Linear diarylheptanoids as potential anticancer therapeutics: synthesis, biological evaluation, and structure–activity relationship studies

Article abstract of DOI:10.1007/s12272-018-1004-8

In efforts to develop effective anticancer therapeutics with greater selectivity toward cancerous cell and reduced side-effects, such as emetic effects due to detrimental action of the drug toward the intestinal flora, a series of linear diarylheptanoids (LDHs) were designed and synthesized in 7 steps with good-to-moderate yields. All synthesized compounds were evaluated for their antibacterial, antiproliferative, and topoisomerase-I and -IIα inhibitory activity. Overall, all compounds showed little to no activity against the bacterial strains tested. Most of the synthesized compounds showed good antiproliferative activity against human breast cancer cell lines (T47D); specifically, the IC₅₀ values of compounds 6a, 6d, 7j, and 7e were 0.09, 0.64, 0.67, and 0.99 μM, respectively. Among the tested compounds, 7b inhibited topo-I by 9.3% (camptothecin 68.8%), 7e and 7h inhibited topo-IIα by 38.4 and 47.4% (etoposide 76.9%), respectively, at the concentration of 100 μM. These results suggest that a set of promising anticancer agents can be obtained by reducing inhibitory actions on different microbes to provide enhanced selectivity against cancerous cells.

Full text of DOI:10.1007/s12272-018-1004-8

Arch. Pharm. Res.
Online ISSN 1976-3786
Print ISSN 0253-6269
https://doi.org/10.1007/s12272-018-1004-8
RESEARCH ARTICLE
Linear diarylheptanoids as potential anticancer therapeutics:
synthesis, biological evaluation, and structure–activity
relationship studies
A. F. M. Motiur Rahman1 Yang Lu2 Hwa-Jong Lee3 Hyunji Jo3
•
•
•
•
Wencui Yin1 Mohammad Sayed Alam4 Hyochang Cha2 Adnan A. Kadi1
Youngjoo Kwon3 Yurngdong Jahng2
•
•
•
•
•
Received: 16 March 2017 / Accepted: 6 January 2018
Ó The Pharmaceutical Society of Korea 2018
Abstract In efforts to develop effective anticancer thera-
peutics with greater selectivity toward cancerous cell and
reduced side-effects, such as emetic effects due to detri-
mental action of the drug toward the intestinal flora, a
series of linear diarylheptanoids (LDHs) were designed and
synthesized in 7 steps with good-to-moderate yields. All
synthesized compounds were evaluated for their antibac-
terial, antiproliferative, and topoisomerase-I and -IIa inhi-
bitory activity. Overall, all compounds showed little to no
activity against the bacterial strains tested. Most of the
synthesized compounds showed good antiproliferative
activity against human breast cancer cell lines (T47D);
specifically, the IC50 values of compounds 6a, 6d, 7j, and
7e were 0.09, 0.64, 0.67, and 0.99 lM, respectively.
Among the tested compounds, 7b inhibited topo-I by 9.3%
(camptothecin 68.8%), 7e and 7h inhibited topo-IIa by
38.4 and 47.4% (etoposide 76.9%), respectively, at the
concentration of 100 lM. These results suggest that a set of
promising anticancer agents can be obtained by reducing
inhibitory actions on different microbes to provide
enhanced selectivity against cancerous cells.
Keywords Linear diarylheptanoids Á Topoisomerase-I Á
Topoisomerase-IIa Á Antiproliferative activity
Introduction
Cancer is a life-threatening disease that often leads to death
(Simone 2000). Topoisomerases have been established as
molecular targets for anticancer drugs (Li and Liu 2001;
Pommier 2009). Two different classes of topoisomerases
exist in humans, type I topoisomerase (topo-I) and type II
topoisomerase (topo-II). A major challenge in cancer
treatment is developing effective drugs that possess high
selectivity toward cancerous cells with low side-effects.
Common adverse effects, including gastrointestinal diar-
rhea, nausea, and vomiting, are due to the toxic effect of
these drugs on the normal gut and intestinal flora (Kata-
kami et al. 2013; Ding et al. 2016). Therefore, the devel-
opment of anticancer drugs should focus on candidates that
have the least potential side-effects on non-cancerous
mammalian cells (Crespo-Ortiz and Wei 2012). Com-
pounds with limited antibacterial activity often have
reduced harmful effects on the intestinal flora, suggesting a
promising new strategy for the development of oncother-
apies (Roy et al. 2008).
A. F. M. Motiur Rahman and Yang Lu are equally contributed.
& A. F. M. Motiur Rahman
afmrahman@ksu.edu.sa
& Yurngdong Jahng
ydjahng@ynu.ac.kr
1
Department of Pharmaceutical Chemistry, College of
Pharmacy, King Saud University, Riyadh 11451,
Saudi Arabia
Diarylheptanoids, natural products with 1,7-diphenyl-
heptane as the basic skeleton, are classified under three
major groups: linear diarylheptanoids (LDHs), cyclic
biphenylheptanoids ([7.0]-metacyclophanes) (CDHs) and
cyclic diphenyl ethers (14-oxa-[7.1]-metaparacyclophanes)
2
College of Pharmacy, Yeungnam University,
Gyeongsan 38541, South Korea
3
College of Pharmacy, Ewha Womans University,
Seoul 03760, Republic of Korea
4
´ ´
(Keseru¨ and Nogradi 1995; Zhu et al. 2000; Lv and She
Department of Chemistry, Jagannath University, Dhaka 1100,
Bangladesh
2010) (Fig. 1). Among these, LDHs have gained the
123

