Heteroaromatic analogs of the resveratrol analog DMU-212 as potent anti-cancer agents

Article abstract of DOI:10.1016/j.bmcl.2015.05.019

Heteroaromatic analogs of DMU-212 (8-15) have been synthesized and evaluated for their anti-cancer activity against a panel of 60 human cancer cell lines. These novel analogs contain a trans-3,4,5-trimethoxystyryl moiety attached to the C2 position of indole, benzofuran, benzothiazole or benzothiophene ring (8, 11, 13 and 14, respectively) and showed potent growth inhibition in 85% of the cancer cell lines examined, with GI₅₀ values <1 μM. Interestingly, trans-3,4- and trans-3,5-dimethoxystyryl DMU-212 analogs 9, 10, 12 and 15 exhibited significantly less growth inhibition than their 3,4,5-trimethoxystyryl counterparts, suggesting that the trans-3,4,5-trimethoxystyryl moiety is an essential structural element for the potent anti-cancer activity of these heterocyclic DMU-212 analogs. Molecular modeling studies showed that the four most active compounds (8, 11, 13 and 14) all bind to the colchicine binding site on tubulin, and that their binding modes are similar to that of DMU-212.

Full text of DOI:10.1016/j.bmcl.2015.05.019

Accepted Manuscript
Heteroaromatic analogs of the resveratrol analog DMU-212 as potent anti-can-
cer agents
Narsimha Reddy Penthala, Shraddha Thakkar, Peter A. Crooks
PII:
S0960-894X(15)00469-2
DOI:
http://dx.doi.org/10.1016/j.bmcl.2015.05.019
BMCL 22709
Reference:
Bioorganic & Medicinal Chemistry Letters
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Received Date:
Revised Date:
Accepted Date:
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8 May 2015
12 May 2015
Please cite this article as: Penthala, N.R., Thakkar, S., Crooks, P.A., Heteroaromatic analogs of the resveratrol analog
DMU-212 as potent anti-cancer agents, Bioorganic & Medicinal Chemistry Letters (2015), doi: http://dx.doi.org/
10.1016/j.bmcl.2015.05.019
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.c om
Heteroaromatic analogs of the resveratrol analog DMU-212 as potent anti-
cancer agents
Narsimha Reddy Penthala, Shraddha Thakkar and Peter A. Crooks*
Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205
ARTICLE INFO
ABSTRACT
Article history:
Received
Heteroaromatic analogs of DMU-212 (8-15) have been synthesized and evaluated for their anti-
cancer activity against a panel of 60 human cancer cell lines. These novel analogs contain a
trans-3,4,5-trimethoxystyryl moiety attached to the C2 position of indole, benzofuran,
benzothiazole or benzothiophene ring (8, 11, 13 and 14, respectively) and showed potent growth
inhibition in 85% of the cancer cell lines examined, with GI50 values <1 µM. Interestingly,
trans-3,4- and trans-3,5-dimethoxystyryl DMU-212 analogs 9, 10, 12 and 15 exhibited
significantly less growth inhibition than their 3,4,5-trimethoxystyryl counterparts, suggesting
that the trans-3,4,5-trimethoxystyryl moiety is an essential structural element for the potent anti-
cancer activity of these heterocyclic DMU-212 analogs. Molecular modeling studies showed
that the four most active compounds (8, 11, 13 and 14) all bind to the colchicine binding site on
tubulin, and that their binding modes are similar to that of DMU-212.
Revised
Accepted
Available online
Keywords:
Heterocyclic resveratrol analogs
Anti-cancer activity
Indole,
Benzofuran,
Benothiophene,
Benzothiazole
.
