Anti-proliferative effect of chalcone derivatives through inactivation of NF-κB in human cancer cells

Article abstract of DOI:10.1016/j.bmc.2014.04.045

To investigate the anti-proliferative effect of NF-κB inhibitor, a series of analogs of (E)-1-(2-hydroxy-6-(isopentyloxy)phenyl)-3-(4- hydroxyphenyl)prop-2-en-1-one (5a) were prepared and evaluated for their NF-κB inhibition and anti-proliferative activity against various human cancer cell lines. Compounds (E)-1-(2-(3,3-dimethylbutoxy)-6-hydroxyphenyl)-3- (4-hydroxyphenyl)prop-2-en-1-one (5e) and (E)-4-(3-(2-(3,3-dimethylbutoxy)-6- hydroxyphenyl)-3-oxoprop-1-enyl)benzenesulfonamide (5p) showed good NF-κB inhibition as well as potent anti-proliferative activity. SAR studies showed that all the compounds with potent or moderate NF-κB inhibition displayed good anti-proliferative activity. All the analogs (5b-r) maintained a good correlation between their NF-κB inhibition and anti-proliferative activity though the extent is not directly proportional to each other.

Full text of DOI:10.1016/j.bmc.2014.04.045

Bioorganic & Medicinal Chemistry xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Anti-proliferative effect of chalcone derivatives through inactivation
of NF-jB in human cancer cells
Eeda Venkateswararao a, Vinay K. Sharma a, Jieun Yun b, Youngsoo Kim c, Sang-Hun Jung a,
⇑
a College of Pharmacy and Institute of Drug Research and Development, Chungnam National University, Daejeon 305-764, South Korea
b Bioevaluation Center, Korea Research Institute of Bioscience and Biotechnology, Cheongwon 363-883, South Korea
c College of Pharmacy, Chungbuk National University, Cheongju 361-763, South Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
To investigate the anti-proliferative effect of NF-
(isopentyloxy)phenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one (5a) were prepared and evaluated for their
j
B inhibitor, a series of analogs of (E)-1-(2-hydroxy-6-
Received 18 February 2014
Revised 22 April 2014
Accepted 23 April 2014
Available online xxxx
NF- B inhibition and anti-proliferative activity against various human cancer cell lines. Compounds
j
(E)-1-(2-(3,3-dimethylbutoxy)-6-hydroxyphenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one (5e) and (E)-4-
(3-(2-(3,3-dimethylbutoxy)-6-hydroxyphenyl)-3-oxoprop-1-enyl)benzenesulfonamide (5p) showed
good NF-
j
B inhibition as well as potent anti-proliferative activity. SAR studies showed that all the
B inhibition displayed good anti-proliferative activity. All
Keywords:
Chalcones
Inactivation of NF-jB
Anti-proliferative activity
compounds with potent or moderate NF-
the analogs (5b–r) maintained a good correlation between their NF-jB inhibition and anti-proliferative
activity though the extent is not directly proportional to each other.
j
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
Till date, a number of natural products28–30 (Fig. 1) has been
identified as chemotherapeutic agents through inhibition of
Eukaryotic transcription factor NF-
j
B is not only essential for
NF-j
B activity. Specially, compounds like curcumin,28 3-dihydro-
regulating the immune and inflammatory processes but also plays
an important role in cell proliferation and survival.1,2 It is also
involved in processes of synaptic plasticity and memory.3–7 There-
3,5-dihydroxy-6-methyl-4H-pyranone (DDMP)29 isolated from
onion and thiacremonone30 from garlic exerted anti-carcinogenic
properties by inhibiting the activation of NF-
j
B. In another study31
fore, an inappropriate regulation of NF-
jB may lead to various dis-
the researchers observed that complete abolition of NF-jB activity
crepancies and diseases such as inadequate immune development,
cancer, inflammatory and autoimmune diseases, septic shock and
viral infection. The above discussion confirms that NF-jB signaling
was responsible for the combined anti-proliferative effect of thiac-
remonone and docetaxel in colon cancer cells. The compound SK
2009, an analog of simplactone32 (Fig. 1), was most effective in
pathway is important for pharmacological intervention, especially
on the situations of chronic inflammation and cancer, where the
suppressing NF-
N-substituted phenyl amide derivatives of indoline-2-carboxylic
acid were studied for their NF- B inhibitory activity as well as
anti-proliferative activity.33 These results indicated that
compounds having NF- inhibitory activity displayed anti-
proliferative effect in various cancer cell lines. However, the anti-
jB activation in KBM-5 leukemic cells. Recently,
pathway is often constitutively active. Thus NF-
j
B could be an
j
important target for the discovery of new anti-cancer or anti-
inflammatory agents. Although the correlation between initiation
of inflammation and abnormal cell proliferation is not yet com-
pletely understood, approximately 15% of all malignancies are
instigated by chronic and prolonged inflammatory diseases.8–14
Flavonoids and chalcones (flavonoid precursors) are abun-
dantly15–17 present in many fruits and vegetables. Chalcones are
associated with remarkably diverse biologic properties like
anti-inflammatory,18,19 anti-oxidative,20 anti-fungal,21 anti-bacte-
rial,22 chemo-preventive and anti-cancer activities.23–27 As chal-
cone derivatives show numerous pharmacological properties,
these compounds have been an important target for the research.
jB
proliferative activity was not directly proportional to the NF-
jB
inhibitory activity.
Previously, we have discovered a novel small molecule, (E)-1-
(2-hydroxy-6-(isopentyloxy)phenyl)-3-(4-hydroxyphenyl)prop-2-
en-1-one (5a, Fig. 1) and successfully established it as an inhibitor
of LPS induced NF-
of about 10
M.34 It is a non-lipid chalcone which not only inhib-
ited the TLR4-mediated NF- activating pathway but also
suppressed the NF- B regulated expression of iNOS, COX-2 or
pro-inflammatory cytokine genes. Thus, to explore structure activ-
ity correlation of NF- B inhibition and anti-proliferative activity of
jB activation in macrophages with an IC50 value
l
jB
j
⇑
Corresponding author. Tel.: +82 42 821 5939; fax: +82 42 823 6566.
E-mail address: jungshh@cnu.ac.kr (S.-H. Jung).
j
http://dx.doi.org/10.1016/j.bmc.2014.04.045
0968-0896/Ó 2014 Elsevier Ltd. All rights reserved.
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2
E. Venkateswararao et al. / Bioorg. Med. Chem. xxx (2014) xxx–xxx
5a analogs, here in the current article we have designed and syn-
thesized analogs (5b–r) of 5a and evaluated their inhibitory activ-
THP-1 cells transfected with pNF-kB-SEAP reporter construct were
treated with 5a–r for 2 h and then stimulated with LPS (1 lg/ml)
ity against NF-
jB and in vitro anti-proliferative activity against
for 16 h. SEAP activity was measured as described previously.36
Accordingly, the aliquots of the culture media were heated at
65 °C for 5 min and reacted with 4-methylumbellifery phosphate
various human cancer cell lines namely, ACHN (renal), NCI-H23
(lung), MDA-MB-231 (breast), HCT-15 (colon), NUGC-3 (stomach)
and PC-3 (prostate).