A. F. M. Motiur Rahman et al.
Fig. 1 Structural example of cyclic and LDHs
´
Narasimhulu et al. 2009; Zhang et al. 2010; Novakovic
interest of scientists due to their intriguing structures,
number of isolation sources, various potent biological
activities and essential role as precursors in the synthesis of
natural cyclic diarylheptanoids (Gonzalez and Zhu 1997;
1999; Wang et al. 2007; Jeong et al. 2007; Pitsinos et al.
2011).
et al. 2014; Liu et al. 2014b; Liu et al. 2014a; Chen et al.
´
2015; Dinic et al. 2016) antioxidative (Masuda et al. 2004;
Zhou et al. 2007; Ponomarenko et al. 2014), osteogenic
(Suksamrarn et al. 2008; Winuthayanon et al. 2009;
Yonezawa et al. 2011; El-Halawany and Hattori 2012),
topo-I and -II inhibiting (Li et al. 2003), leishmanicidal
(Takahashi et al. 2004), antitumor (Berenblum 1941;
Yasukawa et al. 1989; Matsuda et al. 2006; Yasukawa
2012; 2015), triglyceride inhibiting (Zhang et al. 2017),
antifilarial (Yadav et al. 2013), cognition enhancing and
neuroprotective (Lee et al. 2012), trypanocidal (Lagnika
et al. 2012), anti-androgen (Ohtsu et al. 2003), nitric oxide
production (Lee et al. 2010b; Pitsinos et al. 2011),
melanogenesis and free radical-scavenging (Akazawa et al.
2006; Matsuda et al. 2009), farnesyl protein transferase-
inhibiting (Kang et al. 2004) and chemo-protective and
LDHs have been isolated from various sources including
the rhizomes of Alpinia officinarum (Sun et al. 2008;
Yasukawa et al. 2008; Matsuda et al. 2009; An et al. 2010;
Zhang et al. 2010; Liu et al. 2014a, b; Dong et al. 2015;
Sun et al. 2016), Dioscorea septemloba (Zhang et al.
2017), Dioscorea nipponica (Woo et al. 2013), Chinese
ginger (Wei et al. 2005), Curcuma kwangsiensis (Pitsinos
et al. 2011; Chen et al. 2015), Curcuma comosa (Suk-
samrarn et al. 2008; Kaewamatawong et al. 2009; Intapad
et al. 2009; Winuthayanon et al. 2009), Zingiber officinale
(Kikuzaki et al. 1991), Zedoariae rhizoma (Morikawa et al.
2002), Zingiber officinale (Masuda et al. 2004), Neotropi-
cal renealmia (Gilli et al. 2014) and Juglans mandshurica
(Li et al. 2003). They have also been isolated from the bark
of Acer nikoense, (Akazawa et al. 2006; Yonezawa et al.
´
regenerative activities (Dinic et al. 2015). They have been
shown to suppress human colon cancer cell growth through
modulation of the Wnt/b-catenin pathway (Dong et al.
2015), and expression of leukocyte adhesion molecules in
human vascular endothelial cells (Yamazaki et al. 2000).
They can significantly inhibit tumor necrosis factor-a
(TNF-a) production in vitro (Dhuru et al. 2011), and
lipopolysaccharide-activated NF-jB-induced inflammatory
mediator production (Lee et al. 2009; 2010a). The inhibi-
tory effects of LDHs on 12-O-tetradecanoylphorbol-13-
acetate (TPA)-induced inflammation and tumor promotion
(Yasukawa et al. 2008) as well as effects on TNF-a-in-
duced expression of adhesion molecules in endothelial
cells of the human umbilical vein (Han et al. 2007) have
also been tested. They may enhance vascular relaxation in
rat aorta via phytoestrogens (Intapad et al. 2009), are
effective against Leishmania (Alves et al. 2004), inhibit
platelet-derived growth factor-induced proliferation of
human hepatic myofibroblasts (Park et al. 2005), and pro-
tect against D-galactosamine/lipopolysaccharide- or TNF-
a-induced liver injury (Morikawa et al. 2002).
´
2011) Alnus viridis (Dinic et al. 2016), Alnus glutinosa
´
´
(Novakovic et al. 2014, Ponomarenko et al. 2014, Dinic
et al. 2015, 2016), Betula platyphylla (Lee et al. 2012),
Alnus japonica (Tung et al. 2010), Alnus hirsuta (Cho et al.
2002) and Alnus firma (Lee et al. 2010b). Additionally,
LDHs have also been isolated from Alnus formosana (Lai
et al. 2012) and Alnus nepalensis leaves (Yadav et al. 2013;
Saxena et al. 2016), Aframomum melegueta seeds (El-
Halawany and Hattori 2012) and Schrankia lepto-
carpa whole plants (Lagnika et al. 2012). LDHs have
diverse biological functions (Rahman et al. 2015; Sun et al.
2016; Prasain and Barnes 2016), including anti-inflamma-
tory (Lee et al. 2005; 2006; Lai et al. 2012; Saxena et al.
2016), anti-neuroinflammatory (Woo et al. 2013),
antibacterial (Subramanian et al. 2009; Zhang et al. 2010),
antiviral (Ishida et al. 2000; Sawamura et al. 2009; Sawa-
mura et al. 2010; Grienke et al. 2010; Tung et al. 2010;
Konno et al. 2011; Chareonkla et al. 2011; Park et al. 2012;
Konno et al. 2013), antiproliferative (Alves et al. 2003;
Wei et al. 2005; Sun et al. 2008; Yasukawa et al. 2008;
Tian et al. 2009; Tabata et al. 2009; Matsuda et al. 2009;
LDHs can be synthesized from curcumin using reduc-
tive catalysts (Roughley and Whiting 1973; Lee et al. 2005;
Changtam et al. 2010). Other methods of synthesis have
also been reported: 9 steps from D-glucose (Bhosale et al.
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Linear diarylheptanoids as potential anticancer therapeutics: synthesis, biological evaluation…
2011); 14 steps from D-mannitol diacetonide (Narasimhulu
et al. 2009); 8 steps from 3-(3-isopropyloxy-4-methox-
yphenyl)propan-1-ol (Gonzalez and Zhu 1997, 1999); 15
steps from hexanal (Sabitha et al. 2011b), 15 steps from (3-
The organic layers were dried over MgSO4. Evaporation of
the solvent resulted in an oily material, which was chro-
matographed on silica gel eluting with hexanes:EtOAc
(9:1, Rf = 0.2) to yield the desired product 2a (2.95 g,
85%) as a white solid, mp = 67 °C. IR (KBr) m 1686,
hydroxy-4-methoxyphenyl)propanal
using
Sharpless
1
epoxidation and cross-metathesis reactions (Sabitha et al.
2011a), 6 steps with cross-metathesis reactions (Bryant
et al. 2012), 11 steps from 3-benzyloxy-4-methoxyben-
zaldehyde (Keseru¨ et al. 1998); and 6 steps from 2,4-pen-
tanedione (Ohtsu et al. 2003). Additionally, we have
recently reported the synthesis of LDHs from 4-benzyloxy-
3-methoxycinnamaldehyde (Jeong et al. 2007, Wang et al.
2007). Although LDHs have been isolated from various
sources, can be easily synthesized, and have shown diverse
biological activities, their properties, particularly structure–
activity relationships (SARs) remain poorly understood.
We recently identified a number of topo-I and -IIa inhi-
bitors as potential oncotherapeutics with optimized side-
effect profiles (Rahman et al. 2014, Ahmad et al. 2016,
Islam et al. 2017). In this study, we report on the design
and synthesis of a series of LDHs from commercially-in-
expensive substituted benzaldehydes, as well as the eval-
uation of their SARs and antibacterial, antiproliferative,
and topoisomerase-inhibiting activities.
1601 cm-1. H NMR (CDCl3, 250 MHz): d 5.14 (s, 2H),
7.06 (d, 2H, J = 8.7 Hz), 7.38 (m, 5H), 7.82 (d, 2H,
J = 8.7 Hz), 9.87 (s, 1H) ppm. 13C NMR (CDCl3,
62.5 MHz): d 70.2, 115.1, 127.5, 128.3, 128.7, 130.1,
132.0, 135.9, 163.7, 190.8 ppm. ESI mass m/z = 213
[M?H]?.
4-(-Benzyloxy)-3-methoxybenzaldehyde (2b)
Potassium carbonate (10 g, 72.4 mmol, 1.1 eq) was added
to a solution of vanillin (1b, 10 g, 65.8 mmol) in acetone
(50 mL). The resulting reaction mixture was stirred for
15 min; then, benzyl chloride (7.6 mL, 65.8 mmol, 1.1 eq)
was added. NaI (100 mg) was added to the resulting mix-
ture and refluxed overnight under N2. The reaction mixture
was filtered, and the solvent was removed in vacuo. The
residue was recrystallized from EtOH to yield 2b as yellow
1
crystals (14.5 g, 95%). IR (KBr) m 2810, 1685 cm-1. H
NMR (CDCl3, 250 MHz): d 3.91 (s, 3H), 5.22 (s, 2H,
–CH2Ar), 6.96 (d, 1H, J = 8.5 Hz, ArH), 7.43–7.27 (m,
7H), 9.81 (1H, s, –CHO) ppm. (CDCl3, 62.5 MHz): d 56.2,
70.9, 109.3, 112.4, 126.8, 127.3, 128.4, 128.8, 130.4,
136.1, 150.1, 153.7, 191.1 ppm.
Materials and methods
General
3-Bromo-4-methoxybenzaldehyde (2c)
Melting points were determined using a Fischer–Jones
melting point apparatus and were uncorrected. Infrared
(IR) spectra were recorded using a Perkin–Elmer 1330
spectrophotometer. Nuclear magnetic resonance (NMR)
spectra were recorded using a Bruker-250 spectrometer and
reported in parts per million (ppm) from the internal
standard tetramethylsilane (TMS). Chemicals and solvents
were of commercial reagent grade and used without further
purification. Electrospray ionization mass spectrometry
(ESI–MS) experiments were performed using an LCQ
advantage-trap mass spectrometer (Thermo Finnigan, San
Jose, CA, USA). Compounds 5d and 5e were prepared by
using previously reported methods (Jeong et al. 2007,
Wang et al. 2007).
A mixture of 3-bromo-4-hydroxybenzaldehyde (1e, 5.00 g,
0.025 mol), Me2SO4 (1.2 eq.) and K2CO3 (10.32 g,
0.075 mol, 3 eq) in DMF (25 mL) was refluxed for 3 h.
Water (15 mL) was added, and the mixture was extracted
with EtOAc and dried over MgSO4. After evaporation of
the solvent, the residue was purified using flash column
chromatography on silica gel eluting with hexanes:EtOAc
(7:1, Rf = 0.3) to yield 2c (6.44 g, 89%) as colorless
crystals, mp = 70–71 °C (Jeong et al. 2007). IR (KBr) m
805, 1682 cm-1. 1H NMR (CDCl3, 250 MHz): d 5.24 (2H,
s, –CH2Ar), 7.03 (1H, d, J = 8.5 Hz, ArH), 7.40 (5H, m,
ArH), 7.76 (1H, dd, J = 8.5, 1.9 Hz, ArH), 8.09 (1H, d,
J = 1.9 Hz, ArH), 9.82 (1H, s, –CHO) ppm. 13C NMR
(CDCl3, 62.5 MHz): d 56.8, 111.8, 112.8, 130.0, 131.4,
134.8, 160.8, 189.2.
4-(Benzyloxy)benzaldehyde (2a)
Benzyl bromide (2.34 mL, 20 mmol, 1.2 eq) and K2CO3
(6.80 g, 49 mmol, 3 eq) were added to a solution of
4-hydroxybenzaldehyde (1a, 2.00 g, 16 mmol) in acetone
(50 mL). The resulting mixture was refluxed for 3 h. Water
(20 mL) was added to this reaction mixture, and the
resulting mixture was extracted using EtOAc (30 mL 9 3).
(E)-3-[4-(Benzyloxy)phenyl]propenal (3a)
A solution of 10% NaOH in EtOH (6 mL) was added to a
mixture of 2a (3.00 g, 14 mmol) and acetaldehyde (10 mL)
in EtOH (20 mL) at 0 °C. The resulting mixture was stirred
at room temperature for 2 h, acidified with diluted HCl,
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A. F. M. Motiur Rahman et al.
(3E,5E)-6-(4-(Benzyloxy)phenyl)hexa-3,5-dien-2-one
(4a)
and extracted using EtOAc (30 mL 9 3). The organic
layers were dried over MgSO4, the solvent was evaporated,
and the resulting solid was chromatographed on silica gel
hexanes:EtOAc (9:1, Rf = 0.1) to yield 3a (0.67 g, 20%)
as yellow crystals, mp = 61-62 °C. The unreacted com-
pound (2.1 g) was recovered: IR (KBr) m 2796, 1682, 1620,
NaOH (10%, 8 mL) was slowly added to a solution of 3a
(2.01 g, 8.45 mmol) in acetone (50 mL); then, the mixture
was stirred at room temperature for 12 h. The solution was
then rendered acidic to litmus by the addition of dilute HCl
and extracted with EtOAc (30 mL 9 3). The organic layers
were dried over MgSO4. After evaporation of the solvent,
the residue was recrystallized from hexanes:EtOAc (3:1) to
yield 4a (2.18 g, 93%) as yellow crystals,
1
1600 cm-1. H NMR (CDCl3, 250 MHz): d 5.10 (s, 2H),
6.59 (dd, 1H, J = 15.8, 7.7 Hz), 7.00 (d, 2H, J = 8.8 Hz),
7.37 (m, 6H), 7.50 (d, 2H, J = 8.8 Hz), 9.63 (d, 1H,
J = 7.7 Hz) ppm. 13C NMR (CDCl3, 62.5 MHz): d 70.1,
115.4, 126.5, 126.9, 128.2, 128.6, 130.3, 136.1, 152.6,
161.3, 193.7 ppm. ESI mass m/z = 239 [M?H]?.
mp = 105–106°C. IR (KBr)
m 2913, 1652, 1619,
1593 cm-1. H NMR (CDCl3, 250 MHz): d 2.29 (s, 3H, –
COCH3), 5.07(s, 2H, –CH2Ar), 6.20 (d, 1H, J = 15.4 Hz,
–CH=CHCO–), 6.81 (m, 2H), 6.95 (d, 2H, J = 8.7 Hz),
7.26 (m, 1H), 7.38 (m, 7H) ppm. 13C NMR (CDCl3,
62.5 MHz): d 27.3, 70.0, 115.2, 124.6, 127.4, 128.6, 128.8,
129.0, 129.5, 136.5, 141.0, 144.0, 159.7, 198.5 ppm. ESI
mass m/z = 279 [M ? H]?.
1
(E)-3-[4-(Benzyloxy)-3-methoxyphenyl]propenal
(3b)
A mixture containing 2b (2.00 g, 11 mmol), BnBr
(1.60 mL, 13 mmol, 1.2 eq), and K2CO3 (4.66 g,
34 mmol, 3 eq) in acetone (70 mL) was refluxed for 3 h.
Water (20 mL) was added and the resulting mixture was
extracted with EtOAc (30 mL 9 3). The organic layers
were then dried over MgSO4. Evaporation of the solvent
yield 3b (6.93 g, 99%) as yellow crystals, mp = 83°C. IR
(KBr) m 2797, 1680 cm-1. 1H NMR (CDCl3, 250 MHz): d
3.91 (s, 3H, –OCH3), 5.20 (s, 2H, –CH2Ar), 6.58 (dd, 1H,
J = 8.0, 15.8 Hz, –CH=CHCHO), 6.89 (d, 1H,
J = 8.8 Hz, ArH), 7.07 (m, 2H, ArH), 7.36 (m, 6H, –
CH=CHAr, ArH), 9.64 (d, 1H, J = 8.0 Hz, –CHO) ppm.
13C NMR (CDCl3, 62.5 MHz): d 56.0, 70.8, 110.3, 113.3,
123.2, 126.7, 127.1, 127.3, 128.0, 128.6, 136.3, 149.8,
151.0, 152.8, 193.6 ppm.
6-(4-Benzyloxy-3-methoxyphenyl)hexa-3,5-dien-2-
one (4b)
NaOH (10%, 4 mL) was added slowly to a solution of
compound 3b (0.28 g, 1.05 mmol) in acetone (10 mL), and
the mixture was stirred at room temperature for approxi-
mately 4 h. The solution was then rendered acidic to litmus
by the addition of dilute HCl, extracted with EtOAc, and
dried over MgSO4. After evaporation of the solvent, the
residue was purified by recrystallization from hex-
anes:EtOAc (1:1); 4b (0.30 g, 93%) was obtained as yel-
low crystals, mp = 105–106 °C. IR (KBr) m 1661, 1509,
1137, 988 cm-1. 1H NMR (CDCl3, 250 MHz): d 2.29 (3H,
s, –COCH3), 3.91 (3H, s, –OCH3), 5.17 (2H, s, –CH2Ar),
6.20 (1H, d, J = 16.0 Hz, –CH = CHCO–), 6.87 (5H, m,
–CH=CHAr and ArH), 7.32 (6H, m, –CH=CHCO– and
ArH) ppm. 13C NMR (CDCl3, 62.5 MHz): d 27.3, 56.0,
70.8, 109.5, 113.5, 121.2, 124.8, 127.2, 127.9, 128.6,
129.4, 129.5, 136.6, 141.2, 143.8, 149.3, 149.7, 198.4 ppm.
ESI Mass m/z = 309 [M?H]?.
(E)-3-(3-Bromo-4-methoxyphenyl)propenal (3c)
NaOH (10%, 8 mL) was slowly added to a solution of 2c
(4.00 g, 19 mmol) and acetaldehyde (20 mL) in EtOH
(30 mL); then, the mixture was stirred at 0 °C for 12 h.
The solution was then rendered acidic to litmus by the
addition of dilute HCl and extracted using EtOAc (30 mL
9 3). The organic layers were dried over MgSO4. After
evaporation of the solvent, the residue was chro-
matographed on silica gel eluting with hexanes:EtOAc
(8:1, Rf = 0.1) to yield 3c (1.79 g, 40%) as yellow crystals,
(3E,5E)-6-(3-Bromo-4-methoxyphenyl)hexa-3,5-
dien-2-one (4c)
1
mp = 58–59 °C. IR (KBr) m 2800, 1681 cm-1. H NMR
NaOH (10%, 2 mL) was added slowly to a solution of 3c
(0.46 g, 1.91 mmol) in acetone (15 mL), and the mixture
was stirred at room temperature for approximately 4 h. The
solution was then rendered acidic to litmus by the addition
of dilute HCl, extracted with EtOAc, and dried over
MgSO4. After evaporation of the solvent, the residue was
purified by recrystallization from hexanes:EtOAc (1:1) to
yield 4c (0.49 g, 91%) as yellow crystals, mp = 86–87 °C.
IR (KBr) m 1661, 1509, 1137, 988 cm-1. 1H NMR (CDCl3,
(CDCl3, 250 MHz): d 3.93 (s, 3H, –OCH3), 6.58 (dd, 1H,
J = 15.9, 7.6 Hz, –CH = CHCO–), 6.92 (d, 1H,
J = 8.6 Hz), 7.34 (d, 1H, J = 15.9 Hz), 7.48 (dd, 1H,
J = 8.6, 2.0 Hz), 7.76 (d, 1H, J = 2.0 Hz), 9.64 (d, 1H,
J = 7.6 Hz) ppm. 13C NMR (CDCl3, 62.5 MHz): d 56.4,
111.9, 112.5, 127.5, 128.0, 129.3, 133.3, 150.9, 158.1,
193.4 ppm. ESI mass m/z = 241 [M?H]?.
123

