A SAR study on a series of synthetic lipophilic chalcones as Inhibitor of transcription factor NF-κB

Article abstract of DOI:10.1016/j.ejmech.2012.05.019

To define the structural features responsible for the activity of 2,4-dihydroxy-6-isopentyloxychalcone, a newly established inhibitor of LPS induced NF-κB activation (IC₅₀ = 10 μM), a series of its analogues was prepared and studied for their i

Full text of DOI:10.1016/j.ejmech.2012.05.019

European Journal of Medicinal Chemistry 54 (2012) 379e386
Contents lists available at SciVerse ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
A SAR study on a series of synthetic lipophilic chalcones as Inhibitor
of transcription factor NF-
kB
Eeda Venkateswararao a, Vinay K. Sharma a, Ki-Cheul Lee a, Niti Sharma a, Sun-Hong Park b,
,
Youngsoo Kim b, Sang-Hun Jung a
*
a College of Pharmacy and Institute of Drug Research and Development, Chungnam, National University, Daejeon 305-764, Republic of Korea
b College of Pharmacy, Chungbuk National University, Cheongju 361-763, Republic of Korea
h i g h l i g h t s
g r a p h i c a l a b s t r a c t
< SAR of novel 2,4-dihydroxy-6-
isopentyloxychalcone
inhibitor was explored.
as
NF-kB
< Replacement of isopentyl chain with
C8eC14 linear alkyls increases the
activity.
< Hydroxyl group and its location at
4-position on ring B are important.
< The
a,b-unsaturated ketone moiety
appears as a crucial motif.
a r t i c l e i n f o
a b s t r a c t
Article history:
To define the structural features responsible for the activity of 2,4-dihydroxy-6-isopentyloxychalcone,
Received 15 February 2012
Received in revised form
26 April 2012
Accepted 11 May 2012
Available online 19 May 2012
a newly established inhibitor of LPS induced NF-
prepared and studied for their in vitro activities against LPS induced NF-
Among the synthesized derivatives, (E)-1-(2-(decyloxy)-6-hydroxyphenyl)-3-(4-hydroxyphenyl)prop-2-
k
B activation (IC50 ¼ 10
m
k
M), a series of its analogues was
B inhibition in RAW 264.7 cells.
en-1-one (IC50 ¼ 2.7
m
m
M) and (E)-1-(2-hydroxy-6-(tetradecyloxy)phenyl)-3-(4-hydroxyphenyl)prop-2-
M) showed the most potent inhibition. The SAR studies confirmed that the
en-1-one (IC50 ¼ 4.2
length (C8eC14) and C-6 position of linear alkyl chain of ring A is an important factor for the inhibitory
Keywords:
Chalcones
activity. Hydroxyl group and its location at 4-position on ring B is also important for the inhibition. The
a
,b
-unsaturated ketone moiety appears as a crucial motif of chalcones for the activity.
Ó 2012 Elsevier Masson SAS. All rights reserved.
LPS induced NF-
Inflammation
Sepsis
kB inhibition
1. Introduction
response to lipopolysaccharide (LPS) from Gram-negative bacteria
[2]. The molecular mechanism in the pathogenesis of sepsis [3] is
better understood after the discovery of Toll-like receptors (TLRs),
which are important for the activation of the innate immune
system. Among the TLR family, TLR4, is best known for detecting
Sepsis is not
a disease but a life-threatening infectious
syndrome which causes the death of about one-third of affected
patients [1] similar to lung cancer, though the statistics is quite
grim, still not much attention is given to it as compared to the heart
disease or cancer. Sepsis can occur through infection by bacteria,
fungi and viruses while the sepsis syndrome mainly occurs in
lipopolysaccharide (LPS),
a membrane component of Gram-
negative bacteria [4] required for the protection and structural
integrity of the bacteria. All TLR signaling pathways results in
activation of the transcription factor nuclear factor-kappa B (NF-
k
B), which controls the expression of an array of inflammatory
* Corresponding author. Tel.: þ82 42 821 5939; fax: þ82 42 823 6566.
E-mail address: jungshh@cnu.ac.kr (S.-H. Jung).
cytokine genes [5e7]. NF- B is present in a dormant form in the
k
0223-5234/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2012.05.019

380
E. Venkateswararao et al. / European Journal of Medicinal Chemistry 54 (2012) 379e386
cytoplasm of a normal cell by inhibitory
activating stimuli, such as cytokines, viruses, and lipopolysaccha-
ride (LPS), causes the breakdown of inhibitory Bs exposing the
nuclear localization signal of NF- B, causing its nuclear trans-
location, binding to NF- B motifs, and gene transcription [9]. Some
studies established that improper NF- B signaling results in
immunosuppression which initiate and maintains inflammation
[10,11]. Thus, it can be suggested that inhibition of massive NF-
kB (IkB) proteins [8]. NF-kB
k
k
k
k
k
B
activation in vivo leads to reduced inflammatory responses, at least
during certain phases and certain tissues (i.e., parenchymal tissues)
in sepsis [12].
Scheme 1. Synthesis of chalcone analogs 1b-q, 2 and 3 Reagents and conditions: (a) R-
Br, K2CO3,NaI, Acetonitrile, Reflux at 80e82 ꢀC; (b) Substituted benzaldehyde, KOH,
EtOH, Reflux at 78 ꢀC; (c) 1N HCl, MeOH Reflux at 64e65 ꢀC; (d) 10% wet Pd/C; THF; (e)
NaBH4, THF at 5e10 ꢀC. Note* ¼ substitution are located in Table 1.
Till date a number of small molecules have been developed for
the treatment of septic shock [13,14] and most of them are either
synthetic mimics of the lipid A or naturally occurring under-acylated
forms of lipid A that act as antagonists on the TLR4 [15e18]. The
synthetic lipid A analogs E5564 [19] and ethyl(6R)-6-[N-(2-chloro-
4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate (TAK-242)
[20,21] were prepared and reported for their antisepsis effect.
Another class of antisepsis agent is antibiotic cyclic peptide poly-
mixin B [22] (PMB), but it is never used in a clinic because of its high
toxicity. Lastly, the synthetic polycationic amphiphiles, which
includes linear or branched [23,24] spermine derivatives and
“Gemini” amphiphiles [25], have been designed as surfactant but
showed high cytotoxicity and hemolytic activity. Therefore, there is
still a major need for safer and more effective antisepsis agents.
Recently our group has discovered 2,4-dihydroxy-6-isopent
yloxychalcone (1a) and successfully established it as an inhibitor of
NMR spectra of these chalcone derivatives showed that only trans-
chalcones were obtained.
3. Pharmacology
3.1. Secretory alkaline phosphatase (SEAP) reporter assay
Inhibitory activity of the chalcone analogs against NF-
evaluated using RAW 264.7 cells containing pNF- B-SEAP-
neomycin phosphotransferase (NPT) as per our previously reported
procedure [26]. In brief, an NF- B-dependent secretory alkaline
phosphatase (SEAP) reporter construct [28e30] were stimulated
with LPS (0.1 g/mL) for 20 h in the presence of samples. Aliquots of
the culture media were heated to 65 ꢀC for 5 min and then reacted
with 4-methylumbelliferyl phosphate (500 M) in the dark. SEAP
kB was
k
k
m
LPS induced NF-
about 10 M [26]. It is a non-lipid chalcone which not only inhibited
the TLR4-mediated NF- B activating pathway but also suppressed
the NF- B regulated expression of iNOS, COX-2 or pro-inflammatory
kB activation in macrophages with an IC50 value of
m
m
k
activity was measured as RFUs with emission at 449 nm and
excitation at 360 nm. Separately, RAW 264.7 cells containing pNF-
k
cytokine genes. These findings encouraged us to continue our search
for potent analogs of 1a. Therefore, here in the current study we have
designed and synthesized various analogs of 1a (Fig. 1) with LPS
structural characteristics and evaluated for their in vitro activities
k
B-SEAP-NPT were transfected with a constitutively active IKK
b
vector in combination with pSV- -galactosidase control vector,
b
using lipofectamine (Invitrogen) according to the manufacture’s
protocol. These cells were treated with the samples for 20 h, and
then subjected to the SEAP reporter assay, in which SEAP activity
against LPS induced NF-kB inhibition in RAW 264.7 cells using the
SEAP assay.
was normalized to b-galactosidase activity.
3.2. In vitro cytotoxicity of 1bev, 2 and 3 against RAW 264.7 cells
2. Chemistry
For all the above synthesized compounds, cytotoxicity against
RAW 264.7 cells was checked using MTT assay [31,32] and the
results are given as IC50 values in Table 1. IC50 values (>30 mM) of all
compounds were non-toxic at concentration used for SEAP assay.
4. Results and discussion
The syntheses of the desired compounds 1bev, 2, and 3 were
accomplished as outlined in Scheme 1 and Scheme 2. The
key intermediate mono-alkylated hydroxyacetophenone 5 were
synthesized from dihydroxyacetophenone 4 by reacting with
various alkyl bromides in the presence of potassium carbonate and
catalytic amount of sodium iodide [27]. Further, the mono-alkylated
hydroxyacetophenones 5 were subjected to aldol condensationwith
substituted benzaldehydes 6 to the get the intermediates 7beq. The
resulted intermediates were treated with 1 N HCl in methanol to
obtain the final compounds 1beq. The compound 2 was prepared by
the reduction of 1e at room temperature and finally, the reduction of
2 using NaBH4 in methanol at 5e10 ꢀC temperature gave compound
3 (Scheme 1). The compounds 1rev were obtained directly by the
aldol condensation of 5 with appropriate aldehyde 8 under reflux
condition (Scheme 2). The structures of compounds 1bev were
established by physical and spectral analysis. In addition, the 1H
In our previous study we have observed that 1a inhibited LPS
induced NF-
chain length plays an important role for the inhibition of LPS
induced NF- B activation therefore, in the current set of experi-
kB activation with an IC50 value of 10.0 mM [26]. Alkyl
k
ment to optimize the size of alkyl group, 1a analogs 1bev were
prepared with varied lipophilic alkyl chain (C6eC18) at C-6 position
of ring A. In the first set of experiment the 1a analogs 1beh, were
synthesized and evaluated for LPS induced NF-kB inhibition.