(500 lM) in the dark for 1 h. SEAP activity was measured as
relative fluorescence units (RFUs) with emission at 449 nm and
excitation at 360 nm. The results from these tests are summarized
as IC50 values in Table 1.
2. Chemistry
The anti-proliferative activity was measured against ACHN
(renal), NCI-H23 (lung), MDA-MB-231 (breast), HCT-15 (colon),
NUGC-3 (stomach) and PC-3 (prostate) human cell lines using
sulforhodamine B (SRB) colorimetric assay.37 The results from
these tests are given as IC50 values in Table 2.
The syntheses of the desired compounds 5a–r were accom-
plished as outlined in Scheme 1. The key intermediate mono-
alkylated hydroxyacetophenone 3 was synthesized from dihy-
droxyacetophenone 1 by reacting with various alkyl bromides 2
in the presence of potassium carbonate and catalytic amount of
sodium iodide.35 Later the mono-alkylated hydroxyacetophenones
3 were subjected to aldol condensation with 4-substituted benzal-
dehydes 4 to get the final compounds 5a–q. The compound 5r was
obtained from 5e using catalytic hydrogenation under H2 pressure
at 30 psi. All these synthesized compounds were characterized by
physical and spectral analysis data that confirmed their assigned
structures.
4. Results and discussion
In our previous study we have observed that 5a inhibited LPS
induced NF-
length of alkoxy chain at 6th position of ring A in chalcones might
play an important role in the inhibition of LPS induced NF-
jB activation with an IC50 value of 10.0 l
M.34 The
j
B
activation. Therefore, to optimize the size of alkoxy group in the
current set of experiment analogs 5b–r were prepared with varied
lipophilic alkoxy chain.
3. Biologic evaluations
Initially, we want to investigate the effect of alkoxy chain length
and branch at 6th position of ring A in chalcones. Accordingly,
various chalcone analogs with varied alkoxy groups such as
The NF-
by previously reported procedure (SEAP assay).34 In brief, the RAW
264.7 cells harboring pNF- B-SEAP-NPT reporter construct or
jB inhibitory activity of compounds 5a–r was evaluated
j
OH
O
O
O
O
O
O
OH
OH
HO
OH
OCH3
O
CH3
OCH3
HO
DDMP
curcumin
2,4-dihydroxy-6-isopentyloxychalcone (5a)
OH
O
O
O
OH
OH
HO
S
OH
O
O
thiacremonone
Simplactone
Apigenin
Figure 1. Known chemotherapeutic agents through inactivation of NF-jB.
OH
O
CHO
OH
O
OH
OH
O
(b)
(a)
+
+
+
R1 Br
2
O
R1
R2
O
R1
OH
R2
4
5a-p
1
3
O
O
CHO
O
O
O
O
(c)
(b)
O
OH
O
OH
4
5q
3e
6
OH
O
O
OH
O
(d)
OH
O
OH
5r
5e
Scheme 1. Synthesis of 2,4-dihydroxy-6-isopentyloxychalcone analogs 5b–r. Reagents and conditions: (a) K2CO3, NaI, acetonitrile, reflux at 80–82 °C; (b) 3, substituted
benzaldehyde, piperidine, EtOH, reflux at 78 °C; (c) NaH, CH3I; (d) H230psi, Pd/C, methanol, rt for 3 h. Note = substituents are indicated in Table 1.
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E. Venkateswararao et al. / Bioorg. Med. Chem. xxx (2014) xxx–xxx
3
Table 1
In vitro NF-jB inhibitory activity of chalcone analogs 5a–r
Compd no.
R
R2
IC50
(
l
M)a
ClogPb
Compd no.
R
R1
IC50
(
l
M)a
ClogPb
5a34
OH
10.0
5.349
5j
OH
18.0
5.983
5b
5c
OH
OH
11.0
>30
5.878
4.949
5k35
5l
OH
OH
>30
>30
6.013
6.542
5d35
OH
>30
6.007
5m35
OH
>30
5.131
5e
5f
OH
OH
OH
3.0
5.748
4.819
5.878
5n
5o
5p
OH
>30
2.8
1.2
7.680
6.212
4.632
8.0
–COOH
–SO2NH2
5g
12.0
O
O
O
5h
5i
OH
OH
>30
5.064
5.454
5q
5r
>30
>30
5.589
5.802
OH
O
O
OH
13.0
OH
a
IC50 values are taken as a mean from three experiments.
ClogP values were calculated by Chem Draw version 11.0.
b
5c, 5d and 5h failed to show any activity. The compounds 5b and
5f showed almost similar activity as 5a. The above results
emphasized that an increment in the chain length does not have
considerable effect on the activity whereas the activity is enhanced
with an increase in the volume of alkoxy group as in 5e. In the next
set of experiment, the cycloalkyloxy groups at the 6th position of
the ring A were introduced. Accordingly, cyclopentylmethoxy (5i,
Table 2
In vitro anti-proliferative activity of chalcone analogs 5a–r against human cancer cell
lines
Compd no.
Anti-proliferative activity: GI50
ACHN NCI-H23 MDA-MB231 HCI-15 NUGC-3 PC-3
(l
M)a
5a
5b
5c
5d
5e
5f
5g
5h
5i
11.33
3.63
>30
12.12
11.35
>30
10.28
3.48
>30
10.58
11.58
>30
12.36
3.52
>30
11.45
3.60
>30
IC50 = 13
M, ClogP = 5.983), cyclohexylmethoxy (5k, IC50 = >30
=6.013), cyclohexylethoxy (5l, IC50 = >30 M, ClogP = 6.542), ben-
zyloxy (5m, IC50 = >30 M, ClogP = 5.131) and adamantylmethoxy
(5n, IC50 = >30 M, ClogP = 7.680) analogs were prepared and
studied for their NF- B activity. As shown in Table 1, less bulky
lM, ClogP = 5.454), cyclopentylethoxy (5j, IC50 = 18.0
l
lM, ClogP
>30
>30
>30
>30
>30
>30
3.14
3.29
3.37
>30
3.13
3.22
3.21
>30
2.38
3.52
3.13
>30
3.43
2.60
3.42
>30
3.30
2.98
1.96
>30
3.22
2.97
3.39
>30
l
l
l
j
3.51
3.40
>30
3.16
3.37
>30
3.41
3.34
>30
3.41
3.31
>30
2.14
3.20
>30
3.04
3.48
>30
cyclopentylmethoxy analog 5i had far better activity than cyclo-
hexylmethoxy analog 5k. In addition, on increasing the chain
length as in 5j, activity decreased as compared to 5i. The bulky
cyclohexyl derivative (5k) and (5l) did not show any activity pos-
sibly due to increase in hydrophobicity or bulkiness. Similarly, the
bulkier adamantylmethoxy 5n derivatives did not turn up with any
activity. Planar benzyl analog 5m did not show any activity. These
results implicate that the suitable size of branched alkoxy group at
6th position of ring A would be important for binding to the active
site and 3,3-dimethylbutoxy would be optimum.
