Synthesis and evaluation of a series of quinolinyl trans-cyanostilbene analogs as anticancer agents

Article abstract of DOI:10.1039/c4md00115j

A series of novel trans-2-quinolyl-, 3-quinolyl- and 4-quinolyl cyanostilbene derivatives were synthesized as analogs of combretastatin A-4 (CA-4), and evaluated for anticancer activity against a panel of 60 human cancer cell lines. The quinolin-2-yl and

Full text of DOI:10.1039/c4md00115j

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Synthesis and evaluation of a series of quinolinyl
trans-cyanostilbene analogs as anticancer agents
Cite this: DOI: 10.1039/c4md00115j
Narsimha Reddy Penthala, Venumadhav Janganati, Shobanbabu Bommagani
*
and Peter A. Crooks
A series of novel trans-2-quinolyl-, 3-quinolyl- and 4-quinolyl cyanostilbene derivatives were synthesized
as analogs of combretastatin A-4 (CA-4), and evaluated for anticancer activity against a panel of 60 human
cancer cell lines. The quinolin-2-yl and quinolin-3-yl analogs containing trimethoxyphenyl (10 and 16,
respectively) or dimethoxyphenyl (12 and 18, respectively) moieties showed growth inhibition against all
the cancer cell lines in the panel, with GI50 values generally <1 mM. Quinolin-2-yl-analog 10 exhibited
potent growth inhibition against MDA-MB-435 melanoma and NCI-H522 non-small cell lung cancer line
with GI50 values of 33 nM and 37 nM respectively. Quinolin-2-yl-analog 12 showed potent growth
inhibition against NCI-H522 non-small cell lung cancer lines with a GI50 value of 94 nM. Quinolin-3-yl-
analog 18 exhibited potent growth inhibition against MDA-MB-435 melanoma and NCI-H522 non-small
cell lung cancer lines with GI50 values of 53 nM and 69 nM, respectively. Thus, structural modification of
the CA-4 molecule has afforded compounds with potential clinical utility in the treatment a variety of
different solid tumors.
Received 12th March 2014
Accepted 2nd May 2014
DOI: 10.1039/c4md00115j
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water-solubility,6 and on designing cis-analogs that are inca-
pable of cis to trans isomerization in solution.
Introduction
Recently, Jalily et al. and Ohsumi et al. have reported on
some novel trans-cyanocombretastatin analogs (Fig. 1, III) as
potent inhibitors of tubulin polymerization with activities
comparable to that of CA-4; these investigators have demon-
strated that a trans double bond bearing a nitrile moiety would
be an effective replacement for the cis-olenic moiety in CA-4
and its analogues.7
In CA-4 analogs, the Z-isomer incorporates cis-aryl rings
about the double bond (i.e. cis-stilbene geometry) whereas the
isomeric E-CA-4 analogs incorporate aryl rings that are transoid.
It should be noted that according to Cahn–Ingold–Prelog
priority rules,8 the addition of a cyano group onto either of the
carbons of the trans-stilbene double bond will change the E
Different fundamental cellular processes, such as cell division,
formation and maintenance of cell shape, regulation of
motility, cell signaling, secretion, and intracellular transport are
regulated by the microtubule system of eukaryotic cells.1 In
anticancer therapy, the inhibition of microtubule function as a
therapeutic outcome has been validated utilizing the cis-stil-
bene analog, combretastatin A-4 (CA-4; Fig. 1, I). CA-4 is an
antimitotic agent isolated from the bark of the South African
tree Combretum caffrum.2 The potent cytotoxicity of CA-4 against
a wide variety of human cancer cell lines, including multidrug
resistant cells, is believed to be due to its effect on microtubule
dynamics and its affinity for the colchicine binding site.3 SAR
studies have revealed that the trimethoxyphenyl ring system is
essential for the cytotoxic effect of CA-4.4 Inspite of the potent
cytotoxicity of CA-4 the molecule possesses some disadvanta-
geous properties, such as low water-solubility, vascular disrup-
tion, and isomerization to the less active trans-stilbene isomer
(Fig. 1, II) in solution.5 In this respect, the Z-isomer of CA-4
represents the cis-stilbene geometry, and Z-CA-4 analogs are
generally 1000-fold more cytotoxic than the corresponding E-
isomer (trans-stilbene geometry). Efforts to overcome the limi-
tations of CA-4 analogs have focused on incorporating different
aromatic heterocyclic ring systems into the molecule to improve
conguration to the
Z
conguration. Thus, trans
Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas
for Medical Sciences, Little Rock, AR 72205, USA. E-mail: pacrooks@uams.edu; Fax:
+1-501-686-6057; Tel: +1-501-686-6495
Fig. 1 Chemical structures of Z-CA-4 and other structurally related
antitubulin agents.
