Application of Suzuki arylation, Sonogashira ethynylation and Rosenmund-von Braun cyanation in the exploration of substitution effects on the anticancer activity of 2-aroylquinolines

Article abstract of DOI:10.1039/c2ob26614h

A variety of functionalities were introduced at 2-aroylquinoline's C5 position, which is considered equivalent to C-3′ of the B-ring of CA4, via Suzuki arylation, Sonogashira ethynylation, and Rosenmund-von Braun cyanation. These substitutions are rarely

Full text of DOI:10.1039/c2ob26614h

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Organic &
Biomolecular
Chemistry
PAPER
Application of Suzuki arylation, Sonogashira
ethynylation and Rosenmund–von Braun cyanation in
the exploration of substitution effects on the
anticancer activity of 2-aroylquinolines†
Cite this: Org. Biomol. Chem., 2012, 10,
9593
Hsueh-Yun Lee,a Lin-Wen Lee,b Chih-Ying Nien,a Ching-Chuan Kuo,c Pen-Yuan Lin,a
Chi-Yen Chang,c Jang-Yang Chang*c,d and Jing-Ping Liou*a
A variety of functionalities were introduced at 2-aroylquinoline’s C5 position, which is considered equi-
valent to C-3’ of the B-ring of CA4, via Suzuki arylation, Sonogashira ethynylation, and Rosenmund–von
Braun cyanation. These substitutions are rarely utilized in the modification of 3’-OH of CA4. The resulting
products 6 and 7 having cyano and ethynyl groups exhibited comparable antiproliferative and tubulin
inhibitory activities to colchicine.
Received 15th August 2012,
Accepted 22nd October 2012
DOI: 10.1039/c2ob26614h
www.rsc.org/obc
also modified by a variety of bridging groups, such as
Introduction
sulfide,10 amine,11 –X– (bond),12 sulfonamide,13 etc. In this
In the realm of discovering antimitotic agents, CA4 and colchi- decade, we have made lots of efforts towards the development
cine are regarded as significant structural templates for disco- of antimitotic agents based on the characteristic classification
vering novel scaffolds. Colchicine (1) and combretastatin A-4 of modifications of CA4 (Fig. 2). For instance, 3,4,5-14 and
(CA4, 2) are identified as potent anticancer agents inhibiting 4,5,6-trimethoxyindoles,15 which exhibited potent antitubulin
the dynamics of tubulin polymerization. The concise structure activity, were considered as surrogates of the A-ring in our pre-
of CA4 has attracted a number of scientific efforts on the vious study. 3-Aroyl-6-methoxyindoles16 and 2-aroyl-6-methoxy-
development of antimitotic agents.1 For instance, compound 4 quinolines17 were identified as possessing potent antitubulin
having the 3′-OH replaced with 3′-NH2 exhibited potent anti- activity, and 6-OMe-indole and 6-OMe-quinoline were recog-
tubulin activity.2 Notably, prodrugs of CA4 (CA4P) and 4 nized as replacements of ring B. Further investigation of the
(AVE8062) are currently undergoing clinical trials.3 Scientific bridging part revealed that sulfone and carbonyl linkages are
attention to the development of combretastatin derivatives is favored to mimic the cis double bond part in a series of
subdivided into study of three parts: A-ring, B-ring, and the cis 5-amino-2-aroylquinolines.18 In addition to these three places
double bond.4 Regarding the modification of ring A, it is well of modification cited above, the 3′-OH of B-ring is commonly
know that the 3,4,5-trimethoxybenzene ring is significant for replaced with amino groups and halogens, which were applied
antitubulin activity. Heterocyclic rings, including imidazole,5 in our previous work as well.18 However, literature survey indi-
triazole,6 lactam,7 isoxazoline/isoxazole or pyridine,8 or isoxa- cated that examples replacing the C3′-OH with aryl, ethynyl or
zole and imidazole,9 were comprehensively utilized to main- cyano groups are few. Therefore, this study focuses on functio-
tain the Z geometry. In addition, the (Z)-stilbene geometry was nalization at C5 position by using cyano, ethynyl, and various
aryl groups (Fig. 1).
Organometallic chemistry has been comprehensively
aSchool of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wuxing
applied in the area of medicinal chemistry including for
scaffold construction and functionalization.19 In addition, our
Street, Taipei 11031, Taiwan, Republic of China. E-mail: jpl@tmu.edu.tw;
Tel: +886-2-27361661
previous efforts on the utilization of Ullmann-type arylation
bDepartment of Microbiology and Immunology, Taipei Medical University, Taipei,
achieved functionalization at the N1 position of 5,6,7-tri-
Taiwan, Republic of China
cNational Institute of Cancer Research, National Health Research Institutes, Tainan
methoxyindole as well. The introduction of various aryl groups
at the C7 position of indoline-1-benzenesulfonamides via
Suzuki reactions resulted in the finding of potent anticancer
agents.20 This experience encouraged us to apply various
organometallic reactions for advanced structure–activity
relationship investigation at the C5 position of 2-aroyl-
704, Taiwan, Republic of China
dDivision of Hematology/Oncology, Department of Internal Medicine, National Cheng
Kung University Hospital, Tainan 704, Taiwan, Republic of China
†Electronic supplementary information (ESI) available: Spectral data of
compounds 6–16 and HPLC purity data for compounds 6–16. See DOI:
10.1039/c2ob26614h
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Scheme 1 Synthetic route to 5-substituted 6-methoxyquinolines (6, 8–11, and
13): a. for 6: CuCN, DMF, 120 °C, 45%; for 9: 2-methyl-3-butyn-2-ol, Pd(PPh3)4,
diisopropylamine, 1,4-dioxane, reflux, 43%; for 10, 11, and 13: boronic acids, Pd-
(PPh3)4, 2 M K2CO3(aq), toluene, microwave, 180 °C; b. KOH, CH3OH, reflux, 37%.
Fig. 1 Natural antimitotic agents and their derivatives and synthetic 5-substi-
tuted 6-methoxyquinolines.
Scheme 2 Synthetic route to 5-substituted 6-methoxyquinolines (7, 12, and
14–16): a. boronic acids, Pd(PPh3)4, diisopropylamine, 1,4-dioxane, reflux; for
23: trimethylsilylacetylene, Pd(PPh3)4, diisopropylamine, 1,4-dioxane, reflux;
b. selenium dioxide (SeO2), p-xylene, reflux; c. i. 3,4,5-trimethoxyphenylmagne-
sium bromide, 0 °C to rt; ii. pyridinium dichromate (PDC), CH2Cl2, molecular
sieves, rt; d K2CO3, CH3OH, rt, 95%.
