Synthesis and antiproliferative activity of α-branched α,β-unsaturated ketones in human hematological and solid cancer cell lines

Article abstract of DOI:10.1016/j.ejmech.2015.05.012

A series of α-branched α,β-unsaturated ketones were prepared via boron trifluoride etherate mediated reaction between arylalkynes and carboxaldehydes. The evaluation of the antiproliferative activity over hematological (NB4) and solid cancer (A549, MCF-7)

Full text of DOI:10.1016/j.ejmech.2015.05.012

European Journal of Medicinal Chemistry 98 (2015) 30e48
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Research paper
Synthesis and antiproliferative activity of
a-branched a,b-unsaturated
ketones in human hematological and solid cancer cell lines
a
a
,
b
c
a
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Ieva Karpaviciene , Giedre Valiuliene , Vytautas Raskevicius , Indre Lebedyte ,
a
c
,
d
b,
*
a, *
ꢀ
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Algirdas Brukstus , Visvaldas Kairys , Ruta Navakauskiene , Inga Cikotiene
a Department of Organic Chemistry, Faculty of Chemistry, Vilnius University, Naugarduko 24, Vilnius, LT-03225, Lithuania
b Department of Molecular Cell Biology, Institute of Biochemistry, Vilnius University, Mokslininku˛ 12, Vilnius, LT-08662, Lithuania
c
ꢀ ꢁ
Department of Bioinformatics, Institute of Biotechnology, Vilnius University, V. Graiciuno 8, Vilnius, LT-02241, Lithuania
d Department of Applied Chemistry, Faculty of Chemistry, Vilnius University, Naugarduko 24, Vilnius, LT-03225, Lithuania
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of a-branched a,b-unsaturated ketones were prepared via boron trifluoride etherate mediated
Received 19 January 2015
Received in revised form
6 May 2015
Accepted 8 May 2015
Available online 15 May 2015
reaction between arylalkynes and carboxaldehydes. The evaluation of the antiproliferative activity over
hematological (NB4) and solid cancer (A549, MCF-7) cell lines provided a structure-activity relationship.
5-Parameter QSAR equations were built which were able to explain 80%e92% of the variance in activity.
The resulting selective lead compound showed IC50 value 0.6 mM against the hematological cell line and
did not cause apoptosis, but blocked cell cycle in G0/G1. Moreover, it was demonstrated that this
compound enhances and accelerates retinoic acid induced granulocytic differentiation.
© 2015 Published by Elsevier Masson SAS.
Keywords:
a
-branched a,b-unsaturated ketones
Antiproliferative activity
Cell cycle arrest
Apoptosis
QSAR
Granulocytic differentiation
1. Introduction
currently of high priority.
Chemically,
a,b-unsaturated ketones can be prepared by
Various natural and synthetic
a
,
b
-unsaturated ketones are
different methods, including classical aldol-type condensations or
Wittig reactions or some more modern synthetic approaches [8].
Recently, we developed and described a unique reaction between
known to exhibit antitumor activities [1]. The conjugated ketone
functional group has been hypothesized to work in cancer
chemotherapy via thiol alkylation without interaction with amino
or hydroxy groups of cellular constituents, and therefore, enones
could have remarkable advantages over classical alkylators since
these compounds probably could not cause genotoxic effects
associated with a number of anticancer drugs [2]. Moreover, the
antitumor activity of the enone framework containing materials is
linked with various effects including inhibition on NF-KB [3] or
mitochondrial mediated [4] pathways, stimulation of death re-
ceptors (DRS) of the tumor necrosis factor (TFN) [5], inhibition of
cyclin-depended kinases [6] or DNA topoisomerase II [7] and so
propargylic esters and aldehydes leading to a variety of
a-branched
a,b-unsaturated ketones in one atom-economic step [9a]. We also
showed that the outcome of this process strongly depends on the
structure of the starting materials; mechanism of this trans-
formation proved by isotopic labeling studies and quantum
chemical calculations [9b]. Moreover, we recently reported on the
synthesis and the preliminary investigation for the antiproliferative
activity of
a-branched a,b-unsaturated ketones, which showed
remarkable biological activity towards human solid cancer cell lines
[10]. Therefore, our one-step synthetic approach gives a diverse
range of enone functionality containing bioactive materials. As a
continuation of our study, herein we report the synthesis of novel
forth. Thus, the synthesis of new
a,b-unsaturated ketones is
a-branched a,b-unsaturated ketones that have antiproliferative
activity against human hematological (NB4, leukemia) and solid
(A549, lung and MCF-7, breast) cancer cell lines.
* Corresponding authors.
ꢁ
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E-mail addresses: ruta.navakauskiene@bchi.vu.lt (Ruta Navakauskiene), inga.
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cikotiene@chf.vu.lt (I. Cikotiene).
http://dx.doi.org/10.1016/j.ejmech.2015.05.012
0223-5234/© 2015 Published by Elsevier Masson SAS.