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cyanocombretastatin analogs are designated as Z-conguration,
and CA-4 and its non-cyano cis-analogs are also designated as Z-
conguration.
Many reports in the literature have focused on incorporating
heterocycles such as benzothiophene,9 indole,10 pyrazole,11
imidazole,12 isoxazole,13 1,2,3-thiadiazole,14 triazoles,11,15,16 and
1,2,3,4-tetrazole11 into the CA-4 structure. Such compounds
have been shown to be potent anti-cancer agents. In an earlier
communication we have reported on the anti-cancer and anti-
tubulin activity of a series of Z- and E-benzothiophene com-
bretastatin derivatives (Fig. 1, IV and V, respectively)9b and have
demonstrated that Z-benzothiophene cyanocombretastatin
analogs can overcome cell-associated P-glycoprotein (P-gp)-
mediated resistance, since such compounds were equipotent in
inhibiting both OVCAR8 and NCI/ADR-RES cell growth.9b Z-
Quinolinyl CA-4 analogs (Fig. 1, VI) have also been reported as
potent inhibitors of tubulin polymerization and have improved
water-solubility compared to that of other CA-4 analogs.17
However, there have been no reported studies on Z-quinolinyl
cyanocombretastatins, which encouraged us to synthesize a
series of novel 2-, 3-, and 4-quinolyl analogs of Z-cyanocom-
bretatstatin and to evaluate these novel compounds as potent
anti-cancer agents.
In the present communication, we describe the synthesis of a
variety of Z-2-quinolyl, Z-3-quinolyl and Z-4-quinolyl cyano-
combretastatin analogs that incorporate trimethoxyphenyl,
dimethoxyphenyl, monomethoxyphenyl, hydroxyphenyl or
hydroxydimethoxyphenyl moieties, and report the evaluation of
these analogs as anti-cancer agents against an extensive panel
of human cancer cell lines.
Scheme 1 Synthesis of Z-cyanoquinolinyl combretastatins (10–27).
of 60 human cancer cell lines (NCI-60 panel). The NCI 60 cell
panel was divided into subpanels of leukemia, non-small cell
lung, colon, central nervous system, melanoma, ovary, renal,
prostate, and breast cancer cell lines. From the single dose
Chemistry
The 2-quinolyl, 3-quinolyl and 4-quinolyl cyanocombretastatin screen, successful compounds progressed to ve concentration-
analogs 10–27 were synthesized by reuxing quinoline-2- cytotoxicity assays if they exhibited $60% growth inhibition in
carbaldehyde (1), quinoline-3-carbaldehyde (2) or quinoline-4- at least eight of the cancer cell lines screened.
carbaldehyde (3) with 3,4,5-trimethoxyphenyl-acetonitrile (4),
From the preliminary screening data, the quinolinyl cyano-
3,4-dimethoxy phenylacetonitrile (5), 3,5-dimethoxyphenyl- combretastatin analogs incorporating a 3,4,5-trimethoxyphenyl
acetonitrile (6), 4-hydroxyphenylacetonitrile (7), 4-methoxy- moiety (10 and 16) and a 3,5-dimethoxyphenyl group (12 and 18)
phenylacetonitrile
(8),
and
4-hydroxy-3,5-dimethoxy- showed signicant potency and were selected as leads for ve
phenylacetonitrile (9) in methanolic 2% sodium methoxide dose studies. These studies were designed to determine GI50
,
solution (Scheme 1). The desired products were obtained in TGI and LC50 values, which represent the molar drug concen-
yields ranging from 85–93%.18 Conrmation of the structure, tration required to cause 50% growth inhibition, total growth
geometry and purity of these analogs was obtained from 1H- and inhibition, and the concentration that kills 50% of the cells,
13C-NMR spectrometric, and high resolution MS analysis. respectively. These compounds were studied at ve different
Carbon–proton coupling experiments showed that the magni- concentrations by 10-fold dilutions at 10ꢁ4 M, 10ꢁ5 M, 10ꢁ6 M,
tude of the coupling constant (JCH) of the CN carbon doublet at 10ꢁ7 M and 10ꢁ8 M by dissolving each compound in dimethyl
ꢀ118 ppm, arising from coupling with the olenic proton was sulfoxide (DMSO)–water and evaluating the effect of the drug
>12 Hz for the above products, which established the Z-geom- over 48 h of incubation.
etry for these compounds.7a
Compounds 10, 12, 16 and 18 exhibited growth inhibition
against all 60 human cancer cell lines in the ve dose screens.