Among these derivatives, compound 1d with C10 alkyl chain at C-6
Scheme 2. Synthesis of chalcone analogs 1r-v Reagents and conditions: (a) R-Br,
K2CO3,NaI, Acetonitrile, Reflux at 80e82 ꢀC; (b) Substituted benzaldehyde, KOH, EtOH,
Reflux at 78 ꢀC.
Fig. 1. Structural modifications of 1bev, 2 and 3.

E. Venkateswararao et al. / European Journal of Medicinal Chemistry 54 (2012) 379e386
381
Table 1
Inhibition of LPS induced NF-
k
B activation of chalcones 1bev, 2 and 3.
R1
OH
Compd. No.
R
R2
Inhibition At 30
m
M [%]
IC50
[m
M]
Cytotoxicity IC50 [mM]
1a26
1b
1c
1d
1e
1f
6-CH2CH(CH3)2
6-n-C5H11
6-n-C7H15
6-n-C9H19
6-n-C11H23
H
H
H
H
H
H
H
H
H
H
H
H
100
15
10
>30
5.0
2.7
9.4
>30
>30
>30
>30
>30
>30
>30
>30
>30
>30
>30
>30
>30
>30
>30
>30
>30
>30
>30
>30
>30
>30
>30
>30
OH
OH
OH
OH
100
100
100
100
42
22
100
8
60
28
50
100
53
22
45
18
8
26
17
10
52
6-n-C13H27
OH
4.2
1g
1h
1i
6-n-C15H31
6-n-C17H35
6-CH2CH(C6H13)(C8H17
OH
OH
OH
>30
>30
9.6
>30
>30
>30
29.0
9.6
>30
>30
>30
>30
>30
>30
>30
>30
>30
>30
)
1j
1k
1l
(CH2)3CH ¼ CH(CH2)4CH3
6-Cyclohexyl
6-Phenyl
OH
OH
OH
1m
1n
1o
1p
1q
1r
1s
1t
4-n-C13H27
6-n-C9H19
6-n-C9H19
6-n-C9H19
6-n-C9H19
6-n-C9H19
6-n-C9H19
6-n-C9H19
OH
OH
OH
H
H
3-Cl
3,5-OCH3
3-OH
2-OH
H
H
3-Cl
H
H
OCH3
CH3
Cl
1u
1v
2
6-n-C5H11
OC5H11
OC13H27
OH
6-n-C13H27
6-n-C11H23
6-n-C11H23
H
H
H
3
OH
80
a) IC50 values are taken as a mean from 3 experiments.
position of ring A and an electron donating group (hydroxy) at C-4
position of at ring B showed 6-fold more potent inhibition than 1a.
Interestingly, the compounds 1c (C8 alkyl chain) and 1f (C14 alkyl
chain) showed 2-fold more potent inhibition than 1a while the
compound 1e (C12 alkyl chain) showed almost similar inhibition to
1a. However, the compounds 1b (C7 alkyl chain), 1g (C16 alkyl
chain), and 1h (C18 alkyl chain) did not turn up with any inhibition.
Above results indicate that the length of alkyl chain is an important
hydrogen bonding of hydroxyl function regardless of their elec-
tronic properties. Thus, by increasing the bulkiness of these
substituents the activity reduces. This trend well supports the
aforementioned importance of the hydrogen bonding ability of
hydroxyl function in the ring B of 1d.
To determine the importance of hydroxyl function, the location
of hydroxyl group of 1d was changed from C-4 to C-3 or C-2 posi-
tion in ring B as shown in compounds 1p (3-OH) and 1q (2-OH).
These compounds showed very weak activity. These results prove
the importance of C-4 position of hydroxyl group in ring B for the
inhibitory activity of these chalcones.
The LPS has four aliphatic long chains. Therefore, more aliphatic
chains incur more hydrophobic bonding and increase the activity.
In this regard, hydroxyl group at C-4 position in ring B was alkylated
with pentyl or tridecyl group as shown in analogs 1u and 1v. Unlike
expectation, both compounds did not show any activity. These
results again support the importance of hydrogen bonding ability
rather than hydrophobic binding of hydroxyl group at C-4 in ring B
of 1.
factor for the inhibition of LPS induced NF-kB activation and the
optimum length of alkyl chain appears around C10 alkyl group.
In continuation for the optimization of C-6 position of ring A,
alkyloxy group was varied with branched alkyl chains as shown in
1i (hexyldecyl) and 1j ((Z)-dec-4-enyl alkyl chain) and cyclic groups
as in 1kel at C-6 position of ring A. Surprisingly, none of these
compounds turn up with any activity, suggesting that the linear
lipophilic alkyl chain is more favorable than their bulkier counter-
parts. In addition, the position of tetradecyloxy group in 1f was
changed from C-6 to C-4 position of ring A as shown in 1m. This
alteration decreased the activity. Thus, the optimum position of
alkyloxy group in ring A of 1 for their activity is the C-6 position.
Shifting our focus to the ring B, the 4-hydroxyphenyl moiety of
1a was considered to be important for the inhibition of LPS induced
NF-kB activation because this hydroxyl group could achieve
a hydrogen bond with Ser-118 residue at the opening rims of the
pocket of binding site [26]. Therefore, the importance of this
hydroxyl function has to be proved for the design of more potent
analogs. Hydrogen bonding ability of most active compound 1d was
blocked by the replacement of its hydroxyl function with methoxy
(1r), methyl (1s), or 3,4-dichloro (1t). These substitutions nearly
abolished the activity. Therefore, hydrogen bonding ability of
hydroxyl function in ring B of 1d should be essential for the activity.
For examining the substituent effect on the hydrogen bonding
ability of hydroxyl group in ring B of 1d, 3-chloro group (electron
withdrawing group) or 3,5-methoxy group (electron donating
group) was introduced as shown in 1n (3-chloro) and 1o (3,5-
methoxy). In both the analogs the activity decreased as compared
to 1d. Upon these substitutions, the electronic effects were hardly
observed. These decrements in the activity might reflect that these
substituents at 3 or 5-position may act as steric blocker for
In order to explore the role of
a,b-unsaturated ketone of chal-
cones for their LPS induced NF-kB inhibitory activity, compound 2
was prepared by reducing the double bond of 1e and 3 by the
reduction of carbonyl function in 2. Interestingly, compounds 2 and
3 completely lost their activity as compared to 1e. These results
indicate that the
inhibition of NF-
a
,
b
-unsaturated ketone are important for the
k
B activity of chalcones.
From the MTT assay results, it was confirmed that the
compounds 1bev, 2 and 3 do not have any serious toxicity.
Therefore, we can conclude that none of the compounds displayed
any obvious cytotoxicity at the effective concentrations.
5. Conclusion
Non-lipid novel chalcone analogs 1bev, 2 and 3 have been
synthesized and tested for their inhibitory activity against LPS
induced NF-
tionship of 1a. The compounds 1d, 1c and 1f showed 4-fold and
2-fold more potent inhibition toward NF- B activation than 1a,
respectively. The SAR studies confirmed that the length (C8eC14
kB activation for defining the structure activity rela-
k
)

382
E. Venkateswararao et al. / European Journal of Medicinal Chemistry 54 (2012) 379e386
and C-6 position of alkyl chain of ring A is an important factor for
the inhibition of LPS induced NF- B activation. Introduction of
bulky hydrophobic groups such as cyclohexyl or phenyl resulted in
loss of activity. In addition, hydroxyl group and its location at
(neat) 3330.8, 2917, 2848, 1618 cmꢁ1 1H NMR (CDCl3)
; d 13. 27
k
(s, 1H) 7.31 (t, J ¼ 8.2 Hz, 1H), 6.54 (d, J ¼ 7.6 Hz, 1H), 6.35
(d, J ¼ 7.6 Hz, 1H), 4.03 (t, J ¼ 6.4 Hz, 2H), 2.69 (s, 3H),
1.91e1.84(m, 2H), 1.50e1.42(m, 2H), 1.28e1.20 (m, 16H), 0.86
(t, J ¼ 8.0 Hz, 3H).
4-position on ring B are also important for the inhibition. The
unsaturated ketone moiety appears as a crucial motif for the inhi-
bition of NF- B activity of 1. Taken together, current study identifies
the chalcone molecules as a novel scaffold for inhibiting the tran-
scription factor NF- B and makes them potential therapeutic
a,b-
k
6.1.1.5. 1-(2-Hydroxy-6-(tetradecyloxy)phenyl)ethanone (5f). Yield
82.4%; Light green liquid; Rf 0.67 (1:9 Ethyl acetate: Hexane); IR
k
(neat) 3330.8, 2917, 2848, 1618 cmꢁ1 1H NMR (CDCl3)
; d 13. 27
agents against inflammatory disorders including sepsis.
(s, 1H) 7.32 (t, J ¼ 8.2 Hz, 1H), 6.54 (d, J ¼ 7.6 Hz, 1H), 6.35
(d, J ¼ 7.6 Hz, 1H), 4.04 (t, J ¼ 6.4 Hz, 2H), 2.69 (s, 3H),
1.91e1.84(m, 2H), 1.50e1.42 (m, 2H), 1.28e1.20 (m, 20H), 0.87
(t, J ¼ 8.0 Hz, 3H).