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2. Chemistry
4-yn-2-yl acetate 1f, alkynes 1g,h or N-(3-(4-methoxyphenyl)prop-
2-ynyl)-N-methylbenzamide 1i with various aldehydes resulted in
the exclusive formation of E-enones (3) in low or good yields
(Scheme 2, Table 2).
The target compounds were synthesized from aryl alkynes 1 and
aldehydes 2 under our previously determined reaction conditions
[9]. Mixtures of starting materials in dichloromethane were treated
with 1 equivalent of boron trifluoride diethyletherate at room
temperature (Schemes 1 and 2). The outcome of this reaction
strongly depends on the structures of the starting materials. Thus,
reactions between propargylic esters 1a-d and various aldehydes in
principle can lead to the formation of E-(3) or Z-chalcones (4),
Morita-Baylis-Hillman adducts (5 and 5’) or 2:1 adducts (6) or
mixtures of these compounds (Scheme 1). Structures and yields of
the isolated products are shown in Table 1.
To further functionalize the
enones, some of the isolated Morita-Baylis-Hilman adducts 5 were
transformed into the corresponding amino functionalized
substituted -unsaturated ketones 7 by reacting with amines
a-substituent in the synthesized
a
-
a,b
[11], as presented in Scheme 3. All the reactions performed pro-
ceeded smoothly, and the products were isolated in moderate to
good yields. Unfortunately, most of compounds 7 were decom-
posed over time, and therefore were not stable enough to be tested
(Table 3, entries 2, 4, 5, 7).
In contrast to the propargylic esters, reactions of 4-(4-
methoxyphenyl)but-3-ynyl acetate 1e, 5-(4-methoxyphenyl)pent-
3. Antiproliferative activity and SAR's of synthesized
compounds
All synthesized compounds were tested in vitro for their anti-
proliferative activity using three different human cancer cell lines:
NB4 acute promyelocytic leukemia cells, A549 lung cancer cell line
and MCF-7 breast cancer cells. After 48 h treatment, the effect of
compounds was evaluated using XTT assay according to the man-
ufacturer's instructions as described in Experimental section.
For a better evaluation of structure-activity relationship, the
compounds were divided into three main groups: the first group
containing a-substituted chalcones 3, 4 and 7, the second group
representing 2:1 adducts 6, and the third group including Morita-
Baylis-Hillman's adducts 5 and 5’ (Fig. 1). IC50 values of all these
compounds are listed in Tables 4e6, respectively.
Scheme 1. Reaction between propargylic esters 1a-d and aldehydes 2.
The data presented in Tables 4e6 revealed that the A549 cancer
cell line was the most resistant, and therefore almost all com-
pounds showed weak or moderate antiproliferative activities
against this cell line. In contrast, the NB4 hematological cell line
was extremely sensitive to the majority of the tested compounds.
The analysis of the IC50 values allowed us to establish several
SARs. Among compounds of the Group 1 (Table 4), E-chalcone an-
alogues of the subset 3ax-3dx exhibited notable antiproliferative
Scheme 2. Reaction between alkynes 1e-i and aldehydes 2.
Table 1
Data on the reactions between propargylic esters 1a-d and aldehydes 2.
Entry
Alkyne 1
Ar
Ph
R
Aldehyde 2
R1
Products (yields, %)
1
2
3
4
5
6
7
8
1a
Me
2a
2b
2c
2d
2a
2b
2d
2e
2f
2g
2h
2i
2h
2j
2a
2b
2c
2e
2f
2h
2i
2j
2-FC6H4
2,4-Cl2C6H3
4-MeC6H4
4-BzOC6H4
2-FC6H4
2,4-Cl2C6H3
4-BzOC6H4
CHEt2
cHex
Ph
4-O2NC6H4
C6F5
4-O2NC6H4
2-O2NC6H4
2-FC6H4
2,4-Cl2C6H3
4-MeC6H4
CHEt2
cHex
4-O2NC6H4
C6F5
2-O2NC6H4
Me
2-ClC6H4
2,4- (NO2)2C6H3
3aa (51), 4aa (26)
3 ab (46), 4 ab (23)
6ac (22)
6ad (14)
3ba (34), 5ba (31)
5bb (75)
1b
4-MeOC6H4
Me
3bd:4bda (12), 6bd (12)
3be (22), 5be (36)
3bf (37), 5bf (29)
3bg:4bga (53), 6bg (17)
5bh (63)
5bi (60)
5ch (21)
5cj (32)
5da (42), 5'da (9)
5 db (56), 5'db (32)
3dc:4dca (16), 6dc (26)
3de (4), 5de (37)
3df (8), 5df (55)
5dh (43), 5'dh (27)
5di (28), 5'di (38)
5dj (22), 5'djb (47)
3dk (22), 5dk (23)
3 dl (33), 4 dl (20), 5 dl (46), 5'dl (13)
5 dm (31), 5'dm (59)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
1c
2,4-(MeO)2C6H3
4-MeOC6H4
Me
Ph
1d
2k
2l
2m
a
Mixtures of products 3 and 4 were isolated due to same Rf's.
Compound 5'dj contained impurity of 5dj due to very similar Rf's.
b