The growth inhibition results of these four molecules are pre-
sented in Table 1.
The 2-quinolyl analog 10 [(Z)-3-(quinolin-2-yl)-2-(3,4,5-tri-
methoxyphenyl)acrylonitrile] exhibited potent growth inhibi-
Biological evaluation
In vitro growth inhibition and cytotoxicity against human
cancer cell lines
Compounds 10–27 were evaluated for anti-proliferative activity tion against 91% of the cancer cell lines in the panel, with GI50
in a preliminary screen at 10ꢁ5 M concentration against a panel values ranging from 0.033 to 0.943 mM; the average GI50 value
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Table 1 Antitumor activity (GI50/mM)b data for Z-quinolyl cyano- Table 1 (Contd.)
combretastatin analogs on various human tumour cell linesa
10
12
16
18
10
12
16
18
Panel/cell line
GI50 (mM) GI50 (mM) GI50 (mM) GI50 (mM)
Panel/cell line
GI50 (mM) GI50 (mM) GI50 (mM) GI50 (mM)
CAKI-1
RXF 393
SN12C
TK-10
0.068
0.271
0.627
4.69
0.318
0.334
0.661
3.28
0.346
0.579
1.94
2.55
0.580
0.223
0.297
0.661
17.7
Leukemia
CCRF-CEM
HL-60 (TB)
K-562
MOLT-4
RPMI-8226
SR
0.248
0.223
0.080
0.488
0.297
NA
0.332
0.27
0.353
0.419
0.433
NA
1.38
0.332
0.234
0.243
0.378
0.332
NA
0.329
0.444
3.20
2.06
0.569
UO-31
0.762
0.573
ND
Prostate cancer
PC-3
DU-145
0.348
0.446
0.584
0.801
1.08
1.51
0.506
0.505
Lung cancer
A549/ATCC
EKVX
HOP-62
HOP-92
NCI-H226
NCI-H23
NCI-H322M
NCI-H460
NCI-H522
0.375
NA
0.567
0.736
4.78
0.751
0.718
0.361
0.0372
0.649
NA
0.959
0.542
10.8
0.983
3.02
0.339
0.094
0.680
NA
0.556
NA
0.793
3.09
Breast cancer
MCF7
MDA-MB-231/ATCC 0.943
HS 578T
BT-549
0.275
0.537
1.02
0.70
0.342
1.23
1.50
0.429
2.83
1.31
1.43
9.54
0.870
0.333
1.15
0.715
0.388
0.628
0.217
10.3
0.403
>100
2.93
27.4
2.05
0.299
0.689
0.315
4.76
62.2
0.747
0.903
0.362
0.069
T-47D
MDA-MB-468
0.243
a
b
Na: not analyzed, nd: not determined. GI50: 50% growth inhibition,
concentration of drug resulting in a 50% reduction in net cell growth as
compared to cell numbers on day 0.
Colon cancer
COLO 205
HCC-2998
HCT-116
HCT-15
HT29
KM12
SW-620
0.198
0.61
0.234
0.319
0.24
0.374
1.42
0.374
2.01
0.464
1.08
0.421
0.436
NA
0.398
1.45
0.416
0.409
0.367
0.425
0.357
0.420
0.455
0.362
0.409
0.352
for this compound against all the cancer cell lines in the panel
was 0.40 mM. Compound 10 exhibited potent growth inhibition
against MDA-MB-435 melanoma cancer cell lines with a GI50
value of 0.033 mM (Table 1).
0.35
0.164
CNS cancer
SF-268
SF-295
SF-539
SNB-19
SNB-75
U251
Substitution of a 3,5-dimethoxyphenyl moiety in place of the
3,4,5-trimethoxyphenyl group in 10 afforded compound 12 [(Z)-
3-(quinolin-2-yl)-2-(3,5-dimethoxyphenyl)acrylonitrile], which
exhibited potent growth inhibition against 86% of the cells in
the human cancer cell panel, with GI50 ranging from 0.094 to
0.983 mM; the average GI50 value for this compound against all
the cancer cell lines in the panel was 0.49 mM. This compound
exhibited potent growth inhibition against NCI-H522 lung
cancer cell lines with a GI50 value of 0.094 mM (Table 1).