6. Materials and method
6.1. Chemistry
6.1.1.6. 1-(2-(Hexadecyloxy)-6-hydroxyphenyl)ethanone (5g). Yield
80.8%; Light green liquid; Rf 0.69 (1:9 Ethyl acetate: Hexane); IR
All melting points (mp) were determined on Electro thermal 1A
9100 MK2 apparatus and are uncorrected. All SigmaeAldrich/TCI
chemicals were used as obtained. Analytical thin layer Chromatog-
raphy was carried out using glass-backed plates coated with Merck
Kieselgel 60 GF240. Plates were visualized using UV light (254 or
366 nm). Flash column chromatography was performed with E
Merck silica gel(230e400 mesh). Infra redspectrumwas recordedin
the range 4000e500 cmꢁ1 by using Nicolet e 380 models FT-IR
spectrometer. 1H NMR and 13C-NMR spectra were recorded at
400 MHz Varian Unity Inova 400 NMR (400 MHz) spectrometer in
(neat) 3330.8, 2917, 2848, 1618 cmꢁ1 1H NMR (CDCl3)
; d 13. 27
(s, 1H) 7.31 (t, J ¼ 8.2 Hz, 1H), 6.54 (d, J ¼ 7.6 Hz, 1H), 6.35
(d, J ¼ 7.6 Hz, 1H), 4.04 (t, J ¼ 6.4 Hz, 2H), 2.69 (s, 3H), 1.91e1.84
(m, 2H), 1.50e1.42 (m, 2H), 1.28e1.19 (m, 24H), 0.87 (t,
J ¼ 8.0 Hz, 3H).
6.1.1.7. 1-(2-Hydroxy-6-(octadecyloxy)phenyl)ethanone (5h). Yield
76.2%; Light green liquid Rf 0.70 (1:9 Ethyl acetate: Hexane); IR
(neat) 3330.8, 2917, 2848, 1618 cmꢁ1 1H NMR (CDCl3)
; d 13.
the solvent indicated. Chemical shifts are given in
d
values (ppm)
27(s, 1H) 7.31 (t, 1H), 6.54 (d, 1H), 6.36 (d, J ¼ 7.6 Hz, 1H), 4.06
(t, J ¼ 6.4 Hz, 2H), 2.69 (s, 3H), 1.88e1.83 (m, 2H), 1.51e1.43 (m, 2H),
1.28e1.18 (m, 28H), 0.87 (t, J ¼ 8.0 Hz, 3H).
with tetramethylsilane as an internal standard. The following
abbreviations are used: s ¼ singlet, d ¼ doublet, t ¼ triplet,
q ¼ quartet, m ¼ multiplet. Coupling constants (J values) are given in
hertz (Hz). High resolution mass spectra (HRMS) were measured by
using Shimadzu LCMS-IT-TOF spectrometer.
6.1.1.8. 1-(2-(2-Hexyldecyloxy)-6-hydroxyphenyl)ethanone (5i). Yield
76%; Brown liquid; Rf 0.75 (1:9 Ethyl acetate: Hexane); IR (neat)
3330.8, 2917, 2848,1618 cmꢁ1; 1H NMR (CDCl3)
d 13. 27(s,1H) 7.30 (t,
6.1.1. General procedure for preparation of compounds (5)
The solution of dihydroxyacetophenone (4, 1.0 equiv.), anhy-
drous potassium carbonate (2.0 equiv.) and corresponding alkyl
bromides (1.1 equiv.) in acetonitrile was stirred at 70e80 ꢀC for
4e5 h. After evaporation of acetonitrile, the reaction mixture was
diluted with dichloromethane and washed with water three times.
The organic layer was dried with anhydrous sodium sulfate and
evaporated under reduced pressure. The crude product was puri-
fied by column chromatography to give 5.
J ¼ 8.2 Hz, 1H), 6.54 (d, J ¼ 7.6 Hz, 1H), 6.35 (d, J ¼ 7.6 Hz, 1H), 4.03 (t,
J ¼ 6.4 Hz, 2H), 2.69 (s, 3H), 1.86e1.80 (m, 1H), 1.47e1.19 (m, 32H),
0.89e0.85 (m, 6H).
6.1.1.9. (Z)-1-(2-(Dec-4-enyloxy)-6-hydroxyphenyl)ethanone (5j). Yield
55.4%; Colorless liquid Rf 0.59 (1:9 Ethyl acetate: Hexane); IR (neat)
3330.8, 2917, 2848, 1670 cmꢁ1; 1H NMR (CDCl3)
d 13. 30 (s, 1H) 7.31 (t,
1H), 6.54 (d, 1H), 6.36 (d, J ¼ 7.6 Hz, 1H), 5.42e5.30(m, 2H), 4.08 (t,
J ¼ 6.4 Hz, 2H), 2.69 (s, 3H), 2.26e2.21 (m, 2H), 1.98e1.88 (m, 4H),
1.27e1.14 (m, 6H), 0.87 (t, J ¼ 8.0 Hz, 3H).
6.1.1.1. 1-(2-(Hexyloxy)-6-hydroxyphenyl)ethanone (5b). Yield 45%;
Light green liquid Rf 0.60 (1:9 Ethyl acetate: Hexane); IR (neat)
6.1.1.10. 1-(2-(Cyclohexylmethoxy)-6-hydroxyphenyl)ethanone (5k).
Data associated to the compound 5k was reported in the
reference [33].
3335, 2917, 2850, 1618 cmꢁ1
;
1H NMR (CDCl3)
d
13. 22 (s, 1H) 7.31
(t, J ¼ 8.0 Hz, 1H), 6.54 (d, J ¼ 8.0 Hz, 1H), 6.36 (d, J ¼ 8.0 Hz, 1H),
4.03 (t, 6.2 Hz, 2H), 2.69 (s, 3H), 1.91e1.85(m, 2H),
J
¼
1.50e1.43(m, 2H), 1.30e1.17(m, 4H), 0.91 (t, J ¼ 8.0 Hz, 3H).
6.1.1.11. 1-(2-(Benzyloxy)-6-hydroxyphenyl)ethanone (5l). Data asso-
ciated to the compound 5l was reported in the reference [33].
6.1.1.2. 1-(2-Hydroxy-6-(octyloxy)phenyl)ethanone (5c). Yield 78%;
Light green liquid Rf 0.62 (1:9 Ethyl acetate: Hexane); IR (neat)
6.1.1.12. 1-(2-Hydroxy-4-(tetradecyloxy)phenyl)ethanone (5m). Yield
76.3%; Green liquid; Rf 0.71 (1:9 Ethyl acetate: Hexane); IR (neat)
3331, 2917, 2848, 1618 cmꢁ1
;
1H NMR (CDCl3)
d
13. 26 (s, 1H) 7.32
(t, J ¼ 8.0 Hz, 1H), 6.54 (d, J ¼ 8.0 Hz, 1H), 6.36 (d, J ¼ 8.0 Hz, 1H),
4.02 (t, 6.2 Hz, 2H), 2.69 (s, 3H), 1.91e1.85(m, 2H),
3420, 3050, 2900, 1620 cmꢁ1; 1H NMR (CDCl3)
d 13.20 (s, 1H), 7.42
J
¼
(d, J ¼ 8.4 Hz, 1H), 6.56 (dd, J ¼ 8.4, 0.8 Hz, 1H), 6.38 (d, J ¼ 0.8 Hz,
1H), 4.03 (t, J ¼ 6.4 Hz, 2H), 2.69 (s, 3H), 1.91e1.84(m, 2H), 1.50e1.42
(m, 2H), 1.28e1.20 (m, 20H), 0.87 (t, J ¼ 8.0 Hz, 3H).
1.50e1.43(m, 2H), 1.30e1.17(m, 8H), 0.91 (t, J ¼ 8.0 Hz, 3H).
6.1.1.3. 1-(2-(Decyloxy)-6-hydroxyphenyl)ethanone (5d). Yield 80%;
Light green liquid; Rf 0.63 (1:9 Ethyl acetate: Hexane); IR (neat)
6.1.2. General procedure for the preparation of compound 7
3330.8, 2917, 2848, 1618 cmꢁ1; 1H NMR (CDCl3)
d
13. 27(s, 1H) 7.30
The corresponding alkyl substituted-2-hydroxyacetophenone 5
(1.0 equiv) was dissolved in 95% aq. ethanol (8.7%w/w) and
added potassium hydroxide (2.0 equiv) and substituted benzal-
dehydes 6 (1.02 equiv). The resulting mixture was further stirred
for 2e3 h at 78 ꢀC. After completion of reaction, the solvent was
evaporated under reduced pressure. The residue was dissolved in
dichloromethane and washed with water three times. The
(t, J ¼ 8.2 Hz,1H), 6.54 (d, J ¼ 7.6 Hz,1H), 6.35 (d, J ¼ 7.6 Hz,1H), 4.03
(t, J ¼ 6.4 Hz, 2H), 2.69 (s, 3H), 1.91e1.84 (m, 2H), 1.50e1.42 (m, 2H),
1.28e1.20 (m, 12H), 0.87 (t, J ¼ 8.0 Hz, 3H).
6.1.1.4. 1-(2-(Dodecyloxy)-6-hydroxyphenyl)ethanone (5e). Yield
88%; Light green liquid; Rf 0.65 (1:9 Ethyl acetate: Hexane); IR

E. Venkateswararao et al. / European Journal of Medicinal Chemistry 54 (2012) 379e386
383
organic layer was dried with anhydrous sodium sulfate and
evaporated under reduced pressure to get the crude product,
which was further purified by flash column chromatography to
give 7beq.
(d, J ¼ 15.5 Hz, 1H), 7.50 (d, J ¼ 8.7 Hz, 2H), 7.30 (t, J ¼ 8.2 Hz, 1H),
6.86 (d, J ¼ 8.4 Hz, 2H), 6.59 (d, J ¼ 8.4 Hz, 1H), 6.40 (d, J ¼ 8.4 Hz,
1H), 5.20 (s, 2H), 4.06 (t, J ¼ 6.4 Hz, 2H), 3.48 (s, 3H), 2.69 (s, 3H),
1.88e1.84 (m, 2H), 1.51e1.43 (m, 2H), 1.28e1.18 (m, 28H), 0.87
(t, J ¼ 7.2 Hz, 1H).