5j
5k
5l
>30
>30
>30
>30
>30
>30
5m
5n
5o
5p
5q
5r
>30
>30
>30
>30
>30
>30
>30
4.77
4.77
2.95
>30
>30
>30
>30
>30
8.45
3.30
>30
11.23
2.11
>30
2.17
2.93
>30
5.44
1.17
>30
6.50
3.25
>30
>30
>30
>30
>30
>30
>30
ADRb
1.63
1.66
1.79
1.34
1.00
1.65
a
GI50 values are taken as a mean from three experiments.
ADR: Adriamycin.
b
To rationalize the above bioactivity results with the change in
alkoxy groups at 6th position of ring A, a selected set of chalcones
derivatives was chosen for the analysis of steric parameters (Es, MR,
B1, B5 and L).38 It was observed that the steric parameters Es MR
and B1 do not have the correlation with the activity (Table 3).
However, the B5 and the L parameter together showed some corre-
lation with the activity. As shown in Table 3 the most potent com-
pound 5e has values of 4.54 for B5 and 6.17 for L. As on changing
either of the B5 or L values as shown in 5a (B5 = 3.49, L = 6.17),
5b (B5 = 5.59, L = 6.97), 5d (B5 = 5.96, L = 8.22), 5f (B5 = 4.45,
methylpentyloxy (5b, IC50 = 11.0 lM, ClogP = 5.878), butoxy (5c,
IC50 = >30
ClogP = 6.007),
ClogP = 5.748), isobutoxy (5f, IC50 = 8.0
ethylbutoxy (5g, IC50 = 12.0 M, ClogP = 5.878) and methylbut-2-
enyloxy (5h, IC50 = >30 M, ClogP = 5.064) were studied for their
NF- B inhibitory activity. Among these derivatives, 3,3-dimethyl-
butoxy analog 5e showed highly potent inhibitory activity while
lM, ClogP = 4.949), hexyloxy (5d, IC50 = >30
lM,
3,3-dimethylbutoxy (5e, IC50 = 3.0
lM,
lM, ClogP = 4.819),
l
l
j
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4
E. Venkateswararao et al. / Bioorg. Med. Chem. xxx (2014) xxx–xxx
L = 4.92), 5k (B5 = 6.02, L = 4.62) and 5m (B5 = 5.42, L = 6.09), the
activity decreased (5a, 5b and 5f) or completely lost (5d, 5k and
5m). The above results confirmed the importance of optimum vol-
ume of alkoxy group at 6th position of ring A, in which the opti-
mum values of steric parameters for alkoxy group should be
B5 = 4.54 and L = 6.17. This infers that the hydrophobic binding
of this group to putative receptor would be important for the
activity.
not show any activity. Interestingly, the compound 5e (3.14,
3.13, 2.38, 3.43, 3.30, 3.22 M) showed good anti-proliferative
activity as well as good NF- B inhibition. In addition, the com-
pounds 5f (3.29, 3.22, 3.52, 2.60, 2.98, 2.97 M), 5g (3.37, 3.21,
3.13, 3.42, 1.96, 3.39 M), 5i (3.51, 3.16, 3.41, 3.41, 2.14,
3.04 M) and 5j (3.40, 3.37, 3.34, 3.31, 3.20, 3.48 M) showed good
anti-proliferative activity and moderate NF- B inhibition. How-
ever, compounds 5h and 5k–n did not show any anti-proliferative
activity against any cancer cell lines and their NF- B inhibition was
almost negligible. The carboxylic (5o, 8.45, 4.77, 11.23, 2.17, 5.44,
l
j
l
l
l
l
j
As was observed in our previous studies, substitution at 4th
position of ring B greatly affected the activity. Interestingly,
replacement of hydroxyl group of 5e with electron withdrawing
j
6.50
3.25
l
l
M) and sulfonamide (5p, 3.30, 2.95, 2.11, 2.93, 1.17,
M) derivatives showed potent anti-proliferative activity,
group such as carboxylic acid (5o, IC50 = 2.8
or sulfonamide (5p, IC50 = 1.2 M, ClogP = 4.632) showed compat-
ible level of NF- B inhibitory activity. These results imply that
hydrogen bonding capability of substituents at 4th position of ring
lM, ClogP = 6.212)
l
especially compound 5p was more potent than the previous one.
These activities also indicate the role of hydrogen bonding ability
by functional group at 4th position of ring B of these chalcones.
j
B is important for NF-
of their size.
The masking of hydroxyl function at 2nd position of ring A in 5e
by methylation as shown in 5q led to complete loss of activity. This
might indicate that intramolecular hydrogen bonding of this
j
B inhibitory activity of chalcones regardless
As shown by NF-jB inhibitory activity profile, masking of
hydroxyl function at 2nd position of ring A of 5e with methylation
(as in 5q) and saturation of double bond of 5e to ketone (as in 5r)
led to complete loss of anti-proliferative activity. These results
indicate that intramolecular hydrogen bonding of hydroxyl func-
hydroxyl group with carbonyl oxygen of
unit of these chalcones enhance the activity.
Reduction of double bond of 5e to saturated ketone shown in 5r
abolished the activity. This result indicates that ,b-unsaturated
ketone unit of these chalcones is critically important for their
NF- B inhibitory activity.
For finding the correlation between inhibitory activity of NF-
and anti-proliferative activity, all the compounds 5a–r were evalu-
ated for their anti-proliferative against various cancer cell lines
such as ACHN (renal), NCI-H23 (lung), MDA-MB-231 (breast),
HCT-15 (colon), NUGC-3 (stomach) and PC-3 (prostate) cancer cell
lines as shown in Table 2 (GI50 values are listed in parenthesis
below along with this sequence of these cell lines written here).