2015 Elsevier Ltd. All rights reserved
In anticancer therapy, the inhibition of microtubule function as
a therapeutic strategy has been validated by utilizing the natural
product resveratrol (trans-3,5,4ꞌ-trihydroxystilbene) and its
derivatives (Fig. 1; structures I-III) as tubulin targeting agents.1, 2
Resveratrol, a well-known natural polyphenolic phytoalexin
compound extracted from a variety of medicinal plants and from
grapes,3 is a potent anti-oxidant4,5 and also inhibits platelet
aggregation.6,7 Resveratrol and its analogs have been shown to
exhibit various cancer chemo-preventive properties, due to their
modulation of multiple cellular processes, including apoptosis,
cell cycle progression, inflammation, and angiogenesis.8
A number of trans-CA-4 analogs structurally related to DMU-
212, e.g. compound V (Fig.1), has been found to possess potent
anti-cancer activity in cells in culture at cytotoxic
concentrations.15,16 Also, recent studies have shown that trans-
cyanostilbene analogs that are structurally related to both DMU-
212 and trans-CA-4, e.g. compound VI, (Fig. 1), are inhibitors of
tubulin polymerization with potencies comparable to that of CA-
4. 17,18
A series of methoxy derivatives of resveratrol have been
reported as anti-cancer agents against various human cancer cell
lines.2,9 Among these, (E)-3,5,4ꞌ-trimethoxystilbene (Fig. 1;
structure II) and (E)-3,4,5,4ꞌ-tetramethoxystilbene (DMU-212,
Fig. 1; structure III) exhibit potent anti-cancer activity and 30-
to 100-fold enhanced cytotoxicity in comparison to resveratrol.10
These methoxy derivatives have been identified as microtubule-
destabilizing agents endowed with anti-angiogenic and vascular-
targeting propeties.1
Fig. 1 Chemical structures of potent anti-cancer agents
The combretastatins, are another potent group of natural
products that are inhibitors of microtubule function.11,12
Combretastatin analogs have been extracted from the bark of the
South African tree Combretum caffrum, and among these natural
products, combretastatin A-4 (Fig. 1; structure IV), a cis-stilbene
We have previously reported on the synthesis of a wide
variety of cis- and trans-substituted cyanostilbene analogs as
anti-tubulin agents.17 Also, we have recently described the
synthesis and potent anti-cancer activity of some cis- and trans-
cyanostilbene analogs in which one of the phenyl moieties has
analog, is
a
well-known anti-mitotic agent.13 The potent
cytotoxicity of CA-4 against a wide variety of human cancer cell
lines, including multidrug resistant cells, is due to its effect on
microtubule dynamics and its affinity for the colchicine binding
site on tubulin.14
been replaced with
a
heteroaromatic moiety such as
benzothiophene19 and quinoline.20
_____________________________
*Corresponding author. Tel.: +1-501-686-6495; fax: +1-501-686-6057; e-mail: pacrooks@uams.edu

In the present communication, we report on the synthesis and
anti-cancer activities of a variety of heteroaromatic DMU-212
analogs (8-15) in which the 4-methoxyphenyl moiety in the
DMU-212 molecule has been replaced with a variety of well-
known bio-active heterocyclic ring systems such as indole,
benzofuran, benzothiazole and benzothiophene. The methoxy
substitution pattern in the trans-3,4,5-trimethoxystyryl moiety in
these compounds has also been varied.
The four 3,4,5-trimethoxystyryl analogs 8, 11, 13 and 14
exhibited potent cytotoxicity in the 5-dose NCI-60 human cancer
cell assay, and because of their structural similarity to DMU-212,
the cytotoxic activity of these novel heterocyclic analogs likely
results from their interaction with the colchicine binding site on
tubulin. The growth inhibition results for the above compounds
are presented in Table 1, and are summarized below.
The substitution of the trans-3,4,5-trimethoxystyryl moiety at
the C2 position of an indole ring afforded compound 8, which
exhibited potent growth inhibition against 88% of the cancer cell
lines in the panel, affording GI50 values ranging from 0.15 to
0.963 µM, with an average GI50 value of 0.90 µM for all the cell
lines in the panel. This compound exhibited growth inhibition
against MDA-MB-435 melanoma and UO-31 renal cancer cell
lines with GI50 values of 0.15 and 0.17 µM, respectively (Table
1).
A series of indole, benzo[b]furan, benzo[b]thiophen and
benzo[d]thiazole analogs of DMU-212 (8-15) were synthesized
by indole-2-carbaldehyde (1), benzo[b]furan-2-carbaldehyde (2),
benzo[d]thiazole-2-carbaldehyde (3), and benzo[b]thiophen-2-
carbaldehyde (4), with a variety of triphenyl phosphonium
bromide salts (5-7) in 5% sodium methoxide methanol at room
temperature for 3-4 h (Scheme 1).