6.1.2.1. (E)-1-(2-(Hexyloxy)-6-hydroxyphenyl)-3-(4-(methoxymethoxy)
phenyl)prop-2-en-1-one (7b). Yield 56.4%; Yellow solid; Rf 0.82
6.1.2.8. (E)-1-(2-(2-Hexyldecyloxy)-6-hydroxyphenyl)-3-(4-(methox-
(2:8 Ethyl acetate: Hexane); mp 50e55 ꢀC; 1H NMR (CDCl3)
d
13. 26
ymethoxy)phenyl)prop-2-en-1-one (7i). Yield 55.4%; Brown liquid
(s, 1H), 7.87 (d, J ¼ 15.6 Hz, 1H), 7.78 (d, J ¼ 15.6 Hz, 1H), 7.55
(d, J ¼ 8.8 Hz, 2H), 7.32 (t, J ¼ 8.2 Hz, 1H), 7.06 (d, J ¼ 8.4 Hz, 2H), 6.59
(dd, J ¼ 8.4, 0.8 Hz, 1H), 6.41 (dd, J ¼ 8.4, 0.8 Hz, 1H), 5.22 (s, 2H), 4.07
(t, J ¼ 6.4 Hz, 2H), 3.49 (s, 3H), 2.69 (s, 3H), 1.91e1.84 m, 2H, 1.51e1.43
(m, 2H), 1.30e1.21 (m, 4H), 0.82 (t, J ¼ 7.2 Hz, 1H).
Rf 0.63 (1:9 Ethyl acetate: Hexane); 1H NMR (CDCl3)
d 13. 15 (s, 1H)
7.78 (d, J ¼ 16 Hz, 1H), 7.7.76 (d, J ¼ 15.6 Hz, 1H), 7.52 (d, J ¼ 8 Hz,
2H), 7.33 (t,1H), 6.85 (d, J ¼ 8 Hz, 2H), 6.59 (d,1H), 6.42 (d, J ¼ 7.6 Hz,
1H), 5.23 (s, 2H), 5.16 (s, 1H), 3.95 (d, J ¼ 8.0 Hz, 2H) 3.48 (s, 3H),
1.86e1.80 (m, 1H), 1.47e1.19 (m, 24H), 0.88 (t, J ¼ 4.0 Hz, 6H).
6.1.2.2. (E)-1-(2-hydroxy-6-(octyloxy)phenyl)-3-(4-(methoxymethoxy)
6.1.2.9. (E)-1-(2-((Z)-dec-4-enyloxy)-6-hydroxyphenyl)-3-(4-(methox-
phenyl)prop-2-en-1-one (7c). Yield 59.9%; Light green solid; Rf 0.85
ymethoxy)phenyl)prop-2-en-1-one (7j). Yield 55.4%; Colorless liquid Rf
(2:8 Ethyl acetate: Hexane); mp 48e52 ꢀC; 1H NMR (CDCl3)
d
13. 26
0.59 (1:9 Ethyl acetate: Hexane); 1H NMR (CDCl3)
d 13. 30 (s, 1H) 7.87
(s, 1H), 7.87 (d, J ¼ 15.6 Hz, 1H), 7.78 (d, J ¼ 15.6 Hz, 1H), 7.55
(d, J ¼ 8.8 Hz, 2H), 7.32 (t, J ¼ 8.2 Hz, 1H), 7.06 (d, J ¼ 8.4 Hz, 2H), 6.60
(dd, J ¼ 8.0, 0.8 Hz,1H), 6.41 (dd, J ¼ 8.4, 0.8 Hz, 1H), 5.22 (s, 2H), 4.06
(t, J ¼ 6.4 Hz, 2H), 3.49 (s, 3H), 2.69 (s, 3H), 1.91e1.84 (m, 2H),
1.51e1.43 (m, 2H), 1.30e1.21 (m, 4H), 0.82 (t, J ¼ 7.2 Hz, 1H).
(d, J ¼ 16 Hz, 1H), 7.89 (d, J ¼ 15.6 Hz, 1H), 7.52 (d, J ¼ 8 Hz, 2H), 7.31
(t, 1H), 6.86 (d, J ¼ 8 Hz, 2H), 6.54 (d, 1H), 6.36 (d, J ¼ 7.6 Hz, 1H),
5.42e5.30(m, 4H), 4.08 (t, J ¼ 6.4 Hz, 2H), 3.48 (s, 3H), 2.26e2.21
(m, 2H), 1.98e1.88 (m, 4H), 1.27e1.14 (m, 6H), 0.87 (t, J ¼ 8.0 Hz, 3H).
6.1.2.10. (E)-1-(2-(Cyclohexylmethoxy)-6-hydroxyphenyl)-3-(4-
(methoxymethoxy)phenyl)prop-2-en-1-one (7k). Compound 7k
reported in our previous studies [33].
6.1.2.3. E-1-(2-(Decyloxy)-6-hydroxyphenyl)-3-(4-(methoxymethoxy)
phenyl)prop-2-en-1-one (7d). Yield 61.3%; Light green solid; Rf 0.84
(2:8 Ethyl acetate: Hexane); mp 46e50 ꢀC; 1H NMR (CDCl3)
d 13.
26(s, 1H), 7.85 (d, J ¼ 15.6 Hz, 1H), 7.78 (d, J ¼ 15.6 Hz, 1H), 7.51
(d, J ¼ 8.8 Hz, 2H), 7.33 (t, J ¼ 8.2 Hz,1H), 6.85 (d, J ¼ 8.4 Hz, 2H), 6.59
(d, J ¼ 8.4 Hz, 1H), 6.40 (d, J ¼ 8.4 Hz, 1H), 5.20 (s, 2H), 4.06
(t, J ¼ 6.4 Hz, 2H),3.48 (s, 3H), 2.69 (s, 3H), 1.91e1.84 (m, 2H),
1.51e1.43 (m, 2H), 1.28e1.20 (m, 12H), 0.86 (t, J ¼ 7.2 Hz, 1H).
6.1.2.11. (E)-1-(2-(Benzyloxy)-6-hydroxyphenyl)-3-(4-(methoxy-
methoxy)phenyl)prop-2-en-1-one(7l). Compound 7l reported in
our previous studies [33].
6.1.2.12. (E)-1-(2-hydroxy-4-(tetradecyloxy)phenyl)-3-(4-(methox-
ymethoxy)phenyl)prop-2-en-1-one (7m). Yield 76.3%; Yellow
solid; mp 89e94 ꢀC; Rf 0.71 (1:9 Ethyl acetate: Hexane); 1H NMR
6.1.2.4. (E)-1-(2-(Dodecyloxy)-6-hydroxyphenyl)-3-(4-(methoxymetho-
xy)phenyl)prop-2-en-1-one (7e). Yield 53.8%; Light green solid; Rf 0.86
(CDCl3)
d
13.20 (s, 1H), 7.88 (d, J ¼ 15.6 Hz, 1H), 7.78 (d, J ¼ 15.6 Hz,
1
(2:8 Ethyl acetate: Hexane); mp 48e51 ꢀC; H NMR (CDCl3)
d
13. 27
1H), 7.55 (d, J ¼ 8 Hz, 2H), 7.33 (d, J ¼ 8.4 Hz, 1H), 6.79 (d, J ¼ 8.8 Hz,
2H), 6.52 (dd, J ¼ 8.4, 0.8 Hz, 1H), 6.33 (d, J ¼ 0.8 Hz, 1H), 5.24 (s,
2H), 4.06 (t, J ¼ 6.4 Hz, 2H), 3.49 (s, 3H), 1.88e1.83 (m, 2H),
1.51e1.43 (m, 2H), 1.28e1.20 (m, 20H), 0.87 (t, J ¼ 7.2 Hz, 3H).
(s, 1H) 7.78 (d, J ¼ 15.6 Hz, 1H), 7.70 (d, J ¼ 15.6 Hz, 1H), 7.43
(d, J ¼ 8.8 Hz, 2H), 7.25 (t, J ¼ 8.2 Hz, 1H), 6.78 (d, J ¼ 8.4 Hz, 2H), 6.58
(d, J ¼ 8.4 Hz,1H), 6.52 (d, J ¼ 8.4 Hz,1H), 5.21(s, 2H), 4.01 (t, J ¼ 6.4 Hz,
2H),3.48 (s, 3H), 2.69 (s, 3H), 1.91e1.84 (m, 2H), 1.50e1.42 (m, 2H),
1.28e1.20 (m, 16H), 0.86 (t, J ¼ 7.2 Hz, 1H).
6.1.2.13. (E)-3-(3-chloro-4-(methoxymethoxy)phenyl)-1-(2-(decy-
loxy)-6-hydroxyphenyl)prop-2-en-1-one (7n). Yield 72%; Yellow
solid; mp 112e115 ꢀC; Rf 0.54 (2:8 Ethyl acetate: Hexane); 1H NMR
6.1.2.5. (E)-1-(2-hydroxy-6-(tetradecyloxy)phenyl)-3-(4-(methox-
ymethoxy)phenyl)prop-2-en-1-one (7f). Yield 49.3%; Light green
solid; Rf 0.88 (2:8 Ethyl acetate: Hexane); mp 46e51 ꢀC; IR 1H
(CDCl3)
d
13. 06 (s, 1H) 7.91 (d, J ¼ 15.6 Hz, 1H), 7.69 (d, J ¼ 2 Hz,
1H), 7.63 (d, J ¼ 15.6 Hz, 1H), 7.48 (d, J ¼ 8.0 Hz, 1H), 7.41 (dd,
J ¼ 7.4, 0.8, 1H), 7.36 (t, J ¼ 8.8 Hz, 1H), 6.60 (d, J ¼ 8.4 Hz, 1H), 6.41
(d, J ¼ 8.4 Hz, 1H), 5.20 (s, 2H), 4.08 (t, J ¼ 6.4 Hz, 2H), 3.47 (s, 3H),
1.90e1.83 (m, 2H), 1.47e1.39 (m, 2H), 1.26e1.16 (m, 12H), 0.88 (t,
J ¼ 6.8 Hz, 3H).
NMR (CDCl3)
d
13. 27(s, 1H) 7.77 (d, J ¼ 15.6 Hz, 1H), 7.69
(d, J ¼ 15.6 Hz, 1H), 7.42 (d, J ¼ 8.8 Hz, 2H), 7.25 (t, J ¼ 8.2 Hz, 1H),
6.79 (d, J ¼ 8.4 Hz, 2H), 6.52 (d, J ¼ 8.4 Hz, 1H), 6.45 (d, J ¼ 8.4 Hz,
1H), 5.21(s, 2H), 4.01 (t, J ¼ 6.4 Hz, 2H), 3.48 (s, 3H), 2.69 (s, 3H),
1.91e1.84 (m, 2H), 1.50e1.42 (m, 2H), 1.28e1.20 (m, 20H), 0.86
(t, J ¼ 7.2 Hz, 1H).