Linear diarylheptanoids as potential anticancer therapeutics: synthesis, biological evaluation…
250 MHz): d 2.29 (s, 3H, –COCH3), 3.90 (s, 3H, –OCH3),
6.22 (d, 1H, J = 15.5 Hz, –CH=CHCO–), 6.78 (m, 2H),
6.86 (d, 1H, J = 8.5 Hz), 7.24 (m, 1H), 7.35 (dd, 1H,
J = 8.5, 2.0 Hz), 7.67 (d, 1H, J = 2.0 Hz) ppm. 13C NMR
(62.5 MHz, CDCl3) d 27.3, 56.3, 111.8, 112.3, 125.7,
127.9, 130.2, 131.8, 139.3, 143.3, 156.5, 198.4 ppm. ESI
Mass m/z = 281 [M?H]?.
1H, J = 8.4 Hz, H50 of Ar), 7.02 (dd, 1H, J = 8.4, 2.0 Hz,
H60 of Ar), 7.32 (d, 1H, J = 2.0 Hz, H20 of Ar) ppm. 13C
NMR (CDCl3, 62.5 MHz): d 23.2, 29.9, 30.9, 34.4, 44.4,
56.2, 111.3, 111.8, 128.2, 133.0, 135.8, 153.9, 208.9 ppm.
ESI mass m/z = 286 [M?H]?.
6-(4-Benzyloxyphenyl)hexan-2-one (5d)
6-(4-Hydroxyphenyl)hexan-2-one (5a)
A mixture of 5a (2.78 g, 14.5 mmol) and K2CO3 (2.40 g,
1.2 eq.) in acetone (20 mL) was stirred for 30 min., and
then benzyl bromide (2.95 g, 17.4 mmol) was added. The
resulting mixture was refluxed for 6 h, cooled to room
temperature, and filtered. Evaporation of the solvent pro-
duced an oily material, which was dissolved in CH2Cl2
(30 mL) washed with 5% NaHCO3 and, water, and dried
over MgSO4. The solvent was removed under reduced
pressure and flash chromatographed on silica gel eluting
with hexanes: EtOAc (9:1) afforded 5d as an oil. IR (thin
A mixture of 4a (2.18 g, 7.84 mol) and Pd/C (10%, 0.22 g)
in CHCl3 (60 mL) was stirred under H2 at room tempera-
ture for 24 h. Pd/C was filtered, and the solvent was
evaporated to yield 5a (1.49 g, 99%), as a colorless oil. IR
(KBr) m 3363, 1701, 1614 cm-1 1H NMR (CDCl3,
.
250 MHz): d 1.56 (m, 4H, –CH2CH2CH2CH2–), 2.12 (s,
3H, –COCH3), 2.43 (t, 2H, J = 6.8 Hz, –CH2CO–), 2.51
(t, 2H, J = 6.8 Hz, –CH2Ar), 6.03 (s, 1H, –OH), 6.74 (d,
1H, J = 8.5 Hz, ArH), 6.99 (2H, d, J = 8.5 Hz, ArH) ppm.
13C NMR (CDCl3, 62.5 MHz): d 23.3, 29.9, 31.1, 34.7,
43.6, 115.1, 129.3, 133.9, 153.9, 210.5 ppm. ESI mass m/
z = 193 [M?H]?.
film) m 2910, 1650, 1610 cm-1
.
1H NMR (CDCl3,
250 MHz): d 1.60 (m, 4H, –CH2CH2CH2CH2–), 2.11 (s,
3H, –COCH3), 2.42 (t, 2H, J = 6.8 Hz, –CH2CO–), 2.56
(t, 2H, J = 6.8 Hz, –CH2Ar), 5.03 (s, 2H), 6.99 (d, 1H,
J = 8.0 Hz, ArH), 7.07 (2H, d, J = 8.4 Hz, ArH),
7.30–7.43 (m, 5H) ppm. 13C NMR (CDCl3, 23.6, 30.0,
32.3, 35.0, 43.8, 70.3, 115.0, 127.6, 128.0, 128.7, 129.4,
134.8, 137.5, 157.2, 209.1 ppm. ESI mass m/z = 223
[M?H]?.
6-(4-Hydroxy-3-methoxyphenyl)hexan-2-one (5b)
A mixture of 4b (4.16 g, 0.014 mol) and Pd/C (10%,
0.416 g) in CHCl3 (60 mL) was stirred under H2 at room
temperature for 24 h. Pd/C was filtered, and the solvent
was evaporated and purified by recrystallization from
hexanes:EtOAc (1:1) to yield 5b (2.97 g, 99%) as colorless
6-(4-Benzyloxy-3-methoxyphenyl)hexan-2-one (5e)
crystals, mp = 43°C. IR (KBr) m 3393, 1708, 1514 cm-1
.
The same procedure described above for 5d was used for
5b to obtain 5e. 5b (2.18 g, 9.82 mmol), K2CO3 (1.63 g,
1.2 eq) and benzyl bromide (2.00 g, 11.8 mmol) in acetone
(20 mL) was used to produce 5e (2.60 g, 94%) as a col-
1H NMR (CDCl3, 250 MHz): d 1.56 (m, 4H, –CH2CH2-
CH2CH2–), 2.10 (s, 3H, –COCH3), 2.42 (t, 2H,
J = 6.6 Hz, –CH2CO–), 2.52 (t, 2H, J = 6.6 Hz, –CH2-
Ar), 3.84 (s, 3H, –OCH3), 5.62 (s, 1H, –OH), 6.63 (d, 1H,
J = 7.8 Hz, ArH), 6.64 (s, 1H, ArH), 6.79 (d, 1H,
J = 7.8 Hz, ArH) ppm. 13C NMR (CDCl3, 62.5 MHz): d
22.8, 29.2, 30.6, 34.7, 42.8, 55.2, 110.5, 113.8, 120.2,
133.4, 143.1, 146.0, 208.9 ppm. ESI mass m/z = 223
[M?H]?.
orless oil. IR (thin film) m 3625, 1714, 1610 cm-1 1H
.
NMR (CDCl3, 250 MHz): d 1.58 (overlapped quintet, 4H,
–CH2CH2CH2CH2–), 2.10 (s, 3H, –COCH3), 2.42 (t, 2H,
J = 6.8 Hz, –CH2CO–), 2.53 (t, 2H, J = 6.8 Hz, –CH2-
Ar), 3.86 (s, 3H, OCH3), 5.10 (s, 1H, –OH, D2O
exchangeable), 6.21 (dd, 1H, J = 8.0, 1.0 Hz, H5 of
trisubstd. Ph), 6.69 (d, 1H, J = 1.0 Hz, H2 of trisubstd.
Ph), 6. 77 (d, 1H, J = 8.0 Hz, tri-substd. Ph), 7.26–7.43
(m, 5H, ArH) ppm. 13C NMR (CDCl3, 62.5 MHz): d 23.7,
30.1, 31.3, 35.6, 43.8, 56.3, 71.6, 112.7, 114.7, 120.5,
127.5, 127.9, 128.7, 135.6, 137.4, 146.6, 149.9, 209.1 ppm.
ESI mass m/z = 283 [M?H]?.
6-(4-Methoxy-3-bromophenyl)hexan-2-one (5c)
A mixture of 4c (4.08 g, 0.014 mol) and Pd/C (10%,
0.416 g) in CHCl3 (60 mL) was stirred under H2 at room
temperature for 24 h. Pd/C was filtered, and the solvent
was evaporated, purified using column chromatography on
silica gel eluting with hexanes:EtOAc (8:1, Rf = 0.2) to
yield 5c (3.97 g, 96%) as a colorless oil. IR (KBr) m 2938,
(E)-1-(3-Bromophenyl)-7-(4-hydroxyphenyl)hept-1-
en-3-one (6a)
1714, 1603 cm-1
.
1H NMR (CDCl3, 250 MHz): d
1.56–1.54 (m, 4H, –CH2CH2CH2CH2–), 2.10 (s, 3H,
–COCH3), 2.41 (t, 2H, J = 6.8 Hz, –CH2CO–), 2.52
(t, 2H, J = 6.8 Hz, –CH2Ar), 3.84 (s, 3H, –OCH3), 6.78 (d,
NaOH (10%, 10 mL) was added to a solution of 5a (1.92 g,
10 mmol) and 3-bromobenzaldehyde (1.03 eq) in EtOH
(150 mL). The resulting mixture was stirred at room
123