Fig. 2 Diagram showing previous efforts on the modification of the A-, B-ring,
cis-stilbene, and 3’-OH.
nitrile 6, which was subsequently hydrolyzed to provide the
corresponding carboxamide 8 in 37% yield. The treatment of
17 with 2-methyl-3-butyn-2-ol under Sonogashira conditions
yielded 9 in 43% yield. The starting material 17 was reacted
with 4-hydroxyphenylboronic acid, pyridine-4-boronic acid,
and 4-cyanophenylboronic acid under Suzuki conditions with
the aid of microwave irradiation to afford 10, 11, and 13,
respectively. Scheme 2 summarizes the synthesis of 7, 12, and
14–16. Compound 18 was reacted with a variety of boronic
acids under Suzuki conditions to furnish 19–22, and 23 was
afforded by the reaction of 18 with trimethylsilylacetylene
under Sonogashira conditions. The following benzylic oxi-
dation was carried out by selenium dioxide (SeO2) to obtain
the corresponding aldehydes 24–28. The removal of the tri-
methylsilane group of 28 took place in the presence of K2CO3
and methanol, yielding 29 in 95% yield. These resulting alde-
hydes were reacted with 3,4,5-trimethoxymagnesium bromide
followed by the oxidation carried out by pyridinium dichro-
mate (PDC) to afford 7, 12, and 14–16.
6-methoxyquinolines. In this study, we would like to introduce
several groups such as ethynyl, cyano, and various aryl groups
(6–16). The aim of this study would be fulfilled by utilizing
several sorts of organometallic reactions, such as Suzuki aryla-
tion, Sonogashira ethynylation, and Rosenmund–von Braun
cyanation. These reactions have been widely applied in the
realm of medicinal chemistry and, therefore, are expected to
widen the diversity of our designed structures.
Chemistry
Schemes 1 and 2 illustrate the synthesis of designed 5-substi-
tuted 2-3′,4′,5′-trimethoxybenzoyl-6-methoxyquinolines (6–16).
Scheme 1 outlines the synthesis of 6, 8–11, and 13. Reaction of
copper(I) cyanide with 17,18 also known as the Rosenmund–
von Braun reaction,21 achieved the preparation of aromatic
9594 | Org. Biomol. Chem., 2012, 10, 9593–9600
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activity. In addition, both 3-hydroxy-3-methylbutyn-1-yl (9) and
4-pyridinyl (10) groups caused a decrease in the antiprolifera-
tive activity, which is brought down to the three-digit nano-
Biological evaluation
A. In vitro cell growth inhibitory activity
With the aim of exploring the effect of C-5 substitution on molar range. Aryl substitutions (11–16) led to dramatic loss of
their cancer cell inhibitory ability, all synthetic compounds cytotoxic activity, indicating that aryl substitutions at the C-5
(6–16), along with reference compound colchicine, were evalu- position are detrimental to cytotoxic activity. In brief, the C-5
ated for their antiproliferative activities against three human position of 2-aroyl-6-methoxyquinoline favors cyano and
cancer cell lines, cervical carcinoma KB cells, colorectal carci- ethynyl groups in this study, which is seldom discussed and is
noma HT29 cells, and stomach carcinoma MKN45 cells the first finding on the modification of the 3′-OH of B-ring.
(Table 1).
The heteroatom within the triple bond contributed to the
Briefly, the results indicate that replacement at the C-5 pos- improvement of biological activity. To improve our under-
ition with a smaller substituent is favored. Compounds 6 and standing of their efficacy against drug-resistant cell lines, com-
7 exhibited remarkable antiproliferative activity among all the pounds 6 and 7 were evaluated for antiproliferative activity
synthetic molecules, with IC50 values in the two-digit nano- against a variety of resistant cell lines as shown in Table 2.
molar range. 6 possessing a cyano group showed comparable Despite the high level of expression of drug-resistant efflux
anticancer activity to colchicine, with the exception of in the protein (MDR/P-gp or MRP) in KB-Vin10, KB-S15, and KB-7D
HT29 cancer cell line. It inhibited the growth of KB, HT29, and cells, compounds 6 and 7 showed similar cytotoxic efficacy
MKN45 cells with IC50 values of 17.2, 49.6, and 23.4 nM, between parental cells and these resistant cell lines.
respectively. In a comparison of 6 with previously synthesized
2-aroyl-6-methoxyquinolines, the order of influence of the C-5
substitution on the antiproliferative activity is as follows: –NH2
(IC50 = 0.3 nM) > –OH (IC50 = 3.46 nM) > –CN (IC50 = 30.06 nM)
> halogen (IC50 = >50 nM).18 The replacement of nitrogen (6)
with carbon (7) at the terminal end of the triple bond led to a
2-fold decrease of activity. The conversion of cyano (6) to
aminocarbonyl (8) resulted in a remarkable loss of cellular
B. Inhibition of tubulin polymerization and colchicine
binding activity
Compounds 6, 7, and reference compounds colchicine and
CA4 were evaluated for antitubulin activity as well as colchicine
binding activity (Table 3). The results of tubulin inhibitory
activity indicated that the introduction of cyano (6) and
ethynyl (7) groups contributed activity comparable to colchi-
cine, but a 2-fold decrease in activity when compared with
CA4. The binding affinities of 6 and 7 to the colchicine
binding site are respectively 47% and 44%, which are 2-fold
weaker than CA4 (90%). As shown in Fig. 3, 6 and 7 inhibited
polymerization of pure MAP-rich tubulins in a concentration-
dependent manner and disrupted tubulin assembly almost
Table 1 IC50 values (nM SDa) of compounds 6–16 and colchicine
Cell type (IC50 SDa nM)
Compd
KB
HT29
MKN45
6
17.2 3.2
37.5 15.4
>10 000
495.7 43.7
472.0 190.8
>10 000
>10 000
4892.4 2919.7
5516.8
2404.8 447.3
>10 000
10.3 0.9
49.6 29.9
92.2 27.3
>10 000
23.4 6.4
7
41.3 4.0
Table 3 Inhibition of tubulin polymerization and colchicine binding by com-
pounds 6, 7, colchicine and CA4
8
9
>10 000
758.3 163.9
937.2 130.6
>10 000
468.0 15.0
451.1 28.4
>10 000
10
Compd
Tubulina IC50 SD (μM) Colchicine bindingb (% SD)
11
12
>10 000
>10 000
6
7
4.5
3.5
47
44
13
>10 000
7263.2 1346.1
9108.6 2499.9
7708.5 1423.3
>10 000
14
9809.4
Colchicine 4.5
CA4 1.9
15
>10 000
90
16
>10 000
Colchicine
16.2 2.9
19.2 1.0
a Inhibition of tubulin polymerization.24 b Inhibition of [3H]
colchicine binding.17 Tubulin was at 1 μM; both [3H]colchicine
and inhibitor were at 5 μM.
a SD: standard deviation. All experiments were independently
performed at least three times.