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Table 2
Data on the reactions between propargylic esters 1e-i and aldehydes 2.
Entry
Alkyne 1
Ar
R
Aldehyde 2
R1
Product (yield, %)
1
2
3
4
5
6
7
8
1e
4-MeOC6H4
CH2OAc
2a
2b
2e
2f
2h
2i
2-FC6H4
2,4-Cl2C6H3
CHEt2
cHex
4-O2NC6H4
C6F5
2-ClC6H4
4-ClC6H4
2,4-Cl2C6H3
cHex
3ea (50)
3eb (61)
3ee (21)
3ef (40)
3eh (53)
3ei (21)
3el (55)
3en (25)
3 fb (70)
3ff (30)
3fi (8)
3fn (21)
3gb (70)
3gh (76)
3gn (46)
3go (71)
3 hb (50)
3ho (54)
3ib (51)
3if (49)
2l
2n
2b
2f
9
1f
4-MeOC6H4
4-MeOC6H4
CHMeOAc
CHMe2
10
11
12
13
14
15
16
17
18
19
20
2i
C6F5
2n
2b
2h
2n
2o
2b
2o
2b
2f
4-ClC6H4
2,4-Cl2C6H3
4-O2NC6H4
4-ClC6H4
4-F3CC6H3
2,4-Cl2C6H3
4-F3CC6H3
2,4-Cl2C6H3
cHex
1g
1h
1i
4-MeOC6H4
4-MeOC6H4
cHex
NMeBz
activities. Moreover, E-enones showed better activities than their
corresponding Z-isomers against the NB4 and MCF-7 cell lines, as
shown in the comparisons of 3aa, 3 ab and 3 dl vs 4aa, 4 ab and 4 dl,
respectively (Table 4, entries 1, 2, 4e7). This result was consistent
with our previous observation [10]. However, the E-chalcones 3aa
and 3 ab (Table 4, entries 1,4) were less potent than the respective
Z-isomers 4aa and 4 ab (Table 4, entries 2, 5) towards the A549 cell
Incorporation of a tertiary amino functionality in a-position
along with a combination of electron-donating (methoxy) and
electron withdrawing (nitro) groups on the aromatic rings of the
chalcone scaffold, as in 7a and 7c (Table 4, entries 33, 34), gave an
effective growth inhibition of both leukemic (NB4) and breast
(MCF-7) cancer cell lines. Compound 7f (entry 35) bearing
dichlorophenyl portion in
b-position was less active against the
line. Also, E-enones bearing alkyl substituent in
b
-position did not
MCF-7 cell line, but retained satisfactory activity and selectivity
towards the leukemic cell line (NB4).
show any significant activity against the A549 cell line, while dis-
played moderate antiproliferative activities against the other cell
lines (Table 4, entries 8e10). Incorporation of benzoyloxy func-
tionality at the a-substituent (compound 3df, entry 12) seems to
favor antiproliferative activity towards all cancer cell lines, as
Group 2 of the tested compounds includes a small number of 2:1
adducts (Table 5), which exhibited satisfactory micromolar growth
inhibitory activity against the leukemic cancer cells (NB4), the most
active and selective being the bis(methoxy) substituted analogue
6bd (Table 5, entry 5). However, its unsubstituted counterpart 6ad
was less selective and showed weak activities towards the A549
and MCF-7 solid cancer cells (Table 5, entry 4). Noticeably,
enhanced anti-A549 and MCF-7 activities were observed in the
cases of compounds 6ac, 6dc and 6bg (Table 5, entries 1e3), indi-
cating that absence of the benzoate functionality had a favorable
effect on the antiproliferative activity over the A549 and MCF-7 cell
lines.
exemplified by comparing 3df to its counterpart 3bf (Table 4, entry
11). Elongation of the
(Table 4, entries 13e20) led to a substantial loss of activity for all
cell lines. Introduction of the CH2CH(CH3)OAc moiety at the -po-
sition of the -unsaturated ketone framework or replacement of
the ester group in the -substituent by the N-methylbenzamide
a-substituent by one CH2 group, as in 3ea-3ei
a
a,b
a
functionality gave compounds with modest to negligible activities
(Table 4, entries 21e26).
Interestingly, E-chalcones 3 bearing a branched aliphatic sub-
The third group of the tested compounds represents the class of
Morita-Baylis-Hilman adducts 5 and 5' (Table 6), which were found
to be the most potent over all cancer cell lines, although their
majority showed low to moderate growth inhibitory activities
against the A549 cell line. It is evident from Table 6 that the pres-
stituent (isobutyl or cyclohexylmethyl groups) at the
a-position
displayed a selective activity towards the leukemia cancer cells line
(Table 4, entries 27e32), with 3gh (entry 28) being active at sub-
micromolar concentration. However, the presence of the more
bulky cyclohexylmethyl substituent caused a decrease in potency
against the above cancer cells, as exemplified by comparing 3gb
(entry 27) vs 3 hb (entry 31) and 3go (entry 30) vs 3ho (entry 32).
Moreover, benzene ring C4-methoxy substitution adjacent to the
ence of the ortho-halogenaryl portion in the
a-substituent was
responsible for enhanced anti-NB4 activity (entries 6, 8e11).
Furthermore, the acylated derivatives (entries 6, 11, 16) were more
potent than their respective benzoylated counterparts (entries 7,
12, 18). Dimethoxyphenyl moiety present in compounds 5cj and
carbonyl function in combination with C4-substitution on the b-
phenyl moiety with nitro, chloro and trifluoromethyl groups led to
a very effective growth inhibition of the leukemia cancer cells, as
evidenced by compounds 3gh, 3gn and 3go.
Table 3
Data on the reactions between compounds 5 and secondary amines.
Entry
Comp. 5
R1
Amine
Product
Yield, %
1
2
3
4
5
6
7
5bh
4-O2NC6H4
diethylamine
piperidine
morpholine
aniline
diethylamine
morpholine
aniline
7a
7b
7c
7d
7e
7f
48
80a
77
99a
84a
53
5bb
2,4-Cl2C6H3
7g
70a
a
Scheme 3. Nucleophilic modification of compounds 5.
Unstable product over time at room temperature.

