Synthesis and cytotoxic effects on pancreatic cancer cells of resveratrol analogs

Article abstract of DOI:10.1007/s00044-019-02351-3

In this study, a series of resveratrol analogs was synthesized and the effects on the viability of pancreatic cancer cell lines were evaluated. The new molecules were designed by removing the 3- and 5-OH groups of resveratrol, and by incorporating other s

Full text of DOI:10.1007/s00044-019-02351-3

MEDICINAL
CHEMISTRY
RESEARCH
Medicinal Chemistry Research
https://doi.org/10.1007/s00044-019-02351-3
ORIGINAL RESEARCH
Synthesis and cytotoxic effects on pancreatic cancer cells
of resveratrol analogs
Barbara De Filippis1 Laura De Lellis2,3 Rosalba Florio2,3 Alessandra Ammazzalorso1 Pasquale Amoia1
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Marialuigia Fantacuzzi1 Letizia Giampietro1 Cristina Maccallini1 Rosa Amoroso
Alessandro Cama2,3
Serena Veschi2,3
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Received: 13 February 2019 / Accepted: 22 April 2019
© Springer Science+Business Media, LLC, part of Springer Nature 2019
Abstract
In this study, a series of resveratrol analogs was synthesized and the effects on the viability of pancreatic cancer cell lines
were evaluated. The new molecules were designed by removing the 3- and 5-OH groups of resveratrol, and by incorporating
other substituents in 4-position, or by replacing the dihydroxybenzene with other aromatic systems. In all compounds the 4′-
OH was kept unalterated. The effects of the compounds on cell viability were analyzed in three pancreatic cancer cell lines
with distinct genetic profiles. Several compounds (e.g., 5, 9, and 12) exhibited improved cytotoxic activities as compared to
the reference compounds, making them potential candidates for further evaluation as anticancer drugs.
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Keywords Antiproliferative Resveratrol 4-Hydroxystilbene Cytotoxicity Pancreatic cancer
Abbreviations
skin and red wine, is a component of Asian traditional
medicine used to treat cardiovascular diseases. Several
studies showed that RSV, as well as its analogs and deri-
vatives, exhibits antioxidant (Sadeghi et al. 2017), anti-
inflammatory (de Sá Coutinho et al. 2018), and protective
activities against cardiac (Bonnefont-Rousselot 2016),
neurodegenerative (Ono et al. 2003; Zhang et al. 2005), and
metabolic disorders (Chou et al. 2018; Diaz-Gerevini et al.
2016). RSV has also been reported to have a cancer che-
moprotective effect (Huang and Zhu 2011; Elshaer et al.
2018). Since 1997, RSV has also gained considerable
attention as anticancer agent (Block et al. 1992; Jang et al.
1997), because of its potential use in chemoprevention and
chemotherapy of various tumors, including colon, breast,
and prostate cancers, mediated via effects on cell growth,
apoptosis, angiogenesis, and metastasis (Carter et al. 2014).
The cancer chemoprevention effects of RSV could be
mainly attributed to its antioxidant activity (De la Castra
and Villegas 2007; Kruk and Aboul-Enein 2017), since
free-radical-mediated peroxidation of membrane lipids and
oxidative damage of DNA play an important role in cancer
(Telek et al. 2001; Shang et al. 2009). The antioxidant
mechanism of RSV has been studied in detail and several
studies have shown that the OH in 4′-position is essential
for the scavenging of free radicals (Queiroz et al. 2009;
Garcia et al. 2013; Scherzberg et al. 2015; Deck et al. 2017).
The 4′-OH is also responsible for other biological activities;
indeed, the interaction between the 4′-hydroxystyryl moiety
RSV
PC
SLB
resveratrol
pancreatic cancer
stilbene
4-HSLB 4′-hydroxystilbene
TBSCl
NEt3
t-butyldimethylsilyl chloride
triethylamine
TBAF
tetra-n-butylammonium fluoride
Introduction
Resveratrol (trans-3,5,4′-trihydroxystilbene, RSV), a well-
known natural polyphenolic phytoalexin present in grape
These authors contributed equally: Barbara De Filippis, Laura
De Lellis
* Rosa Amoroso
rosa.amoroso@unich.it
1
Unit of Medicinal Chemistry, Department of Pharmacy, University
of Chieti “G. d’Annunzio”, Chieti, Italy
2
Unit of General Pathology, Department of Pharmacy, University
of Chieti “G. d’Annunzio”, Chieti, Italy
3
Center on Aging Sciences and Translational Medicine (Ce.S.I.-
MeT), University of Chieti “G. d’Annunzio”, Chieti, Italy

Medicinal Chemistry Research
4'
OH
OH
4'
and DNA polymerase has been described as a mechanism
underlying the inhibition of cell cycle progression (Britton
et al. 2015), and 4′-OH in trans-configuration was required
for inhibition of cell proliferation (Stivala et al. 2001).