Table 2 Growth inhibition of compounds 6 and 7 against drug-resistant cell lines
IC50 SDa
Cell lines
Resistant type
Vincristineb
Paclitaxelb
3.3 1.2 nM
VP-16b
CA4c
6
7
KB
Parental
MDR ↑
MDR ↑
MRP ↑
0.4 0.1 nM
90.1 7.4 nM
17.6 2.2 nM
1.2 0.4 nM
1.1 0.5 μM
23 3 μM
3.5 0.3 μM
54 3.5 μM
1.5 0.4 nM
17.2 3.2 nM
29.9 9.4 nM
18.8 6.5 nM
21.9 16.6 nM
37.5 15.4 nM
38.3 3.9 nM
31.9 7.9 nM
36.7 2.1 nM
KB-VIN10
KB-S15
KB-7D
1650 0 707 nM
273 15 nM
1.5 0.4 nM
—
—
7.9 0.5 nM
a SD: standard deviation. All experiments were independently performed at least three times. b Data from ref. 22. c Data from ref. 23.
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colchicine binding site affinity indicated that 6 and 7 likely
interact with tubulin at an alternative binding site. In
summary, the conversion of –OH, –NH2, and halogens into
cyano and ethynyl groups maintains the antiproliferative and
antitubulin activities, but changes the manner of the inter-
action with tubulin.
Experiments
(A) Chemistry
GENERAL INFORMATION. Nuclear magnetic resonance (1H and
13C NMR) spectra were obtained with a Bruker DRX-500 spec-
trometer, with chemical shift in parts per million (ppm, δ)
downfield from TMS as an internal standard. Infrared spectra
were measured on a Spectrum Two FT-IR Spectrometer; values
are expressed in wavenumbers (cm−1). 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). All reactions were carried out
under an atmosphere of dry nitrogen.
5-CYANO-6-METHOXY-2-(3′,4′,5′-TRIMETHOXYBENZOYL)QUINOLINE (6). A
mixture of 17 (0.20 g, 0.46 mmol), CuCN (0.08 g, 0.93 mmol),
and DMF (3 mL) was stirred at 120 °C for 17 h. The reaction
mixture was cooled to room temperature, triturated with ethyl
acetate, filtered through silica, concentrated in vacuum, and
the product was purified by silica gel flash column chromato-
graphy (EtOAc : n-hexane = 1 : 2) to afford compound 6, yield
45%; mp 191–192 °C. IR (cm−1): 2225, 2842, 2931. 1H NMR
(500 MHz, CDCl3): δ 3.90 (s, 6H), 3.97 (s, 3H), 4.14 (s, 3H), 7.56
(s, 2H), 7.59 (d, J = 9.4 Hz, 1H), 8.25 (d, J = 8.7 Hz, 1H), 8.39 (d,
J = 9.4 Hz, 1H), 8.58 (d, J = 8.7 Hz, 1H). MS (EI) m/z: 378
(100%). 13C NMR (75 MHz, CDCl3): 56.23, 57.00, 60.97, 95.14,
109.00, 114.27, 116.28, 123.71, 129.93, 130.62, 133.34, 137.41,
141.18, 141.89, 152.71, 154.03, 162.82, 191.35. HRMS (EI) for
C21H18N2O5 (M+): calcd, 378.1216; found, 378.1216.
Fig. 3 Effect of compounds 6 and 7 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 6 and 7). The absorbance at 350 nm was measured every 30 s for
30 min and is presented as the increased polymerized microtubule.
completely at 10.0 μM. The comparable antiproliferative and
tubulin inhibitory activities to colchicine demonstrated that 6
and 7 cause the death of cancer cells through ruining the
dynamic of tubulin polymerization. However, the slight colchi-
cine binding site affinity revealed that 6 and 7 may bind to an
alternative binding site of tubulin. Whether this inconsistency
between potent tubulin inhibition and ambiguous colchicine
binding site affinity is owing to the introduction of cyano and
ethynyl groups requires further investigation.
5-ETHYNYL-6-METHOXY-2-(3′,4′,5′-TRIMETHOXYBENZOYL)QUINOLINE (7).
solution of 3,4,5-trimethoxyphenylmagnesium bromide
Conclusions
A
Functionalization at the C5 position of 2-(3′,4′,5′-trimethoxy)- (1.6 mL, 1.0 M in THF, prepared in advance) was added slowly
benzoyl-6-methoxyquinoline by exploiting Suzuki, Sonoga- to a solution of compound 29 (0.33 g, 1.6 mmol) in THF
shira, and Rosenmund–von Braun cyanation reactions broad- (2.5 mL) at 0 °C. The reaction mixture was warmed to room
ens the diversity of C5 substitutions mimicking the C3′-OH of temperature and stirred for additional 16 hours. A saturated
the B-ring of CA4. As a consequence, a series of 5-cyano-, NH4Cl solution was slowly added at 0 °C and extracted with
5-ethynyl-, and 5-aryl-2-aroylquinolines (6–16) were developed EtOAc (2 × 15 mL) and CH2Cl2 (2 × 15 mL). The combined
and a set of biological activities evaluated. The biological organic extract was dried over MgSO4 and evaporated to give a
results indicated that compounds possessing cyano (6) and crude residue. To the residue was added molecular sieves (4 Å,
ethynyl (7) groups exhibited comparable antiproliferative 0.60 g), pyridinium dichromate (0.72 g, 1.92 mmol) and
activity to colchicine with mean IC50 values of 30 and 57 nM CH2Cl2 (50 mL), and stirred at room temperature for 16 hours.
against KB, HT29, and MKN45 cancer cell lines. In addition to The reaction mixture was filtered through a pad of Celite and
anticancer activity, 6 and 7 exhibited comparable tubulin the filtrate was purified by column chromatography to afford
1
polymerization inhibitory activity to colchicine. The inconsis- 7, yield 32%; mp 204–205 °C. IR (cm−1): 2842, 2937, 3243. H
tency of the tubulin polymerization inhibitory ability with the NMR (500 MHz, CDCl3): δ 3.78 (s, 1H), 3.90 (s, 6H), 3.96 (s,
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3H), 4.11 (s, 3H), 7.55 (d, J = 9.0 Hz, 1H), 7.59 (s, 2H), 8.16 (d, and toluene (3 mL). The vessel was sealed and placed into the
J = 9.0 Hz, 1H), 8.20 (d, J = 9.0 Hz, 1H), 8.73 (d, J = 8.5 Hz, 1H). microwave cavity. The reaction mixture was held at 180 °C for
13C NMR (75 MHz, CDCl3): 56.19, 56.71, 60.91, 76.67, 81.34, 10 min. After it was cooled to room temperature, the mixture
104.89, 109.06, 116.35, 122.21, 130.82, 130.97, 133.01, 134.43, was poured into water and then extracted with EtOAc and
141.57, 142.64, 152.63, 153.22, 161.04, 191.82. MS (EI) m/z: 377 NaHCO3(aq). The organic layers were combined and evaporated
(M+, 1.3%), 195 (100%). HRMS (EI) for C22H19NO5 (M+): calcd, to give a residue which was purified by flash chromatography
377.1263; found, 377.1263.