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Table 4
In vitro antiproliferative activity of compounds 3, 4 and 7 against human cancer cell lines (IC50 in
m
M).
Entry
Compound
Structure
IC 50% (
NB4
mM)
A549
MCF-7
1
3aa
5.8 ( 1.2)
68.7 ( 0.04)
14.6 ( 2.16)
2
4aa
8.3 ( 0.55)
20.3 ( 0.15)
39.8 ( 0.67)
3
4
3ba
8.2 ( 1.24)
6.6 ( 0.84)
22.5 ( 0.17)
97 ( 0.13)
30 ( 0.27)
8.7 ( 1.01)
3 ab
5
4 ab
12.6 ( 0.72)
74.5 ( 0.13)
31.7 ( 0.68)
6
7
3 dl
4 dl
7 ( 0.76)
20.1 ( 1.01)
52 ( 0.15)
9 ( 0.05)
18 ( 0.69)
36 ( 0.93)
8
9
3be
3de
9.5 ( 0.22)
>100
>100
13.7 ( 0.94)
28 ( 0.35)
26.8 ( 0.06)
10
11
12
13
3dk
3bf
3df
3ee
16.2 ( 1. 18)
23.3 ( 0.29)
10.2 ( 1.09)
91.1 ( 0.09)
>100
29.8 ( 0.29)
24 ( 0.30)
13.7 ( 0.75)
>100
90 ( 0.22)
36 ( 0.19)
>100
14
15
3ef
>100
>100
>100
>100
>100
3ea
>100
(continued on next page)

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Table 4 (continued )
Entry
Compound
Structure
IC 50% (
NB4
mM)
A549
MCF-7
16
17
18
3el
51.6 ( 0.06)
36.3 ( 0.28)
34.8 ( 0.19)
>100
>100
3en
3eb
86 ( 0.09)
>100
69.2 ( 0.04)
83.4 ( 0.03)
19
20
3eh
3ei
>100
>100
>100
>100
28.5 ( 0.20)
58.1 ( 0.08)
21
22
3ff
33.4 ( 0.17)
36.8 ( 0.09)
98 ( 0.09)
>100
>100
3 fb
40.3 ( 0.10)
23
24
3fi
49 ( 0.10)
91.7 ( 0.11)
>100
>100
3fn
62 ( 0.17)
73.2 ( 0.13)
25
26
3ib
3if
24 ( 0.38)
32.4 ( 0.22)
69.7 ( 0.01)
>100
39.7 ( 0.22)
32.7 ( 0.18)
27
28
3gb
3gh
14.6 ( 0.05)
0.6 ( 0.02)
80.3 ( 0.27)
>100
>100
>100
29
30
3gn
3go
12.1 ( 0.07)
12.6 ( 0.01)
>100
>100
>100
>100

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Table 4 (continued )
Entry
Compound
Structure
IC 50% (
NB4
mM)
A549
MCF-7
31
32
3 hb
48.9 ( 0.21)
>100
>100
3ho
18.2 ( 0.06)
>100
>100
33
34
35
7a
7c
7f
1.2 ( 0.99)
5.6 ( 1.01)
8.5 ( 0.32)
22 ( 0.18)
70.1 ( 0.06)
>100
4.3 ( 1.06)
7 ( 0.88)
42.3 ( 0.59)
5ch had a negative effect on their antiproliferative activity towards
the A549 and MCF-7 cancer cell lines (Table 6, eg entry 16 vs entry
antiproliferative activity over the same cell line, (Table 6, entries
12,18, 20, 22).
17). Changing the aromatic component in the
aliphatic residue did not inhibit the cell growth to a considerable
a
-substituent for an
In summary, the following structural features of unsaturated
ketones were found to improve the antiproliferative activity and
extent (Table 6, entries 1e5). Compounds with electron deficient
selectivity (Fig. 2): (a) the aryl group in the b-position of the enone
aryl moieties at the
functionalities gave improved growth inhibitory activity against the
MCF-7 cell line (Table 6, entries 11, 13, 16, 21), while the benzoyloxy
a
-substituent along with acetyloxy or hydroxyl
fragment is always a better option compared to an aliphatic chain
or the cyclohexyl ring; (b) the presence of the methylene linker
between the
a-position and the acetoxy, benzoyloxy, dialkylamino,
functionalized
analogues
displayed
significantly
lower
or branched alkyl groups is important for the notable
Table 5
In vitro antiproliferative activity of compounds 6 against human cancer cell lines (IC50 in mM).
Entry
1
Compound
Structure
IC 50% (
mM)
NB4
A549
MCF-7
6ac
7.6 ( 1.04)
20.9 ( 0.04)
15.9 ( 1.11)
2
3
6dc
6bg
11.4 ( 1.07)
43.8 ( 0.57)
22.9 ( 0.47)
26.9 ( 0.43)
27.1 ( 0.65)
7.4 ( 0.74)
8 ( 0.79)
4
5
6ad
6bd
44.4 ( 0.06)
61.6 ( 0.17)
6.7 ( 0.25)
>100
>100