6.1.2.14. (E)-1-(2-(Decyloxy)-6-hydroxyphenyl)-3-(3,5-dimethoxy-4-
(methoxymethoxy)phenyl)prop-2-en-1-one (7o). Yield 56%; Yellow
solid; Rf 0.50 (2:8 Ethyl acetate: Hexane); mp 96e99 ꢀC; 1H NMR
6.1.2.6. (E)-1-(2-(Hexadecyloxy)-6-hydroxyphenyl)-3-(4-(methox-
ymethoxy)phenyl)prop-2-en-1-one (7g). Yield 64.7%; Light green
solid; Rf 0.90 (2:8 Ethyl acetate: Hexane); mp 49e52 ꢀC; 1H NMR
(CDCl3)
d
13. 25 (s, 1H) 7.83 (d, J ¼ 15.2 Hz, 1H), 7.74 (d, J ¼ 15.2 Hz,
1H), 7.33 (t, J ¼ 8.4 Hz, 1H), 6.87 (s, 2H), 6.60 (d, J ¼ 8.4, 1H), 6.40 (d,
J ¼ 8.4 Hz, 1H), 5.80 (s, 1H), 5.24 (s, 2H), 4.07 (t, J ¼ 6.4 Hz, 2H), 3.50
(s, 2H), 3.94 (s, 6H), 1.94e1.86 (m, 2H), 1.47e1.39 (m, 2H), 1.27e1.16
(m, 12H), 0.87 (t, J ¼ 6.8 Hz, 3H).
(CDCl3)
d
13. 26 (s, 1H), 7.85 (d,
J
¼ 15.6 Hz, 1H), 7.77
(d, J ¼ 15.6 Hz, 1H), 7.51 (d, J ¼ 8.8 Hz, 2H), 7.33 (t, J ¼ 8.2 Hz, 1H),
6.85 (d, J ¼ 8.4 Hz, 2H), 6.59 (d, J ¼ 8.4 Hz, 1H), 6.40 (d, J ¼ 8.4 Hz,
1H), 5.20 (s, 2H), 4.06 (t, J ¼ 6.4 Hz, 2H), 3.48 (s, 3H), 2.69 (s, 3H),
1.91e1.84 (m, 2H), 1.51e1.43 (m, 2H), 1.28e1.20 (m, 24H), 0.87
(t, J ¼ 7.2 Hz, 1H).
6.1.2.15. (E)-1-(2-(Decyloxy)-6-hydroxyphenyl)-3-(3-(methoxymet-
hoxy)phenyl)prop-2-en-1-one (7p). Yield 88%; Yellow solid; Rf
0.58 (2:8 Ethyl acetate: Hexane); mp 109e114 ꢀC; 1H NMR
6.1.2.7. (E)-1-(2-hydroxy-6-(octadecyloxy)phenyl)-3-(4-(methox-
ymethoxy)phenyl)prop-2-en-1-one (7h). Yield 64.7%; Light green
solid; Rf 0.60 (1:9 Ethyl acetate: Hexane); mp 50e55 ꢀC; 1H NMR
(CDCl3)
d
13. 26 (s, 1H), 7.85 (d, J ¼ 15.6 Hz, 1H), 7.77 (d,
J ¼ 15.6 Hz, 1H), 7.43 (t, J ¼ 8.4 Hz, 1H), 7.18 (t, J ¼ 8.4 Hz, 1H),
6.88 (dd, J ¼ 8.8 Hz, 2H), 6.72 (d, J ¼ 0.8 Hz, 1H), 6.54 (dd, J ¼ 8.4,
0.8 Hz, 1H), 5.22 (s, 2H), 4.02 (t, J ¼ 6.4 Hz, 2H), 3.48 (s, 3H),
(CDCl3)
d
13. 26 (s, 1H), 7.84 (d,
J
¼ 15.5 Hz, 1H), 7.76

384
E. Venkateswararao et al. / European Journal of Medicinal Chemistry 54 (2012) 379e386
1.91e1.84 (m, 2H), 1.50e1.43 (m, 2H), 1.30e1.17 (m, 12H), 0.88 (t,
J ¼ 7.2 Hz, 3H).
2H), 1.50e1.43 (m, 2H), 1.30e1.17 (m, 16H), 0.87 (t, J ¼ 7.2 Hz, 3H);
13C NMR (CDCl3)
194.7, 164.9, 160.6, 158.0, 142.6, 135.7, 130.1,
128.9, 125.8, 116.0, 112.0, 110.5, 102.3, 68.9, 31.9, 29.7, 29.5, 29.4,
26.3, 22.7, 26.0, 14.1; HRMS: Calculated for C27H36O4: m/z
424.2613, Found: 424.2610.
d
6.1.2.16. (E)-1-(2-(Decyloxy)-6-hydroxyphenyl)-3-(2-(methox-
ymethoxy)phenyl)prop-2-en-1-one (7q). Yield 88%; Yellow solid;
Rf 0.60 (2:8 Ethyl acetate: Hexane); mp 100e112 ꢀC; 1H NMR
(CDCl3)
d
13. 26 (s, 1H), 7.89 (d, J ¼ 15.6 Hz, 1H), 7.77 (d, J ¼ 15.6 Hz,
6.1.3.5. (E)-1-(2-hydroxy-6-(tetradecyloxy)phenyl)-3-(4-hydroxyphenyl)
prop-2-en-1-one (1f). Yield 77%; Orange solid; Rf 0.61 (2:8 Ethyl
acetate: Hexane); mp 110e116 ꢀC; IR (neat) 3400, 3100, 2850,
1H), 7.11e7.22 (m, 4H), 6.78e6.86 (m, 3H), 5.23 (s, 2H), 4.02 (t,
J ¼ 6.4 Hz, 2H), 3.48 (s, 3H), 1.91e1.84 (m, 2H), 1.50e1.43 (m, 2H),
1.30e1.17 (m, 12H), 0.88 (t, J ¼ 7.2 Hz, 3H).
1690 cmꢁ1; 1H NMR (CDCl3)
d
13. 26(s, 1H), 7.78 (d, J ¼ 15.6 Hz, 1H),
7.69 (d, J ¼ 15.6 Hz, 1H), 7.44 (d, J ¼ 8.4 Hz, 2H), 7.25 (t, J ¼ 8.4 Hz, 1H),
6.79 (d, J ¼ 8.8 Hz, 2H), 6.52 (dd, J ¼ 8.0, 0.8 Hz, 1H), 6.33 (dd, J ¼ 8.4,
0.8 Hz, 1H), 4.06 (t, J ¼ 6.4 Hz, 2H), 1.88e1.83 (m, 2H), 1.51e1.43 (m,
2H), 1.28e1.20 (m, 20H), 0.87 (t, J ¼ 7.2 Hz, 3H); 13C NMR (CDCl3)
6.1.3. General procedure for the preparation of compounds 1beq
The above corresponding methoxymethyl protected chalcone
derivatives (7beq) 1.0 equivalent was added to 5 volumes of
methanol at room temperature to this added 2 volumes 1N HCl and
0.5 volumes 0.1% trifluroacetic acid solution slowly heat to reflux
temperature for 3e4 h for completion of reaction after completion
of reaction cooled to room temperature stirred for 3 h at the same
temperature product precipitated filtered and recrystalized from
methanol dried the material at 45e50 ꢀC for 5 h to give pure
titled product as a yellow color solid (1beq).
d
194.6, 164.9, 160.5, 158.9, 142.8, 135.8, 130.4, 128.2, 125.5, 116.0, 112.0,
110.6, 102.2, 69.0, 31.9, 29.9, 29.7, 29.5, 29.3, 26.4, 26.0, 22.7, 22.0, 14.1;
HRMS: calculated for C29H40O4: m/z 452.2926, Found: 452.2920.
6.1.3.6. (E)-1-(2-(Hexadecyloxy)-6-hydroxyphenyl)-3-(4-hydroxyphenyl)
prop-2-en-1-one (1g). Yield 75%; Yellow solid; Rf 0.66 (2:8 Ethyl
acetate: Hexane); mp 110e116 ꢀC; IR (neat) 3400, 3100, 2850,
1690 cmꢁ1; 1H NMR (CDCl3)
d
13. 26 (s, 1H), 7.84 (d, J ¼ 15.6 Hz, 1H),
6.1.3.1. (E)-1-(2-(Hexyloxy)-6-hydroxyphenyl)-3-(4-hydroxyphenyl)
prop-2-en-1-one (1b). Yield 56.4%; Yellow solid; Rf 0.58 (2:8 Ethyl
acetate: Hexane); mp 86e90 ꢀC; IR (neat) 3330, 2917, 2848,
7.77 (d, J ¼ 15.6 Hz, 1H), 7.52 (d, J ¼ 8.4 Hz, 2H), 7.32 (t, J ¼ 8.4 Hz, 1H),
6.86 (d, J ¼ 8.8 Hz, 2H), 6.59 (dd, J ¼ 8.0, 0.8 Hz, 1H), 6.40 (dd, J ¼ 8.4,
0.8 Hz, 1H), 4.06 (t, J ¼ 6.4 Hz, 2H), 1.91e1.84 (m, 2H), 1.51e1.43 (m, 2H),
1690 cmꢁ1; 1H NMR (CDCl3)
d
13. 26 (s, 1H), 7.87 (d, J ¼ 15.6 Hz, 1H),
1.28e1.20 (m, 24H), 0.86 (t, J ¼ 7.2 Hz, 3H); 13C NMR (CDCl3)
d 194.6,
7.78 (d, J ¼ 15.6 Hz, 1H), 7.55 (d, J ¼ 8.8 Hz, 2H), 7.32 (t, J ¼ 8.2 Hz,
1H), 7.06 (d, J ¼ 8.4 Hz, 2H), 6.59 (dd, J ¼ 8.0, 0.8 Hz, 1H), 6.40 (dd,
J ¼ 8.0, 0.8 Hz, 1H), 4.06 (t, J ¼ 6.4 Hz, 2H), 1.91e1.84 (m, 2H),
1.51e1.43 (m, 2H), 1.30e1.21 (m, 4H), 0.87 (t, J ¼ 7.2 Hz, 3H); 13C
164.8, 160.6, 158.8, 142.8, 135.8, 130.4, 128.2, 125.5, 116.0, 112.0, 110.6,
102.2, 69.0, 31.9, 29.9, 29.7, 29.5, 29.3, 26.4, 26.2,26.0, 22.7, 22.0, 14.1;
HRMS: calculated for C31H44O4: m/z 480.3239, Found: 480.3234.