(EtOAc : n-hexane = 1 : 4) to afford compound, yield 65%; mp
1
6-METHOXY-2-(3′,4′,5′-TRIMETHOXYBENZOYL)QUINOLINE-5-CARBOXAMIDE 201–203 °C. H NMR (500 MHz, DMSO): δ 3.79 (s, 3H), 3.82 (s,
(8). Compound 6 (0.3 g, 0.79 mmol) and KOH (0.22 g, 6H), 3.86 (s, 3H), 6.90 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.4 Hz,
3.95 mmol) were dissolved in MeOH (4 mL) in a sealed tube. 2H), 7.55 (s, 2H), 7.85 (d, J = 9.3 Hz, 1H), 7.94 (d, J = 8.9 Hz,
The mixture was then heated at 65 °C for 18 hours. The result- 1H), 8.01 (d, J = 8.9 Hz, 1H), 8.19 (d, J = 9.3 Hz, 1H), 9.60 (s,
ing solution was poured into 15 mL of water and extracted 1H). MS (EI) m/z: 445 (100%). HRMS (EI) for C26H23NO6 (M+):
three times with EtOAc. The organic layers were combined and calcd, 445.1525; found, 445.1526.
evaporated to give a residue which was purified by silica gel
6-METHOXY-5-(4′′-METHOXYPHENYL)-2-(3′,4′,5′-TRIMETHOXYBENZOYL)-
flash column chromatography (CH3OH : CH2Cl2 = 1 : 49) to QUINOLINE (12). The title compound was obtained in 73%
afford compound 8, yield 37%; mp 262–263 °C. 1H NMR overall yield from 24 in a similar manner as described for the
(500 MHz, CDCl3 + CD3OD): δ 3.83 (s, 6H), 3.90 (s, 3H), 4.01 (s, preparation of 7; mp 177–179 °C. 1H NMR (500 MHz, CDCl3): δ
3H), 7.47 (s, 2H), 7.55 (d, J = 9.5 Hz, 1H), 8.02 (d, J = 9.0 Hz, 3.90 (s, 3H), 3.92 (s, 9H), 3.97 (s, 3H), 7.07 (d, J = 8.5 Hz, 2H),
1H), 8.20 (d, J = 9.0 Hz, 1H), 8.63 (d, J = 9.0 Hz, 1H). MS (EI) 7.30 (d, J = 8.5 Hz, 2H), 7.64–7.65 (m, 3H), 7.97 (d, J = 9.5 Hz,
m/z: 396 (M+, 75%), 195 (100%). HRMS (EI) for C21H20N2O6 1H), 8.08 (d, J = 9.0 Hz, 1H), 8.22 (d, J = 9.0 Hz, 1H). 13C NMR
(M+): calcd, 396.1321; found, 396.1323.
(75 MHz, CDCl3): 55.22, 56.17, 56.55, 60.91, 109.06, 113.86,
5-(3′′-HYDROXY-3′′-METHYLBUT-1′′-YNYL)-6-METHOXY-2-(3′,4′,5′-TRI- 117.14, 121.04, 124.48, 126.55, 129.53, 131.14, 131.94, 134.55,
METHOXYBENZOYL)QUINOLINE (9). A mixture of 17 (0.10 g, 142.03, 142.46, 152.39, 152.59, 155.45, 159.01, 192.06. MS (EI)
0.23 mmol), tetrakis(triphenylphosphine)palladium (0.03 g, m/z: 459 (M+, 12%), 105 (100%). HRMS (EI) for C27H25NO6
0.03 mmol), 2-methyl-3-butyn-2-ol (0.27 mL, 2.73 mmol), diiso- (M+): calcd, 459.1682; found, 459.1681.
propylamine (0.42 mL), and 1,4-dioxane (2 mL) was refluxed
5-(4′′-CYANOPHENYL)-6-METHOXY-2-(3′,4′,5′-TRIMETHOXYBENZOYL)-
for 16 hours under nitrogen. The reaction mixture was concen- QUINOLINE (13). The title compound was obtained in 47%
trated in vacuum, and the residue was extracted with CH2Cl2. overall yield from 4-cyanophenylboronic acid and 17 in a
The organic layers were combined and evaporated to give a similar manner as described for the preparation of 11; mp
1
residue which was purified by flash chromatography (EtOAc : 209–211 °C. H NMR (500 MHz, CDCl3): δ 3.91 (s, 6H), 3.92 (s,
n-hexane
= 1 : 1) to give the solids 9, yield 43%; mp 3H), 3.97 (s, 3H), 7.50 (d, J = 8.0 Hz, 2H), 7.63 (s, 2H), 7.66 (d,
1
151–153 °C. H NMR (500 MHz, CDCl3): δ 1.76 (s, 6H), 3.90 (s, J = 9.5 Hz, 1H), 7.82 (d, J = 8.0 Hz, 2H), 7.92 (d, J = 9.0 Hz, 1H),
6H), 3.96 (s, 3H), 4.07 (s, 3H), 7.53 (d, J = 9.3 Hz, 1H), 7.60 (s, 8.00 (d, J = 9.0 Hz, 1H), 8.28 (d, J = 9.5 Hz, 1H). 13C NMR
2H), 8.14 (d, J = 8.0 Hz, 1H), 8.16 (d, J = 7.5 Hz, 1H), 8.65 (d, (75 MHz, CDCl3): 56.19, 56.47, 60.93, 109.10, 111.57, 116.86,
J = 8.7 Hz, 1H). 13C NMR (75 MHz, CDCl3): 31.63, 56.21, 56.69, 118.78, 121.66, 122.51, 128.57, 130.93, 131.86, 132.16, 132.49,
60.93, 65.97, 76.57, 104.42, 105.66, 109.10, 116.58, 121.99, 133.54, 139.90, 141.88, 142.66, 152.65, 152.75, 155.20, 191.74.
130.48, 131.03, 132.38, 134.43, 141.67, 142.66, 152.64, 153.10, MS (EI) m/z: 454 (M+, 98%), 195 (100%). HRMS (EI) for
160.11, 191.86. MS (EI) m/z: 435 (100%). HRMS (EI) for C27H22N2O5 (M+): calcd, 454.1529; found, 454.1527.