The 3-quinolyl isomer of 10, compound 16 [(Z)-3-(quinolin-
0.835
0.277
0.197
0.578
0.182
0.355
0.476
0.341
0.286
0.728
0.311
0.425
9.17
0.556
0.361
5.23
1.49
1.70
0.654
0.243
0.289
0.614
0.224
0.374
Melanoma
LOX IMVI
MALME-3M
M14
MDA-MB-435
SK-MEL-2
SK-MEL-28
SK-MEL-5
UACC-257
UACC-62
0.766
NA
0.61
0.348
0.36
0.147
0.522
0.896
0.406
ND
0.645
0.691
0.540
0.227
1.05
3.27
0.410
ND
0.672
0.635
0.310
0.053
0.709
1.40
0.249
12.8
0.357
0.173
0.033
0.483
0.518
0.243
0.761
0.092
3-yl)-2-(3,4,5-trimethoxyphenyl)
acrylonitrile]
exhibited
potent growth inhibition against 47% of the cell lines in the
human cancer cell panel, with GI50 values ranging from 0.227
to 0.911 mM; the average GI50 value of this compound against
all the human cancer cell lines in the panel was 2.49 mM.
Compound 16 exhibited potent growth inhibition against
MDA-MB-435 melanoma cancer cell lines with a GI50 value of
0.227 mM (Table 1).
The 3-quinolyl isomer of 12, compound 18 [(Z)-3-(quinolin-
3-yl)-2-(3,5-dimethoxyphenyl)acrylonitrile] exhibited potent
growth inhibition against 81% of the cell lines in the human
cancer cell panel with GI50 values ranging from 0.053 to
0.903 mM; the average GI50 value of this compound against all
the human cancer cell line in the panel is 2.21 mM. Compound
18 exhibited potent growth inhibition against MDA-MB-435
melanoma cancer cell lines with a GI50 value of 0.053 mM
(Table 1).
0.449
0.478
Ovarian cancer
IGROV1
OVCAR-3
OVCAR-4
OVCAR-5
OVCAR-8
NCI/ADR-RES
SK-OV-3
0.846
0.163
1.43
0.580
0.446
0.112
0.524
0.958
0.309
0.788
0.716
0.659
0.283
0.804
3.15
0.263
13.8
3.94
3.41
0.343
1.34
3.50
0.279
1.73
0.587
0.584
0.224
0.576
Renal cancer
786-0
A498
0.445
0.295
1.04
0.501
0.275
0.773
6.29
0.678
0.911
0.484
0.333
1.19
ACHN
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CDCl3): d 3.90 (s, 3H), 3.95 (s, 6H), 6.92 (s, 2H), 7.60–7.63 (m,
2H), 7.76–7.80 (t, J1 ¼ 7.2 Hz, J2 ¼ 15.6 Hz, 1H), 7.92–7.94 (d, J ¼
8 Hz, 1H), 8.10–8.12 (d, J ¼ 8.4 Hz, 1H), 8.9 (s, 1H), 9.1 (s, 1H)
ppm. 13C NMR (100 MHz, CDCl3): d 56.36, 61.02, 103.48, 113.92,
117.66, 126.78, 127.38, 127.56, 128.77, 129.32, 129.46, 131.09,
135.06, 137.39, 139.62, 148.34, 151.21, 153.67 ppm. HRMS calcd
for C21H18N2O3, (M+): 346.1317. Found 346.1311.
Conclusion
A series of novel Z-quinolinyl cyanocombretastatin analogs were
synthesized and evaluated for anticancer activity against a panel
of 60 human cancer cell lines. 2- and 3-quinolyl analogs con-
taining a 3,4,5-trimethoxyphenyl moiety (10 and 16), or a 3,5-
dimethoxyphenyl (12 and 18) moiety exhibited the most potent
growth inhibition with GI50 values generally <1 mM against most
of the human cancer cell lines in the panel. The 4-quinolyl 3,4,5-
trimethoxyphenyl and 4-quinolyl 3,5-dimethoxyphenyl analogs
were found to be inactive. Compound 10 exhibited potent
growth inhibition against MDA-MB-435 melanoma and NCI-
H522 non-small cell lung cancer lines with GI50 values of 33 nM
and 37 nM, respectively. Compounds 12 and 18 exhibited
potent growth inhibition against NCI-H522 non-small cell lung
cancer lines with GI50 values of 94 nM and 69 nM, respectively.
Thus, structural modication of the CA-4 molecule to afford 2-
quinolyl and 3-quinolyl analogs of Z-cyanocombretatstatin have
produced compounds with potential clinical utility in the
treatment a variety of different solid tumors.
(Z)-2-(3,5-Dimethoxyphenyl)-3-(quinolin-3-yl)acrylonitrile (18).