NMR (CDCl3)
d
194.6, 164.7, 160.5, 157.7, 142.8, 135.8, 130.4, 128.2,
6.1.3.7. (E)-1-(2-hydroxy-6-(octadecyloxy)phenyl)-3-(4-hydroxyphenyl)
prop-2-en-1-one (1h). Yield 78%; Yellow solid; Rf 0.68 (2:8 Ethyl
acetate: Hexane); mp 115e120 ꢀC; IR (neat) 3400, 3100, 2850,
125.5, 115.9, 112.0, 110.5, 102.3, 68.9, 31.9, 29.6, 26.3, 22.8, 14.1;
HRMS: Calculated for C21H24O4: m/z 340.1674, Found: 340.1668.
1690 cmꢁ1; 1H-NMR (CDCl3)
d
13. 28 (s, 1H), 7.85 (d, J ¼ 15.6 Hz, 1H),
6.1.3.2. (E)-1-(2-hydroxy-6-(octyloxy)phenyl)-3-(4-hydroxyphenyl)
prop-2-en-1-one (1c). Yield 85%; Orange solid; Rf 0.60 (2:8 Ethyl
acetate: Hexane); mp 105e110 ꢀC; IR (neat) 3400, 3100, 2850,
7.77 (d, J ¼ 15.6 Hz, 1H), 7.51 (d, J ¼ 8.4 Hz, 2H), 7.34 (t, J ¼ 8.4 Hz, 1H),
6.85 (d, J ¼ 8.8 Hz, 2H), 6.59 (dd, J ¼ 8.0, 0.8 Hz, 1H), 6.33 (dd, J ¼ 8.4,
0.8 Hz,1H), 4.06 (t, J ¼ 6.4 Hz, 2H),1.91e1.84 (m, 2H), 1.58e1.43 (m, 3H),
1690 cmꢁ1; 1H NMR (CDCl3)
d
13. 26 (s, 1H), 7.85 (d, J ¼ 15.6 Hz, 1H),
1.29e1.19 (m, 28H), 0.87 (t, J ¼ 7.2 Hz, 3H); 13C NMR (CDCl3)
d 194.6,
7.77 (d, J ¼ 15.6 Hz, 1H), 7.51 (d, J ¼ 8.8 Hz, 2H), 7.32 (t, J ¼ 8.2 Hz,
1H), 6.86 (d, J ¼ 8.4 Hz, 2H), 6.59 (dd, J ¼ 8.0, 0.8 Hz, 1H), 6.40 (dd,
J ¼ 8.4, 0.8 Hz, 1H), 4.07 (t, J ¼ 6.4 Hz, 2H), 1.91e1.84 (m, 2H),
1.50e1.43 (m, 2H), 1.30e1.17 (m, 8H), 0.87 (t, J ¼ 7.2 Hz, 3H); 13C
164.9, 160.5, 158.9, 142.8, 135.8, 130.4, 128.2, 125.5, 116.0, 112.0, 110.6,
102.2, 69.0, 31.9, 29.9, 29.7, 29.5, 29.7, 29.3, 26.4, 26.3,26.0, 22.7, 22.8,
14.1; HRMS: calculated for C33H48O4: m/z 508.3552, Found: 508.3551.
NMR (CDCl3)
d
194.5, 164.8, 160.6, 157.7, 142.8, 135.8, 130.4, 128.2,
6.1.3.8. (E)-1-(2-(2-Hexyldecyloxy)-6-hydroxyphenyl)-3-(4-(methoxy
methoxy)phenyl)prop-2-en-1-one (1i). Yield 76%; Brown semisolid;
Rf 0.75 (1:9 Ethyl acetate: Hexane); IR (neat) 3330.8, 2917, 2848,
125.5, 115.9, 112.0, 110.5, 102.3, 69.1, 31.8, 29.4, 26.3, 22.6, 14.1;
HRMS: Calculated for C23H28O4: m/z 368.1987, Found: 368.1990.
1618 cmꢁ1
;
1H NMR (CDCl3)
d
13. 15 (s, 1H) 7.82 (d, J ¼ 16 Hz, 1H),
6.1.3.3. (E)-1-(2-(Decyloxy)-6-hydroxyphenyl)-3-(4-hydroxyphenyl)
prop-2-en-1-one (1d). Yield 88%; Orange solid; Rf 0.64 (2:8 Ethyl
acetate: Hexane); mp 105e106 ꢀC; IR (neat) 3400, 3100, 2850,
7.78 (d, J ¼ 16 Hz 1H), 7.52 (d, J ¼ 8 Hz, 2H), 7.33 (t, J ¼ 8 Hz,1H), 7.85
(d, J ¼ 8 Hz, 2H), 6.61 (dd, J ¼ 8.0, 0.8 Hz,1H), 6.44 (dd, J ¼ 8.4, 0.8 Hz,
1H),5.17(s, 1H), 3.96 (d, J ¼ 4 Hz, 2H), 1.86e1.80 (m, 1H), 1.47e1.19
1690 cmꢁ1; 1H NMR (CDCl3)
d
13. 26 (s, 1H), 7.85 (d, J ¼ 15.6 Hz, 1H),
(m, 32H), 0.89e0.85 (m, 6H); 13C NMR (CDCl3)
d 189.6, 164.9,
7.77 (d, J ¼ 15.6 Hz, 1H), 7.51 (d, J ¼ 8.4 Hz, 2H), 7.33 (t, J ¼ 8.4 Hz,
1H), 6.86 (d, J ¼ 8.8 Hz, 2H), 6.59 (dd, J ¼ 8.0, 0.8 Hz, 1H), 6.40 (dd,
J ¼ 8.4, 0.8 Hz, 1H), 4.00 (t, J ¼ 6.4 Hz, 2H), 1.91e1.84 (m, 2H),
1.50e1.43 (m, 2H), 1.30e1.17 (m, 12H), 0.86 (t, J ¼ 7.2 Hz, 3H); 13C
160.5,158.9,142.8,135.8,130.4,128.2,125.5,116.0, 112.0,110.6,102.2,
75.0, 38.1, 31.9, 29.9, 29.7, 29.5, 29.3, 26.4, 26.0, 22.7, 22.0, 14.1;
HRMS: calculated for C35H54O4: m/z 536.7849, Found: 536.7854.
NMR (CDCl3)
d
194.6, 164.7, 160.5, 157.7, 142.8, 135.8, 130.4, 128.2,
6.1.3.9. (E)-1-(2-((Z)-dec-4-enyloxy)-6-hydroxyphenyl)-3-(4-(methoxy
methoxy)phenyl)prop-2-en-1-one (1j). Yield 55.4%; Colorless liquid Rf
0.59 (1:9 Ethyl acetate: Hexane); IR (neat) 3330.8, 2917, 2848,
125.5, 115.9, 112.0, 110.5, 102.3, 69.1, 31.8, 29.5, 29.4, 29.2, 26.3, 22.6,
14.1; HRMS: calculated for C25H32O4: 396.2300, Found: 396.2298.
1670 cmꢁ1; 1H NMR (CDCl3)
d
13. 30 (s, 1H) 7.87 (d, J ¼ 16 Hz, 1H), 7.89
6.1.3.4. (E)-1-(2-(Dodecyloxy)-6-hydroxyphenyl)-3-(4-hydroxyphenyl)
prop-2-en-1-one (1e). Yield 87%; Orange solid; Rf 0.59 (2:8 Ethyl
acetate: Hexane); mp 110e116 ꢀC; IR (neat) 3400, 3100, 2850,
(d, J ¼ 15.6 Hz, 1H), 7.52 (d, J ¼ 8 Hz, 2H), 7.31 (t, 1H), 6.86 (d, J ¼ 8 Hz,
2H), 6.54 (d, 1H), 6.36 (d, J ¼ 7.6 Hz, 1H), 5.42e5.30(m, 2H), 4.08 (t,
J ¼ 6.4 Hz, 2H), 2.26e2.21 (m, 2H), 1.98e1.88 (m, 4H), 1.27e1.14 (m,
1690 cmꢁ1
;
1H NMR (CDCl3)
d
13. 26 (s, 1H), 7.79 (d, J ¼ 15.6 Hz,
6H), 0.87 (t, J ¼ 8.0 Hz, 3H); 13C NMR (CDCl3)
d 194.6, 164.7, 160.5,
1H), 7.69 (d, J ¼ 15.6 Hz, 1H), 7.44 (d, J ¼ 8.4 Hz, 2H), 7.25 (t,
J ¼ 8.4 Hz, 1H), 6.79 (d, J ¼ 8.8 Hz, 2H), 6.52 (dd, J ¼ 8.4, 0.8 Hz, 1H),
6.40 (dd, J ¼ 8.4, 0.8 Hz, 1H), 4.07 (t, J ¼ 6.4 Hz, 2H), 1.91e1.84 (m,
157.7, 142.8, 135.8, 131.6, 130.4, 128.2, 125.5, 115.9, 112.0, 110.5, 102.3,
69.1, 29.5, 29.2, 26.3, 22.6, 14.1; HRMS: calculated for C25H30O4:
394.5033, Found: 394.5038.