C25H25NO6 (M+): calcd, 435.1682; found, 435.1681.
5-(4′′-FLUOROPHENYL)-6-METHOXY-2-(3′,4′,5′-TRIMETHOXYBENZOYL)QUINO-
6-METHOXY-5-PYRIDINYL-2-(3′,4′,5′-TRIMETHOXYBENZOYL)QUINOLINE (10). LINE (14). The title compound was obtained in 53% overall
The title compound was obtained in 68% overall yield from yield from 25 in a similar manner as described for the prep-
pyridine-4-boronic acid and 17 in a similar manner as aration of 7; mp 172–174 °C. 1H NMR (500 MHz, CDCl3): δ
1
described for the preparation of 11; mp 203–205 °C. H NMR 3.92 (s, 9H), 3.97 (s, 3H), 7.21–7.25 (m, 2H), 7.32–7.35 (m, 2H),
(500 MHz, DMSO): δ 3.80 (s, 3H), 3.82 (s, 6H), 3.91 (s, 3H), 7.41 7.64 (s, 2H), 7.65 (d, J = 9.5 Hz, 1H), 7.98 (d, J = 8.5 Hz, 1H),
(d, J = 5.5 Hz, 2H), 7.55 (s, 2H), 7.91–7.99 (m, 3H), 8.30 (d, J = 8.01 (d, J = 9.0 Hz, 1H), 8.24 (d, J = 9.0 Hz, 1H). 13C NMR
9.0 Hz, 1H), 8.73 (d, J = 5.5 Hz, 2H,). 13C NMR (75 MHz, (75 MHz, CDCl3): 56.16, 56.49, 60.91, 109.06, 115.32, 115.60,
CDCl3): 56.23, 56.51, 60.97, 109.16, 116.94, 121.72, 121.76, 117.02, 121.27, 123.59, 129.28, 130.35, 130.38, 131.05, 131.62,
126.08, 128.39, 130.99, 132.55, 133.62, 141.91, 142.72, 143.21, 132.44, 132.55, 134.15, 141.93, 142.52, 152.51, 152.61, 191.94.
149.97, 152.69, 152.83, 155.18, 191.82. MS (EI) m/z: 430 MS (EI) m/z: 447 (100%). HRMS (EI) for C26H22FNO5 (M+):
(100%). HRMS (EI) for C25H22N2O5 (M+): calcd, 430.1529; calcd, 447.1482; found, 447.1484.
found, 430.1529.
5-(3′′,4′′-DIFLUOROPHENYL)-6-METHOXY-2-(3′,4′,5′-TRIMETHOXYBENZOYL)-
5-(4′′-HYDROXYPHENYL)-6-METHOXY-2-(3′,4′,5′-TRIMETHOXYBENZOYL)- QUINOLINE (15). The title compound was obtained in 65% overall
QUINOLINE (11). In a 10 mL glass tube were placed a magnetic yield from 26 in a similar manner as described for the prep-
stir bar, 17 (0.10 g, 0.23 mmol), 4-hydroxyphenylboronic acid aration of 7; mp 184–185 °C. 1H NMR (500 MHz, CDCl3): δ
(0.19 g, 1.18 mmol), tetrakis(triphenylphosphine)palladium 3.92 (s, 6H), 3.93 (s, 3H), 3.97 (s, 3H), 7.07–7.09 (m, 1H),
(0.02 g, 0.02 mmol) and 2 M potassium carbonate (0.64 mL) 7.18–0.22 (m, 1H), 7.29–0.34 (m, 1H), 7.63–7.66 (m, 3H), 8.00
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(s, 2H), 8.26 (d, J = 9.5 Hz, 1H). 13C NMR (75 MHz, CDCl3): was heated to reflux and stirred for 5 hours. The reaction
56.13, 56.41, 60.85, 109.06, 116.86, 117.13, 117.35, 119.86, mixture was filtered through a pad of Celite. The filtrate was
120.09, 121.44, 122.32, 127.03, 127.09, 127.16, 128.94, 130.97, evaporated to give a residue which was purified by silica gel
131.29, 131.35, 131.43, 132.04, 133.76, 141.81, 142.58, 152.59, flash column chromatography (EtOAc : n-hexane = 1 : 2) to
1
155.34, 191.72. MS (EI) m/z: 465 (100%). HRMS (EI) for afford compound 24, yield 61%. H NMR (500 MHz, CDCl3): δ
C26H21F2NO5 (M+): calcd, 465.1388; found, 465.139.
3.90 (s, 3H), 3.93 (s, 3H), 7.06 (d, J = 8.5 Hz, 2H), 7.27 (d, J =
6-METHOXY-5-(4′′-NITROPHENYL)-2-(3′,4′,5′-TRIMETHOXYBENZOYL)QUINO- 8.5 Hz, 2H), 7.68 (d, J = 9.5 Hz, 1H), 7.87 (d, J = 8.5 Hz, 1H),
LINE (16). The title compound was obtained in 57% overall 8.03 (d, J = 9.0 Hz, 1H), 8.29 (d, J = 9.5 Hz, 1H), 10.20 (s, 1H).
yield from 27 in a similar manner as described for the prep-
5-(4′-FLUOROPHENYL)-6-METHOXYQUINOLINE-2-CARBOXALDEHYDE (25).
aration of 7; mp 207–208 °C. 1H NMR (500 MHz, CDCl3): δ The title compound was obtained in 78% overall yield from 20
1
3.92 (s, 6H), 3.94 (s, 3H), 3.97 (s, 3H), 7.57 (d, J = 8.5 Hz, 2H), in a similar manner as described for the preparation of 24. H
7.63 (s, 2H), 7.68 (d, J = 9.5 Hz, 1H), 7.94 (d, J = 8.5 Hz, 1H), NMR (500 MHz, CDCl3): δ 3.93 (s, 3H), 7.21 (t, J = 8.5 Hz, 2H),
8.01 (d, J = 9.0 Hz, 1H), 8.30 (d, J = 9.5 Hz, 1H), 8.40 (d, J = 8.5 7.30 (dd, J = 3.0, 5.5 Hz, 2H), 7.68 (d, J = 9.0 Hz, 1H), 7.88 (d,
Hz, 2H). 13C NMR (75 MHz, CDCl3): 56.17, 56.45, 60.91, J = 9.0 Hz, 1H), 7.96 (d, J = 9.5 Hz, 1H), 8.31 (d, J = 9.5 Hz, 1H),
109.08, 116.82, 121.71, 122.09, 123.57, 128.51, 130.92, 132.04, 10.19 (s, 1H).