Light yellow crystalline solid, mp: 150–152 ꢂC, 1H NMR (400
MHz, CDCl3): d 3.85 (s, 6H), 6.52 (s, 1H), 6.85 (s, 2H), 7.58–7.62
(t, 1H, J1 ¼ 8.0 Hz, J2 ¼ 15.2 Hz), 7.66 (s, 1H), 7.76–7.80 (t, 1H, J1
¼ 8.0 Hz, J2 ¼ 15.6 Hz), 7.92–7.94 (d, 1H, J ¼ 8.0 Hz), 8.10–8.12
(d, 1H, J ¼ 8.8 Hz), 8.93 (s, 1H), 9.09 (d, 1H, J ¼ 1.6 Hz) ppm; 13
C
NMR (100 MHz, CDCl3): d 55.52, 101.63, 104.33, 113.92, 117.59,
126.69, 127.37, 127.49, 127.62, 128.78, 129.29, 129.36, 131.16,
135.23, 135.84, 138.33, 148.40, 151.26, 161.31 ppm. HRMS calcd
for C20H16N2O2, (M+): 316.1212. Found 346.1208.
Acknowledgements
We are grateful to the Arkansas Research Alliance (ARA) for
nancial support and to the NCI Developmental Therapeutic
Program (DTP) for screening data.
General synthetic procedure: synthesis of (Z)-quinolinyl-2-
alkoxyphenylacrylonitriles (10–27)
The 2-, 3-, or 4-quinolylcarbaldehyde (1 mole) and the appro-
priate substituted phenylacetonitrile (1.1 mole equivalent) were
added to 2% sodium methoxide in methanol and the mixture
heated under reux for 3 to 6 h. The resulting solution was then
cooled to room temperature and poured into ice-cold water to
afford a crude yellow solid. The solid was ltered off, washed
with water, and nally washed with cold methanol. The
obtained crude solid was recrystallized from methanol to afford
the desired condensation product as a pure crystalline solid.
Notes and references
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Analytical data for the most potent compounds
(Z)-3-(Quinolin-2-yl)-2-(3,4,5-trimethoxyphenyl)acrylonitrile (10).
Yellow uffy solid. mp: 106–108 ꢂC, 1H NMR (400 MHz, CDCl3):
d 3.91 (s, 3H), 3.96 (s, 6H), 7.02 (s, 2H), 7.61 (t, 1H, J1 ¼ 7.6 Hz, J2
¼ 14.8 Hz), 7.78–7.79 (d, 1H, J ¼ 7.2 Hz), 7.86 (s, 1H), 7.86–7.88
(d, 1H, J ¼ 8.40 Hz), 8.14–8.20 (m, 2H), 8.27–8.29 (d, 1H, J ¼ 8.8
Hz) ppm; 13C NMR (100 MHz, CDCl3): d 56.29, 60.96, 103.74,
115.91, 117.44, 120.54, 127.55, 127.64, 127.73, 127.86, 129.43,
129.60, 130.35, 137.00, 139.73, 140.74, 140.87, 148.10, 152.21,
153.59 ppm. HRMS calcd for C21H18N2O3, (M+): 346.1317.
Found 346.1309.
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(Z)-2-(3,5-Dimethoxyphenyl)-3-(quinolin-2-yl)acrylonitrile (12).
Yellow crystalline solid, mp: 110–112 ꢂC, 1H NMR (400 MHz,
CDCl3): d 3.84 (s, 6H), 6.52 (s, 1H), 6.92 (s, 2H), 7.56–7.60 (t, 1H,
J1 ¼ 7.2 Hz, J2 ¼ 15.2 Hz), 7.73–7.77 (t, 1H, J1 ¼ 8.0 Hz, J2 ¼ 15.2
Hz), 7.81 (s, 1H), 7.83–7.85 (d, 1H, J ¼ 8.8 Hz), 8.11–8.15 (t, 2H, J1
¼ 9.6 Hz, J2 ¼ 18 Hz), 8.26 (d, 1H, J ¼ 8.8 Hz) ppm; 13C NMR (100
MHz, CDCl3): d 55.52, 101.63, 104.33, 113.92, 117.59, 126.69,
127.37, 127.49, 127.62, 128.78, 129.29, 129.36, 131.16, 135.23,
135.84, 138.33, 148.40, 151.26, 161.31 ppm. HRMS calcd for
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C
20H16N2O2, (M+): 316.1212. Found 346.1204.
(Z)-3-(Quinolin-3-yl)-2-(3,4,5-trimethoxyphenyl)acrylonitrile (16).
8 R. S. Cahn, C. K. Ingold and V. Prelog, Angew. Chem., Int. Ed.,
1966, 5, 385–415.
Yellow crystalline solid, mp: 155–157 ꢂC, 1H NMR (400 MHz,
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