Incorporating the trans-3,4,5-trimethoxystyryl moiety at the
C2 position of a benzofuran ring afforded compound 11. This
compound exhibited potent growth inhibition against 78% of the
cancer cell lines in the panel, with GI50 values ranging from
0.078 to 0.895 µM, and an average GI50 value of 1.42 µM for all
the cells in the panel. Compound 11 exhibited growth inhibition
against MDA-MB-435 melanoma, SR leukemia, and HOP-92
lung cancer cancer cell lines with GI50 values of 0.078, 0.094 and
0.170 µM, respectively (Table 1).
Scheme 1 Synthesis of heteroaromatic analogs of DMU-212 (8-15)
Table 3. Anti-tumor activity (GI50/µM)a data for the heteroaromatic DMU-
212b analogs 8, 11, 13, 14 from the 5-dose human cancer cell panel assay
Confirmation of the structure and purity of these analogs was
obtained from 1H- and 13C-NMR, and high resolution mass
spectroscopic analysis. The geometry of the double bond in these
8
11
13
14
Panel/cell line
GI50
GI50
GI50
GI50
1
molecules was established as the trans-configuration from H-
Leukemia
0.368
0.425
0.133
0.262
NMR studies [the trans-stilbene olefinic proton J-values range
from 15-16 Hz, while the cis-stilbene olefinic protons have J-
value ranging from 7.4-8.6 Hz].21
CCRF-CEM
HL-60(TB)
K-562
0.347
0.393
0.854
0.388
0.241
0.356
0.267
0.852
0.700
0.094
0.037
0.041
1.28
0.246
0.088
0.424
0.268
0.120
MOLT-4
RPMI-8226
SR
All the synthesized molecules were evaluated for their anti-
cancer activity in a preliminary screen against a panel of 60
human cancer cell lines (NCI-60 panel) at a concentration of 10-5
M utilizing the procedure described by Rubinstein et al.22 In this
cellular assay the growth inhibition of the test compounds is
measured by determining percentage cell growth (PG) inhibition.
Optical density (OD) measurements of sulforhodamine B (SRB)-
derived color, just before exposing the cells to the test compound
(ODtzero), and after 48 h exposure to the test compound (ODtest) or
the control vehicle (ODctrl) is recorded. The growth percentage
compared to control is calculated utilizing the reported
formulas.23 The NCI 60 cell panel includes different subpanels
representing leukemia, non-small cell lung, colon, central
nervous system, melanoma, ovary, renal, prostate, and breast
cancer cell lines.
0.158
0.036
Lung Cancer
0.624
0.615
0.118
0.310
A549/ATCC
EKVX
na
na
na
10.3
HOP-62
0.933
0.201
0.559
0.677
nd
0.775
0.170
1.10
0.393
0.036
0.245
0.726
nd
0.420
0.322
0.442
0.324
0.649
0.351
0.153
HOP-92
NCI-H226
NCI-H23
3.09
NCI-H322M
NCI-H460
NCI-H522
Colon Cancer
15.9
0.374
0.294
0.416
0.436
0.117
0.163
0.343
0.406
0.049
0.209
COLO 205
HCC-2998
HCT-116
HCT-15
2.25
0.334
0.522
0.402
0.375
0.508
0.444
2.23
0.307
0.246
0.328
0.234
0.213
0.293
0.534
0.469
0.335
0.436
0.333
0.072
0.063
0.038
0.072
0.043
A single dose preliminary screening of the compounds was
carried out on all the synthesized compounds (8-15) at 10-5
HT29
M
KM12
concentration. From the preliminary screening the compounds
which showed 60% or more growth inhibition in at least eight of
the cell lines were further screened at five different
concentrations (10-4M, 10-5 M, 10-6 M, 10-7 M and 10-8 M)
following 48 h of incubation. From the single dose studies, four
(9, 10, 12, 15) of the eight compounds evaluated were not
considered for subsequent 5-dose studies because they only
showed 60% or more growth inhibition in two to six cell lines in
the panel. Compounds 8, 11, 13 and 14 were each evaluated in 5-
dose studies designed to determine growth inhibition (GI50)
values, which represent the molar drug concentration required to
cause 50% cell growth inhibition.