132.64, 133.44, 141.83, 141.93, 142.66, 147.30, 152.63, 152.77,
5-(3′,4′-DIFLUOROPHENYL)-6-METHOXYQUINOLINE-2-CARBOXALDEHYDE (26).
155.22, 191.68. MS (EI) m/z: 474 (100%). HRMS (EI) for The title compound was obtained in 72% overall yield from 21
1
C26H22N2O7 (M+): calcd, 474.1427; found, 474.1426.
in a similar manner as described for the preparation of 24. H
6-METHOXY-2-METHYL-5-(4′-METHOXYPHENYL)QUINOLINE
(19). The NMR (500 MHz, CDCl3): δ 3.94 (s, 3H), 7.05–7.06 (m, 1H),
title compound was obtained in 93% overall yield from 7.15–7.19 (m, 1H), 7.28–7.33 (m, 1H), 7.68 (d, J = 9.0 Hz, 1H),
4-methoxyphenylboronic acid and 18 in a similar manner as 7.90 (d, J = 8.5 Hz, 1H), 7.95 (d, J = 9.0 Hz, 1H), 8.32 (d, J = 9.0
described for the preparation of 11. 1H NMR (500 MHz, CDCl3): Hz, 1H), 10.19 (s, 1H).
δ 2.69 (s, 3H), 3.85 (s, 3H), 3.89 (s, 3H), 7.03 (d, J = 8.5 Hz, 2H),
6-METHOXY-5-(4′-NITROPHENYL)QUINOLINE-2-CARBOXALDEHYDE
(27).
7.13 (d, J = 8.5 Hz, 1H), 7.26 (d, J = 9.0 Hz, 2H), 7.53 (d, J = 9.5 The title compound was obtained in 61% overall yield from 22
1
Hz, 1H), 7.79 (d, J = 9.0 Hz, 1H), 8.03 (d, J = 9.5 Hz, 1H).
in a similar manner as described for the preparation of 24. H
5-(4′-FLUOROPHENYL)-6-METHOXY-2-METHYLQUINOLINE (20). The title NMR (500 MHz, CDCl3): δ 3.95 (s, 3H), 7.54 (d, J = 9.0 Hz, 2H),
compound was obtained in 88% overall yield from 4-fluoro- 7.72 (d, J = 9.0 Hz, 1H), 7.89 (d, J = 9.0 Hz, 1H), 7.92 (d, J = 8.5
phenylboronic acid and 18 in a similar manner as described Hz, 1H), 8.38 (d, J = 9.5 Hz, 1H), 8.39 (d, J = 8.5 Hz, 2H), 10.20
for the preparation of 11. 1H NMR (500 MHz, CDCl3): δ 2.70 (s, (s, 1H).
3H), 3.85 (s, 3H), 7.14 (d, J = 9.0 Hz, 1H), 7.16–7.20 (m, 2H),
7.29–7.31 (m, 2H), 7.53 (d, J = 9.0 Hz, 1H), 7.72 (d, J = 8.5 Hz, (28). The title compound was obtained in 58% overall yield
1H), 8.06 (d, J = 9.5 Hz, 1H). from 23 in a similar manner as described for the preparation
6-METHOXY-5-[(TRIMETHYLSILYL)ETHYNYL]QUINOLINE-2-CARBOXALDEHYDE
1
5-(3′,4′-DIFLUOROPHENYL)-6-METHOXY-2-METHYLQUINOLINE (21). The of 24. H NMR (500 MHz, CDCl3): δ 0.35 (s, 9H), 4.09 (s, 3H),
title compound was obtained in 93% overall yield from 3,4- 7.55 (d, J = 9.5 Hz, 1H), 8.06 (d, J = 8.5 Hz, 1H), 8.21 (d, J = 9.0
difluorophenylboronic acid and 18 in a similar manner as Hz, 1H), 8.65 (d, J = 8.5 Hz, 1H), 10.18 (s, 1H).
described for the preparation of 11. 1H NMR (500 MHz,
5-ETHYNYL-6-METHOXYQUINOLINE-2-CARBOXALDEHYDE (29). The 28
CDCl3): δ 2.70 (s, 3H), 3.68 (s, 3H), 7.03–7.06 (m, 1H), (0.1 g, 0.35 mmol) and K2CO3 (0.1 g, 0.04 mmol) was added to
7.15–7.19 (m, 2H), 7.25–7.30 (m, 1H), 7.53 (d, J = 9.0 Hz, 1H), CH3OH (1 mL). After stirring for 2 h, the reaction mixture was
7.71 (d, J = 9.0 Hz, 1H), 8.07 (d, J = 9.0 Hz, 1H).
quenched and extracted by water and CH2Cl2. The organic
6-METHOXY-2-METHYL-5-(4′-NITROPHENYL)QUINOLINE (22). The title layers were combined and evaporated to give a residue which
compound was obtained in 48% overall yield from 4-nitrophe- was purified by flash chromatography (EtOAc : n-hexane = 1 : 1) to
1
nylboronic acid and 18 in a similar manner as described for give the solid, yield 95%. H NMR (500 MHz, CDCl3): δ 3.76 (s,
the preparation of 11. 1H NMR (500 MHz, CDCl3): δ 2.72 (s, 1H), 4.11 (s, 3H), 7.58 (d, J = 9.0 Hz, 1H), 8.06 (d, J = 8.5 Hz, 1H),
3H), 3.88 (s, 3H), 7.18 (d, J = 9.0 Hz, 1H), 7.54 (d, J = 8.5 Hz, 8.26 (d, J = 9.5 Hz, 1H), 8.69 (d, J = 8.5 Hz, 1H), 10.18 (s, 1H).
2H), 7.56 (d, J = 9.0 Hz, 1H), 7.66 (d, J = 9.0 Hz, 1H), 8.12 (d, J =
(B) Biology
9.0 Hz, 1H), 8.36 (d, J = 8.5 Hz, 2H).
6-METHOXY-2-METHYL-5-[(TRIMETHYLSILYL)ETHYNYL]QUINOLINE
(23).
(A) MATERIALS. Regents for cell culture were obtained from
The title compound was obtained in 52% overall yield from 18 Gibco-BRL Life Technologies (Gaithersburg, MD). Micro-
and trimethylsilylacetylene in a similar manner as described tubule-associated protein (MAP)-rich tubulin was purchased
1
for the preparation of 9. H NMR (500 MHz, CDCl3): δ 0.34 (s, from Cytoskeleton, Inc. (Denver, CO). [3H]Colchicine (specific
9H), 2.71 (s, 3H), 4.02 (s, 3H), 7.32 (d, J = 9.0 Hz, 1H), 7.39 (d, activity, 60–87 Ci mmol−1) was purchased from PerkinElmer
J = 9.5 Hz, 1H), 7.98 (d, J = 9.5 Hz, 1H), 8.41 (d, J = 9.0 Hz, 1H).