Pancreatic cancer (PC) is the fourth common cause of
cancer death in occidental countries with a very limited
median survival time (<6 months) and a 5-year survival
time ranging from 1% to 4% (Teague et al. 2015). Surgical
resection is the best therapeutic option for PC, but it is
possible for less than 20% of patients, since this tumor
develops without early symptoms and is frequently diag-
nosed at advanced stages. At present, systematic che-
motherapy includes gemcitabine, the combination of
gemcitabine and nab-paclitaxel or, alternately, the Folfir-
inox protocol (5-FU, leucovorin, irinotecan, and oxalipla-
tin), although survival outcomes for PC patients remain
very poor (Ansari et al. 2016). Moreover, these agents have
a significant toxicity that becomes more marked when they
are used in combination. Thus, the limited success of cur-
rent standard therapies underlines an urgent need to identify
new therapeutic strategies and agents to treat this deadly
disease. In this light, several natural and synthetic mole-
cules, including RSV and its derivatives, have been
explored as single agents or in combination with standard
chemotherapy in cell and animal models of PC manifesting
significant cytotoxicity, thus suggesting their potential as
agents for PC prevention and treatment (Ding and Adrian
2002; Xu et al. 2015; Duan et al. 2016; Murty et al. 2016;
Tsang et al. 2016; Ammazzalorso et al. 2017; Herrera-R
et al. 2018).
Recently, we modified the structure of RSV by introducing
various substituents on the two aromatic rings or replacing the
distal phenyl with other aromatic rings, and generating
hybrids with alkanoic chains, with the aim to act on nuclear
receptor PPAR (De Filippis et al. 2011, 2015a, 2015b;
Leporini et al. 2017; Giampietro et al. 2012, 2014, 2019; dos
Santos et al. 2015) In order to better explore the importance of
the stilbene (SLB) scaffold contained in RSV, and taking into
account the well-established multiple activities of SLB-
containing compounds (De Filippis et al. 2017, 2019;
Giacomini et al. 2016; Chillemi et al. 2007; Kondratyuk et al.
2011), in this study we focused on the possibility of changing
the structure of RSV to obtain analogs active on PC. Bearing
in mind that the 4′-OH was considered essential for the
antioxidant/antitumor activity, we synthesized analogs of the
RSV in which the 4′-OH was preserved, and the 3,5-OH
moiety was replaced with 4-substituted phenols (compounds
1–9). Other analogs were synthesized by introducing another
aromatic ring instead of 3,5-OH phenyl (compounds 10–12).
All new derivatives can be considered analogs of the RSV but
also of the 4-hydroxystilbene (4-HSLB, Fig. 1), which was
therefore considered in the biological tests as a further refer-
ence compound.
3
HO
1
5
OH
4-HSLB
RSV
OH
OH
N
1 CN
2 OMe
3 NO2
4 CF3
5 Me
6 iPro
7 Cl
8 CH2OH
9 NH2
OH
10
11
4'
R
1
S
1-9
OH
12
Fig. 1 Resveratrol, 4-hydroxystilbene, and general structure of new
analogs 1–12
We evaluated the cytotoxicity of compounds 1–12 in
three PC cell lines, AsPC-1, Capan-2, and BxPC-3, with the
aim to identify the influences of substituents added in p-
position and different aromatics instead of distal phenyl of
RSV on the viability of the PC cells.
Materials and methods
Chemistry
General
Commercial reagents, RSV, and 4-HSLB were used as
received from Aldrich or Fluka. Flash chromatography was
performed on silica gel 60 (Merck) and TLC on F254 silica
gel 60 TLC plates. Melting points (m.p.) were determined
on a Büchi B-540 apparatus and are uncorrected. Infrared
spectra were recorded on an FT-IR 1600 PerkinElmer
spectrometer. NMR spectra were run at 300 MHz on a
Varian instrument using TMS as internal standard; chemical
shifts (δ) are reported in ppm. Microanalyses were carried
out with a Eurovector EuroEA3000 model analyzer. Ana-
lyses indicated by the symbols of the elements were within
0.4% of the theoretical values.
Preparation of arylethenylphenols 1–8 and 10–12
A stirred mixture of piperidine (10.23 mmol), appropriately
4-substituted arylacetic acid (4.91 mmol), and 4-
hydroxybenzaldeyde (4.09 mmol) was heated gradually to

Medicinal Chemistry Research
130 °C. After 4–24 h, the residue was cooled at room
temperature (r.t.) and portioned between EtOAc (3 × 30 mL)
and water (20 mL). The organic phases were dried over
Na2SO4 and concentrated under reduced pressure to yield
the crude products that were purified by column chroma-
tography (eluent CH2Cl2/MeOH 95:5 or cyclohexane/
EtOAc 6:4) giving the pure phenols 1–8 and 10–12.