The compounds with variable alkoxy chain length and branch
(5a–b, 5e–g) showed good anti-proliferative activity against all
cancer cell lines. Even though compounds 5a–b showed similar
a
,b-unsaturated ketone
tion at 2nd position of ring A and
these chalcones are critically important for their anti-proliferative
activity as well as NF-jB inhibitory activity.
a,b-unsaturated ketone unit of
a
5. Conclusion
j
jB
For defining the correlation between NF-jB inhibition and anti-
proliferative activity a number of analogs of 2,40-dihydroxy-6-
isopentyloxychalcone (5a) have been prepared and tested for their
anti-proliferative activity against cancer cell lines. Among these
analogs compounds 5e and 5p showed potent NF-jB inhibition
as well as anti-proliferative activity. The structure activity relation-
ship showed that 6-branched alkoxy-2-hydroxychalcone with
hydrogen bonding capable substituents at 4th position of ring B
should be essential scaffold for the inhibition of NF-jB. The opti-
mum size of 6-branched alkoxy and the intramolecular hydrogen
level of NF-jB activity, their anti-proliferative activities were
somewhat different as compound 5b was better compared to 5a
especially against ACHN, MDA-MB231, NUGC-3 and PC-3 cell lines.
As expected for inhibitory activity of NF-jB, compounds 5c–d did
bonding of the hydroxyl group at 2nd position of ring A with car-
bonyl oxygen of
should be critical factors for NF-
pounds with potent or moderate NF-
a
,b-unsaturated ketone unit of these chalcones
B inhibitory activity. All the com-
B inhibitory activity showed
j
j
good anti-proliferative activity. Taken together, all the chalcone
analogs (5a–r) maintained a good correlation between their
Table 3
NF-jB inhibition and anti-proliferative activity, though the extent
was not directly proportional to each other.23 This might indicate
that these chalcones achieve their anti-proliferative activity
Descriptors for alkyl substituents on oxygen at 6th position of ring A for chalcone
analogs 5a–b, 5d–f, 5k and 5m
Descriptorsa
MR B1 B5
IC50
(
lM)
b
Compd no. Substituents
through inactivation of NF-jB.
Es
L
6. Materials and methods
6.1. Chemistry
5a
5b
ꢀ1.59 2.43 1.52 3.49 6.17 10.0
ꢀ1.67 2.89 1.52 5.59 6.97 11.0
Melting points (mp) were determined on Electro thermal 1A
9100 MK2 apparatus and are uncorrected. All commercial chemi-
cals were used as obtained and all solvents were purified by the
standard procedures prior to use. Flash column chromatography
was performed with E Merck silica gel (230–400 mesh). FT-IR
spectrum was recorded by Nicolet-380 model. NMR spectra were
measured against the peak of tetramethylsilane by JNM-AL 400
NMR (400 MHz, JEOL, Japan) spectrometers. High resolution mass
spectra (HRMS) were measured by using Shimadzu LCMS-IT-TOF
spectrometer.
5d
5e
ꢀ1.54 2.89 1.52 5.96 8.22 >30
ꢀ1.58 2.90 1.52 4.54 6.17 3.0
5f
ꢀ2.17 1.96 1.52 4.45 4.92 8.0
ꢀ2.22 3.13 1.52 5.42 6.09 >30
ꢀ1.61 3.00 1.52 6.02 4.62 >30
5k
5m
6.1.1. General procedure for preparation of compounds (3)
The solution of dihydroxyacetophenone (1, 1.0 equiv), anhy-
drous potassium carbonate (2.0 equiv) and corresponding alkyl
a
Descriptors Es, MR, B1, B5 and L are taken from Ref. 38.
In vitro NF-jB inhibitory activity of chalcone analogs.
b
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E. Venkateswararao et al. / Bioorg. Med. Chem. xxx (2014) xxx–xxx
5
bromides (2, 1.1 equiv) in acetonitrile was stirred at 70–80 °C for
4–5 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 3.
(t, J = 8.4 Hz, 1H), 6.53 (dd, J = 0.8, 8.4 Hz, 1H), 6.34 (d, J = 8.2 Hz, 1H),
4.09 (t, J = 6.3 Hz, 2H), 2.68 (s, 3H), 2.02 (d, J = 7.8 Hz, 1H), 1.90 (q,
J = 6.7 Hz, 2H), 1.72–1.82 (m, 2H), 1.55–1.66 (m, 2H), 1.42–1.55 (m,
2H), 1.06–1.20 (m, 2H).
6.1.1.11. 1-(2-(Cyclohexylmethoxy)-6-hydroxyphenyl)ethanone
(3k). Data associated to the compound 3k was reported in our pre-
vious work.35
6.1.1.1. 1-(2-Hydroxy-6-(isopentyloxy)phenyl)ethanone (3a). Data
associated to the compound 3a was reported in our previous work.34
6.1.1.12. 1-(2-(2-Cyclohexylethoxy)-6-hydroxyphenyl)ethanone
6.1.1.2. 1-(2-Hydroxy-6-(4-methylpentyloxy)phenyl)ethanone
(3l). Yield 50%; colorless liquid; Rf 0.63 (0.5:9.5 EA: HX); IR (KBr)
(3b). Yield 45%; light green liquid; Rf 0.60 (1:9 EA: HX); IR (KBr)
3230, 2919, 2848, 1618 cmꢀ1 1H NMR (CDCl3) d 13.27 (s, 1H),
;
3335, 2917, 2850, 1618 cmꢀ1
;
1H NMR (CDCl3) d 13.26 (s, 1H),
7.32 (t, J = 8.4 Hz, 1H), 6.53 (dd, J = 0.8, 8.4 Hz, 1H), 6.34 (d,
J = 8.2 Hz, 1H), 4.11 (t, J = 6.4 Hz, 2H), 2.70 (s, 3H), 1.78 (q,
J = 6.5 Hz, 2H), 1.60–1.74 (m, 5H), 1.55–1.49 (m, 1H), 1.05–1.20
(m, 3H), 0.93 (d, J = 9.0 Hz, 2H).
7.31 (t, J = 8.2 Hz, 1H), 6.54 (dd, J = 0.8, 8.4 Hz, 1H), 6.36 (d,
J = 8.2 Hz, 1H), 4.01 (t, J = 6.5 Hz, 2H), 2.70 (s, 3H), 1.92–1.85 (m,
2H), 1.58–1.51 (m, 1H), 1.38–1.31 (m, 2H) 0.84 (d, J = 6.5 Hz, 6H).
6.1.1.3. 1-(2-Butoxy-6-hydroxyphenyl)ethanone (3c). Yield 80%;
colorless liquid; Rf 0.55 (0.5:9.5 EA: HX); IR (KBr) 3333, 2917, 2852,
1616 cmꢀ1; 1H NMR (CDCl3) d 13.22 (s, 1H), 7.30 (t, J = 8.4 Hz, 1H),
6.55–6.57 (m, 1H), 6.38 (d, J = 8.2 Hz, 1H), 4.08 (t, J = 6.1 Hz, 2H),
2.70 (s, 3H), 1.80–1.92 (m, 2H), 1.53–1.51 (m, 2H), 0.92 (t, J = 1.8,
Hz, 3H).