SW-620
CNS Cancer
0.708
0.861
0.568
0.985
SF-268
SF-295
SF-539
0.311
0.231
0.356
0.273
0.070
0.076
0.442
0.299
SNB-19
SNB-75
U251
0.461
0.329
0.442
0.584
0.475
0.668
0.095
0.162
0.088
0.362
0.190
0.338
Melanoma
0.664
0.895
1.90
0.382
LOX IMVI
MALME-3M
M14
0.388
0.332
0.413
0.479
0.072
0.063
0.826
0.169

the RSCB protein data bank (pdb id: 4O2B). For preparation of
tubulin to perform the docking calculations, the geometry of the
protein molecule was optimized using energy minimization
techniques after the addition of hydrogen atoms. Since no structured
water molecule was present in the binding pocket, all the water
molecules in the protein were deleted during the preparation of
protein structure for docking calculations. Amino acid side chain
bumps were fixed and terminal amino acids were charged to mimic
the biological environment. Hydrogen atoms were added to the
structure. The Kollman force field was applied and the protein was
minimized using the Powell method and Pullman charges. Structures
of compounds were initially generated in 2-D format in Chem Draw.
MDA-MB-435
SK-MEL-2
0.150
0.426
0.944
0.305
nd
0.078
0.767
0.837
0.345
16.4
0.024
0.064
0.313
0.047
15.0
0.036
0.323
0.346
0.267
0.520
0.185
SK-MEL-28
SK-MEL-5
UACC-257
UACC-62
0.465
0.507
0.050
Ovarian Cancer
0.504
0.807
0.249
0.520
IGROV1
OVCAR-3
OVCAR-4
OVCAR-5
OVCAR-8
NCI/ADR-RES
SK-OV-3
0.234
0.691
0.963
0.587
0.365
0.676
0.429
1.15
0.069
1.81
0.224
0.553
0.547
0.352
0.070
0.263
2.94
0.939
0.396
0.106
0.165
2.05
0.511
0.656
For generating energy-minimized structures, the 2-D structures of
the molecules were converted to 3-D using Chemdraw3D and the
structures saved in Mol2 format. All the structures were imported to
Sybyl in the Mol2 format. In SYBYL, the TRIPOS force field was
applied and 3-D structure coordinates went through a series of
minimization processes. Firstly, all the structures were minimized
using the BFGS method. After that, MOPAC charges were
calculated for each molecule followed by steepest decadence
minimization step. Each molecule was then checked for charges,
bond angle, torsion angles and geometry. All the molecules were
saved in one directory and prepared for docking via the ligand
preparation tool. For the docking analysis using the Surflex program,
a protomol was generated at the colchicine-binding site in tubulin.
This protomol is the representation of the binding site that simulates
the binding environment experienced by the ligand. The docking
analysis was performed using the Suflex Dock-Gemox module and
lists the C-scores (consolidated scores) for each molecule (Table. 2).
C-score is a measure of the goodness of fit. The C-score function
combines the binding score obtained from five different scoring
algorithms, namely: total score, G-score, PMF score, D-score and
Chem Score. In these docking calculations, the flexibilities of the
ligands were accounted for by considering 20 different
conformational states and scoring each of them. Docking analysis at
the cochicine-binding site demonstrated the binding mode of the
resveratrol analogs. Among the tested DMU-212 analogs,
compounds 13 and 14 exhibited the strongest binding interaction at
the colchicine-binding site on tubulin compared to the other two
analogs. All five compounds exhibited hydrogen bonding
interactions with ASN 258. Interestingly, compound 8 also exhibited
hydrogen bonding with THR 353, and compound 14 exhibited two
hydrogen bonding interactions with ASN 258 (Fig. 2).
Renal Cancer
0.802
0.850
1.32
0.445
786-0
A498
0.281
0.620
0.382
0.275
1.64
0.408
0.863
0.580
0.329
4.09
0.041
1.22
0.213
0.810
4.35
ACHN
CAKI-1
RXF 393
SN12C
0.143
0.142
9.37
0.168
0.666
0.566
0.513
TK-10
21.6
8.46
11.1
UO-31
0.172
1.15
0.376
Prostate Cancer
0.381
0.524
0.138
0.276
PC-3
DU-145
0.384
0.395
1.86
0.272
0.313
0.402
0.285
Breast Cancer
0.373
MCF7
MDA-MB-231/ATCC
HS 578T
1.30
1.17
0.713
0.171
0.450
0.275
0.257
0.499
BT-549
0.938
nd
1.09
0.693
0.662
3.72
0.961
0.825
0.326
nd
T-47D
MDA-MB-468
0.285
na
na: Not analyzed; nd: not determined; aGI50: concentration of drug resulting in
a 50% reduction in net cell growth, as compared to cell numbers on day 0.