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Table 6
In vitro antiproliferative activity of compounds 5 and 5’ against human cancer cell lines (IC50 in mM).
Entry
1
Compound
Structure
IC 50% (
NB4
mM)
A549
MCF-7
5dk
15.7 ( 0.34)
>100
14.5 ( 0.63)
2
3
4
5be
5de
5bf
11.8 ( 0.31)
32.9 ( 0.33)
35.2 ( 0.25)
>100
38.9 ( 0.19)
17.9 ( 0.56)
14 ( 1.73)
13 ( 0.56)
10.5 ( 0.57)
5
5df
10 ( 1.07)
62.1 ( 0.02)
34.3 ( 0.01)
6
7
5ba
5da
9.5 ( 1.43)
67.3 ( 0.07)
73.7 ( 0.12)
18 ( 0.54)
14.3 ( 0.47)
34.2 ( 0.18)
8
9
5'da
5 dl
6.9 ( 0.78)
8.5 ( 0.85)
15.7 ( 0.08)
30.5 ( 0.14)
30.9 ( 0.04)
36 ( 0.94)
10
11
5'dl
5bb
8.1 ( 0.80)
5.4 ( 1.01)
28.5 ( 0.11)
17.6 ( 0.01)
29.6 ( 1.20)
8.3 ( 0.78)
12
5 db
9.7 ( 0.28)
79.2 ( 0.09)
26.8 ( 0.27)
13
14
5'db
5cj
26.1 ( 0.33)
8.8 ( 2.23)
70 ( 0.07)
9 ( 0.07)
>100
70.1 ( 0.36)
15
16
5dj
12.7 ( 0.42)
10.3 ( 1.19)
45.5 ( 0.14)
21.3 ( 0.27)
11.8 ( 0.48)
6.1 ( 0.86)
5bh

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Table 6 (continued )
Entry
Compound
Structure
IC 50% (
NB4
mM)
A549
MCF-7
17
18
5ch
5 ( 1.53)
43.5 ( 0.04)
10.4 ( 0.79)
5dh
13.2 ( 0.83)
66.6 ( 0.16)
56.1 ( 2.03)
19
20
5'dh
5.4 ( 0.76)
10 ( 1.07)
23.8 ( 0.14)
13 ( 0.41)
11 ( 0.73)
5 dm
>100
21
22
5bi
5di
12.6 ( 1.12)
12.9 ( 0.74)
14.8 ( 1.19)
32.1 ( 0.32)
6.7 ( 0.79)
45.3 ( 0.17)
antiproliferative activities of compounds 3 and 7; (c) Morita-Baylis-
Hillman adducts 5 are generally more active towards all the tested
cancer cell lines, but they are less selective; (d) compounds 5 and 5’
bearing hydroxyl or acetyloxy groups show improved activity to-
wards all the tested cancer cells lines; (e) the presence of ortho-
halogenaryl group could be associated with improved activities
electron deficient aryl groups are exhibit better activities towards
MCF-7 cells.
It should be noted, that we did not evaluate the cytotoxicity of
synthesized compounds on normal cells, so at this stage of the
investigation we can only speculate about possible selective
toxicity. In principle, both cancer cells and healthy cells are sensi-
tive to cytotoxic agents, only effective drug concentrations can vary.
Our results showed that there are some selective compounds for
different cancer cells (e.g. compounds 3gh, 3gn, 3go, 3ho, 6bd
exhibited satisfactory growth inhibitory activity against the
leukemic cancer cells NB4 but were inactive towards solid human
cancer cells); so we can presume that some of the active com-
pounds could exert quit different antiproliferative activities to-
wards cancer and healthy cells.
towards NB4 cells; (f) a,b-unsaturated ketones motifs containing
4. QSAR studies
The Quantitative Structure-Activity Relationships (QSAR) for the
tested compounds were further explored using computational
methods.
Fig. 1. The three main structural groups of the tested compounds.
4.1. Data set
A total data set of 62 molecules was divided into two sets
classified based on presence of the terminal alkene group: Set 1
accommodated compounds 3, 4 and 7 (35 molecules), and Set 2
included compounds 5, 5′ and 6 (27 molecules). The IC50 activities
of compounds were converted to pIC50 ¼ -log(IC50) for the sake of
convenience. For computational purposes, compounds with
IC50 > 100
mM (‘inactives’) were assumed to have pIC50 ¼ 4.
4.2. Molecular modeling
Compound structures were sketched and afterwards optimized
in 3-D using Avogadro v.1.1.1 [12]. Activity data for some chiral
molecules present in the Set 1 were for the racemic mixtures, with
undetermined enantiomer activities. For these molecules, the same
Fig. 2. A summary of the main structural features of the active compounds.