4-[(E)-2-(4-hydroxyphenyl)ethenyl]benzonitrile (1):
4-[(E)-2-(4-methylphenyl)ethenyl]phenol (5): white
amorphous solid, 21% yield. H NMR (acetone-d6) δ 2.3
1
(3H, s), 6.91 (2H, d, J = 8.7 Hz), 7.05 (2H, q, J = 10.8 Hz),
7.15 (2H, d, J = 7.8 Hz), 7.35 (2H, d, J = 8.4 Hz), 7.42 (2H,
d, J = 7.2 Hz); 13C NMR (CDCl3) δ 25.99 (CH3), 116.09
(CHArC), 126.22 (CHAr), 126.88 (CH=CH), 126.95 (CHAr),
127.72 (CH=CH), 128.77 (CHAr), 129.45 (CHAr), 135.46
(CHAr), 136.75(CHAr), 158.38 (CHAr); IR (neat) 3436,
2932, 2853, 1603, 1497.3, and 1263 cm−1; anal. calc. for
C15H14O: C, 85.68; H, 6.71; Cl, 7.61; O, 6.94; found: C,
85.38; H, 6.72.
1
green solid, 24% yield, m.p. 218–220 °C. H NMR (acet-
one-d6) δ 6.87 (d, J = 8.7 Hz, 2H), 7.1 (q, J = 49.5 Hz,
2H), 7.38 (d, J = 9.0 Hz, 2H), 7.51 (q, J = 12.9 Hz, 4H);
13C NMR (acetone-d6) δ 114.0 (CArCN), 115.02 (CHAr),
119.41 (CN), 126.76 (CHAr), 128.48 (CHAr), 129.15
(CH=CH), 129.69 (CH=CH), 130.37 (CHAr), 132.69
(CHAr), 142.47 (CHAr), 159.74 (CHAr), 179.0 (CO); IR
(neat) 3313, 2234, 1595, and 1209 cm−1; anal. calc. for
C15H11NO: C, 81.43; H, 5.01; N, 6.33; O, 7.23; found:
C, 81.15; H, 5.00; N, 6.34.
4-[(E)-2-(4-isopropylphenyl)ethenyl]phenol (6): white
1
solid, 19% yield, m.p. 159−161 °C. H NMR (CD3OD)
δ 1.23 (d, J = 6.6 Hz, 6H), 2.84–2.92 (m, 1H), 6.76 (d, J =
8.4 Hz, 2H), 6.96 (q, J = 14.4 Hz, 2H), 7.16 (d, J = 7.5 Hz,
2H), 7.37 (d, J = 2.1 Hz, 4H); 13C NMR (CD3OD) δ 23.21
(CH3), 33.95 (CH), 115.29 (CHAr), 125.52 (CH=CH),
126.00 (CHAr), 126.42 (CHAr), 127.47 (CH=CH), 127.52
(CHAr), 129.44 (CAr), 135.73 (CAr), 147.82 (CAr), 157.08
(CArOH); IR (neat) 3437, 2935, 2853, 1603, 1497, and
1263 cm−1; anal. calc. for C17H18O: C, 85.67; H, 6.61; O,
6.71; found: C, 85.99; H, 7.57.
4-[(E)-2-(4-methoxyphenyl)ethenyl]phenol (2): yellow
1
solid, 17% yield, m.p. 206–207 °C. H NMR (acetone-d6)
δ 3.79 (s, 3H), 6.83 (d, J = 8.7 Hz, 2H), 6.91 (d, J = 9.0 Hz,
2H), 7.00 (s, 2H), 7.41 (d, J = 8.7 Hz), 7.48 (d, J = 8.7 Hz,
2H), 8.44 (s, 1H, OH); 13C NMR (acetone-d6) δ 54.88
(CH3), 114.23 (CAr), 115.72 (CAr), 125.47 (CH=CH),
126.48 (CH=CH), 127.52 (CAr), 127.75 (CAr), 129.7 (CAr),
130.8 (CAr), 157.2 (CAr), 159.3 (CArOCH3); IR (neat) 3423,
3019, 2955, 2838, 2360, 1607, 1514, and 1250 cm−1; anal.
calc. for C15H14O2: C, 79.62; H, 6.24; O, 14.14; found: C,
79.35; H, 6.25.
