubulin activity as compared to 1a (IC50 = 2.1 μM)
and 3 (IC50 = 4.2 μM), which positively correlated with its
antiproliferative activity. Unexpectedly, the moderate cytotoxic
compounds 5and 14 did not inhibit microtubule assembly up to
10 μM. Results of the [3H]-colchicine binding assay indicated
that the 5-amino-6-methoxy-(30,40,50-trimethoxybenzoyl)quin-
oline (15) was strongly bound to the colchicine-binding domain
of tubule with binding affinity comparable to 1a.
6-Methoxy-2-(30,40,50-trimethoxybenzoyl)quinoline (12). The
title compound was obtained in 68% overall yield from 3,4,5-
trimethoxyphenylmagnesium bromide and 6-methoxy-2-quino-
linecarboxaldehyde (27) in a similar manner as described for the
preparation of 9; TLC (EtOAc:n-hexane = 3:2), Rf 0.37, mp
143-145 °C. 1H NMR (500 MHz, CDCl3): δ 3.91 (s, 6H), 3.96
(s, 3H), 3.98 (s, 3H), 7.15 (d, J = 2.7 Hz, 1H), 7.44 (dd, J = 4.0,
9.1 Hz, 1H), 7.64 (s, 2H), 8.06-8.12 (m, 1H), 7.96 (d, J = 8.1 Hz,
1H), 8.22 (d, J = 8.5 Hz, 1H). MS (EI) m/z: 353 (Mþ, 100%).
HRMS (EI) for C20H19NO5 (Mþ): calcd, 353.1263; found,
353.1262. Anal. (C20H19NO5) C, H, N.
5-Amino-6-methoxy-2-(30,40,50-trimethoxybenzoyl)quinoline
(15). To a stirred suspension of 29 (0.2 g, 0.5 mmol), sodium
sulfide nonahydrate (0.87 g, 3.61 mmol) and sodium hydroxide
(0.34 g, 8.48 mmol) in ethanol (4 mL) and water (11 mL) was
heated at reflux for 16 h and then left to stand overnight. The
resulting precipitate was collected by filtration and repeatedly
washed with water. Recrystallization from methanol afforded
the desired product 15, yield 78%; TLC (EtOAc:n-hexane =
1:1), Rf 0.33, mp 184.3-185.2 °C. 1H NMR (500 MHz, CDCl3) δ
3.91 (s, 6H), 3.96 (s, 3H), 4.03 (s, 3H), 4.34 (br, 2H), 7.51 (d, J =
9.2 Hz, 1H), 7.64 (s, 2H), 7.69 (d, J = 9.1 Hz, 1H), 8.04 (d, J =
8.8 Hz, 1H), 8.30 (d, J = 8.8 Hz, 1H). MS (EI) m/z: 368 (Mþ,
100%). HRMS (EI) for C20H20N2O5 (Mþ): calcd, 368.1373;
Conclusion
Synthesis and structure-cell inhibitory activity10 studies
for 2-, 3-, 4-, 5-, 6-, 7-, 8-aroylquinolines as anticancer agents
were performed. 2-Aroylquinolines (12, 15) and 6-aroylqui-
nolines (9) were identified as a novel class of potent micro-
tubule inhibitors acting through the colchicine-binding site of
tubulin. The lead compound 5-amino-6-methoxy-2-aroylqui-
noline 15 displayed potent antiproliferative activity, with IC50
values ranging from 0.2 to 0.4 nM in a diverse set of human
cancer cell lines from different organs, including the MDR-
positive resistant cell line (KB-vin 10). It also showed stronger
found, 368.1374. Anal. (C20H20N2O5 0.25H2O) C, H, N.
3
Acknowledgment. We thank Dr. Neeraj Mahindroo of St.
Jude Children’s Research Hospital for his valuable suggestions

Brief Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 5 2313
concerning the manuscript. This research were supported by
the National Science Council of the Republic of China (grant
no. NSC 98-2323-B-038-003, NSC 98-2113-M-038-002-MY2,
and NSC 96-2752-B-400-001-PAE), the Center of Excellence
for Clinical Trial and Research in Neurology and Neurosur-
gery, Taiwan (grant no. DOH-TD-B-111-002), and National
Health Research Institutes, Taiwan (grant no. CA-097-PP-02).
istry Update. Expert. Opin. Ther. Patents 2006, 16, 647–691.
(e) Chaplin, D. J.; Horsman, M. R.; Siemann, D. W. Current Develop-
ment Status of Small-Molecule Vascular Disrupting Agents. Curr.
Opin. Investig. Drugs 2006, 7, 522–528. (f) Romagnoli, R.; Baraldi,
P. G.; Sarkar, T.; Carrion, M. D.; Cara, C. L.; Cruz-Lopez, O.; Preti, D.;
Tabrizi, M. A.; Tolomeo, M.; Grimaudo, S.; Cristina, A. D.; Zonta, N.;
Balzarini, J.; Brancale, A.; Hsieh, H. P.; Hamel, E. Synthesis and
Biological Evaluation of 1-Methyl-2-(30,40,50-trimethoxybenzoyl)-3-
aminoindoles as a New Class of Antimitotic Agents and Tubulin
Inhibitors. J. Med. Chem. 2008, 51, 1464–1468. (g) Liou, J. P.; Wu,
C. Y.; Hsieh, H. P.; Chang, C. Y.; Chen, C. M.; Kuo, C. C.; Chang, J. Y.
4- and 5-Aroylindoles as Novel Classes of Potent Antitubulin Agents.