A. F. M. Motiur Rahman et al.
temperature for 30 min. The solution was then rendered
acidic to litmus by the addition of 3 N HCl, extracted with
EtOAc, and dried over MgSO4. After evaporation of the
solvent, the residue was purified using flash chromatogra-
phy on silica gel eluting with hexanes:EtOAc (9:1) yielding
6a (0.5 g, 14%) as an oil. IR (thin film) m 3620, 1667,
1610 cm-1. 1H NMR (CDCl3, 250 MHz): d 1.61–1.67 (m,
4H, –CH2CH2CH2CH2–), 2.56 (t, J = 7.0 Hz, 2H), 2.64 (t,
2H, J = 7.0 Hz, 2H), 4.54 (s, 1H, –OH), 6.68 (d, 1H,
J = 15.5 Hz, COCH = CHAr), 6.73 (dm, 2H, J = 8.0 Hz,
ArH for phenol), 7.01 (dm, 2H, J = 8.0 Hz, ArH for
phenol), 7.24 (t, 1H, = 8.0 Hz), 7.41 (dm, 1H,
J = 8.0 Hz), 7.42 (d, 1H, J = 16.1 Hz, COCH=CHAr),
7.50 (dm, 1H, J = 8.0 Hz), 7.67 (t, 1H, J = 2.0 Hz) ppm.
13C NMR (CDCl3, 62.5 MHz): d 23.8, 31.4, 35.0, 41.3,
115.4, 123.3, 127.2, 127.3, 129.6, 130.6, 131.1, 133.4,
136.8, 141.0, 153.9, 200.5 ppm. ESI mass m/z = 360
[M?H]?.
addition of 3 N HCl and extracted with EtOAc
(30 mL 9 3). The combined organic layer was washed
with water and dried over MgSO4. After evaporation of the
solvent, the residue was chromatographed on silica gel
eluting with hexanes:EtOAc (8.5:1.5, Rf = 0.2), to yield 6c
(200 mg, 11.7%) with a mixture of Z- and E-isomer.
However, hydrogenation had no significant effect on this
mixture. Thus, the next step was proceded without further
purification. 1H NMR (CDCl3, 250 MHz): d 1.70–1.63 (m,
4H, CH2CH2CH2CH2), 2.57 (t, J = 7.2 Hz, 2H, CH2Ar),
2.65 (t, J = 6.95 Hz, 2H, CH2Ar), 3.85 (s, 1H, OCH3),
5.44 (s, 1H, OH), 6.64 (d, J = 1.8 Hz, 1H), 6.67 (s, 1H),
6.68 (d, J = 2.1 Hz, 1H), 6.82-6.77 (m, 2H, –CH=CHCO
and ArH), 7.02 (dd, J = 8.1, 2.1 Hz, 2H), 7.39 (d,
J = 16.1 Hz, 1H, –CH=CHCO) ppm. 13C NMR (CDCl3,
62.5 MHz): d 23.9, 31.4, 35.6, 41.4, 56.1, 105.7 (t,
2
2JC–F = 24.5 Hz, C4), 111.1 (d, JC–F = 25.4 Hz, C20 and
C50), 111.2, 114.4, 121.1, 128.3, 134.3, 138.1 (t,
4
3JC–F = 12.5 Hz, C40), 139.8 (t, JC–F = 3.1 Hz, C10),
1
3
(E)-1-(3-Bromophenyl)-7-(4-hydroxy-3-
methoxyphenyl)hept-1-en-3-one (6b)
143.9, 146.6, 163.4 (dd, JC–F = 248, JC–F = 12.5 Hz,
C30 and C50), 199.9 ppm. ESI mass m/z = 347 [M?H]?.
NaOH (10%, 10 mL) was added to a solution of 5b (1.9 g,
9.36 mmol)
(E)-1-(5-Bromo-2-fluorophenyl)-7-(4-hydroxy-3-
methoxyphenyl)hept-1-en-3-one (6d)
and
3-bromobenzaldehyde
(1.78 g,
9.62 mmol, 1.03 eq) in EtOH (150 mL). The resulting
mixture was stirred at room temperature for 30 min. The
solution was then rendered acidic to litmus by the addition
of 3 N HCl, extracted with EtOAc, and dried over MgSO4.
After evaporation of the solvent, the residue was purified
using flash chromatography on silica gel eluting with
hexanes:EtOAc (9:1) to yield 6b (710 mg, 20.5%) as an
NaOH (10%, 5 mL) and 5-bromo-2-fluorobenzaldehyde
(1 eq) in EtOH (10 mL) were added to a solution of 5b
(1.0 g, 4.5 mmol) in EtOH (50 mL). The resulting mixture
was stirred at room temperature for 2 h. The solution was
then rendered acidic to litmus by the addition of 3 N HCl
and extracted with EtOAc (30 mL 9 3). The combined
organic layer was washed with water and dried over
MgSO4. After evaporation of the solvent, the residue was
chromatographed on silica gel eluting with hexanes:EtOAc
(4:1, Rf = 0.2) to yield 6d (0.4 g, 22%) with a mixture of
oil. IR (thin film) m 3615, 1665, 1600 cm-1 1H NMR
.
(CDCl3, 250 MHz): d 1.62–1.70 (m, 4H, –CH2CH2CH2-
CH2–), 2.56 (t, J = 7.0 Hz, 2H), 2.66 (t, 2H, J = 7.0 Hz,
2H), 3.85 (s, 3H, –OCH3), 5.46 (s, 1H, –OH), 6.65 (d, 1H,
J = 7.8 Hz, ArH), 6.67 (s, 1H, ArH), 6.69 (d, 1H,
J = 16.1 Hz, COCH=CHAr), 6.81 (d, 1H, J = 8.6 Hz),
7.25 (d, 1H, J = 8.0 Hz), 7.45 (d, 1H, J = 16.1 Hz,
COCH=CHAr), 7.44 (dm, 1H, J = 7.8 Hz), 7.55 (dm, 1H,
J = 8.6 Hz), 7.66 (t, 1H, J = 1.7 Hz) ppm. 13C NMR
(CDCl3, 62.5 MHz): d 24.0, 31.5, 35.6, 41.3, 56.0, 111.1,
114.3, 121.1, 123.3, 127.1, 127.4, 130.7, 131.0, 133.4,
134.3, 136.8, 140.8, 143.8, 146.5, 200.2 ppm. ESI mass m/
z = 390 [M?H]?.
1
Z and E isomers in a ratio of 1:18. (E)-Isomer. H NMR
(CDCl3, 250 MHz): d 1.60–1.73 (m, 4H, CH2CH2CH2-
CH2), 2.56 (t, J = 7.2 Hz, 2H, CH2Ar), 2.66 (t,
J = 6.95 Hz, 2H, CH2Ar), 3.85 (s, 3H, OCH3), 5.44 (s, 1H,
OH), 6.64 (dd, J = 8.1, 2.2 Hz, 1H), 6.67 (s, 1H), 6.75 (d,
J = 16.4 Hz, 1H, –CH=CHCO), 6.80 (dd, J = 8.1, 1.8 Hz,
1H), 6.98 (dd, J = 9.8, 2.2 Hz, 1H), 7.56 (d, J = 16.4 Hz,
1H, –CH=CHCO), 7.65 (dd, J = 7.5, 2.2 Hz, 1H) ppm.
13C NMR (CDCl3, 62.5 MHz): d 23.9, 31.4, 35.6, 41.2,
3
56.1, 111.1, 114.4, 117. (d, JC–F = 3.1 Hz, C2), 118.1 (d,
3
(E)-1-(3,5-Difluorophenyl)-7-(4-hydroxy-3-
methoxyphenyl)hept-1-en-3-one (6c)
2JC–F = 23.5 Hz, C10), 121.0, 124.9 (d, JC–F = 12.5 Hz,
3
C10), 129.4 (d, JC–F = 12.5 Hz, C40/C60), 131.5
4
(4JC–F = 3.1 Hz, C1), 133.3 (d, JC–F = 3.1 Hz, C50),
2
3
NaOH (10%, 5 mL) and 3,5-difluorobenzaldehyde (0.7 g,
4.93 mmol, 1 eq) in EtOH (10 mL) were added to a
solution of 5b (1.0 g, 4.93 mmol, 1 eq) in EtOH (50 mL).
The resulting mixture was stirred at room temperature for
2 h. The solution was then rendered acidic to litmus by
134.4 (d, JC–F = 23.5 Hz, C30), 134.6 (d, JC–F
=
12.5 Hz, C60/C40), 143.5, 145.2, 160.6 (d, 1JC–F = 252 Hz,
C20), 200.0 ppm. ESI mass m/z = 408 [M?H]?.
123