4-[(E)-2-(4-chlorophenyl)ethenyl]phenol (7): white
1
solid, 16% yield, m.p. 184–185 °C. H NMR (CD3OD) δ
6.83 (d, J = 9.0 Hz, 2H), 6.95 (q, J = 20.7 Hz, 2H), 7.28 (d,
J = 9.0 Hz, 2H), 7.38 (d, J = 9.0 Hz, 2H), 7.40 (d,
J = 9.0 Hz, 2H); 13C NMR (CD3OD) δ 115.33 (CHAr),
124.08 (CH=CH), 127.33 (CHAr), 127.81 (CHAr), 128.50
(CHAr), 129.29 (CH=CH), 130.22 (CAr), 132.17 (CArCl),
136.97 (CAr), 157.49 (CArOH); IR (neat) 3267, 2728, 1606,
1513, 1245 cm−1; anal. calc. for C14H11ClO: C, 72.89; H,
4.81; Cl, 15.37; O, 6.94; found: C, 72.66; H, 4.80.
4-[(E)-2-(4-nitrophenyl)ethenyl]phenol (3): red solid,
1
30% yield, m.p. 201 °C dec. H NMR (acetone-d6) δ 6.89
(d, J = 8.7 Hz, 2H), 7.19 (d, J = 16.5 Hz, 1H), 7.44 (d, J =
16.5 Hz, 1H), 7.54 (d, J = 8.7 Hz), 7.79 (d, J = 8.7 Hz, 2H),
8.20 (d, J = 9.0 Hz, 2H); 13C NMR (acetone-d6) δ 115.96
(CHAr), 123.49 (CH=CH), 124.14 (CHAr), 126.87 (CHAr),
128.45 (CAr), 128.97 (CHAr), 133.59 (CH=CH), 145.13
(CAr), 163.26 (CAr), 190.40 (CArNO2); IR (KBr) 3422
(broad), 1585, 1504, 1336, and 1108 cm−1; anal. calc. for
C14H11NO3: C, 69.70; H, 4.60; N, 5.81; O, 19.90; found: C,
69.87; H, 4.60; N, 5.80.
4-[(E)-2-(4-trifluoromethylphenyl)ethenyl]phenol (4):
white solid, 23% yield, m.p. 161–163 °C. 1H NMR (acetone-
d6) δ 6.87 (d, J = 8.4 Hz, 2H, CHAr), 7.13 (d, J = 16.2 Hz,
1H, CH=CH), 7.34 (d, J = 16.5 Hz, 1H, CH=CH), 7.50 (d,
J = 8.1 Hz, 2H, CHAr), 7.66 (d, J = 8.4 Hz, 2H, CHAr), 7.75
(d, J = 7.8 Hz, 2H, CHAr); 13C NMR (acetone-d6) δ 115.85
(CHAr), 124.08 (CH=CH), 125.65 (q, CHAr), 126.69 (CHAr),
128.00 (CHAr), 128.70 (CAr), 131.62 (CF3), 128.70
(CH=CH), 142.27 (CAr), 158.13 (CAr); IR (neat) 3614, 3419,
3271, 1599, 1511, 1327, 1254, 1181, and 836 cm−1; anal.
calc. for C15H11F3O: C, 68.18; H, 4.20; F, 21.57; O, 6.05;
found: C, 68.35; H, 4.22.
4-[(E)-2-(4-hydroxymethylphenyl)ethenyl]phenol (8):
the crude product was directly crystallized from MeOH/
water obtaining a brown amorphous solid, 38% yield, m.p.
1
170–175 °C. H NMR (CD3OD) δ 3.85 (2H, s), 6.11 (d,
J = 8.1 Hz, 2H), 6.35 (q, J = 19.5 Hz, 2H), 6.65 (d, J =
7.5 Hz, 2H), 6.73 (d, J = 8.1 Hz, 2H), 6.81 (d, J = 7.5 Hz,
2H); 13C NMR (CD3OD) δ 64.33 (CH2), 113.09 (CHArC),
126.22 (CHAr), 126.88 (CH=CH), 126.95 (CHAr), 127.72
(CH=CH), 128.77 (CHAr), 129.45 (CHAr), 140.46 (CHAr),
142.75(CHAr), 157.38 (CHAr); IR (neat) 3436, 2932, 2850,
1603, 1497.3, and 1263 cm−1; anal. calc. for C15H14O: C,
85.68; H, 6.71; found: C, 85.69; H, 6.69.
4-[(E)-2-(pyridin-4-yl)ethenyl]phenol (10): yellow
powder, 14% yield, m.p. 267–268 °C. 1H NMR (CD3OD) δ
6.79 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 16.5 Hz, 1H), 7.41 (d,
J = 16.8 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.51 (d, J =
4.5 Hz, 2H), 8.41 (d, J = 4.5 Hz, 2H); 13C NMR (CD3OD) δ
116.34 (CHAr), 121.16 (CHAr), 123.12 (CH=CH), 127.86
(CAr), 129.35 (CHAr), 133.72 (CH=CH), 145.48 (CAr),
150.58 (CHAr), 158.89 (CAr); IR (neat) 3532, 2990, 1586,

Medicinal Chemistry Research
1464, and 1256 cm−1; anal. calc. for C13H11NO: C, 79.16;
H, 5.62; N, 7.10; O, 8.11; found: C, 78.88; H, 5.62; N, 7.10.