Supporting Information Available: Spectral data of com-
pounds 5-8, 10-11, 13-14, 16-17, 26-29, and 31-32, experi-
mental procedures for synthesis and biological evaluations, and
elemental analyses. This material is available free of charge via
the Internet at http://pubs.acs.org.
€
J. Med. Chem. 2007, 50, 4548–4552. (h) Prinz, H.; Schmidt, P.; Bohm,
K. J.; Baasner, S.; M€uller, K.; Unger, E.; Gerlach, M.; G€unther, E. G.
10-(2-oxo-2-Phenylethylidene)-10H-anthracen-9-ones as Highly Ac-
tive Antimicrotubule Agents: Synthesis, Antiproliferative Activity, and
Inhibition of Tubulin Polymerization. J. Med. Chem. 2009, 52, 1284–
1294. (i) Liou, J. P.; Wu, Z. Y.; Kuo, C. C.; Chang, C. Y.; Lu, P. Y.; Chen,
C. M.; Hsieh, H. P.; Chang, J. Y. Discovery of 4-Amino and 4-Hydroxy-
1-Aroylindoles as Potent Tubulin Polymerization Inhibitors. J. Med.
Chem. 2008, 51, 4351–4355. (j) Reddy, G. R.; Kuo, C. C.; Tan, U. K.;
Coumar, M. S.; Chang, C. Y.; Chiang, Y. K.; Lai, M. J.; Wu, S. Y.;
Chang, J. Y.; Liou, J. P.; Hsieh, H. P. Synthesis and Structure-
Activity Relationships of 2-Amino and 2-Hydroxy-1-Aroylnaphtha-
lenes as Potent Antitubulin Agents. J. Med. Chem. 2008, 51, 8163–
8167. (k) Simoni, D.; Romagnoli, R.; Baruchello, R.; Rondanin, R.;
Grisolia, G.; Eleopra, M.; Rizzi, M.; Tolomeo, M.; Giannini, G.;
Alloatti, D.; Castorina, M.; Marcellini, M.; Pisano, C. Novel A-Ring
and B-Ring Modified Combretastatin A-4 (CA-4) Analogues Endowed
with Interesting Cytotoxic Activity. J. Med. Chem. 2008, 51, 6211–
6215.
References
(1) Jordan, M. A.; Wilson, L. Microtubules as a Target for Anticancer
Drugs. Nat. Rev. Cancer 2004, 4, 253–265.
(2) (a) Dark, G. G.; Hill, S. A.; Prise, V. E.; Tozer, G. M.; Pettit, G. R.;
Chaplin, D. J. Combretastatin A-4, an Agent that Displays Potent
and Selective Toxicity toward Tumor Vasculature. Cancer Res.
1997, 57, 1829–1834. (b) Hinnen, P.; Eskens, F. A. L. M. Vascular
Disrupting Agents in Clinical Development. Br. J. Cancer 2007, 96,
1159–1165. (c) Lippert, J. W., III. Vascular Disrupting Agents. Bioorg.
Med. Chem. 2007, 15, 605–615. (d) Siemann, D. W. Vascular-Targeted
Therapies in Oncology. John Wiley & Sons: New York, 2006.
(e) Siemann, D. W.; Bibby, M. C.; Dark, G. G.; Dicker, A. P.; Eskens,
F. A. L. M.; Horsman, M. R.; Marme, D.; LoRusso, P. M. Differentiation
and Definition of Vascular-Targeted Therapies. Clin. Cancer Res.
2005, 11, 416–420. (f) Gaya, A. M.; Rustin, G. J. Vascular Disrupting
Agents: a New Class of Drug in Cancer Therapy. Clin. Oncol. 2005, 17,
277–290. (g) Tozer, G. M.; Kanthou, C.; Baguley, B. C. Disrupting
tumour blood vessels. Nat. Rev. Cancer 2005, 5, 423–435.
(h) Patterson, D. M.; Rustin, G. J. S. Vascular Damaging Agents. Clin.
Oncol. 2007, 19, 443–456. (i) Siemann, D. W.; Chaplin, D. J.; Walicke,
P. A. A Review and Update of the Current Status of the Vasculature-
Disabling Agent Combretastatin-A4 Phosphate (CA4P). Expert Opin.
Investig. Drugs 2009, 18, 189–197. (j) Tozer, G. M.; Akerman, S.;
(5) Joule, J. A.; Mills, K.; Smith, G. F. Heterocyclic Chemistry, 3rd ed.;
Chapman & Hall: London, 1995; Chapter 6.