Life Sciences (Boston, MA).
6-METHOXY-5-(4′-METHOXYPHENYL)QUINOLINE-2-CARBOXALDEHYDE (24).
(B) CELL GROWTH INHIBITORY ASSAY. Human oral epidermoid
To a suspension of SeO2 (0.18 g, 1.59 mmol) and p-xylene carcinoma KB cells, colorectal carcinoma HT29 cells, and
(3 mL) was added a solution of 19 (0.22 g, 0.79 mmol) in stomach carcinoma MKN45 cells were maintained in
p-xylene (4 mL) dropwise at room temperature. The solution RPMI-1640 medium supplied with 5% fetal bovine serum.
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KB-VIN10 cells were maintained in growth medium sup-
plemented with 10 nM vincristine, generated from vincristine-
driven selection, and displayed overexpression of P-gp170/
MDR. Cells in logarithmic phase were cultured at a density of
5000 cells per mL per well in a 24-well plate. KB-VIN10 cells
were cultured in drug-free medium for 3 days prior to use. The
cells were exposed to various concentrations of the test drugs
for 72 h. The methylene blue dye assay was used to evaluate
the effect of the test compounds on cell growth as described
previously.25 The IC50 value resulting from 50% inhibition of
cell growth was calculated graphically as a comparison with
the control. Compounds were examined in at least three in-
dependent experiments, and the values shown for these com-
pounds are the mean and standard deviation of these data.
(C) TUBULIN POLYMERIZATION IN VITRO ASSAY.24,26 Turbidimetric
assays of microtubules were performed as described by Bollag
et al.27 In brief, microtubule-associated protein (MAP)-rich
tubulin (from bovine brain, Cytoskeleton, Denver, C.O.) had
been dissolved in reaction buffer (100 mM PIPES (pH 6.9),
2 mM MgCl2, 1 mM GTP) in preparing of 4 mg mL−1 tubulin
solution. Tubulin solution (240 g MAP-rich tubulin per well)
was placed in 96-well microtiter plate in the presence of test
compounds or 2% (v/v) DMSO as vehicle control. The increase
in absorbance was measured at 350 nm in a PowerWave X
Microplate Reader (BIO-TEK Instruments, Winooski, VT) at
37 °C and recorded every 30 s for 30 min. The area under the
curve (AUC) was used to determine the concentration that
inhibited tubulin polymerization to 50% (IC50). The AUC of
the untreated control and 10 μM of colchicine was set to 100%
and 0% polymerization, respectively, and the IC50 was calcu-
lated by nonlinear regression in at least three experiments.
(D) TUBULIN COMPETITION-BINDING SCINTILLATION PROXIMITY ASSAY.28
This assay was performed in a 96-well plate. In brief, 0.08 μM
of [3H]colchicine was mixed with the test compound and
0.5 μg special long-chain biotin-labeled tubulin (0.5 μg) and
then incubated in 100 μL of reaction buffer (80 mM PIPES, pH
6.8, 1 mM EGTA, 10% glycerol, 1 mM MgCl2, and 1 mM GTP)
for 2 h at 37 °C. Then 80 μg of Streptavidin-labeled SPA beads
were added to each reaction mixture. Then the radioactive
counts were directly measured by a scintillation counter.
(b) H. P. Hsieh, J. P. Liou and N. Mahindroo, Curr. Pharm.
Des., 2005, 11, 1655; (c) Q. Li and H. L. Sham, Expert Opin.
Ther. Pat., 2002, 12, 1663; (d) N. Mahindroo, J. P. Liou and
J. Y. Chang, Expert Opin. Ther. Pat., 2006, 16, 647;
(e) D. J. Chaplin, M. R. Horsman and D. W. Siemann, Curr.
Opin. Investig. Drugs, 2006, 7, 522.
2 K. Ohsumi, R. Nakagawa, Y. Fukuda, T. Hatanaka,
Y. Morinaga, Y. Nihei, K. Ohishi, Y. Suga, Y. Akiyama and
T. Tsuji, J. Med. Chem., 1998, 41, 3022.
3 (a) C. Dumontet and M. A. Jordan, Nat. Rev. Drug Discov-
ery, 2010, 9, 790; (b) A. Jordan and L. Wilson, Nat. Rev.
Cancer, 2004, 4, 253.G. R. Pettit, C. J. Temple,
V. L. Narayanan, R. Varma, M. J. Simpson, M. R. Boyd,
G. A. Rener and N. Bansal, Anti-Cancer Drug Des., 1995,
10, 299.
4 G. C. Tron, T. Pirali, G. Sorba, F. Pagliai, S. Busacca and
A. A. Genazzani, J. Med. Chem., 2006, 49, 3033.
5 L. Wang, K. W. Woods, Q. Li, K. J. Barr, R. W. McCroskey,
S. M. Hannick, L. Gherke, R. B. Credo, Y. H. Hui, K. Marsh,
R. Warner, J. Y. Lee, N. Zielinski-Mozng, D. Frost,
S. H. Rosemberg and H. L. Sharm, J. Med. Chem., 2002, 45,
1697.
6 (a) Q. Zhang, Y. Peng, X. I. Wang, S. M. Keeman, S. Aurora
and W. J. Welsh, J. Med. Chem., 2007, 50, 749;
(b) R. Romagnoli, P. G. Baraldi, O. Cruz-Lopez, C. Lopez
Cara, M. D. Carrion, A. Brancale, E. Hamel, L. Chen,
R. Bortolozzi, G. Basso and G. Viola, J. Med. Chem., 2010,
53, 4248.
7 N. M. O’Boyle, M. Carr, L. M. Greene, O. Bergin,
S. M. Nathwani, T. McCabe, D. G. Lloyd, D. M. Zisterer and
M. J. Meegan, J. Med. Chem., 2010, 53, 8569.
8 D. Simoni, G. Grisolia, G. Giannini, M. Roberti,
R. Rondanin, L. Piccagli, R. Baruchello, M. Rossi,
R. Romagnoli, F. P. Invi-diata, S. Grimaudo, M. K. Jung,
E. Hamel, N. Gebbia, L. Crosta, V. Abbadessa, A. Di Cris-
tina, L. Dusonchet, M. Meli and M. Tolomeo, J. Med.
Chem., 2005, 48, 723.