bFive dose NCI cancer cell screening data for DMU-212 has been previously
reported.15
Placing the trans-3,4,5-trimethoxystyryl moiety at the C2
position of a benzothiazole ring afforded compound 13, which
exhibited significant growth inhibition against 81% of the cancer
cell lines in the panel with GI50 values ranging from 0.024 to
0.961 µM and an average GI50 value of 1.02 µM. This compound
exhibited growth inhibition against 3 out of 6 of the cell lines in
the leukemia sub-panel (GI50 values 0.036-0.041 µM); 5 out of 7
of the cell lines in the colon cancer sub-panel (GI50 values 0.038-
0.072 µM); 4 out of 6 of the cell lines in the CNS cancer sub-
panel (GI50 values of 0.070-0.095 µM); and 6 out of 9 of the cell
lines in the melanoma sub-panel (GI50 values 0.024-0.072 µM).
Compound 13 also exhibited potent growth inhibition of HOP-92
lung, OVCAR-3 ovarian, and A498 renal cancer cell lines with
GI50 values of 0.036. 0.069, and 0.041 µM, respectively (Table
1).
Compounds 8 and 13 also exhibited hydrophobic interactions
with Gln 247, and compound 14 exhibited interactions with Met
325, Gln 247, Leu 248. DMU-212 had interactions with Lys 352,
but no strong hydrophobic interactions were identified for
compound 11.
Table 2. Docking results for DMU-212, 8, 11, 13, and 14 at the
colchicine-binding site on tubulin
The substitution of the trans-3,4,5-trimethoxyphenyl moiety at
the C2 position of a benzothiophene ring afforded compound 14,
which exhibited potent growth inhibition against 95% of all the
cancer cell lines in the panel with GI50 values ranging from 0.036
to 0.985 µM and an average GI50 value of 0.59 µM. This
compound exhibited growth inhibition against MDA-MB-435
melanoma, NCI/ADR-RES ovarian, and K-562 leukemia cancer
cell lines with GI50 values of 0.036, 0.070 and 0.088 µM,
respectively (Table 1).
No. of positions
with maximum
C-score/20
No. of
H-bonds
Maximum
C-score
Comp.
DMU-212
1
2
1
1
2
4
4
4
5
5
1
2
2
1
2
8
11
13
14
Molecular modeling studies were performed for DMU-212 (II)
and the four heterocyclic analogs 8, 11, 13 and 14 utilizing SYBYL-
X 2.1 software. Binding interactions of these analogs were studied by
docking them at the colchicine-binding site on tubulin. 3-D
coordinates for the tubulin-colchicine complex were obtained from
In summary, compounds DMU-212, 8, 11, 13 and 14 all exhibited
similar binding interactions with tubulin at the colchicine-binding
site, with compounds 13 and 14 exhibiting the most favorable
interactions.

Fig. 2 Molecular docking studies of compounds 13, 14 and DMU-212 at the colchicine binding site on tubulin
6. Pace-Asciak, C. R.; Hahn, S.; Diamandis, E. P.; Soleas, G.; Goldberg, D.
M. Clin. Chim. Acta, 1995, 235, 207-219.
Conclusion
Novel heteroaromatic DMU-212 analogs (8-15) have been
synthesized and evaluated for their anti-cancer activity against a
panel of 60 human cancer cell lines. Compounds containing a
trans-3,4,5-trimethoxystyryl moiety (8, 11, 13, and 14) showed
potent growth inhibition with GI50 values generally <1 µM
against most of the cancer cell lines in the panel. The removal of
just one aromatic methoxy group from these compounds to afford
either trans-3,4-dimethoxystyryl (9) or trans-3,5-dimethoxy
styryl (10, 12, 15) analogs results in a decrease in anti-cancer
activity, which indicates that the 3,4,5-trimethoxystyryl moiety is
an essential structural element for the observed potent anti-cancer
activity of these DMU-212 analogs. Compounds 8, 11, 13 and 14
all exhibited significant growth inhibition against most of the
human cancer cells in the 60-cell panel, and the results from the
molecular modeling studies are consistent with the in vitro anti-
cancer activities of these molecules being mediated via their
binding to the colchicine binding site on tubulin. The above four
molecules were considered as important lead compounds for
further development as anti-cancer drugs.