4-[(E)-2-thien-3-ylvinyl]phenol (11): white solid, 15%
mixture was stirred at 95 °C for an additional 1 h. After
being cooled to r.t., the mixture was filtered through Celite
and the filtrate was washed with saturated NaHCO3
(20 mL × 4); the organic phase was dried with Na2SO4 and
the solvent was evaporated. The product 15 (brown solid,
1
yield, m.p. 199–200 °C. H NMR (CDCl3) δ 6.8 (d, J =
9.0 Hz, 2H), 6.93 (q, J = 15.3 Hz, 2H), 7.20–7.21 (m, 1H),
7.31 (2H, t), 7.36 (d, J = 8.4 Hz, 2H); 13C NMR (CDCl3) δ
115.82 (CHAr), 121.23 (CH=CH), 121.84 (CHTh), 125.06
(CHTh), 126.33 (CH=CH), 127.89 (CHAr), 128.33 (CHTh),
130.23 (CAr), 140.6 (CTh), 158.82 (CAr); IR (KBr) 3430,
3092, 1601, 1504, and 1249 cm−1; anal. calc. for C12H10OS:
C, 71.25; H, 4.98; O, 7.91; S, 15.85; found: C, 71.45;
H, 4.98.
1
68% yield) was used without further purification. H NMR
(DMSO-d6) δ 0.16 (s, 2H), 0.925 (s, 3H), 5.24 (s, 2H), 6.51
(d, J = 8.4 Hz, 2H), 6.77 J 8.1 (d, J = 8.1 Hz, 2H), 6.83
(q, J = 9.6 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 7.35 (d, J =
8.7 Hz, 2H); 13C NMR (DMSO-d6) δ 2.78 (CH3), 18.23 (C),
26.22 (CH3), 114.39 (CHAr), 115.88 (CHAr), 127.45 (CHAr),
127.54 (CHAr), 129.42 (C=C), 129.80 (CAr), 130.04 (CAr),
148.55 (CArNH2), 156.77 (CAr); anal. calc. for C20H27NOSi:
C, 73.79; H, 8.36; N, 4.30; O, 4.92; Si, 8.63; found: C,
73.73; H, 8.37; N, 4.32.
4-[(E)-2-(2-naphthyl)vinyl]phenol (12): green solid,
1
15% yield, m.p. 212–213 °C. H NMR (acetone-d6) δ 6.87
(d, J = 8.7 Hz, 2H), 7.28 (q, J = 15.3 Hz, 2H), 7.41–7.52
(m, 2H), 7.52 (d, J = 8.7 Hz, 2H), 7.85 (d, J = 6.0 Hz, 4H),
7.92 (s, 1H), 8.53 (s, OH); 13C NMR (acetone-d6) δ 115.82
(CHArCOH), 123.65 (CHArCCH), 125.80 (CHAr), 125.83
(CHAr), 126.05 (CHArCCH), 126.50 (CHAr), 127.83
(CH=CH), 128.02 (CH=CH), 128.19 (CHArCCH), 128.39
(CHArC), 129.24 (CHArC), 129.34 (CArCH), 133.12 (CAr),
134.19 (CArCH), 135.82 (CAr), 157.69 (CAr); IR (neat)
3395, 3051, 1597, 1510, and 1250 cm−1; anal. calc. for
C18H14O: C, 87.77; H, 5.73; O, 6.50; found: C, 88.99;
H, 5.71.
4-[(E)-2-(4-aminophenyl)ethenyl]phenol (9): tetra-n-
butylammonium fluoride (TBAF, 1.0 M in THF, 6.15 mL,
6.15 mmol) was added into a solution of 15 (2.46 mmol) in
THF (15 mL). After being stirred for 2 h at r.t., the mixture
was quenched with water (25 mL) and extracted with EtOAc
(3 × 30 mL). The organic phase was washed with brine
(30 mL), dried over Na2SO4, and the solvent was evaporated.
The crude product was purified by silica chromatography by
using cyclohexane/EtOAc (1:1) as eluent to give 9 as brown
1
solid, 47% yield, m.p. 250 °C dec. H NMR (CDCl3) δ 6.64
(d, J = 8.4 Hz, 2H, 6.82 (d, J = 8.7 Hz, 2H), 6.85 (2H, s),
7.28 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.7 Hz, 2H); 13C NMR
(CDCl3) δ 114.82 (CHAr), 115.46 (CHAr), 124.92 (CH=CH),
126.78 (CH=CH), 127.42 (CHAr), 127.63 (CHAr), 128.57
(CAr), 130.87 (CAr), 146.02 (CAr), 158.40 (CAr); IR (neat)
3437, 1614, 1512, 1250 cm−1; anal. calc. for C14H13NO: C,
79.59; H, 6.20; N, 6.63; O, 7.57; found: C,79.29; H, 6.21; N,
6.61.