E. Venkateswararao et al. / European Journal of Medicinal Chemistry 54 (2012) 379e386
385
6.1.3.10. (E)-1-(2-(Cyclohexylmethoxy)-6-hydroxyphenyl)-3-(4-hydro-
xyphenyl)prop-2-en-1-one (1k). Data associated to the compound 1k
was reported in the reference [35].
160.5,157.7, 142.8,135.8, 130.4,128.2, 125.5,115.9, 112.0, 110.5, 102.3,
69.1, 31.8, 29.5, 29.4, 29.2, 26.3, 22.6, 14.1; HRMS: calculated for
C25H32O4: 396.2300, Found: 396.2307.
6.1.3.11. (E)-1-(2-(Benzyloxy)-6-hydroxyphenyl)-3-(4-hydroxyphenyl)
prop-2-en-1-one (1l). Data associated to the compound 1l was
reported in the reference [35].
6.1.4. General procedure for the preparation of compounds 1rev
Compounds 1rev were prepared using the same procedure for
the preparation of 7.
6.1.3.12. (E)-1-(2-hydroxy-4-(tetradecyloxy)phenyl)-3-(4-hydroxy-
phenyl)prop-2-en-1-one (1m). Yield 76.3%; Yellow solid; mp
89e94 ꢀC; Rf 0.71 (1:9 Ethyl acetate: Hexane); IR (neat) 3420,
6.1.4.1. (E)-1-(2-(Decyloxy)-6-hydroxyphenyl)-3-(4-methoxyphenyl)
prop-2-en-1-one (1r). Yield 83%; Yellow solid; mp 89e93 ꢀC; Rf
0.66 (2:8 Ethyl acetate: Hexane); IR (neat) 3400, 3100, 2850,
3050, 2900, 1614 cmꢁ1
;
1H NMR (CDCl3)
d
13.20 (s, 1H), 7.88 (d,
1690 cmꢁ1; 1H NMR (CDCl3)
d
13. 20 (s, 1H), 8.16 (d, J ¼ 15.6 Hz, 1H),
J ¼ 15.6 Hz, 1H), 7.78 (d, J ¼ 15.6 Hz, 1H), 7.55 (d, J ¼ 8 Hz, 2H), 7.33
(d, J ¼ 8.4 Hz, 1H), 6.79 (d, J ¼ 8.8 Hz, 2H), 6.52 (dd, J ¼ 8.4, 0.8 Hz,
1H), 6.33 (d, J ¼ 0.8 Hz, 1H), 4.06 (t, J ¼ 6.4 Hz, 2H), 1.88e1.83 (m,
2H), 1.51e1.43 (m, 2H), 1.28e1.20 (m, 20H), 0.87 (t, J ¼ 7.2 Hz, 3H);
7.92 (d, J ¼ 15.6 Hz, 1H), 7.63 (d, 8.0 Hz, 2H), 7.33 (t, J ¼ 8.4 Hz, 1H),
7.15 (d, J ¼ 8.4 Hz, 2H), 6.93 (dd, J ¼ 8.0, 4.0 Hz, 1H), 6.87 (d,
J ¼ 8.0 Hz, 1H), 4.06 (t, J ¼ 6.4 Hz, 2H), 3.86 (s, 3H), 1.88e1.83 (m,
2H), 1.51e1.43 (m, 2H), 1.28e1.20 (m, 12H), 0.87 (t, J ¼ 7.2 Hz, 3H);
13C NMR (CDCl3)
d
194.6, 164.9, 160.5, 158.9, 142.8, 135.8, 130.4,
13C NMR (CDCl3)
d 194.6, 164.9, 160.5, 158.9, 142.8, 135.8, 130.4,
128.2, 125.5, 116.0, 112.0, 110.6, 102.2, 69.0, 31.9, 29.9, 29.7, 29.5,
29.3, 26.4, 26.0, 22.7, 22.0, 14.1; HRMS: calculated for C29H40O4:
m/z 452.2926, Found: 452.2930.
128.2, 125.5, 116.0, 112.0, 110.6, 102.2, 69.0, 31.9, 29.9, 29.7, 29.5,
29.3, 26.4, 26.0, 22.7, 22.0, 14.1; HRMS: calculated for C26H34O4: m/z
410.5457, Found: 410.5463.
6.1.3.13. (E)-3-(3-chloro-4-hydroxyphenyl)-1-(2-(decyloxy)-6-hydroxy-
6.1.4.2. (E)-1-(2-(Decyloxy)-6-hydroxyphenyl)-3-p-tolylprop-2-en-
1-one (1s). Yield 83%; brown liquid; Rf 0.76 (2:8 Ethyl acetate:
phenyl)prop-2-en-1-one (1n). Yield 72%; Yellow solid; mp 112e115 ꢀC;
Rf 0.54 (2:8 Ethyl acetate: Hexane); 1H NMR (CDCl3)
d
13. 06 (s, 1H)
Hexane); 1H NMR (CDCl3)
d
13. 21 (s, 1H) 7.95 (d, J ¼ 15.6 Hz, 1H),
7.91 (d, J ¼ 15.6 Hz, 1H), 7.69 (d, J ¼ 2 Hz, 1H), 7.63 (d, J ¼ 15.6 Hz,
1H), 7.48 (d, J ¼ 8.0 Hz, 1H), 7.41 (dd, J ¼ 7.4, 0.8, 1H), 7.36 (t,
J ¼ 8.8 Hz, 1H), 6.60 (d, J ¼ 8.4 Hz, 1H), 6.41 (d, J ¼ 8.4 Hz, 1H), 4.08
(t, J ¼ 6.4 Hz, 2H), 1.90e1.83 (m, 2H), 1.47e1.39 (m, 2H), 1.26e1.16
7.76 (d, J ¼ 15.6 Hz, 1H), 7.41 (d, J ¼ 7.2 Hz, 2H), 7.34 (t, J ¼ 8.4 Hz,
1H), 7.28 (d, J ¼ 7.2 Hz, 2H), 6.59 (d, J ¼ 8.4 Hz, 1H), 6.40 (d,
J ¼ 8.4 Hz, 1H), 4.07 (t, J ¼ 6.4 Hz, 2H), 2.39 (s, 3H), 1.92e1.85 (m,
2H), 1.49e1.41 (m, 2H), 1.25e1.17 (m, 12H), 0.87 (t, J ¼ 6.8 Hz, 3H);
(m, 12H), 0.88 (t, J ¼ 6.8 Hz, 3H); 13C NMR (CDCl3)
d
190.4, 163.8,
13C NMR (CDCl3)
d 190.6, 162.0, 160.5, 142.8, 137.7, 130.4, 128.2,
160.1, 158.3, 144.0, 138,4, 133.2, 128.7, 126.9, 119.0, 110.5, 68.8, 32.1,
29.9, 27.2, 25.5, 14.1; HRMS: calculated for C25H31ClO4: m/z
430.9642, Found: 430.9649.
125.5, 116.0, 112.0, 110.6, 102.2, 69.0, 30.5, 25.1, 29.7, 26.4, 26.0,
22.7, 14.1; HRMS: calculated for C26H34O3: m/z 394.5463, Found:
394.5469.
6.1.3.14. (E)-1-(2-(Decyloxy)-6-hydroxyphenyl)-3-(4-hydroxy-3,5-
dimethoxyphenyl)prop-2-en-1-one (1o). Yield 56%; Yellow solid;
Rf 0.50 (2:8 Ethyl acetate: Hexane); mp 96e99 ꢀC; 1H NMR
6.1.4.3. (E)-1-(2-(Decyloxy)-6-hydroxyphenyl)-3-(3,4-dichlorophenyl)
prop-2-en-1-one (1t). Yield 79%; Yellow solid; mp 117e120 ꢀC; Rf
0.67 (2:8 Ethyl acetate: Hexane); 1H NMR (CDCl3)
d 13. 06 (s, 1H)
(CDCl3)
d
13. 25 (s, 1H) 7.83 (d, J ¼ 15.2 Hz, 1H), 7.74 (d, J ¼ 15.2 Hz,
7.91 (d, J ¼ 16 Hz, 1H), 7.69 (d, J ¼ 0.8 Hz, 1H), 7.63 (d, J ¼ 16 Hz, 1H),
7.40 (dd, J ¼ 8.0, 0.8 Hz, 1H), 7.36 (t, J ¼ 8.8 Hz, 1H), 6.60 (d,
J ¼ 8.4 Hz, 1H), 6.41 (d, J ¼ 8.4 Hz, 1H), 4.08 (t, J ¼ 6.4 Hz, 2H),
1.89e1.85 (m, 2H), 1.45e1.42 (m, 2H), 1.31e1.16 (m, 12H), 0.87 (t,
1H), 7.33 (t, J ¼ 8.4 Hz, 1H), 6.87 (s, 2H), 6.60 (d, J ¼ 8.4, 1H), 6.40
(d, J ¼ 8.4 Hz, 1H), 5.80 (s, 1H), 4.07 (t, J ¼ 6.4 Hz, 2H), 3.94 (s, 6H),
1.94e1.86 (m, 2H), 1.47e1.39 (m, 2H), 1.27e1.16 (m, 12H), 0.87 (t,
J ¼ 6.8 Hz, 3H); 13C NMR (CDCl3)
d
194.6, 164.7, 160.5, 152, 157.7,
J ¼ 6.8 Hz, 3H); 13C NMR (CDCl3)
d 193.3, 164.8, 160.1, 158.3, 144.0,
142.8, 135.8, 130.4, 128.2, 115.9, 112.0, 110.5, 102.3, 57.1, 69.1, 31.8,
29.5, 29.4, 29.2, 26.3, 22.6, 14.1; HRMS: calculated for C27H36O6:
456.5711, Found: 456.5719.
138,4, 133.5, 133.1, 128.7, 126.9, 119.0, 110.5, 68.8, 32.1, 29.9, 27.2,
25.5, 14.1; HRMS: calculated for C25H30Cl2O3: m/z 449.4099, Found:
449.4096.