Linear diarylheptanoids as potential anticancer therapeutics: synthesis, biological evaluation…
(E)-1-(3-Bromo-4-fluorophenyl)-7-(4-
benzyloxyphenyl)hept-1-en-3-one (6e)
then, the mixture was stirred at room temperature for
approximately 7 h. The solution was rendered acidic to
litmus by the addition of 3 N HCl, extracted with EtOAc
(30 mL 9 3), and dried over MgSO4. After evaporation of
the solvent, the residue was purified using flash chro-
matography on silica gel eluting with hexanes:EtOAc (9:1,
Rf = 0.4) to yield 6g (110 mg, 16.1%) as a colorless oil. IR
NaOH (10%, 5 mL) was added to a solution of 5d (700 mg,
2.48 mmol) in EtOH (50 mL). After stirring for 10 min,
3-bromo-4-fluoro benzaldehyde (600 mg, 2.98 mmol,
1.2 eq) in EtOH (10 mL) was added slowly; then, the mix-
ture was stirred at room temperature for approximately 2 h.
The solution was then rendered acidic to litmus by the
addition of 3 N HCl, extracted with EtOAc (20 mL x 3), and
dried over MgSO4. After evaporation of the solvent, the
residue was purified using flash chromatography on silica
gel eluting with hexanes:EtOAc (9:1, Rf = 0.4) to yield 6f
(400 mg, 34.5%) as a colorless oil. IR (thin film) m 3615,
1
(thin film) m 3610, 1656, 1605 cm-1. H NMR (CDCl3,
250 MHz): d 1.64–1.70 (m, 4H, –CH2CH2–), 2.58 (t, 2H,
J = 7.1 Hz, –CH2CH2–), 2.67 (t, 2H, J = 6.9 Hz, –CH2-
CH2–), 3.85 (s, 1H, –OCH3), 5.02 (s, 2H, Bn–CH2), 6.71
(d, 1H, J = 16.6 Hz, COCH=CHAr), 6.77 (d, 1H,
J = 8.9 Hz, Ar–H), 6.87–6.92 (m, 2H, Ar–H), 7.07–7.13
(m, 2H, Ar–H), 7.30–7.44 (m, 6H, Ar–H), 7.62 (d, 1H,
J = 2.5 Hz, Ar–H), 7.78 (d, 1H, J = 16.4 Hz, COCH=-
CHAr) ppm. 13C NMR (CDCl3, 62.5 MHz): d 24.1, 31.5,
35.0, 40.8, 56.0, 70.2, 113.0, 113.2, 114.8, 125.7, 127.7,
127.8, 128.1, 128.7, 129.5, 130.9, 134.1, 134.8, 136.1,
137.4, 157.1, 157.5, 200.7 ppm. ESI mass m/z = 480
[M?H]?.
1665, 1610 cm-1
.
1H NMR (CDCl3, 250 MHz): d
1.64–1.66 (m, 4H, –CH2CH2–), 2.38–2.66 (m, 4H, –CH2-
CH2–), 5.01 (s, 2H, Bn–CH2), 6.62 (d, 1H, J = 16.1 Hz,
COCH=CHAr), 6.87 (d, 2H, J = 7.9 Hz, ArH of phenol
moiety), 7.04–7.15 (m, 3H, ArH of phenol moiety),
7.28–7.46 (m, 7H, ArH of phenol moiety), 7.73 (dd, 1H,
J = 2.0, 3.1 Hz) ppm. ESI mass m/z = 470 [M?H]?.
(E)-1-(4-Benzyloxy-3-bromophenyl)-7-(4-hydroxy-3-
methoxyphenyl)hept-1-en-3-one (6h)
(E)-1-(5-Bromo-2-methoxyphenyl)-7-(4-hydroxy-3-
methoxyphenyl)hept-1-en-3-one (6f)
A solution of NaOH (10%, 10 mL) was slowly added to a
solution of 5b (0.63 g, 7.88 mmol) and 3-bromo-4-benzy-
loxybenzaldehyde (2.30 g, 0.013 mol) in EtOH (200 mL).
The resulting mixture was stirred at room temperature for
7 h. The solution was then rendered acidic to litmus by the
addition of 3N HCl and extracted with EtOAc. The com-
bined organic layers were washed and dried with MgSO4.
Evaporation of the solvent yielded an oily substance, which
was purified using flash column chromatography on silica
gel eluting with hexanes:EtOAc (8:1) to yield 6h (1.20 g,
85%) as yellow crystals after slow evaporation of the
eluent, mp = 88–89 °C. IR (KBr) m 3530, 1644, 1593,
1496 cm-1. 1H NMR (250 MHz, CDCl3): d 1.69–1.60 (m,
4 H), 2.56 (t, J = 6.8 Hz, 2 H), 2.63 (t, J = 6.8 Hz, 2 H),
3.85 (s, 3 H, OCH3), 5.19 (s, 2 H, Ph-CH2), 5.44 (s, 1 H,
OH, D2O exchangeable), 6.58 (d, J = 16.3 Hz, 1 H, H2),
6.66 (d, J = 8.0 Hz, 1 H, H6), 6.67 (d, J = 2.0 Hz, 1 H,
H2), 6.80 (d, J = 8.0 Hz, 1 H, H5), 6.91 (d, J = 8.0 Hz,
1H, H5), 7.46–7.31 (m, 7 H), 7.76 (d, J = 1.9 Hz, 1 H, H2)
ppm. 13C NMR (62.5 MHz, CDCl3): d 23.93, 31.32, 35.43,
40.90, 55.82, 70.79, 110.87, 112.99, 113.45, 114.09,
120.85, 125.05, 126.92, 128.14, 128.67, 128.73, 129.04,
132.81, 134.17, 135.87, 140.53, 143.56, 146.28, 156.56,
200.05 ppm. ESI mass m/z = 496 [M?H]?.
NaOH (10%, 9 mL) was slowly added to a solution of 5b
(900 mg, 4.05 mmol) and 3-bromo-2-methyloxybenzalde-
hyde (1.3 g, 6.08 mmol, 1.5 eq) in EtOH (150 mL); then,
the mixture was stirred at room temperature for approxi-
mately 7 h. The solution was rendered acidic to litmus by
the addition of 3 N HCl, extracted with EtOAc (30 mL 9
3), and dried over MgSO4. After evaporation of the solvent,
the residue was purified using flash chromatography on
silica gel eluting with hexanes:EtOAc (9:1, Rf = 0.1) to
yield 6f (400 mg, 23.6%) as a colorless oil. IR (thin film) m
1
3605, 1660, 1600 cm-1. H NMR (CDCl3, 250 MHz): d
1.62-1.73 (m, 4H, –CH2CH2–), 2.56 (t, 2H, J = 7.16 Hz,
CH2CH2–), 2.66 (t, 2H, J = 6.9 Hz, CH2CH2), 3.84 (s, 6H,
–OCH3, –OCH3), 5.49 (s, 1H, –OH), 6.64-6.82 (m, 5H, Ar–
H), 7.41 (dd, 1H, J = 2.4, 8.8 Hz, ArH of phenol moiety),
7.61 (d, 1H, J = 2.5 Hz, ArH of phenol moiety), 7.77 (dd,
1H, J = 16.4, 7.8 Hz, COCH=CHAr) ppm. 13C NMR
(CDCl3, 62.5 MHz): d 24.1, 31.5, 40.8, 55.9, 56.0, 111.1,
113.1, 114.3, 121.0, 125.6, 127.8, 130.9, 134.1, 134.4,
136.2, 143.7, 146.5, 157.5, 200.9 ppm. ESI mass m/
z = 420 [M?H]?.
(E)-1-(5-Bromo-2-methoxyphenyl)-7-(4-
benzyloxyphenyl)hept-1-en-3-one (6g)
NaOH (10%, 1 mL) was added to a solution of 5d
(400 mg, 1.43 mmol) and 5-bromo-2-methyloxybenzalde-
hyde (600 mg, 2.86 mmol, 2.0 eq) in EtOH (150 mL);
123

A. F. M. Motiur Rahman et al.
(E)-1-(3-Bromo-4-methoxyphenyl)-7-(4-
hydroxyphenyl)hept-1-en-3-one (6i)
1-(3-Bromophenyl)-7-(4-hydroxyphenyl)heptan-3-
one (7a)
Compound 5a (0.20 g, 1.04 mmol) was added to a stirred
mixture of acetic acid (0.060 mL) and pyrrolidine
(0.090 mL) in Et2O (10 mL). A solution of 3-boromo-4-
methoxybenaldehyde (0.225 g, 1.05 mmol) in tetrahydro-
furan (THF; 7 mL) was slowly added to the resulting
solution at room temperature, and the mixture was stirred
for 1 day. The mixture was then rendered acidic to litmus
by the addition of 3 N HCl and extracted with EtOAc. The
organic layers were combined and washed successively
with water, saturated with NaHSO3, and water, and then
dried with MgSO4. After evaporation of the solvent, the
residue was purified using flash column chromatography on
silica gel eluting with hexanes:EtOAc (3:1) to yield 6i
(0.296 g, 73%) as a colorless oil. IR (thin film) m 3365,
Pd/C (10%, 30 mg) was added to a solution of 6a (300 mg,
0.83 mmol) in CHCl3 (50 mL); then, the mixture was
stirred under H2 (50 psi) at room temperature for about
2.5 h. Pd/C was filtered, the solvent was evaporated, and
the residue was purified using flash chromatography on
silica gel eluting with hexanes:EtOAc:CH2Cl2 (8:1:1,
Rf = 0.4) to yield 7a (170 mg, 57%) as a colorless oil. IR
1
(thin film) m 3605, 1700, 1605 cm-1. H NMR (CDCl3,
250 MHz): d 1.52–1.60 (m, 4H, –CH2CH2CH2CH2–),
2.34–2.41 (m, 2H), 2.45–2.58 (m, 2H), 2.61–2.72 (m, 2H),
2.76–2.86 (m, 2H), 6.72 (d, 2H, J = 8.1 Hz, ArH), 6.99 (d,
2H, J = 8.5 Hz, ArH), 6.98–7.20 (m, 2H, ArH), 7.28–7.47
(m, 2H) ppm. 13C NMR (CDCl3, 62.5 MHz): d 23.2, 29.2,
31.0, 34.9, 43.0, 45.1, 115.8, 121.5, 127.2, 128.9, 129.8,
1646, 1592 cm-1
.
1H NMR (250 MHz, CDCl3): d
130.5, 133.0, 133.9, 140.8, 155.7, 210.4 ppm. ESI mass m/
?
1.68–1.56 (m, 4H), 2.54 (t, J = 6.8 Hz, 2H), 2.64 (t,
J = 6.8 Hz, 2H), 3.88 (s, 3H), 6.46 (br. s, 1H, OH, D2O
exchangeable), 6.59 (d, J = 16.0 Hz, 1H, H2), 6.76 (d,
J = 7.8 Hz, 2H, H3 and H5), 6.86 (d, J = 8.0 Hz, 1H, H5),
7.00 (d, J = 7.8 Hz, 2H, H2 and H6), 7.43–7.39 (m, 2H, H1
and H6), 7.71 (d, J = 2.0 Hz, 1H, H2) ppm. 13C NMR
(62.5 MHz, CDCl3): d 23.89, 31.17, 34.70, 40.77, 56.29,
111.76, 112.19, 115.16, 124.66, 128.26, 129.31 (2 C),
z = 362 [M?H]
.
(3-Bromophenyl)-7-(4-hydroxy-3-
methoxyphenyl)heptan-3-one (7b)
Pd/C (10%, 30 mg) was added to a solution of 6b (300 mg,
0.81 mmol) in CHCl3 (50 mL); then, the mixture was
stirred under H2 (50 psi) at room temperature for approx-
imately 2.5 h. Pd/C was filtered, the solvent was evapo-
rated, and the residue was purified using flash
chromatography on silica gel eluting with hex-
anes:EtOAc:CH2Cl2 (8:1:1, Rf = 0.4) to yield 7b (160 mg,
53.1%) as a colorless oil. IR (thin film) m 3605, 1705,
1610 cm-1. 1H NMR (CDCl3, 250 MHz): d 1.54–1.59 (m,
4H, –CH2CH2CH2CH2–), 2.38 (t, J = 6.8 Hz, 2H), 2.51 (t,
2H, J = 6.8 Hz, 2H), 2.68 (t, 2H, J = 6.9 Hz), 2.80 (t, 2H,
J = 6.9 Hz), 3.85 (s, 3H, –OCH3), 5.48 (s, 1H, –OH), 6.63
(d, 1H, J = 7.8 Hz, ArH), 6.64 (s, 1H, ArH), 6.80 (d, 1H,
J = 7.8 Hz, ArH), 7.08-7.11 (m, 2H), 7.28–7.31 (m, 2H)
ppm. 13C NMR (CDCl3, 62.5 MHz): d 23.5, 29.4, 31.4,
35.6, 43.2, 44.0, 56.0, 111.1, 114.3, 121.0, 122.6, 127.2,
132.71, 133.80, 141.20, 153.95, 157.47, 201.14 ppm. ESI
?
mass m/z = 390 [M?H]
.
(E)-1-(4-Hydroxyphenyl)-7-(3-bromo-4-
methoxyphenyl)hept-1-en-3-one (6j)
The same procedure described for 6a was applied to 5c
(0.84 g, 2.94 mmol) and 4-hydroxybenzaldehyde (0.41 g,
3.36 mmol) to yield 6j (0.86 g, 75%) as white crystals after
flash column chromatography on silica gel eluting with
hexanes:EtOAc (3:1), mp = 113 °C. IR (KBr) m 3359,
1
2932, 1635, 1600 cm-1. H NMR (250 MHz, CDCl3): d
1.68–1.58 (m, 4H), 2.54 (t, J = 6.7 Hz, 2H), 2.65 (t,
J = 6.7 Hz, 2H), 3.83 (s, 3H), 6.17 (s, 1H, OH, D2O
exchangeable), 6.59 (d, J = 16.0 Hz, 1H, H2), 6.78 (d,
J = 8.4 Hz, 1H, H5), 6.86 (d, J = 8.6 Hz, 2H, H3 and H5),
7.04 (dd, J = 8.6, 2.0 Hz, 1H, H6), 7.34 (d, J = 2.0 Hz,
1H, H2), 7.43 (d, J = 8.6 Hz, 2H, H2 and H6), 7.49 (d,
J = 16.0 Hz, 1H, H1) ppm. 13C NMR (62.5 MHz, CDCl3):
d 23.98, 31.04, 34.45, 40.46, 56.24, 111.32, 111.83,
116.02, 123.66, 126.94, 128.28, 130.31, 133.05, 135.88,
129.4, 130.2, 131.5, 134.3, 143.7, 143.8, 146.5, 209.8 ppm.
?
ESI mass m/z = 392 [M?H]
.
1-(3,5-Difluorophenyl)-7-(4-hydroxy-3-
methoxyphenyl)heptan-3-one (7c)
Pd/C (10%, 20 mg) was added to a solution of 6c (200 mg,
0.58 mmol) in CHCl3 (30 mL); then, the mixture was
stirred under H2 (50 psi) at room temperature for approx-
imately 24 h. Pd/C was filtered, the solvent was evapo-
rated, and the residue was chromatographed on silica gel
eluting with hexanes:EtOAc (95:5, Rf = 0.1) to yield 7c
(140 mg, 70%) as a colorless oil. IR (thin film) m 3615,
142.92, 153.90, 158.24, 201.15 ppm. ESI mass m/z = 390
?
[M?H]
.
1700, 1608 cm-1
.
1H NMR (CDCl3, 250 MHz): d
123