6.1.1.13. 1-(2-(Benzyloxy)-6-hydroxyphenyl)ethanone (3m). Data
associated to the compound 3m was reported in our previous work.35
6.1.1.14. 1-(2-(Adamantylmethoxy)-6-hydroxyphenyl)ethanone
(3n). Yield 38%; light green liquid; Rf 0.60 (1:9 EA: HX); 1H NMR
(CDCl3) d 12.69 (s, 1H), 7.33 (t, J = 8.4 Hz, 1H), 6.59 (d, J = 8.2 Hz,
1H), 6.42 (d, J = 8.2 Hz, 1H), 5.29 (s, br s, 1H), 3.60 (s, 2H), 2.66 (s,
3H), 1.85 (s, 3H), 1.56–1.62 (m, 8H), 1.41 (m, 3H).
6.1.1.4. 1-(2-(Hexyloxy)-6-hydroxyphenyl)ethanone (3d). Data
associated to the compound 3d was reported in our previous
work.34
6.1.2. General procedure for the preparation of compound (5)
The corresponding alkyl substituted-2-hydroxyacetophenone 3
(1.0 equiv) was dissolved in ethanol and piperidine (2.0 equiv) and
benzaldehydes 4 (1.02 equiv) were added. The resulting mixture
was stirred for 5 h at 78 °C. After completion of reaction, the sol-
vent was evaporated under reduced pressure. The residue was dis-
solved in dichloromethane and washed with 1N-HCl followed by
water. The 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 5b–p.
6.1.1.5. 1-(2-(3,3-Dimethylbutoxy)-6-hydroxyphenyl)ethanone
(3e). Yield 38%; light yellow liquid; Rf 0.52 (0.5:9.5 EA: HX); IR
(KBr) 3233, 2919, 2852, 1611 cmꢀ1 1H NMR (CDCl3) d 13.28 (s,
;
1H), 7.33 (t, J = 8.4 Hz, 1H), 6.55 (dd, J = 0.8, 8.4 Hz, 1H), 6.38 (d,
J = 8.2 Hz, 1H), 4.13 (t, J = 7.4 Hz, 2H), 2.68 (2, 3H), 1.89 (t,
J = 7.4 Hz, 2H), 0.98 (s, 9H).
6.1.1.6. 1-(2-Hydroxy-6-isobutoxyphenyl)ethanone (3f). Yield
65%; colorless liquid; Rf 0.45 (0.5:9.5 EA: HX); IR (KBr) 3298,
2910, 2855, 1616 cmꢀ1 1H NMR (CDCl3) d 13.27 (s, 1H), 7.32 (t,
;
J = 8.4 Hz, 1H), 6.53–6.57 (m, 1H), 6.36 (d, J = 8.2 Hz, 1H) 3.85 (d,
J = 6.5 Hz, 2H), 2.71 (s, 3H), 2.12–2.28 (m, 1H), 1.08 (d, J = 6.5 Hz,
6H).
6.1.2.1. (E)-1-(2-Hydroxy-6-(4-methylpentyloxy)phenyl)-3-(4-
hydroxyphenyl)prop-2-en-1-one (5b). Yield 88%; yellow solid;
Rf 0.43 (3:7 EA: HX); mp 131–134 °C; IR (KBr) 3255.1, 2959.4,
1610.5, 1439.9, 1202.6, 831.3 cmꢀ1 1H NMR (CDCl3) d 13.25 (s,
;
6.1.1.7. 1-(2-(2-Ethylbutoxy)-6-hydroxyphenyl)ethanone (3g). Yield
68%; white semi solid; Rf 0.58 (0.5:9.5 EA: HX); IR (KBr) 3235,
1H), 7.85 (d, J = 16.0 Hz, 1H), 7.78 (d, J = 16.0 Hz, 1H), 7.52 (d,
J = 8.7 Hz, 2H), 7.33 (t, J = 8.0 Hz, 1H), 6.86 (d, J = 8 8.5 Hz, 2H),
6.60 (d, J = 8.5 Hz, 1H), 6.41 (d, J = 8.2 Hz, 1H), 5.33 (s, 1H), 4.06
(t, J = 6.5 Hz, 2H), 1.92–1.85 (m, 2H), 1.58–1.51 (m, 1H), 1.38–
1.31 (m, 2H) 0.84 (d, J = 6.5 Hz, 6H); 13C NMR (CDCl3) d 194.8,
164.9, 160.7, 157.8, 143.0, 135.9, 130.6, 128.3, 125.6, 116.0,
110.7, 102.4, 77.4, 77.1, 76.7, 76.7, 69.4, 35.2, 27.9, 22.4; HRMS cal-
culated for C21H24O4: m/z 340.1675, found: 340.1671.
2917, 2852, 1619 cmꢀ1 1H NMR (CDCl3) d 13.29 (s, 1H), 7.31 (t,
;
J = 8.4 Hz, 1H), 6.53 (dd, J = 0.8, 8.4 Hz, 1H), 6.39 (d, J = 8.2 Hz,
1H), 3.93 (d, J = 6.4 Hz, 2H), 2.69 (s, 3H), 1.68–1.75 (m, 1H),
1.49–1.52 (m, 4H), 0.95 (t, J = 7.6 Hz, 6H).
6.1.1.8. 1-(2-Hydroxy-6-(3-methylbut-2-enyloxy)phenyl)etha-
none (3h). Yield 24%; light green liquid; Rf 0.46 (1:9 EA: HX); 1H
NMR (DMSO-d6) d 10.78 (s, 1H), 7.46 (t, J = 8.2 Hz, 1H), 6.99 (d,
J = 15.1 Hz, 1H), 6.83–6.90 (m, J = 08.5 Hz, 2H), 4.55 (d, J = 6.3 Hz,
2H), 4.26–4.41 (m, 1H), 2.69 (s, 3H), 1.54–1.64 (m, 6H).
6.1.2.2. (E)-1-(2-Butoxy-6-hydroxyphenyl)-3-(4-hydroxyphenyl)
prop-2-en-1-one (5c). Yield 85%; yellow solid; Rf 0.40 (3:7 EA:
HX); mp 129–132 °C; IR (KBr) 3343.2, 2956.1, 1616.4, 1202.6,
831.6 cmꢀ1 1H NMR (CDCl3) d 13.37 (s, 1H), 7.86 (d, J = 16.0 Hz,
;
6.1.1.9. 1-(2-(Cyclopentylmethoxy)-6-hydroxyphenyl)ethanone
1H), 7.79 (d, J = 16.0 Hz, 1H), 7.50 (d, J = 8.5 Hz, 2H), 7.33 (t,
J = 8.0 Hz, 1H), 6.87 (dd, J = 8.4 Hz, 2H), 6.59 (d, J = 8.0 Hz, 1H),
6.41 (d, J = 8.0 Hz, 1H), 5.69 (br s, 1H) 4.08 (t, J = 6.1 Hz, 2H),
1.80–1.92 (m, 2H), 1.53–1.51 (m, 2H), 0.92 (t, J = 1.8, Hz, 3H); 13C
NMR (CDCl3) d 194.9, 165.0, 160.8, 157.9, 143.1, 136.0, 130.6,
128.3, 125.6, 116.1, 110.7, 102.4, 77.4, 76.8, 68.9, 31.5, 19.6, 13.8;
HRMS calculated for C19H20O4: m/z 312.3597, found: 312.3595.