Preparation of of 4-[(E)-2-(4-aminophenyl)ethenyl]phenol (9)
t-Butyl(dimethyl){4-[(E)-2-(4-nitrophenyl)ethenyl]phe-
noxy}silane (13): a solution of t-butyldimethylsilyl chloride
(TBSCl, 1.20 mmol) in dry CH2Cl2 (6.0 mL) was added
dropwise at 0 °C into a solution of 3 (4.14 mmol) and
triethylamine (NEt3, 0.012 mmol) in dry CH2Cl2 (14 mL).
The reaction mixture was stirred at r.t. for 22 h and then
quenched with water (4 mL). The organic layer was washed
with brine (30 mL × 3), dried over MgSO4, filtered, and
concentrated in vacuo. The final red waxy solid (76% yield)
Biology
Cell cultures, treatments, and the MTT assay
1
was used without further purification. H NMR (CDCl3)
δ 0.07 (s, 6H), 0.83 (s, 9H), 6.69 (d, J = 8.4 Hz, 2H), 6.84
(d, J = 16.2 Hz, 1H), 7.05 (d, J = 16.2 Hz, 1H), 7.27 (d,
J = 8.4 Hz, 2H), 7.42 (d, J = 8.7 Hz, 2H), 8.03 (d, J =
8.4 Hz, 2H); 13C NMR (CDCl3) δ 2.78 (CH3), 18.23 (C),
26.22 (CH3), 114.39 (CHAr), 115.88 (CHAr), 127.45 (CHAr),
127.54 (CHAr), 129.42 (C=C), 134.0 (CAr), 137.5 (CAr),
148.8 (CArNO2), 161.1 (CArO); anal. calc. for C20H25NO3Si:
C, 67.57; H, 7.09; N, 3.94; O, 13.50; Si, 7.90; found: C,
67.58; H, 7.07; N, 3.92.
4-[(E)-2-(4-{[t-butyl(dimethyl)silyl]oxy}phenyl)ethe-
nyl]phenylamine (14): Fe powder (1.83 mmol) in 5%
acetic acid (6.8 mL) was stirred at 95 °C for 30 min and
cooled to 50 °C for 3 h. The solution of 14 (0.36 mmol) in
EtOAc (2.5 mL) was added into the reaction mixture. The
Human PC cell lines AsPC-1, Capan-2, and BxPC-3 were
cultured in RPMI 1640 medium (EuroClone) supple-
mented with 10% fetal bovine serum (Sigma-Aldrich, St.
Louis, MO, USA), at 37 °C, 5% CO2. Stock solutions
were prepared dissolving compounds in DMSO (Euro-
Clone), which were then diluted to the final working
concentrations in culture media. In this way, the solutions
were completely clear and devoid of any undissolved
material by microscopic inspection. The final concentra-
tion of DMSO in the experiments was 0.1% and showed
no cell toxicity.
The effects of compounds 1–12, RSV, and 4-HSLB on
PC cell viability were tested by the MTT assay (Sigma-
Aldrich, St. Louis, MO, USA) following the

Medicinal Chemistry Research
O
O
manufacturer’s instructions. Briefly, cells were seeded in
96-well plates (4 × 103 cells/well) and incubated for 72 h
with vehicle, or the test compounds. For initial screening,
the compounds were tested at concentrations of 0, 20, and
100 μM (five replica wells per each condition). Subse-
quently, the reference and the novel compounds showing
the most relevant activities on cell viability were also
tested at five different concentrations ranging from 0 to
100 μM (data not shown, five replica wells per each
condition). At the end of the incubation time, cells were
incubated with MTT solution for at least 3 h, until purple
precipitate was visible. Then, the MTT solution was
removed and crystalline precipitate in each well was
dissolved into DMSO. Absorbance of each well at 540 nm
with background subtraction at 690 nm was quantified
using a Synergy H1 microplate reader (BioTek Instru-
ments Inc., Winooski, VT, USA).
Ar
Ar
a
+
H
OH
OH
OH
1-8, 10-12
Scheme 1 Reagents and conditions. a: 4-hydroxybenzaldehyde (1.0
eq), arylacetic acid (1.2 eq), and piperidine (2.5 eq), 130 °C, 4–24 h,
14–38%
Antiproliferative activities of target compounds
O2N
O2N
a
OH
OTBS
13
3
H2N
H2N
Statistical analysis and IC50 calculation
c
b
Comparisons of mean values were performed using the
independent samples t-test, using the Dunnett’s test for
multiple comparisons where appropriate. A p-value of
0.05 was considered statistically significant. IC50 values
were calculated using the GraphPad software.