(6) (a) Cushman, M.; Nagarathnam, D.; Gopal, D.; He, H. M.; Lin,
C. M.; Hamel, E. Synthesis and Evaluation of Analogues of (Z)-
1-(4-Methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)ethane as Poten-
tial Cytotoxic and Antimitotic Agents. J. Med. Chem. 1992, 35,
2293–2306. (b) Pettit, G. R.; Toki, B.; Herald, D. L.; Verdier-Pinard, P.;
Boyd, M. R.; Hamel, E.; Pettit, R. K. Antineoplastic Agents. 379.
Synthesis of Phenstatin Phosphate. J. Med. Chem. 1998, 41, 1688–
1695. (c) Cushman, M.; Nagarathnam, D.; Gopal, D.; Chakraborti,
A. K.; Lin, C. M.; Hamel, E. Synthesis and Evaluation of Stilbene and
Dihydrostilbene Derivatives as Potential Anticancer Agents That In-
hibit Tubulin Polymerization. J. Med. Chem. 1991, 34, 2579–2588.
(d) Pettit, G. R.; Anderson, C. R.; Herald, D. L.; Jung, M. K.; Lee, D. J.;
Hamel, E.; Pettit, R. K. Antineoplastic Agents. 487. Synthesis and
Biological Evaluation of the Antineoplastic Agents 3,4-Methylene-
dioxy-5,40-dimethoxy-30-amino-Z-stilbene and Derived Amino Acid
Amides. J. Med. Chem. 2003, 46, 525–531.
(7) Yoshino, H.; Ueda, N.; Niijima, J.; Sugumi, H.; Kotake, Y.;
Koyanagi, N.; Yoshimatsu, K.; Asada, M.; Watanabe, T.; Nagaau,
T.; Tsukahara, K.; Iijima, A.; Kitoh, K. Novel Sulfonamides as
Potential, Systemically Active Antitumor Agents. J. Med. Chem.
1992, 35, 2496–2497.
(8) Liou, J. P.; Hsu, K. S.; Kuo, C. C.; Chang, C. Y.; Chang, J. Y. A
Novel Oral Indoline-Sulfonamide Agent, J30, Exhibits Potent
Activity against Human Cancer Cells in Vitro and in Vivo through
the Disruption of Microtubule. J. Pharmacol. Exp. Ther. 2007, 323,
398–405.
€
Cross, N. A.; Barber, P. R.; Bjorndahl, M. A.; Greco, O.; Harris, S.; Hill,
S. A.; Honess, D. J.; Ireson, C. R.; Pettyjohn, K. L.; Prise, V. E.; Reyes-
Aldasoro, C. C. Blood Vessel Maturation and Response to Vascular-
Disrupting Therapy in Single Vascular Endothelial Growth Factor-A
Isoform-Producing Tumors. Cancer Res. 2008, 68, 2301–2311.
(3) (a) Mauer, A. M.; Cohen, E. E.; Ma, P. C.; Kozloff, M. F.;
Schwartzberg, L.; Coates, A. I.; Qian, J.; Hagey, A. E.; Gordon,
G. B. A Phase II Study of ABT-751 in Patients with Advanced
Non-small Cell Lung Cancer. J. Thorac. Oncol. 2008, 3, 631–636.
(b) Fox, E.; Maris, J. M.; Widemann, B. C.; Goodspeed, W.; Goodwin,
A.; Kromplewski, M.; Fouts, M. E.; Medina, D.; Cohn, S. L.; Krivoshik,
A.; Hagey, A. E.; Adamson, P. C.; Balis, F. M. A Phase I Study of ABT-
751, an Orally Bioavailable Tubulin Inhibitor, Administered Daily for
21 Days Every 28 Days in Pediatric Patients with Solid Tumors. Clin.
Cancer Res. 2008, 14, 1111–1115.
(4) (a) Tron, G. C.; Pirali, T.; Sorba, G.; Pagliai, F.; Busacca, S.;
Genazzani, A. A. Medicinal Chemistry of Combretastatin A4:
Present and Future Directions. J. Med. Chem. 2006, 49, 3033–
3044. (b) Hsieh, H. P.; Liou, J. P.; Mahindroo, N. Pharmaceutical
Design of Antimitotic Agents Based on Combretastatins. Curr. Pharm.
Des. 2005, 11, 1655–1677. (c) Li, Q.; Sham, H. L. Discovery and
Development of Antimitotic Agents That Inhibit Tubulin Polymerisa-
tion for the Treatment of Cancer. Expert Opin. Ther. Patents 2002, 12,
1663–1702. (d) Mahindroo, N; Liou, J. P.; Chang, J. Y.; Hsieh, H. P.
Antitubulin Agents for the Treatment of Cancer—A Medicinal Chem-
(9) Kuo, C. C.; Hsieh, H. P.; Pan, W. Y.; Chen, C. P.; Liou, J. P.; Lee,
S. J.; Chang, Y. L.; Chen, L. T.; Chang, J. Y. BPR0L075, a Novel
Synthetic Indole Compound with Antitumoral Activity in Vivo.
Cancer Res. 2004, 64, 4621–4628.
(10) Because the form of evaluations involves more than binding to the
receptor or target, for example, transport and solubility, we use
this term, structure-cell inhibitory activity, instead of structure-
activity relationship.