7. Bertelli, A. A.; Giovannini, L.; Giannessi, D.; Migliori, M.; Bernini, W.;
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Acknowledgements
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We are grateful to NCI/NIH (Grant Number CA 140409), to
the Arkansas Research Alliance (ARA) for financial support, and
to the NCI Developmental Therapeutic Program (DTP) for
screening data.
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References and notes
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24. General procedure for the synthesis of heteroaromatic analogs of DMU-
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212 (8-15):
A mixture of carbaldehyde (0.001 mol), alkoxy triphenyl
phosphonium bromide (0.001 mol), and sodium methoxide (2.5 gm) in
methanol (50 ml) was stirred at room temperature for 3-4 h. Crushed ice was
then added to afford a solid product. The crude solid was isolated by filtration
and washed several times with cold methanol (3 x 5 ml). The resulting pale
yellow solid was then recrystallized from methanol to afford the desired (E)-
2-(3,4,5-trimethoxystyryl)heteroaromatic product. (E)-2-(3,4,5-trimethoxy
styryl)-1H-indole (8): mp: 228-2300C, 1H NMR (CDCl3); δ 3.87 (s, 3H), 3.92
(s, 6H), 6.61 (s, 1H), 6.72 (s, 2H), 6.82-6.86 (d, J=16.4 Hz, 1H), 7.01-7.05 (d,
J=16 HZ, 1H), 7.079-7.11 (t, J=7.2 Hz, 14.8Hz, 1H), 7.17-7.21 (t, J=7.2 Hz,
3. Soleas, G. J.; Diamandis, E. P.; Goldberg, D. M. Clin. Biochem., 1997,
30, 91-113.
4. Fauconneau, B.; Waffo-Teguo, P.; Huguet, F.; Barrier, L.; Decendit, A.;
Merillon, J. M. Life Sci., 1997, 61, 2103-2110.
5. Chanvitayapongs, S.; Draczynska-Lusiak, B.; Sun, A. Y. Neuroreport,
1997, 8, 1499-1502.

15.2 Hz 1H), 7.33-7.35 (d, J=7.6 Hz, 1H), 7.57-7.59 (d, J=7.6 Hz, 1H), 8.27
(brs, 1H, NH). 13C NMR (CDCl3): δ 56.22, 60.89, 103.30, 103.69, 110.46,
118.53, 120.23, 120.50, 120.70, 122.85, 127.04, 127.08, 128.96, 132.57,
136.18, 136.91, 138.05, 153.46. HRMS calcd for C19H20NO3, (MH+):
310.1438. Found 310.1435. (E)-2-(3,4-dimethoxystyryl)-1H-indole (9):
1
mp:203-205 0C; H NMR (CDCl3); δ 3.91 (s, 3H), 3.95 (s, 3H), 6.58 (s, 1H),
6.83-6.86 (d, J=10.4 Hz, 1H), 6.88 (s, 1H), 6.97 (s, 1H), 7.01- 7.11 (m, 3H),
7.16-7.20 (t, J=7.2 and 15.2 Hz, 1H), 7.32-7.34 (d, J=8Hz, 1H), 7.56-7.58 (d,
J=8Hz, 1H), 8.22 (brs, 1H, NH);13C NMR (CDCl3): δ 55.87, 55.95, 103.23,
108.40, 110.48, 111.27, 117.18, 119.82, 120.13, 120.48, 122.65, 127.00,
129.04, 129.92, 136.53, 136.84, 149.06, 149.21 ppm. HRMS calcd for
C18H18NO2, (MH+): 280.1332. Found 280.1327. (E)-2-(3,5-dimethoxystyryl)-
1H-indole (10): mp:134-136 0C, 1H NMR (CDCl3): δ 3.84 (s, 6H), 6.42 (s,