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38
chirality was used to prevent introduction of noise. The generated
molecular structure files were merged into a single sdf molecular
format file with Open Babel v.2.3.1 [13]. The combined sdf file was
used as an input to E-DRAGON program [14]. E-DRAGON calculates
numerous descriptor families such as (a) 2D-descriptors: topolog-
ical indices, walk and path counts, connectivity indices, information
indices, 2D-autocorrelations, Burden eigenvalues, Galvez topolog-
ical charge indices; and (b) 3D-descriptors: aromaticity indices,
Randic molecular profiles, geometrical indices, radial distribution
functions, 3D-MoRSE descriptors, WHIM (Weighted Holistic
Invariant Molecular) descriptors, GETAWAY (Geometry, Topology
and Atoms-Weighted Assembly) descriptors, and charge indices
[15]. The resulting pool consisted of 1666 structural descriptors.
Linear regression QSAR models where developed within R software
environment using leaps package. Leaps warned about issues
arising from the linear dependence of the descriptors, and such
QSAR models were rejected. The final QSAR equations were built
using 5 descriptors according to the generally accepted rule that at
least 5 molecules should be present for each selected descriptor
[16].
R2 ¼ 0:80; RA2DJ ¼ 0:75; Q2 ¼ 0:67; Fð5; 21Þ ¼ 16:4; p < 10ꢀ5
pIC50ðMCF ꢀ 7; Set 2Þ ¼ 0:0149$CSI ꢀ 0:109$UNIP
ꢀ 0:0475$MPC10 þ 0:815$X2
ꢀ 0:909$GATS1v þ 1:11
(6)
R2 ¼ 0:89; RA2DJ ¼ 0:87; Q2 ¼ 0:83; Fð5; 21Þ ¼ 34:7; p < 10ꢀ5
The models are described by several statistical parameters
which are provided below each equation. The acceptance of the
model was based on the correlation coefficients R2, the adjusted
correlation coefficients R2ADJ, and the F-test (F) values. The perfor-
mance of the models was validated using the Leave One Out (LOO)
method with the variance Q2. The molecular descriptors appearing
in the Equations (1)e(6) are listed in the Supporting Information.
Plots of the experimentally determined versus predicted pIC50
values are presented in Fig. 3. A straight line represents an ideal
agreement between the observed and calculated values. Interest-
ingly, the correlation coefficients R2 are similar for the same cell
line, regardless of the compound set, even though the QSAR
equations are different. For the A549 cell line measured pIC50 data
4.3. QSAR results
Using the activity data against the NB4, A549 and MCF-7 targets,
several QSAR models were developed for the compound sets 1 and
2. The best models are presented below.
pIC50ðNB4;Set1Þ ¼ 5:111$MATS1mꢀ1:83$MATS5p
ꢀ2:47$HOMAþ14:1$E2uꢀ10:4$E2eþ4:27
(1)
R2 ¼ 0:86; RA2DJ ¼ 0:83; Q2 ¼ 0:75; Fð5; 29Þ ¼ 35:1; p < 10ꢀ5
pIC50ðA549; Set1Þ ¼ 0:968$ATS6e þ 1:55$MATS8m
þ 0:370$Mor05v ꢀ 0:484$Mor11p
þ 0:765$Mor20p þ 1:59
(2)
R2 ¼ 0:81; RA2DJ ¼ 0:78; Q2 ¼ 0:75; Fð5; 29Þ ¼ 25:3; p < 10ꢀ5
pIC50ðMCF ꢀ 7; Set 1Þ ¼ 0:0457$RDF050u ꢀ 0:119$RDF035p
ꢀ 0:620$Mor20m ꢀ 3:20$H7u
ꢀ 9:44$HATS2u þ 8:73
(3)
R2 ¼ 0:92; RA2DJ ¼ 0:90; Q2 ¼ 0:88; Fð5; 29Þ ¼ 64:8; p < 10ꢀ5
pIC50ðNB4; Set 2Þ ¼ ꢀ5:17$MATS2mþ5:25$MATS2eꢀ3:90$E3u
þ8:17$G2sꢀ1:29$R4vþ5:69
(4)
R2 ¼ 0:86; RA2DJ ¼ 0:82; Q2 ¼ 0:77; Fð5; 21Þ ¼ 24:8; p < 10ꢀ5
pIC50ðA549; Set 2Þ ¼ ꢀ25:0$X3Av þ 1:34$Mor16u
Fig. 3. Plot of experimentally determined versus predicted pIC50 values. Straight line
represents agreement between experimental and calculated values. The scaling of x-
and y-axes is the same for all subplots for a better comparison.
þ 7:19$G3u8:85$G3p ꢀ 0:140$Htv þ 7:97
(5)