Linear diarylheptanoids as potential anticancer therapeutics: synthesis, biological evaluation…
1.54–1.57 (m, 4H, –CH2CH2CH2CH2–), 2.39 (t,
J = 6.8 Hz, 2H), 2.51 (t, 2H, J = 6.8 Hz, 2H), 2.68 (t, 2H,
J = 6.9 Hz), 2.84 (t, 2H, J = 6.9 Hz), 3.85 (s, 3H,
–OCH3), 5.43 (s, 1H, –OH), 6.60–6.68 (m, 5H), 6.80 (d,
1H, J = 8.5 Hz, ArH) ppm. 13C NMR (CDCl3, 62.5 MHz):
d 23.6, 29.5, 31.4, 35.6, 43.1, 43.6, 56.1, 101.8 (t,
C30), 129.9 (d, 3JC–F = 12.5 Hz, C20 and C60), 134.6, 136.9
4
(d, JC–F = 2.5 Hz, C10), 137.0, 153.8, 161.6 (d,
2JC–F = 243 Hz, C40), 210.3 ppm. ESI mass m/z = 380
[M?H]?.
1-(5-Bromo-2-methoxyphenyl)-7-(4-hydroxy-3-
methoxyphenyl)heptan-3-one (7f)
3
2JC–F = 24.5 Hz, C40), 109.1 (d, JC–F = 12.5 Hz, C10),
4
111.1 (d, JC–F = 3.1 Hz, C1), 111.2 (d, JC–F = 25.4 Hz,
2
C20 and C60), 114.3, 121.1, 134.3, 143.9, 146.5, 163.4 (dd,
Pd/C (10%, 40 mg) was added to a solution of 6f (400 mg,
0.95 mmol) in CHCl3 (50 mL); then, the mixture was
stirred under H2 (50 atm) at room temperature for
approximately 3 h. Pd/C was filtered, the solvent was
evaporated, and the residue was purified using flash chro-
matography on silica gel eluting with hexanes:EtOAc (9:1,
Rf = 0.3) to yield 7f (300 mg, 75%) as a colorless oil. IR
(1JC–F = 248, 3JC–F = 12.5 Hz), C30 and C50), 209.3 ppm.
?
ESI mass m/z = 349 [M?H]
.
1-(5-Bromo-2-fluorophenyl)-7-(4-hydroxy-3-
methoxyphenyl)heptan-3-one (7d)
1
Pd/C (10%, 20 mg) was added to a solution of 6d (200 mg,
0.5 mmol) in CHCl3 (30 mL); then, the mixture was stirred
under H2 (50 psi) at room temperature for approximately
24 h. Pd/C was filtered, the solvent was evaporated, and the
residue was chromatographed on silica gel eluting with
hexanes:EtOAc (4:1, Rf = 0.4) to yield 7d (140 mg, 68%)
(thin film) m 3585, 1710, 1609 cm-1. H NMR (CDCl3,
250 MHz): d 1.55–1.61 (m, 4H, –CH2CH2–), 2.36–2.47
(m, 2H, –CH2CH2–), 2.48–2.56 (m, 2H, –CH2CH2),
2.60–2.69 (m, 2H, –CH2CH2–), 2.75–2.82 (m, 2H, –CH2-
CH2–), 3.76 (s, 3H, –OCH3), 3.85 (s, 3H, –OCH3), 5.46(s,
1H, –OH), 6.61–6.65 (m, 3H, Ar–H), 6.74-6.84 (m, 2H,
Ar–H), 7.20–7.27 (m, 1H, Ar–H) ppm. 13C NMR (CDCl3,
62.5 MHz): d 23.6, 24.8, 25.2, 31.2, 42.5, 42.9, 55.4, 55.6,
111.1, 112.7, 114.3, 120.6, 121.0, 127.6, 129.5, 130.2,
131.9, 132.8, 134.4, 156.7, 211.1 ppm. ESI mass m/
z = 422 [M?H]?.
as a colorless oil. IR (thin film) m 3615, 1710, 1600 cm-1
.
1H NMR (CDCl3, 250 MHz) d 1.51–1.60 (m, 4H, –CH2-
CH2CH2CH2–), 2.39 (t, J = 6.8 Hz, 2H), 2.51 (m, 2H),
2.67 (t, 2H, J = 6.9 Hz), 2.84 (t, 2H, J = 6.9 Hz), 3.85 (s,
3H, –OCH3), 5.47 (s, 1H, –OH), 6.60–6.68 (m, 2H),
6.76–6.83 (m, 1H), 6.85–6.70 (m, 1H), 7.25–7.36 (m, 2H)
ppm. 13C NMR (CDCl3, 62.5 MHz): d 23.9, 31.6, 36.0,
1-(5-Bromo-2-methoxyphenyl)-7-(4-
hydroxyphenyl)heptan-3-one (7g)
2
41.3, 29.5, 56.2, 111.1, 111.4, 118.4 (d, JC–F = 24.5 Hz,
3
C10), 120.5, 121.0, 125.1 (d, JC–F = 12.5 Hz, C40/C6),
3
127.6, 129.6 (d, JC–F = 12.5 Hz, C60/C40), 133.0 (d,
Pd/C (10%, 10 mg) was added to a solution of 6g (110 mg,
0.23 mmol) in CHCl3 (50 mL); then, the mixture was
stirred under H2 (50 psi) at room temperature for approx-
imately 6 h. Pd/C was filtered, the solvent was evaporated,
and the residue was purified using flash chromatography on
silica gel eluting with hexanes:EtOAc (9:1, Rf = 0.3) to
yield 7g (67 mg, 75%) as a colorless oil. IR (thin film) m
2
4JC–F = 3.1 Hz, C50), 134.4, 134.6 (d, JC–F = 23.5 Hz,
1
C30), 143.5, 143.7, 161.0 (d, JC–F = 246 Hz, C20),
200.2 ppm. ESI mass m/z = 410 [M?H]?.
1-(3-Bromo-4-fluorophenyl)-7-(4-
hydroxyphenyl)heptan-3-one (7e)
1
3605, 1710, 1605 cm-1. H NMR (CDCl3, 250 MHz) d
Pd/C (10%, 40 mg) was added to a solution of 6e (400 mg,
0.86 mmol) in CHCl3 (50 mL); then, the mixture was
stirred under H2 (50 psi) at room temperature for approx-
imately 12 h. Pd/C was filtered, the solvent was evapo-
rated, and the residue was purified using flash
chromatography on silica gel eluting with hexanes:EtOAc
(4:1, Rf = 0.4) to yield 7e (30 mg, 7.5%) as a colorless oil.
IR (thin film) m 3576, 1707, 1615 cm-1. 1H NMR (CDCl3,
250 MHz): d 1.50–1.58 (m, 4H, –CH2CH2CH2CH2–), 2.36
(t, J = 6.9 Hz, 2H), 2.50 (t, 2H, J = 6.8 Hz, 2H), 2.66 (t,
2H, J = 6.9 Hz), 2.83 (t, 2H, J = 6.9 Hz), 4.90 (s, 1H,
–OH), 6.70-6.74 (m, 2H, ArH), 6.89–7.00 (m, 3H, ArH),
7.07–7.13 (m, 2H) ppm. 13C NMR (CDCl3, 62.5 MHz): d
23.5, 29.1, 31.4, 35.0, 43.3, 44.5, 115.3, 115.4 (d,
1.56–1.69 (m, 4H, CH2CH2), 2.37–2.44 (m, 2H, CH2CH2),
2.50 (t, 2H, J = 6.6 Hz, CH2), 2.67 (t, 2H, J = 7.3 Hz,
CH2), 2.86 (t, 2H, J = 7.4 Hz, CH2), 3.78 (s, 3H, OCH3),
6.74 (d, 2H, J = 6.5 Hz, Ar–H), 6.80–6.88 (m,1H, Ar–H),
7.09-7.20 (m, 2H, Ar–H) ppm. 13C NMR (CDCl3,
62.5 MHz): d 23.5, 29.2, 31.4, 35.0, 43.1, 44.7, 55.5, 112.1,
114.0, 115.5, 128.5, 129.5, 129.6, 133.3, 133.4, 154.1,
157.9, 210.7 ppm. ESI mass m/z = 392 [M?H]?.
1-(4-Benzyloxy-3-bromophenyl)-7-(4-hydroxy-3-
methoxyphenyl)heptan-3-one (7h)
The same procedure described for 7a was applied to 6h
(1.29 g, 2.61 mmol) to yield an oily material which was
flash column chromatographed on silica gel eluting with
2
2JC–F = 22.5 Hz, C50), 129.6, 129.8 (d, JC–F = 22.5 Hz,
123