OH
OTBS
14
9
Scheme 2 Reagents and conditions. a: TBSCl (3 eq), Et3N (3 eq),
DCM, 0 °C - r.t. overnight, 76%; b: Fe powder (5 eq), 5% acetic acid,
95 °C, 68%; c: TBAF 1M (2 eq), THF, r.t., 3 h, 47%
Results and discussion
The effects of new compounds on the viability of AsPC-1,
Capan-2, and BxPC-3, three human PC cell lines with
distinct genetic profiles, were evaluated by the MTT assay,
one of the most sensitive and reliable indicators of cell
metabolic activity, which is widely used to assess cell via-
bility (Mosmann 1983; Florio et al. 2017, 2018; Veschi
et al. 2018). It relies on the ability of dehydrogenases
occurring in the mitochondria of living cells to reduce the
tetrazolium dye MTT to its water-insoluble formazan salt;
purple formazan crystals can be finally solubilized and
quantified using a spectrophotometer. In our study, RSV
and 4-HSLB were used as references. Figure 2 shows the
results of the screening of the effects of novel and reference
compounds on PC cell viability.
In general, all compounds affected viability of the three
PC cell lines in a dose-dependent manner; in fact, the
inhibition effect on viability at 100 µM is always higher
than that observed at 20 µM. Specifically, at the highest
concentration of 100 µM, a cell viability of <50% was
observed for all tested compounds in the three cell lines,
showing a good cytotoxicity, with the exception of 8 in
BxPC-3 and Capan-2, and 9 and RSV in Capan-2.
Chemistry
The synthesis of compounds 1–8 and 10–12 was carried
out as reported in the literature (Zhang et al 2005; De
Filippis et al. 2015a, 2015b; Lazer et al. 1990). The 4-
hydroxybenzaldehyde and the appropriate aryl acetic acid
were mixed in the presence of piperidine at 130 °C. The
usual aqueous work-up and purification using silica gel
column chromatography produced the desired phenols.
The synthetic route is provided in Scheme 1.
The p-aminostilbene 9 was obtained starting from the
corresponding nitro derivative 3, treated with TBSCl in
the presence of NEt3 to form the O-silylated nitrostilbene
13 in CH2Cl2 (Kim et al. 2010). Subsequent reduction of
the nitro group to the primary amine was achieved by
using Fe powder in 5% acetic acid in EtOAc to give the p-
aminostilbene O-protected 14. The deprotection of 14 was
carried out with TBAF in THF, giving phenol 9 (Scheme 2).
Confirmation of the structure and purity of all compounds
1
was obtained from H and 13C NMR and the geometry of
the double bond was established by J-values range from 15
to 16 Hz of trans-olefinic proton respect of cis-stilbene
olefinic protons from 7.4 to 8.6 Hz reported in the literature
(Orgován et al. 2017).
The cell viability inhibition was more pronounced in
AsPC-1 and BxPC-3 cell lines, where compounds 4–7 and 12
exhibited the most drastic effects, with a minimal residual cell
viability. In Capan-2, only compounds 5 and 6 induced a

Medicinal Chemistry Research
Table 1 IC50 values for compounds 1–12, RSV, and 4-HSLB on PC
cell line viability
a
Compound
IC50 (μM)
AsPC-1
BxPC-3
Capan-2
1
19.72 0.73
21.47 1.26
19.83 1.26
34.52 14.42
15.30 0.01
30.09 12.70
19.84 0.09
22.95 0.29
3.23 0.57
21.20 0.52
31.04 11.87
20.01 0.85
22.48 0.68
19.16 0.13
20.83 0.25
20.49 0.71
22.92 1.03
22.50 6.46
20.64 0.71
18.38 0.43
16.62 1.07
27.98 5.26
11.73 2.11
18.43 0.93
21.10 0.00
19.15 0.08
20.34 0.06
21.36 0.52
21.22 0.04
19.85 0.08
21.90 0.27
3.03 0.49
2
3
4
5
6
7
8
9
10
20.39 0.04
18.18 0.33
9.46 1.74
19.29 0.37
18.05 0.33
11.84 1.71
26.49 7.40
35.34 0.15
11
12
RSV
4-HSLB
24.96 0.83
8.21 0.29
aData shown are the means SD of 2–3 independent experiments with
quintuplicate determinations
Fig. 2 Effect of compounds 1–12, RSV, and 4-HSLB on PC cell
viability. Data shown are the means SD of 2–3 independent MTT
experiments with quintuplicate determinations. Statistically significant
differences between control and each drug concentration (*p < 0.05;
**p < 0.01; ***p < 0.001)
100 μM, indicating that the potent effect obtained at lower
concentrations was not followed by a substantially increased
effect at higher concentrations, because it had already reached
a plateau at low concentrations. Overall, most of the novel
compounds showed IC50 values lower than RSV in the three
PC cell lines. As regards the AsPC-1 and BxPC-3 cell lines, it
is interesting to note that 4-HSLB had lower IC50 values than
RSV, suggesting that the presence of 3,5-dihydroxy motif of
RSV is not essential for cytotoxic activity in these cell lines.