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39
ranges are only 0.7 and 0.9 log units for Sets 1 and 2, respectively,
and this partly explains a lower QSAR model quality for A549
compared to others. It is interesting to investigate how well the
models are able to classify compounds as ‘actives’ and ‘inactives’.
For the numerous points in Fig. 3 corresponding to ‘inactives’ with
the experimental IC50 > 100
mM (pIC50 ¼ 4), QSAR models predict
pIC50 in the range from 3.76 to 4.25, i.e. the “true negatives” are
reasonably well predicted by the QSAR equations. There are only
two “false negatives” 3ei and 3fn (Set 1, NB4 cell line) with the
predicted pIC50 lower than 4.0 and the experimental activity
pIC50>¼4.2, a relatively small error. Thus, we show that the QSAR
models are able to distinguish between the active and inactive
compounds, and they can be useful for designing molecules with
improved antiproliferative properties.
5. Effect on cell cycle distribution and induction of apoptosis
Cytotoxic compounds are known to be capable of altering cell
cycle progression [17]. Via various molecular effects, cytotoxic
agents have an impact on a cell cycle arrest at G0/G1, S or G2/M
phases. These effects may also be followed by a programmed cell
death (apoptosis) [18].
In order to determine if cell growth inhibition was mediated by
the cell cycle arrest, a flow cytometrical cell cycle analysis was
performed. For this study, we selected the most efficacious and
selective compounds for each cell line: 3aa, 3gh, 5bb, 5ch, 5'dh,
6bd, 7a for the NB4 cells; 3 dl, 5bb, 5bi, 5 dm, 5'da for the A549
cells, and 3 dl, 3 ab, 5bb, 5bi, 5'dh,7a for the MCF-7 cells.
Cell cycle phase distributions were examined in the NB4, A549
and MCF-7 cells after a 48 h treatment with the selected com-
pounds. The cells were exposed to the compounds using the
average effective concentrations depending on IC50 values for each
cell line. Control cells were incubated with an appropriate amount
of solvent (DMSO).
Fig. 4. Cell cycle phase distribution in NB4 (a), A549 (b) and MCF-7 (c) cells after 48 h
treatment with selected compounds. Values are mean of two independent experi-
ments (n ¼ 2). SDs (not indicated) were less than 10%. The compound concentrations
in (a) and (c) are 10
mM; in (b), “High” and “low” in (b) refer to 30 and 20 mM con-
centration, respectively.
Cell cycle distribution data indicated high sub-G1 peaks and cell
death after treating the NB4 cells using 10
compounds. For this reason, it was difficult to evaluate the specific
cell cycle arrest phases. Therefore the experiment was conducted
using a lower concentration of the compounds (5
shows that the chosen compounds arrested the NB4 cells in the S
(3aa, 5bb, 5ch, 7a), G0/G1 (3gh), or G2/M cell cycle phase (5'dh and
6bd).
mM concentration of
Previously, it has been demonstrated that the NB4 cell cycle
arrest in the G0/G1 phase may be accompanied by a granulocytic
differentiation [19]. Therefore, the effect of the compound 3gh on
the acute promyelocytic leukemia (APL) NB4 cell granulocytic dif-
ferentiation induced by all-trans retinoic acid (RA) was also eval-
uated (results presented in Section 6). In contrast to 3gh, other
tested compounds displayed an obvious pro-apoptotic effect on the
NB4 cells. The most potent apoptosis inducing agents at early time
mM). Fig. 4a
A treatment of the A549 cells using 20 mM concentration of the
compounds did not have a marked effect on the cell cycle phase
distribution (Fig. 4b). Only a slight increase in the G2/M phase
accumulation was observed after the treatment with 3 dl, 5bb, 5bi
and 5 dm. Using a larger 30 mM concentration had a more notice-
able impact on the cell cycle phase distribution. The compounds
points were 3aa, 5bb, 5ch (24 h treatment using 5 mM concentra-
tion caused death of >50% of the cell population). This effect is
comparable to the effect of other drugs already used for leukemia
therapy. Recently we demonstrated that a treatment of the NB4
cells with histone deacetylase inhibitor Belinostat caused around
20% of the cell population to undergo apoptosis [19c]. Additionally,
it has been reported that after a treatment with chemotherapeutic
drugs As2O3 and Doxorubicin nearly 27% and 80% of the NB4 cells
were dead, respectively [20].
The most prominent apoptotic effect in the A549 cells was
detected upon treatment with agents 3 dl, 5bb and 5bi using low
and high concentrations (Fig. 5b). Compound 7a (Fig. 5c) had the
most pronounced effect on apoptosis induction as well as the
strongest effect on the MCF-7 cell cycle arrest in the G2/M and S
phases. This tendency of the strong apoptotic effect of compounds
arresting the cell cycle in S phase was evident in the NB4 and A549
cell lines as well.
3 dl, 5bb, 5bi only slightly arrested cells in the G2/M and S phases at
20
accumulate in the S phase at 30
Similar to the other cell lines, MCF-7 cell cycle was also arrested
in the S and G2/M phases after a treatment with 10 M concen-
mM concentration, but had a pronounced potency to force cells
mM.
m
tration of the agent (Fig. 4c). The accumulation in the S and the G2/
M phases was the most evident for the compounds 3 ab and 7a.
Annexin V binding assay was performed for the elucidation of
apoptosis as described in the Experimental section. The apoptotic
effect was studied using the following concentrations of the
selected compounds: 5
mM for the NB4 cell line (Fig. 5a), 20
mM and
30 M for the A549 cell line (Fig. 5b), and 10
m
mM for the MCF-7 cell
line (Fig. 5c). The percentage of the apoptotic cancer cells was
measured after 24 and 48 h of treatment.
Notably, 3gh did not induce apoptosis of the leukemia NB4 cells,
even though it was the most active in arresting NB4 cell cycle in the
G0/G1 cycle phase.
There is some evidence that G2/M arrest may enhance apoptotic
cancer cell death [21]. Therefore, combination therapies with drugs,
capable of arresting cells in the G2/M or S cell cycle phase may
suggest more potent therapy strategies.