9 R. Schobert, B. Biersack, A. Dietrich, K. Effenberger,
S. Knauer and T. Mueller, J. Med. Chem., 2010, 53, 6595.
10 G. La Regina, M. C. Edler, A. Brancale, S. Kandil,
A. Coluccia, F. Piscitelli, E. Hamel, G. D. Martino,
R. Matesanz, J. F. Díaz, A. I. Scovassi, E. Prosperi,
A. Lavecchia, E. Novellino, M. Artico and R. Silvestri,
J. Med. Chem., 2007, 50, 2865.
Acknowledgements
This research were supported by the National Science Council, 11 A. Gangjee, Y. Zhao, L. Lin, S. Raghavan, E. G. Roberts,
Taiwan (grant no. NSC 100-2628-M-038-001-MY3, NSC 101-
2325-B-038-002, NSC 100-2325-B-038-005-CC2, NSC-101-2325-
A. L. Risinger, E. Hamel and S. L. Mooberry, J. Med. Chem.,
2010, 53, 8116.
B-400-007), Department of Health (DOH101-TD-C-111-004), 12 (a) B. L. Flynn, E. Hamel and M. K. Jung, J. Med. Chem.,
and National Health Research Institutes (CA-101-PP-22),
Taiwan, ROC).
2002, 45, 2670; (b) R. Gastpar, M. Goldbrunner, D. Marko
and E. von Angerer, J. Med. Chem., 1998, 41, 4965.
13 K. Yamamoto, K. Noda, A. Yoshimura, M. Kukuoka,
K. Furuse and H. Niitani, Cancer Chemother. Pharmacol.,
1998, 42, 124.
14 H. Y. Lee, J. Y. Chang, L. Y. Chang, W. Y. Lai, M. J. Lai,
K. H. Shih, C. C. Kuo, C. Y. Chang and J. P. Liou, Org.
Biomol. Chem., 2011, 9, 3154.
Notes and references
1 (a) G. C. Tron, T. Pirali, G. Sorba, F. Pagliai, S. Busacca and
A. A. Genazzani, J. Med. Chem., 2006, 49, 3033;
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15 M. J. Lai, J. Y. Chang, H. Y. Lee, C. C. Kuo, M. H. Lin, 21 (a) K. W. Rosenmund and E. Struck, Chem. Ber., 1919, 52,
H. P. Hsieh, C. Y. Chang, J. S. Wu, S. Y. Wu, K. S. Shey and
J. P. Liou, Eur. J. Med. Chem., 2011, 46, 3623.
16 J. P. Liou, Y. L. Chang, F. M. Kuo, C. W. Chang,
1749; (b) A. Gangjee, Y. Zhao, L. Lin, S. Raghavan,
E. G. Roberts, A. L. Risinger, E. Hamel and S. L. Mooberry,
J. Med. Chem., 2010, 53, 8116.
H. Y. Tseng, C. C. Wang, Y. N. Yang, J. Y. Chang, S. J. Lee 22 J. P. Liou, K. S. Hsu, C. C. Kuo, C. Y. Chang and
and H. P. Hsieh, J. Med. Chem., 2004, 47, 4247. J. Y. Chang, J. Pharmacol. Exp. Ther., 2007, 323, 398.
17 C. Y. Nien, Y. C. Chen, C. C. Kuo, H. P. Hsieh, C. Y. Chang, 23 J. Y. Chang, M. F. Yang, C. Y. Chang, C. M. Chen, C. C. Kuo
J. S. Wu, S. Y. Wu, J. P. Liou and J. Y. Chang, J. Med. Chem.,
2010, 53, 2309.
18 H. Y. Lee, J. Y. Chang, C. Y. Nien, C. C. Kuo, K. H. Shih,
C. H. Wu, C. Y. Chang, W. Y. Lai and J. P. Liou, J. Med.
Chem., 2011, 54, 8517.
and J. P. Liou, J. Med. Chem., 2006, 49, 6412.
24 C. C. Kuo, H. P. Hsieh, W. Y. Pan, C. P. Chen, J. P. Liou,
S. J. Lee, Y. L. Chang, L. T. Chen, C. T. Chen and
J. Y. Chang, Cancer Res., 2004, 64, 4621.
25 G. J. Finlay, B. C. Baguley and W. R. Wilson, Anal. Biochem.,
1984, 139, 272.
19 (a) D. M. D’Souza and T. J. J. Müller, Chem. Soc. Rev., 2007,
36, 1095; (b) J. J. Song, J. T. Reeves, F. Gallou, Z. Tan, 26 J. P. Liou, J. Y. Chang, C. W. Chang, C. Y. Chang,
N. K. Yee and C. H. Senanayake, Chem. Soc. Rev., 2007, 36,
1120; (c) R. Hersperger, K. B. French, L. Mazzoni and
N. Mahindroo, F. M. Kuo and H. P. Hsieh, J. Med. Chem.,
2004, 47, 2897.
T. Müller, J. Med. Chem., 2000, 43, 675; (d) H. C. Zhang, 27 D. M. Bollag, P. A. McQueney, J. Zhu, O. Hensens,
C. K. Derian, D. F. McComsey, K. B. White, H. Ye,
L. R. Hecker, J. Li, M. F. Addo, D. Croll, A. J. Eckardt,
L. Koupal, J. Liesch, M. Goetz, E. Lazarides and
C. M. Woods, Cancer Res., 1995, 55, 2325.
C. E. Smith, Q. Li, W. M. Cheung, B. R. Conway, S. Emanuel, 28 (a) S. K. Tahir, P. Kovar, S. H. Rosenberg and S. C. Ng, Bio-
K. T. Demarest, P. A. Gordon, B. P. Damiano and
B. E. Maryanoff, J. Med. Chem., 2005, 48, 1725;
(e) S. Theeramunkong, A. Caldarelli, A. Massarotti, S. Aprile,
D. Caprioglio, R. Zaninetti, A. Teruggi, T. Pirali, G. Grosa,
G. C. Tron and A. A. Genazzani, J. Med. Chem., 2011, 54, 4977.
20 J. Y. Chang, M. J. Lai, Y. T. Chang, H. Y. Lee, Y. C. Cheng,
C. C. Kuo, M. C. Su, C. Y. Chang and J. P. Liou, Med. Chem.
Commun., 2010, 1, 152.
Techniques, 2000, 29, 156; (b) S. K. Tahir, E. K. Han,
B. Credo, H. S. Jae, J. A. Pietenpol, C. D. Scatena, J. R. Wu-
Wong, D. Frost, H. Sham, S. H. Rosenberg and S. C. Ng,
Cancer Res., 2001, 61, 5480; (c) S. K. Tahir, M. A. Nukkala,
N. A. Zielinski Mozny, R. B. Credo, R. B. Warner, Q. Li,
K. W. Woods, A. Claiborne, S. L. Gwaltney II, D. J. Frost,
H. L. Sham, S. H. Rosenberg and S. C. Ng, Mol. Cancer
Ther., 2003, 2, 227.
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