6.1.3.15. (E)-1-(2-(Decyloxy)-6-hydroxyphenyl)-3-(3-hydroxyphenyl)
prop-2-en-1-one (1p). Yield 88%; Yellow solid; Rf 0.58 (2:8 Ethyl
acetate: Hexane); mp 109e114 ꢀC; IR (neat) 3400, 3100, 2850,
6.1.4.4. (E)-1-(2-(Hexyloxy)-6-hydroxyphenyl)-3-(4-(hexyloxy)phenyl)
prop-2-en-1-one (1u). Yield 72.4%; Orange solid; Rf 0.90 (2:8 Ethyl
acetate: Hexane); mp 55e60 ꢀC; IR (neat) 3330, 2917, 2848,
1690 cmꢁ1
;
1H NMR (CDCl3)
d
13. 26 (s, 1H), 7.85 (d, J ¼ 15.6 Hz,
1690 cmꢁ1
;
1H NMR (CDCl3)
d
13. 26 (s, 1H), 7.88 (d, J ¼ 15.6 Hz,
1H), 7.77 (d, J ¼ 15.6 Hz, 1H), 7.43 (t, J ¼ 8.4 Hz, 1H), 7.18 (t,
J ¼ 8.4 Hz, 1H), 6.88 (dd, J ¼ 8.8 Hz, 2H), 6.72 (d, J ¼ 0.8 Hz, 1H),
6.54 (dd, J ¼ 8.4, 0.8 Hz, 1H), 4.02 (t, J ¼ 6.4 Hz, 2H), 1.91e1.84 (m,
2H), 1.50e1.43 (m, 2H), 1.30e1.17 (m, 12H), 0.88 (t, J ¼ 7.2 Hz, 3H);
1H), 7.78 (d, J ¼ 15.6 Hz, 1H), 7.55 (d, J ¼ 8.8 Hz, 2H), 7.32 (t,
J ¼ 8.2 Hz, 1H), 7.06 (d, J ¼ 8.4 Hz, 2H), 6.60 (dd, J ¼ 8.0, 0.8 Hz,
1H), 6.41 (dd, J ¼ 8.4, 0.8 Hz, 1H), 4.06 (t, J ¼ 6.4 Hz, 2H), 4.00 (t,
J ¼ 6.4 Hz, 2H), 1.91e1.84 (m, 4H), 1.51e1.43 (m, 4H), 1.30e1.21 (m,
13C NMR (CDCl3)
d
194.6, 164.7, 160.5, 157.7, 142.8, 135.8, 130.4,
8H), 0.87 (t, J ¼ 7.2 Hz, 6H); 13C NMR (CDCl3)
d 194.6, 164.7, 160.5,
128.2, 125.5, 115.9, 112.0, 110.5, 102.3, 69.1, 31.8, 29.5, 29.4, 29.2,
26.3, 22.6, 14.1; HRMS: calculated for C25H32O4: 396.2300, Found:
396.2307.
157.7, 142.8, 135.8, 130.4, 128.2, 125.5, 115.9, 112.0, 110.5, 102.3,
68.9, 31.9, 29.6, 26.3, 22.8, 14.1; HRMS: calculated for C27H36O4:
m/z 424.2613, Found: 424.2610.
6.1.3.16. (E)-1-(2-(Decyloxy)-6-hydroxyphenyl)-3-(2-hydroxyphenyl)
prop-2-en-1-one (1q). Yield 88%; Yellow solid; Rf 0.60 (2:8 Ethyl
acetate: Hexane); mp 100e112 ꢀC; IR (neat) 3400, 3100, 2850,
6.1.4.5. (E)-1-(2-hydroxy-6-(tetradecyloxy)phenyl)-3-(4-(tetradecy-
loxy)phenyl)prop-2-en-1-one (1v). Yield 66.9%; Orange solid; Rf
0.88 (2:8 Ethyl acetate: Hexane); mp 48e56 ꢀC; IR (neat) 3400,
1690 cmꢁ1; 1H NMR (CDCl3)
d
13. 26 (s, 1H), 7.89 (d, J ¼ 15.6 Hz, 1H),
3100, 2850, 1690 cmꢁ1 1H NMR (CDCl3)
; d 13. 29 (s, 1H), 7.86 (d,
7.77 (d, J ¼ 15.6 Hz, 1H), 7.11e7.22 (m, 4H), 6.78e6.86 (m, 3H), 4.02
(t, J ¼ 6.4 Hz, 2H), 1.91e1.84 (m, 2H), 1.50e1.43 (m, 2H), 1.30e1.17
J ¼ 15.6 Hz, 1H), 7.79 (d, J ¼ 15.6 Hz, 1H), 7.54 (d, J ¼ 8.4 Hz, 2H), 7.32
(t, J ¼ 8.4 Hz, 1H), 6.90 (d, J ¼ 8.8 Hz, 2H), 6.60 (dd, J ¼ 8.0, 0.8 Hz,
1H), 6.41 (dd, J ¼ 8.4, 0.8 Hz, 1H), 4.06 (t, J ¼ 6.4 Hz, 2H),1.90e1.78
(m, 12H), 0.88 (t, J ¼ 7.2 Hz, 3H); 13C NMR (CDCl3)
d 194.6, 164.7,

386
E. Venkateswararao et al. / European Journal of Medicinal Chemistry 54 (2012) 379e386
(m, 4H), 1.51e1.43 (m, 4H), 1.28e1.20 (m, 40H), 0.87 (t, J ¼ 7.2 Hz,
6H); 13C NMR (CDCl3)
194.0, 164.9, 160.5, 158.9, 142.8, 135.8, 130.4,
funded by the Ministry of Education, Science and Technology
(2009-0093815)
d
128.2, 125.5, 116.0, 112.0, 110.6, 102.2, 69.0, 31.9, 29.9, 29.7, 29.5,
29.3, 26.4, 26.0, 22.7, 22.0, 14.1; HRMS: calculated for C43H68O4:
m/z 648.5117, Found: 648.5119.
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P. Skehan, D.A. Scudiero, A. Monks, M.R. Boyd, J. Natl. Cancer Inst. 82 (1990)
1113e1118.
Yield 87.9%; Light green liquid; Rf 0.66 (2:8 Ethyl acetate:
Hexane); IR (neat) 3320, 2918, 2848, 1700 cmꢁ1; NMR (CDCl3)
d
13.26 (s, 1H), 7.30 (t, J ¼ 8.4 Hz, 1H), 7.09 (d, J ¼ 8.8 Hz, 2H), 6.74 (d,
J ¼ 8.4 Hz, 2H), 6.55 (d, J ¼ 8.4 Hz, 1H), 6.35 (d, J ¼ 8.4 Hz, 1H), 4.02
(t, J ¼ 6.5 Hz, 2H), 3.42 (t, J ¼ 8.0 Hz, 2H), 2.96 (t, J ¼ 8.0 Hz, 2H),
1.81e1.74 (m, 2H), 1.50e1.42 (m, 2H), 1.28e1.20 (m, 16H), 0.89 (t,
J ¼ 7.5 Hz, 3H); 13C NMR (CDCl3)
d
220.2, 164.6, 153.6, 135.8, 133.6,
129.3, 115.1, 110.5, 101.8, 69.0, 46.7, 31.9, 29.6, 29.5, 29.3, 29.2, 29.1,
26.4, 22.6, 14.1; HRMS: calculated for C27H38O4: m/z 426.2770,
Found: 426.2780.
6.1.6. Preparation of 3-(Dodecyloxy)-2-(1-hydroxy-3-(4-
hydroxyphenyl)propyl)phenol (3)
Compound 2 (100 mg, 0.023 mmol) was dissolved in tetrahy-
drofurane (5 mL) and then NaBH4 (8 mg, 0.023 mmol) was added.
The resulting solution was stirred for 3 h at room temperature.
After completion of reaction was quenched with ethyl acetate
(1 mL) and then water (1 mL). After the resulting mixture was
evaporated under reduced pressure for removal of tetrahyrofurane
used for the reaction, the mixture was extracted with ethyl acetate
two times. Combined organic layers were dried with anhydrous
sodium sulfate and evaporated under reduced pressure. The crude
product was purified by column chromatography to give 3.
Yield 49.2%; Light green liquid; Rf 0.62 (2:8 Ethyl acetate:
Hexane); IR (neat) 3520, 2918, 2848 cmꢁ1; NMR (CDCl3)
d 13.26 (s,
1H), 8.55 (s, 1H) 7.09 (d, J ¼ 5.2 Hz, 2H); 7.06 (t, J ¼ 5.2 Hz, 1H), 6.74
(d, J ¼ 5.2 Hz, 1H), 6.48 (d, J ¼ 8.4 Hz, 1H), 6.35 (d, J ¼ 8.4 Hz, 1H),
5.43e5.38 (m, 1H), 4.52 (s, 1H), 3.90 (t, J ¼ 8.0 Hz, 2H), 2.79e2.74
(m, 1H), 2.43 (d, 1H), 2.18e2.16 (m, 1H), 2.10e1.98 (m, 1H),
1.69e1.54 (m, 2H), 1.50e1.42 (m, 2H), 1.28e1.20 (m, 16H), 0.86 (t,
J ¼ 7.5 Hz, 3H); 13C NMR (CDCl3)
d 220.2, 164.6, 153.6, 135.8, 133.6,
129.3, 115.1, 110.5, 101.8, 69.0, 56.4, 46.7, 31.9, 29.6, 29.5, 29.3, 29.2,
29.1, 26.4, 22.6, 14.1; HRMS: calculated for C27H40O4: m/z 428.2926,
Found: 428.2920.
[32] P. Skehan, R. Storeng, D.A. Scudiero, A. Monks, J. McMahon, D.T. Vistica,
J.T. Warren, H. Bokesch, F. Kenny, M.R. Boyd, J. Natl. Cancer Inst. 82 (1990)
1107e1112.
Acknowledgment
[33] H.-M. Yang, H.-R. Shin, S.eH. Cho, S.-C. Bang, G.-Y. Song, J.-H. Ju, M.-K. Kim,
S.-H. Lee, J.-C. Ryu, Y. Kim, S.-H. Jung, Bioorg. Med. Chem. 15 (2007)
104e111.
This work was supported by Priority Research Centers Program
through the National Research Foundation of Korea (NRF)