(3i). Yield 50%; white semi solid; Rf 0.61 (0.5:9.5 EA: HX); IR
(KBr) 3239, 2911, 2840, 1614 cmꢀ1 1H NMR (CDCl3) d 13.23 (s,
;
1H), 7.29 (t, J = 8.4 Hz, 1H), 6.52 (dd, J = 0.8, 8.4 Hz, 1H), 6.39 (d,
J = 8.2 Hz, 1H), 3.94 (d, J = 7.07 Hz, 2H), 2.70 (s, 3H), 2.33–2.57
(m, 1H), 1.85 (dd, J = 5.73, 6.95 Hz, 2H), 1.52–1.63 (m, 4H), 1.31–
1.45 (m, 2H).
6.1.1.10. 1-(2-(2-Cyclopentylethoxy)-6-hydroxyphenyl)ethanone
6.1.2.3. (E)-1-(2-(Hexyloxy)-6-hydroxyphenyl)-3-(4-hydroxyphe
nyl)prop-2-en-1-one (5d). Data associated to the compound 5d
was reported in our previous work.35
(3j). Yield 47%; light green liquid; Rf 0.66 (0.5:9.5 EA: HX); IR (KBr)
3239, 2915, 2840, 1614 cmꢀ1 1H NMR (CDCl3) d 13.28 (s, 1H), 7.32
;
Please cite this article in press as: Venkateswararao, E.; et al. Bioorg. Med. Chem. (2014), http://dx.doi.org/10.1016/j.bmc.2014.04.045

6
E. Venkateswararao et al. / Bioorg. Med. Chem. xxx (2014) xxx–xxx
6.1.2.4. (E)-1-(2-Hydroxy-6-(3,3-dimethylbutoxy)phenyl)-3-(4-
hydroxyphenyl)prop-2-en-1-one (5e). Yield 77%; yellow solid;
Rf 0.49 (3:7 ethyl acetate: hexane); mp 118–121 °C; IR (KBr)
1441.9, 1203.7, 831.7 cmꢀ1 1H NMR (CDCl3) d 13.36 (s, 1H), 7.87
;
(d, J = 15.6 Hz, 1H), 7.78 (d, J = 15.6 Hz, 1H), 7.48–7.56 (m,
J = 8.5 Hz, 2H), 7.33 (t, J = 8.2 Hz, 1H), 6.82–6.91 (m, J = 8.5 Hz,
2H), 6.60 (d, J = 8.5 Hz, 1H), 6.42 (d, J = 8.2 Hz, 1H), 5.57 (br s,
1H), 4.09 (t, J = 6.3 Hz, 2H), 2.02 (d, J = 7.8 Hz, 1H), 1.90 (q,
J = 6.7 Hz, 2H), 1.72–1.82 (m, 2H), 1.55–1.66 (m, 2H), 1.42–1.55
(m, 2H), 1.06–1.20 (m, 2H); 13C NMR (CDCl3) d 194.8, 164.9,
160.6, 157.8, 142.9, 135.9, 130.5, 128.3, 125.6, 115.9, 110.6,
102.3, 76.7, 68.3, 36.6, 35.5, 32.5, 24.9; HRMS calculated for
3293.8, 2954.5, 1614.6, 1469.2, 1205.5, 825.2 cmꢀ1
;
1H NMR
(CDCl3)
d 13.34 (s, 1H), 7.88 (d, J = 15.6 Hz, 1H), 7.77 (d,
J = 15.6 Hz, 1H), 7.54 (d, J = 8.0 Hz, 2H), 7.34 (t, J = 8.2 Hz, 1H),
6.88 (d, J = 8.0 Hz, 2H), 6.60 (d, J = 8.2 Hz, 1H), 6.43 (d, J = 8.2 Hz,
1H), 5.20 (s, 1H), 4.13 (t, J = 7.4 Hz, 2H), 1.87 (t, J = 7.4 Hz, 2H),
0.98 (s, 9H); 13C NMR (CDCl3) d 194.7, 165.0, 160.6, 157.7, 142.7,
135.9, 130.5, 128.3, 125.7, 115.9, 112.0, 110.7, 102.3, 76.7, 66.4,
42.7, 29.7, 29.6; HRMS calculated for C21H24O4: m/z 340.4129,
found: 340.4126.
C22H24O4: m/z 352.4326, found: 352.4322.
6.1.2.10. (E)-1-(6-Cyclohexylmethoxy-2-hydroxyphenyl)-3-(4-
hydroxyphenyl) prop-2-en-1-one (5k). Data associated to the
compound 5k was reported in our previous work.35
6.1.2.5. (E)-1-(2-Hydroxy-6-isobutoxyphenyl)-3-(4-hydroxyphe-
nyl)prop-2-en-1-one (5f). Yield 81%; yellow solid; Rf 0.37 (3:7 EA:
HX); mp 128–131 °C; IR (KBr) 3192.3, 3033.0, 1680.9, 1201.9,
6.1.2.11. (E)-1-(2-(2-Cyclohexylethoxy)-6-hydroxyphenyl)-3-(4-
hydroxyphenyl)prop-2-en-1-one (5l). Yield 92%; yellow solid; Rf
0.43 (2:8 EA: HX); mp 166–168 °C; IR (KBr) 3254.1, 2959.4,
828.9 cmꢀ1 1H NMR (CDCl3) d 13.22 (s, 1H), 7.88 (d, J = 16.0 Hz,
;
1H), 7.79 (d, J = 16.0 Hz, 1H), 7.52 (d, J = 8.2 Hz, 2H), 7.33 (t,
J = 8.2 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 6.60 (dd, J = 0.9, 8.2 Hz,
1H), 6.41 (d, J = 8.2 Hz, 1H), 5.48 (br s, 1H), 3.85 (d, J = 6.5 Hz,
2H), 2.12–2.28 (m, 1H), 1.04 (d, J = 6.5 Hz, 6H); 13C NMR (CDCl3)
d 194.8, 164.7, 160.6, 157.8, 143.0, 135.8, 130.6, 128.2, 125.5,
115.9, 112.1, 110.6, 102.3, 77.3, 76.7, 75.6, 28.4, 19.4; HRMS calcu-
lated for C21H24O4: m/z 340.1675, found: 340.1671.