Moreover, 4-HSLB had lower IC50 values than most com-
pounds in AsPC-1 and BxPC-3, with the exception of com-
pound 9, with IC50 of 3.23 μM in AsPC-1. Also analogs 5 and
12 had relatively low IC50s in these cell lines. In Capan-2,
differently from what observed in other cell lines, RSV had
lower IC50 than 4-HSLB. Conversely, all novel p-substituted
analogs had IC50 values lower than RSV and compounds 9
and 12 had the lowest IC50 in Capan-2 (3.03 μM and
11.84 μM, respectively). In general, the results of IC50 deter-
mination showed that the substitution of 3,5-dihydroxy motif
of RSV with p-substitued phenyl (compounds 1–9) or another
aromatic ring (compounds 10–12) played a key role in
determining the inhibitory activity on PC cell lines, although it
is not possible to accurately evaluate the effects of the single
substituents. Another important aspect of our study on PC was
the different cytotoxicity of the tested compounds against the
three cell lines AsPC-1, BxPC-3, and Capan-2. Probably, this
behavior was related to the inherent differences in genetic
profiles, indicating cell specific effects. Compound 9, with the
polar electrondonor amino group in p-position, showed the
lowest IC50 in both AsPC-1 and Capan-2 (3.23 μM and
pronounced reduction of viability at 100 µM. At 20 µM, the
results were less homogeneous, since there was a greater
variability in the effects on PC cell viability, depending both
by the cell line and by the tested compounds. In particular, a
reduction in viability below 50% was observed only for
compounds 5, 11, and 12 both in AsPC-1 and in BxPC-3, and
for compounds 9 and 4-HSLB in AsPC-1, while other com-
pounds had poor inhibitory activity. In Capan-2, all com-
pounds showed a poor inhibitory effect on cell viability, which
remained always above 50%, suggesting that this cell line is
less sensitive to the new compounds. Regarding the reference
compounds, 4-HSLB provided a better reduction of cell via-
bility in all cases as compared to RSV, except at 100 μM for
AsPC-1, suggesting that the 3,5-dihydroxy motif of RSV is
not essential for the activity on PC cells. We also determined
the IC50 values corresponding to the drug concentrations
achieving a 50% inhibition of cell viability. RSV and 4-HSLB
were used as reference compounds and the results are shown
in Table 1.
The IC50 values for all tested compounds ranged from
3.03 μM to 35.34 μM. It should be noted that low IC50s did not
always reflect the maximum potency of cell viability inhibi-
tion. For instance, the compound showing the lowest IC50
(compound 9 in Capan-2 and in AsPC-1) was associated with
a high residual viability in the corresponding cell lines at

Medicinal Chemistry Research
3.03 μM, respectively), whereas its IC50 in BxPC-3 was higher
(22.50 μM). Also the incorporation of naphthalene instead of
the 3,5-dihydroxyphenyl of RSV improves the cytotoxic
activity. In fact, compound 12 showed relatively low IC50
values, ranging from 9.46 μM to 16.62 μM in the tested cell
lines. Finally, also the p-methyl substituted analog 5 showed
relatively low IC50 values, ranging from 15.30 μM and
21.36 μM in the tested cell lines.
An interesting question that is currently being investigated
is how known, or novel compounds exert their anti-
proliferative effects. For example, it has been shown that
repurposed drugs may act on different targets in cancer cells
and it is unclear whether these disparate targets are equally
important for anticancer actions or some may be more rele-
vant than others (Shim and Liu 2014). Therefore, also for
novel molecules it is possible that antitumor activities repor-
ted could be mediated by multiple molecular targets. It is
worth noting that many antitumor effects in PC have been
reported also for RSV, but its mechanism of action should be
further clarified. In this regard, future studies will be necessary
to unravel potential biological targets mediating antitumor
effects in our RSV analogs.
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In the present study, a series of RSV analogs was synthesized
and evaluated for the cytotoxic activity in three PC cell lines.
Nine compounds were 4-substituted analogs of RSV without
3,5-hydroxy motif, and three compounds were obtained by
introducing another aromatic ring instead of 3,5-OH phenyl.
All novel compounds affected PC cell viability, with a
variability that appeared structure- and cell-dependent. Several
compounds (e.g., 5, 9, and 12) showed an improved cytotoxic
activity as compared to reference compounds, making them
potential candidates for further evaluation as anticancer drugs.
Acknowledgements This study was supported by University “G.
d’Annunzio” of Chieti local grants. The authors gratefully acknowl-
edge Prof. Massimiliano Baldassarre of Institute of Medical Sciences,
University of Aberdeen, for helpful comments and suggestions.
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Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
Publisher’s note: Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.
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