A. F. M. Motiur Rahman et al.
Antibacterial screening
hexanes:EtOAc (7:1) to afford 7h (0.66 g, 51%) as a col-
orless oil. IR (thin film) m 3563, 1714 cm-1 1H NMR
.
The in vitro antibacterial activities of the synthesized
compounds were measured against six bacterial strains
using the filter paper disc diffusion method. Briefly, triptic
soya agar (TSA) media (Sigma-Aldrich, St. Louis, MO,
USA) was used as a basal medium for the test bacteria.
These agar media were inoculated with 0.2 mL of 24-h
liquid cultures containing the microorganisms. The sample
discs were placed gently on pre-inoculated agar plates and
then incubated aerobically at 37 °C for 24 h. Discs with
only dimethyl sulfoxide (DMSO) were used as a control,
and ciprofloxacin was used as a positive control. Inhibitory
activity was assessed by measuring the diameters (mm) of
the observed inhibition zones.
(250 MHz, CDCl3): d 1.63–1.51 (m, 4H), 2.40 (t,
J = 7.3 Hz, 2H), 2.51 (t, J = 7.0 Hz, 2H), 2.65 (t,
J = 7.0 Hz, 2H), 2.78 (t, J = 7.3 Hz, 2H), 3.85 (s, 3H,
OCH3), 5.10 (s, 2H, Ph-CH2), 5.48 (s, 1H, OH, D2O
exchangeable), 6.63 (dd, J = 8.5, 1.5 Hz, 1H, H6), 6.64 (d,
J = 2.0 Hz, 1H, H2), 6.80 (d, J = 8.8 Hz, 2H), 7.00 (dd,
J = 8.2, 2.0 Hz, 1H, H6), 7.57–7.30 (m, 6H) ppm. 13C
NMR (62.5 MHz, CDCl3): d 23.15, 28.91, 30.89, 34.40,
42.80, 44.50, 56.23, 70.90, 110.85, 112.27, 113.83, 114.08,
120.77, 126.92, 127.83, 128.22, 128.49, 133.01, 134.05,
135.09, 136.54, 143.54, 146.25, 153.26, 209.78 ppm ESI
mass m/z = 498 [M?H]?.
1-(3-Bromo-4-methoxyphenyl)-7-(4-
hydroxyphenyl)heptan-3-one (7i)
Anti-proliferative activity assay
Anti-proliferative activity was evaluated using diverse
cancer cell lines, according to a previously described
method (Park et al. 2013). HCT15 (human colon cancer
cell lines), T47D (human breast cancer cell line) and
DU145 (human prostate cancer cell line) were grown in
RPMI1640 (Hyclone, South Logan, UT, USA), HEK293
(human kidney embryonic cell line) was cultured in
DMEM (Hyclone, South Logan, UT, USA). Cells were
seeded in 96-well plates at a density of 2–4 9 104 cells per
well and incubate overnight in 0.1 mL of media supple-
mented with 10% Fetal Bovine Serum (FBS, Hyclone,
South Logan, UT, USA) in a 5% CO2 incubator at 37 °C.
Following this, the culture medium was exchanged with
0.1 mL aliquots of medium containing graded concentra-
tions of each compound and incubated continuously for
72 h. Then 5 lL of the cell counting kit-8 solution (Do-
jindo, Tokyo, Japan) was added to each well the cells were
incubated for an additional 4 h. The absorbance of each
well was measured using an Automatic ELISA Reader
System (Bio-Rad 3550; Bio-Rad, Hercules, CA, USA) at
450 nm. The IC50 values were calculated using TableCurve
(Jandel Scientific Software, San Jose, CA, USA).
The same procedure described for 7a was applied to 6i
(1.94 g, 5 mmol) to yield an oily material, which was flash
column chromatographed on silica gel eluting with hex-
anes:EtOAc (7:1) to yield 7i (1.5 g, 77%) as a colorless oil.
IR (thin film) m 3580, 1708, 1600 cm-1 1H NMR
.
(250 MHz, CDCl3): d 1.60–1.45 (m, 4H), 2.37 (t,
J = 7.0 Hz, 2H), 2.50 (t, J = 7.0 Hz, 2H), 2.64 (t,
J = 7.0 Hz, 2H), 2.78 (t, J = 7.0 Hz, 2H), 3.84 (s, 3H,
OCH3), 6.72 (dd, J = 8.5, 2.1 Hz, 2H), 6.77 (d,
J = 8.4 Hz, 1H), 6.99 (d, J = 8.4 Hz, 2H), 7.05 (dd,
J = 8.4, 2.1 Hz, 1H), 7.33 (d, J = 2.1 Hz, 1H) ppm. 13C
NMR (62.5 MHz, CDCl3): d 23.5, 28.6, 31.4, 35.0, 43.1,
44.4, 56.4, 111.6, 112.1, 115.3, 128.6, 129.6, 133.2, 134.5,
134.9, 153.8, 154.4, 210.2 ppm. ESI mass m/z = 392
[M?H]?.
1-(4-Hydroxyphenyl)-7-(3-bromo-4-
methoxyphenyl)heptan-3-one (7j)
The same procedure described for 7a was applied to 6j
(0.64 g, 1.65 mmol) to yield 7j (0.64 g, 99%) as a colorless
oil after column chromatography on silica gel eluting with
hexanes:EtOAc (3:1). IR (thin film) m 3411, 1699,
1616 cm-1. 1H NMR (250 MHz, CDCl3): d 1.60–1.49 (m,
4H), 2.35 (t, J = 7.2 Hz, 2H), 2.47 (t, J = 7.2 Hz, 2H),
2.66 (t, J = 6.8 Hz, 2H), 2.79 (t, J = 8.0 Hz, 2H), 3.84 (s,
3H, OCH3), 5.04 (s, 1H, OH, D2O exchangeable), 6.73 (d,
J = 8.8 Hz, 2H, H3 and H5), 6.78 (d, J = 8.8 Hz, 1H, H6),
7.45–6.99 (m, 3H, H5, H2 and H6), 7.31 (d, J = 2.0 Hz,
1H, H2) ppm. 13C NMR (62.5 MHz, CDCl3): d 23.27,
28.40, 31.16, 35.33, 42.79, 44.04, 55.78, 111.29, 111.80,
115.26, 128.25, 129.40, 133.00, 133.03, 135.82, 153.87 (2
C), 210.61 ppm. ESI mass m/z = 392 [M?H]?.
Topo-I and topo-IIa relaxation assay
Inhibition of topo-I and topo-IIa were measured by
assessing the relaxation of supercoiled pBR322 plasmid
DNA as previously described (Jun et al. 2014). A mixture
of 100 ng of supercoiled DNA pBR322 (Thermo Scientific,
Waltham, MA, USA) and 1 unit of human topo-I (Topo-
Gen, Buena Vista, CO, USA) or topo-IIa (USB Corp.,
Cleveland, OH, USA) was incubated in the absence or
presence of the prepared compounds at 37 °C for 1 h in a
reaction buffer. The topo-I reaction buffer contained
10 mM
Tris
HCl
(pH
7.9)
with
1 mM
123

Linear diarylheptanoids as potential anticancer therapeutics: synthesis, biological evaluation…
Antibacterial screening
ethylenediaminetetraacetate (EDTA), 0.15 M NaCl, 0.1%
bovine serum albumin (BSA), 0.1 mM spermidine, and 5%
glycerol; the topo-IIa reaction buffer contained 10 mM
Tris HCl (pH 7.9) with 50 mM NaCl, 50 mM KCl, 5 mM
MgCl2, 0.1 mM EDTA, 15 lg/mL BSA, and 1 mM ATP.
A final volume of 10 lL of the reaction mixture was ter-
minated by adding 2.5 lL of the stop solution (topo-I: 0.5%
sarcosyl containing 0.00025% bromophenol blue and 2.5%
glycerol; topo-IIa: 0.7 mM EDTA). The reaction mixture
was then electrophoresed on a 0.8% agarose gel at 60 V for
1 h with Tris–acetate-EDTA (TAE) as the running buffer.
Gels were stained for 15 min in an aqueous solution of
ethidium bromide (0.5 lg/mL). DNA bands were visual-
ized using trans-illumination with ultraviolet light and were
quantitated using an Alpha Tech Imager (Alpha Innotech
Corporation, San Leandro, CA, USA). Camptothecin
(Sigma-Aldrich) and etoposide (Sigma-Aldrich) were used
as positive controls for the topo-I and topo- IIa inhibitors,
respectively.
The newly synthesized twenty LDHs (6a–j and 7a–j) were
evaluated for their in vitro antibacterial activity against
three gram-positive bacteria (Bacillus cereus, Staphylo-
coccus aureus, and Listeria monocytogenes) and three
gram-negative bacteria (Escherichia coli, Salmonella
typhi, and Klebsiella pneumoniae) using the disc diffusion
method. Although none of the synthesized compounds
showed significant antibacterial activity at 100–200 lg/
disc, some demonstrated antibacterial activity at 300 lg/
disc (Table 1). Specifically, compounds 6c, 6f, 6g, 6h, 6i,
7d, and 7h modestly suppressed the growth of B. cereus,
E. coli, S. typhi, and K. pneumonia at a dose of 300 lg/disc,
whereas 7e was effective against all strains tested. How-
ever, these effects were negligible compared to those of the
positive control, ciprofloxacin (25 lg/disc).
Antiproliferative activity of synthesized LDHs (6
and 7)
The inhibition of cell proliferation of the compound 6 and 7
series are listed in Table 2 as IC50 values. A total of 17
compounds were tested, with almost all demonstrated
significant antiproliferative activity against human breast
cancer cell lines (T47D) compared to all positive controls
(adriamycin, etoposide, and camptothecin). Particularly,
the IC50 of 6a, 6d, 7j, and 7e were 0.09 0.01, 0.6
Results
Synthesis of a series of LDHs (6 and 7)
LDHs were synthesized from commercially available
aldehydes (1) in 7 steps using a method modified from a
previously reported procedure (Jeong et al. 2007). First,
compound 1 was reacted with benzyl bromide, in the
presence of K2CO3 in acetone to protect the hydroxyl
group, to produce compound 2 (85–95% yield). This was
followed by cross aldol condensation with acetaldehyde
with a catalytic amount of NaOH in ethanol at 0 °C to
obtain compound 3. Interestingly, although 99% of the
cross-aldol product (3b) was obtained from 2b with
acetaldehyde, only 20 and 40% were produced from
compounds 2a and 2c, respectively. Compound 3 was
subsequently condensed with acetone in the presence of
NaOH at room temperature, producing compound 4 in high
yields (91–93%). Hydrogenation of compound 4 with H2
and 10% Pd/C at room temperature produced compound 5
with excellent to quantitative yields (97–100%). Com-
pound 5 was then treated with various aldehydes contain-
ing halogen at the 3-position, forming cross aldol products
called linear diarylheptanoids (6a–i, 10–75% yield). Next,
we used 5f and 4-hydroxybenzaldehyde to obtain 6j. Cat-
alytic hydrogenation of compounds 6a–j in the presence of
H2 and Pd/C at room temperature generated a series
(Scheme 1) of LDHs (7a–j).
4
0.16, 0.67 0.00, and 0.99 0.03 lM, respectively.
In contrast, adriamycin, etoposide, and camptothecin had
IC50 values of 2.18 0.04, 1.96 0.03, and
3.67 0.03 lM, respectively. However, in T47D cells, 6i
(6.21 0.49), 7e (8.39 0.16), and 7h (6.98 0.04)
demonstrated significant antiproliferative activity com-
pared to adriamycin (7.08 1.61) and etoposide
(35.07 0.0018). Compounds 6i (6.16 0.03) and 7j
(8.02 0.11) showed moderate antiproliferative activity
compared to etoposide (8.02 1.38) against human colon
cancer cells (HCT15). All compounds had very low IC50
values for human cervical cancer cells (HeLa), with the
exception of 6b (5.44 0.31), 6c (2.84 0.18), and 6i
(7.65 0.06) when compared to etoposide (4.71 0.09).
Topo-I and -IIa inhibitory activity of synthesized
LDHs (6 and 7)
Most of the synthesized compounds showed topo-I and
topo-IIa inhibitory activity at 100 lM concentration. The
results are listed in Table 3 and depicted in Fig. 2. The
compounds that demonstrated inhibitory activity [ 30%
were selected for further testing. However, no significant
inhibition was found at 20 lM, though etoposide showed
39% inhibition.
123