1610.5, 1439.9, 1202.6, 831.3 cmꢀ1 1H NMR (CDCl3) d 13.39 (s,
;
1H), 7.88 (d, J = 15.6 Hz, 1H), 7.79 (d, J = 15.6 Hz, 1H), 7.53 (d,
J = 8.0 Hz, 2H), 7.33 (t, J = 8.2 Hz, 1H), 6.87 (d, J = 8.0 Hz, 2H), 6.60
(d, J = 8.0 Hz, 1H), 6.42 (d, J = 8.2 Hz, 1H), 5.23 (s, 1H), 4.11 (t,
J = 6.4 Hz, 2H), 1.78 (q, J = 6.5 Hz, 2H), 1.60–1.74 (m, 5H), 1.55–
1.49 (m, 1H), 1.05–1.20 (m, 3H), 0.93 (d, J = 9.0 Hz, 2H); 13C NMR
(CDCl3) d 194.3, 165.0, 160.6, 157.8, 143.1, 135.9, 130.5, 128.3,
125.6, 115.9, 110.6, 102.3, 76.7, 68.3, 33.2, 36.6, 35.5, 32.5, 28.1,
6.1.2.6. (E)-1-(2-(2-Ethylbutoxy)-6-hydroxyphenyl)-3-(4-hydrox
yphenyl)prop-2-en-1-one (5g). Yield 88%; yellow solid; Rf 0.47
(3:7 EA: HX); mp 69–72 °C; IR (KBr) 3333.5, 2956.9, 1615.7,
25.1; HRMS calculated for
366.4498.
C23H26O4: m/z 366.4501, found:
1465.8, 1199.8, 831.0 cmꢀ1 1H NMR (CDCl3) d 13.15 (s, 1H), 7.81
;
(d, J = 16.0 Hz, 1H), 7.76 (d, J = 16.0 Hz, 1H), 7.52 (d, J = 8.7 Hz,
2H), 7.33 (t, J = 8.4 Hz, 1H), 6.86 (d, J = 8.5 Hz, 2H), 6.60 (d,
J = 8.2 Hz, 1H), 6.44 (d, J = 8.5 Hz, 1H), 5.50 (br s, 1H), 3.97 (d,
J = 5.6 Hz, 2H), 1.73 (m, 1H), 1.48 (m, 4H), 0.89 (t, J = 7.4 Hz, 6H);
13C NMR (CDCl3) d 194.8, 164.9, 160.7, 157.8, 143.0, 135.9, 130.6,
128.3, 125.6, 116.0, 110.7, 102.4, 77.4, 77.1, 76.7, 76.7, 69.4, 35.2,
24.9, 11.4; HRMS calculated for C21H24O4: m/z 340.4129, found:
340.4125.
6.1.2.12. (E)-1-(2-(Benzyloxy)-6-hydroxyphenyl)-3-(4-hydroxy-
phenyl)prop-2-en-1-one (5m). Data associated to the compound
5m was reported in our previous work.35
6.1.2.13. (E)-1-(2-(Adamantylmethoxy)-6-hydroxyphenyl)-3-(4-
hydroxyphenyl)prop-2-en-1-one (5n). Yield 48%; yellow color
solid; Rf 0.39 (3:7 EA: HX); mp 104–108 °C; IR (KBr) 3280, 2897,
2845, 1574, 1445, 1165, 829 cmꢀ1 1H NMR (CDCl3) d 12.67 (s,
;
1H), 7.80 (d, J = 15.6 Hz, 1H), 7.65 (d, J = 15.6 Hz, 1H), 7.55 (d,
J = 8.5 Hz, 2H), 7.33 (t, J = 8.4 Hz, 1H), 6.84 (d, J = 8.5 Hz, 2H), 6.59
(d, J = 8.2 Hz, 1H), 6.42 (d, J = 8.2 Hz, 1H), 5.29 (s, br s, 1H), 3.60
(s, 2H), 1.85 (s, 3H), 1.56–1.62 (m, 8H), 1.41 (m, 3H); 13C NMR d
194.7, 167.4, 163.9, 160.9, 158.2, 157.7, 148.3, 142.5, 135.6,
130.7, 128.2, 126.4, 115.8, 112.9, 110.3, 102.6, 80.0, 44.6, 39.5,
36.6, 34.8, 33.7, 27.9, 24.3, 21.4; HRMS: calculated for C26H28O4:
m/z 404.4981, found: 404.4978.
6.1.2.7. (E)-1-(2-Hydroxy-6-(3-methylbut-2-enyloxy)phenyl)-3-
(4-hydroxyphenyl)prop-2-en-1-one (5h). Yield 27%; yellow color
solid; Rf 0.13 (3:7 EA: HX); mp 246–247 °C; IR (KBr) 3200, 2952,
2358, 1559, 1463, 1225, 740 cmꢀ1 1H NMR (DMSO-d6) d 10.73
;
(s, 1H), 7.68–7.77 (m, 3H), 7.41 (t, J = 8.2 Hz, 1H), 6.99 (d,
J = 15.1 Hz, 1H), 6.83–6.90 (m, J = 8.5 Hz, 2H), 6.71–6.78 (m,
J = 8.2 Hz, 2H), 5.20–5.30 (m, 1H), 4.55 (d, J = 6.3 Hz, 2H), 4.26–
4.41 (m, 1H), 1.54–1.64 (m, 6H); 13C NMR (DMSO-d6) d 171.2,
162.7, 155.9, 155.5, 155.2, 138.1, 133.1, 125.1, 119.2, 116.3,
114.5, 108.8, 107.0, 103.8, 65.0, 55.1, 26.7, 25.2, 22.8, 17.9; HRMS:
calculated for C20H20O4: m/z 324.3704, found: 324.3700.