1H), 6.62 (s, 1H), 6.66 (s, 2H), 6.80-6.84 (d, J=16.4 Hz, 1H), 7.07-7.13 (m,
2H), 7.18-7.22 (t, J=7.2, 15.2Hz, 1H), 7.33-7.35 (d, J=8Hz, 1H), 7.58-7.60 (d,
J=7.6Hz, 1H), 8.25 (brs, 1H, NH), 13C NMR (CDCl3): δ 55.38, 100.01,
104.10, 104.42, 110.63, 119.53, 120.20, 120.66, 122.94, 127.05, 128.94,
136.10, 136.98, 138.84, 161.03 ppm. HRMS calcd for C18H18NO2, (MH+):
280.1332. Found 280.1341. (E)-2-(3,4,5-trimethoxystyryl)benzo[b]furan
0
(11): mp:124-126 C, 1H NMR (CDCl3): δ 3.87 (s, 3H), 3.91 (s, 6H), 6.66 (s,
1H), 6.75 (s, 2H), 6.88-6.92 (d, J=16Hz, 1H), 7.20-7.26 (m, 3H), 7.44-7.46
(d, J=8.4 Hz, 1H), 7.51-7.53 (d, J=7.6Hz, 1H) ppm; 13C NMR (CDCl3): δ
56.11, 60.98, 103.72, 105.04, 110.82, 115.88, 120.79, 122.90, 124.60, 129.11,
130.21, 132.25, 138.36, 153.44, 154.83, 154.94 ppm. HRMS calcd for
C19H19O4, (MH+): 311.1278. Found 311.1273. (E)-2-(3,5-dimethoxystyryl)
benzo[b]furan (12): mp: 29-310C, 1H NMR (CDCl3): δ 3.83 (s, 6H), 6.41-
6.42 (d, J=1.6Hz, 1H), 6.68 (s, 3H), 6.95-6.99 (d, J=16.4Hz, 1H), 7.20-7.26
(m, 3H), 7.45-7.47 (d, J=8.0 Hz, 1H) 7.51-7.53 (d, J= 7.2Hz, 1H); 13C NMR
(CDCl3): δ 55.37, 100.56, 104.71, 105.43, 110.88, 116.92, 120.84, 122.89,
124.68, 129.07, 130.23, 138.53, 154.85, 154.90, 161.01 ppm. HRMS calcd
for C18H17O3, (MH+): 281.1172. Found 281.1170. (E)-2-(3,4,5-trimethoxy
styryl)benzo[d]thiazole (13): mp: 125-127 0C, 1H NMR (CDCl3): δ 3.91 (s,
3H), 3.93 (s, 6H), 6.83 (s, 2H), 7.33-7.48 (m, 4H), 7.87 (s, 1H), 8.0 (s, 1H)
ppm; 13C NMR (CDCl3): δ 56.12, 60.96, 104.47, 121.48, 122.89, 125.32,
126.33, 130.95, 134.26, 137.47, 153.5, 153.8, 166.78 ppm. HRMS calcd for
C18H18NO3S, (MH+): 328.1002. Found 328.1007. (E)-2-(3,4,5-trimethoxy
styryl)benzo[b]thiophene (14): mp:154-156 0C, 1H NMR (CDCl3): δ 3.87 (s
3H), 3.92 (s, 6H), 6.73 (s, 2H), 6.89-6.93 (d, J=16 Hz, 1H), 7.20 (s, 1H), 7.30
(m, 2H), 7.68-7.77 (dd, J1=6.8 Hz, J2=31.2 Hz, 2H). 13C NMR (CDCl3): δ
56.14, 60.96, 103.67, 110.0, 121.79, 122.18, 123.11, 123.35, 124.51, 124.73,
130.78, 132.29, 138.81, 140.18, 142.74, 153.43 ppm. HRMS calcd for
C19H19O3S, (MH+): 327.1049. Found 327.1047. (E)-2-(3,5-dimethoxystyryl)
benzo[b]thiophene (15): mp:103-105 0C, 1H NMR (CDCl3): δ 3.83 (s, 6H),
6.41 (s, 1H), 6.66 (s, 2H), 6.90-6.94 (d, J= 15.6 Hz, 1H), 7.25-7.30 (m, 4H),
7.68-7.78 (dd, J=6.4 Hz, 2H). 13C NMR (CDCl3): δ 55.73, 100.80, 104.93,
122.56, 123.16, 123.78, 123.85, 124.85, 125.14, 131.15, 138.93, 139.28,
140.50, 143.01, 161.35 ppm. HRMS calcd for C18H17O2S, (MH+): 297.0944.
Found 297.0947.

Graphical Abstract
Leave this area blank for abstract info.
Heteroaromatic analogs of the resveratrol analog
DMU-212 as potent anti-cancer agents
Narsimha Reddy Penthala, Shraddha Thakkar and Peter A. Crooks