A. F. M. Motiur Rahman et al.
Scheme 1 Synthesis of LDHs (6 and 7)
Table 1 In vitro bactericidal profiles of LDHs in the zone of inhibition
Entry Gram-positive
Gram-negative
Bacillus cereus Staphylococcus aureus Listeria monocytogenes Escherichia coli Salmonella typhi Klebsilla pneumoniae
6c
6f
10
8
0
0
0
0
0
0
14
20
11
9
6
10
6
6g
6h
6i
10
10
12
15
16
14
26
0
0
0
0
0
0
6
0
0
0
13
10
14
10
35
8
7d
7e
7h
C
9
0
10
13
9
6
12
0
14
0
10
6
29
40
30
28
* Inhibitory activity is expressed as the diameter (mm) of the observed inhibition zone. Concentration of each compound was 300 lg disc-1
whereas that of the positive control (C Ciprofloxacin) was 25 lg/disc
,
123

Linear diarylheptanoids as potential anticancer therapeutics: synthesis, biological evaluation…
Table 2 Antiproliferative
activity of the synthesized
Compounds
IC50 (lM)
LDHs (6 and 7)
HCT15
MCF7
T47D
HeLa
Adriamycin
4.5 0.6
7.08 1.61
35.0718
2.18 0.04
1.96 0.03
3.67 0.03
0.09 0.01
4.26 0.1
0.48 0.16
4.71 0.09
0.17 0.01
13.87 0.12
5.44 0.31
2.84 0.18
36.83 0.26
24.1 0.5
[ 50
Etoposide
8.02 1.38
0.61 0.02
20.21 0.44
10.04 0.04
20.74 0.02
18.14 0.1
18.31 0.04
[ 50
Camptothecin
0.89 0.08
33.08 1.57
10.59 0.3
27.24 0.33
22.34 0.02
25.02 0.72
[ 50
6a
6b
6c
6d
6f
2.67 0.08
0.64 0.16
4.67 0.15
3.76 0.37
1.13 0.03
2.26 0.12
1.74 0.01
4.09 0.02
6.95 0.44
1.55 0.01
0.99 0.03
2.91 0.07
15.13 0.14
2.5 0.07
6g
6h
6i
13 0.24
36.67 0.32
6.21 0.49
16.82 0.56
14.31 0.04
39.79 0.21
15.97 0.12
8.39 0.16
[ 50
[ 50
6.16 0.03
21.61 0.04
12.37 0.22
[ 50
7.65 0.06
23.48 0.18
44.38 0.19
18.96 0.24
8.8 0.24
11.9 0.13
[ 50
6j
7b
7c
7d
7e
7f
10.48 0.27
10.54 0.34
[ 50
7g
7h
7j
24.25 0.49
9.75 0.05
8.02 0.11
26.35 0.28
6.98 0.04
16.56 0.2
15.81 0.06
13.23 0.21
19.36 0.06
0.67
0
Values represent mean standard deviation obtained from three different experiments. Cell lines used as
follows: HCT15 (human colon cancer cells), MCF7 (human breast cancer cells), T47D (human breast
cancer cells), and HeLa (human cervical cancer cells). Adriamycin, etoposide, and camptothecin were used
as positive controls. Compounds labeled [ 50 inhibited the cell growth by less than 50% at 50 lM
and 7h inhibited topo-IIa by 38.4 and 47.4%, respectively,
compared with etoposide (76.9%) at 100 lM concentration.
Table 3 Topo-I and -IIa inhibitory activity of the synthesized LDHs
(6 and 7)
% Inhibition (100 lM)
Entry
Topo-I
75.4
Topo-IIa
Entry
Topo-I
68.8
Topo-IIa
Discussion
C
C
–
SAR studies of LDHs (6 and 7)
E
71.4
2.6
5.2
5.3
1.9
–
E
76.9
–
6a
6b
6c
6d
6e
6f
6g
6h
6i
1.8
0
7a
7b
7c
7d
7e
7f
7g
7h
7i
–
The synthesized LDH (6a) containing a bromo (–Br) group
at the 30-position and a hydroxy group at the 400-position
showed the most potent antiproliferative activity at the
nanomolar scale (6a: IC50 = 90 nM; adriamycin:
IC50 = 2.18 lM; etoposide: IC50 = 1.96 lM; camp-
tothecin: IC50 = 3.67 lM) against human breast cancer
cells. Compound 6a showed reduced inhibition of topo-I
(1.8% versus camptothecin 68.8%) and topo-IIa (2.6%
versus etoposide 71.4%) at 100 lM, though no antibacte-
rial activities were observed. Inserting or replacing sub-
stituents in one and/or both aromatic rings showed
decreased antiproliferative activity, though this was com-
parable to control drugs. Changes in topo-I and -IIa inhi-
bition was not observed. Replacement of the –Br
substituent with fluoro (–F) and insertion of –F at the 50-
position and a methoxy (–OCH3) group at the 300-position
9.3
9.1
5.3
1.8
4.8
4.7
2.5
–
3.8
3.4
0
0
0.3
–
38.4
0.9
5.6
47.4
–
5.9
2.5
0
3.3
4.6
3.2
4.6
3.7
0
6j
3.5
7j
3.2
2.1
C = Camptothecin, E = Etoposide
Among the tested compounds, 7b and 7c inhibited topo-
I by 9.3 and 9.1%, respectively, compared with camp-
tothecin (68.8%) at 100 lM concentration. Additionally, 7e
123

A. F. M. Motiur Rahman et al.
Fig. 2 Topoisomerase I and IIa
inhibitory activity of linear
diarylheptanoids 6 (except 6e)
and 7 (except 7a and 7i). Lane
D: pBR322 DNA; Lane T:
pBR322 DNA ? Topo-I/Topo-
IIa; Lane C: pBR322
DNA ? Topo-
I ? Camptothecin, Lane E:
pBR322 DNA ? Topo-
IIa ? Etoposide; Lane 6a–d,
6f–j, 7b–h, 7j: pBR322
DNA ? Topo-I/Topo-
IIa ? corresponding
synthesized compound
of 6a to form 6c (300 lg) resulted in a 14 mm inhibition
zone against S. typhi and 10 mm against B. cereus, which
are negligible compared to that of ciprofloxacin (25 lg/
disc). In addition, two –OCH3 groups at the 60- and 300-
positions of 6a (compound 6f); –OCH3 at the 60-position
and protection of the hydroxy group by the benzyl group of
6a (compound 6g); benzyloxy (–OBn) group at the 40-po-
sition and –OCH3 at the 300-position of 6a (compound 6h);
and –OCH3 at the 40-position of 6a (compound 6i)
demonstrated no antibacterial activity against B. cereus, S.
typhi, and K. pneumoniae.
However, 7b, which had a –OCH3 substituent at the 300-
position (compared to 7a) showed moderate antiprolifera-
tive activity at the micromolar scale (7b: IC50 = 4.09 lM;
adriamycin: IC50 = 2.18 lM; etoposide: IC50 = 1.96 lM;
camptothecin: IC50 = 3.67 lM). This was comparable to
the IC50 of camptothecin against T47D cells. Among the
tested compounds (6 and 7), only 7b (9.3%) and 7c (9.1%)
demonstrated moderate topo-I inhibitory activity (camp-
tothecin 68.8%). Inserting or replacing substituents in one
and/or both aromatic rings of compound 7b reduced rather
than increase topo-I inhibitory activity. Contrastingly,
insertion of –F at the 400-position of 7a (compound 7e)
resulted in excellent topo-IIa inhibitory activity (38.4%
versus etoposide 76.9%) at 100 lM. Compound 7e also
displayed excellent antiproliferative activity against tested
Thus, the SAR studies of 6a–j, showed that the addition
of fluorine and/or methoxy groups in any or both aromatic
rings decreases cytotoxicity with little to no impact on the
inhibition of topoisomerases (Fig. 3).
SAR studies of the 7a–j series showed that, 7a had no
antiproliferative activity against the tested cell lines, no
antibacterial activity against the gram-positive/negative
strains, and no topoisomerase-inhibiting activity (Fig. 4).
cell
lines
(7e:
IC50 = 0.99 lM;
adriamycin:
IC50 = 2.18 lM; etoposide: IC50 = 1.96 lM; camp-
tothecin: IC50 = 3.67 lM). Although 7e showed antibac-
terial activity against all the gram-positive/negative strains
Fig. 3 SAR studies diagram for compound 6
Fig. 4 SAR studies diagram for compound 7
123

Linear diarylheptanoids as potential anticancer therapeutics: synthesis, biological evaluation…
at 300 lg/disc (inhibition zone of 16 mm against B. cereus,
12 mm against S. aureus, 14 mm against L. monocytoge-
nes, 13 mm against E. coli, 14 mm against S. typhi, and
10 mm against K. pneumonia), this was considered negli-
gible compared to ciprofloxacin (25 lg/disc). In addition,
7h, a compound with –OCH3 at the 300-position and –OBn
at the 40-position of 7a showed excellent topo-IIa inhibi-
tory activity (47.4% versus etoposide 76.9%) at 100 lM.
Compound 7h displayed excellent antiproliferative activity
against T47D cells (7h: IC50 = 2.5 lM; adriamycin:
IC50 = 2.18 lM; etoposide: IC50 = 1.96 lM; camp-
tothecin: IC50 = 3.67 lM). Finally, altering the sub-
stituents of 7a, through elimination of –Br from the 30-
position and introduction of –OH at the 40-position as well
as introduction of –Br at the 300-position and replacement of
the hydroxy group with –OCH3 to produce 7j, resulted in
excellent antiproliferative activity (7j: IC50 = 0.67 lM;
adriamycin: IC50 = 2.18 lM; etoposide: IC50 = 1.96 lM;
camptothecin: IC50 = 3.67 lM) against T47D cells.
Interestingly, this compound did not show any antibacterial
or topoisomerase-inhibiting activity. Furthermore, 7c, a
compound with two –F groups at the 30- and 50-positions
and –OCH3 at the 300-position of 7a; 7d, a compound with –
F at the 60-position and –OCH3 at the 300-position of 7a; 7f,
a compound with two –OCH3 groups at the 60- and 300-
positions of 7a; 7g, a compound with –OCH3 at the 60-
position of 7a; 7i, a compound with –OCH3 at the 40-po-
sition of 7a showed moderate antiproliferative activity
against all tested cell lines, particularly T47D. However,
topoisomerase inhibition and antibacterial activity were not
observed.
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Acknowledgements This work was supported by the NSTIP
Strategic Technologies Program (Number 12-MED-2439-02) in the
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