6.1.2.14. 4-((E)-3-(2-Hydroxy-6-(3,3-dimethylbutoxy)phenyl)-3-
oxoprop-1-enyl)benzoic acid (5o). Yield 28%; yellow color solid;
Rf 0.18 (3:7 EA: HX); mp 185–187 °C; IR (KBr) 2947, 2541, 1684,
1557, 1465, 1227, 735 cmꢀ1 1H NMR (CDCl3) d 13.03 (s, 1H),
;
6.1.2.8. (E)-1-(2-(Cyclopentylmethoxy)-6-hydroxyphenyl)-3-(4-
hydroxyphenyl)prop-2-en-1-one (5i). Yield 92%; yellow solid; Rf
0.42 (3:7 EA: HX); mp 127–129 °C; IR (KBr) 3367.8, 2959.4,
8.12–8.18 (m, J = 8.2 Hz, 2H), 8.03 (d, J = 15.6 Hz, 1H), 7.77 (d,
J = 15.8 Hz, 1H), 7.68–7.73 (m, J = 8.2 Hz, 2H), 7.37 (t, J = 8.2 Hz,
1H), 6.62 (d, J = 8.2 Hz, 1H), 6.44 (d, J = 8.2 Hz, 1H), 4.15 (t,
J = 7.4 Hz, 2H), 1.85 (t, J = 7.3 Hz, 2H), 0.98 (s, 9H); 13C NMR d
194.4, 165.1, 160.7, 140.6, 140.5, 136.5, 130.8, 130.2, 128.3,
112.0, 110.8, 102.3, 66.5, 42.8, 29.7, 29.6; HRMS: calculated for
1659.9, 1202.7, 836.0 cmꢀ1 1H NMR (CDCl3) d 13.27 (s, 1H), 7.85
;
(d, J = 16.0 Hz, 1H), 7.78 (d, J = 16.0 Hz, 1H), 7.52 (d, J = 8.0 Hz,
2H), 7.32 (t, J = 8.41 Hz, 1H), 6.86 (d, J = 8.0 Hz, 2H), 6.59 (dd,
J = 0.85, 8.41 Hz, 1H), 6.42 (d, J = 8.0 Hz, 1H), 5.55 (s, 1H), 3.94 (d,
J = 7.07 Hz, 2H), 2.33–2.57 (m, 1H), 1.85 (dd, J = 5.73, 6.95 Hz,
2H), 1.52–1.63 (m, 4H), 1.31–1.45 (m, 2H); 13C NMR (CDCl3) d
194.8, 164.8, 160.7, 157.7, 142.9, 135.9, 130.5, 128.3, 125.7,
115.9, 112.0, 110.6, 102.3, 77.2, 76.7, 73.2, 39.2, 29.6, 25.2; HRMS
calculated for C21H22O4: m/z 338.3970, found: 338.3966.
C22H24O5: m/z 368.4230, found: 368.4226.
6.1.2.15. 4-((E)-3-(2-Hydroxy-6-(3,3-dimethylbutoxy)phenyl)-3-
oxoprop-1-enyl)benzenesulfonamide (5p). Yield 49%; yellow
color solid; Rf 0.11 (1:9 EA: HX); mp 170–172 °C; IR (KBr) 3413,
2955, 2358, 1588, 1449, 1226, 724 cmꢀ1 1H NMR (DMSO-d6) d
;
10.54 (s, 1H), 7.86–7.90 (m, 2H), 7.81–7.86 (m, 2H), 7.42 (s, 2H),
7.37 (d, J = 5.37 Hz, 2H), 7.27 (t, J = 8.29 Hz, 1H), 6.62 (d,
J = 8.54 Hz, 1H), 6.54 (d, J = 8.29 Hz, 1H), 4.04 (t, J = 7.07 Hz, 2H),
1.58 (t, J = 6.95 Hz, 2H), 0.83–0.90 (m, 9H); 13C NMR (DMSO-d6) d
6.1.2.9. (E)-1-(2-(2-Cyclopentylethoxy)-6-hydroxyphenyl)-3-(4-
hydroxyphenyl)prop-2-en-1-one (5j). Yield 88%; yellow solid; Rf
0.45 (3:7 EA: HX); mp 149–151 °C; IR (KBr) 3264.5, 1613.2,
Please cite this article in press as: Venkateswararao, E.; et al. Bioorg. Med. Chem. (2014), http://dx.doi.org/10.1016/j.bmc.2014.04.045

E. Venkateswararao et al. / Bioorg. Med. Chem. xxx (2014) xxx–xxx
7
194.3, 158.0, 157.7, 145.2, 141.1, 137.8, 132.5, 130.8, 128.8, 126.2,
115.5, 109.0, 103.3, 65.8, 41.9, 29.4, 29.3; HRMS: calculated for
21H25NO5S: m/z 403.4919, found: 403.4916.
References and notes
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Yield 27%; white color solid; Rf 0.22 (3:7 EA: HX); mp 58–60 °C;
IR (KBr) 3286, 2952, 2358, 1560, 1510, 1465, 1232, 740 cmꢀ1 1H
;
NMR (CDCl3) d 7.39 (d, J = 8.4 Hz, 2H), 7.30 (s, 1H), 6.79–6.85 (m,
3H), 6.59 (t, J = 8.9 Hz, 2H), 6.03 (s, 1H), 4.00 (t, J = 7.06 Hz, 2H),
3.76 (s, 3H), 1.59 (t, J = 7.15 Hz, 2H), 0.87 (s, 9H); 13C NMR d
206.5, 164.4, 160.6, 153.5, 135.6, 133.3, 129.2, 114.9, 111.0,
110.3, 101.7, 66.1, 46.2, 41.9, 29.3, 29.2, 28.9; 13C NMR (CDCl3) d
196.1, 158.2, 157.6, 157.1, 145.7, 130.7, 130.4, 127.5, 126.6,
118.8, 116.0, 105.0, 103.9, 66.1, 55.9, 42.1, 29.6; HRMS: calculated
for C22H26O4: m/z 354.4394, found: 354.4390.
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6.1.2.17. 1-(2-(3,3-Dimethylbutoxy)-6-hydroxyphenyl)-3-(4-hyd
roxyphenyl)propan-1-one (5r). Compound 5e (1 mmol) was dis-
solved in methanol and 10% Pd/C was added in Parr’s hydrogena-
tion bottle. After 30 psi hydrogen gas was charged, the reaction
mixture was shaken for 3 h at room temperature. TLC profile of
the reaction indicated completion of reaction. The catalyst was
removed by the filtration using celite aid. The filtrate was evapo-
rated and the residue was purified by flash column chromatogra-
phy to give 5r.
Yield 54%; white color solid; Rf 0.50 (3:7 EA: HX); mp 104–
106 °C; IR (KBr) 3409, 2953, 2358, 1588, 1513, 1449, 1200,
803 cmꢀ1 1H NMR (CDCl3) d 13.21 (s, 1H), 7.32 (t, J = 8.2 Hz, 1H),
;
7.07–7.14 (m, J = 8.2 Hz, 2H), 6.73–6.80 (m, J = 8.2 Hz, 2H), 6.56
(d, J = 8.2 Hz, 1H), 6.39 (d, J = 8.2 Hz, 1H), 4.67 (s, 1H), 4.08 (t,
J = 7.5 Hz, 2H), 3.41 (t, J = 7.5 Hz, 2H), 2.96 (t, J = 7.5 Hz, 2H), 1.74
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160.6, 153.5, 135.6, 133.3, 129.2, 114.9, 111.0, 110.3, 101.7, 66.1,
46.2, 41.9, 29.3, 29.2, 28.9; HRMS: calculated for C21H26O4: m/z
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Acknowledgment
This work was supported by Priority Research Centers Program
through the National Research Foundation of Korea (NRF) funded
by the Ministry of Education, Science and Technology (2009-
0093815).
Please cite this article in press as: Venkateswararao, E.; et al. Bioorg. Med. Chem. (2014), http://dx.doi.org/10.1016/j.bmc.2014.04.045