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40
6. The effect of compound 3gh on the promyelocytic
leukemia cell line NB4 proliferation and the granulocytic
differentiation
The effect of the compound 3gh on leukemia cell granulocytic
differentiation in the APL cell line NB4 is shown in Fig. 6. 1
concentration of 3gh was chosen due to its low IC50 value
(0.6 0.02 M) against the NB4 cell line (Table 4), and also
mM
m
considering the fact that 3gh effectively arrests the NB4 cell growth
in the G0/G1 cell cycle phase (Fig. 4a). To determine the impact on
the leukemia cell differentiation, the NB4 cells were treated with
1
m
M 3gh alone and combined with RA (1
RA is a known granulocytic differentiation inducer and is used to
m
M 3gh þ 1
mM RA).
treat acute promyelocytic leukemia together with other anti-cancer
drugs. It was shown that a treatment of APL leukemic cells with RA
causes them to differentiate into mature granulocytes [22]. The
differentiation therapy is less aggressive treatment compared to
other treatment strategies, such as chemotherapy. However, resis-
tance to the RA cytodifferentiation effects is frequently acquired
[23]; therefore, RA treatment in combination with other drugs that
are capable to resensitize RA-resistant APL cells or drugs that may
strengthen RA's pro-differentiation effect might be beneficial.
Fig. 6 shows that 1 mM of 3gh partly inhibits the NB4 cell pro-
liferation. However, this effect is less pronounced compared to the
treatment using either RA alone or RA combined with 3gh. The
highest drop in the cell viability was detected upon 96 h treatment
with 3gh as a single agent. The effect of the used compounds on the
cell cycle distribution was also evaluated (data not shown). 1 mM
3gh as a single agent had only a negligible impact on the cell cycle
arrest in the G0/G1 phase. However, RA alone or the RA þ 3gh
combination effectively arrested the NB4 cell cycle in G0/G1 phase
after 24 h treatment (the resulting accumulation in the G0/G1 cell
cycle phase was 17.3% and 18.2%, respectively).
Fig. 5. Percent of apoptotic NB4 (a), A549 (b) and MCF-7 (c) cells after 24 h and 48 h
treatment with selected compounds. Values are mean of two independent experi-
ments (n ¼ 2). SDs (not indicated) were less than 10%.
Fig. 6. Cell growth (a) and cell viability (b) of the control NB4 cells and the NB4 cells treated with 1
points, aliquots of the cultures were subjected to 0.2% trypan blue staining. Results are shown as mean SD (n ¼ 3).
m
M 3gh, 1
m
M RA and with 1
m
M 3gh þ 1
mM RA. At each of the indicated time

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41
NBT and CD11b tests (see Experimental section) revealed that
8. Experimental
3gh alone was not sufficient to induce the NB4 cell differentiation
into mature granulocytes (Fig. 7). However, 3gh in combination
with RA enhanced and accelerated the RA induced granulocytic
differentiation up to 8% in comparison with RA alone (Fig. 7). It
should be emphasized that it is a common practice in leukemia
differentiation therapy to use drugs that are incapable of inducing
differentiation alone. However, when used in combination with RA
they effectively promote and accelerate the APL granulocytic dif-
ferentiation. Previously our group demonstrated that histone
deacetylase inhibitor Belinostat did not induce the APL granulocytic
differentiation when used as a single agent, but it enhanced the
NB4 cell differentiation to the mature granulocytes by 13% in
combination with RA [19c]. The same activity pattern was also
shown for histone methyltransferase 2 inhibitor Bix-01294, which
promoted granulocytic differentiation by 10% [18b].
8.1. Biology
8.1.1. Cell lines, culture and plating
Human acute promyelocytic leukemia cells NB4, lung cancer cell
line A549 and breast cancer cells MCF-7 were used in this study.
NB4 cells were maintained in RPMI 1640 þ GlutaMAX medium
supplemented with 10% fetal bovine serum, 100 U/ml penicillin and
100 mg/ml streptomycin (Gibco, Grand Island, NY, USA) in a hu-
midified incubator at 37 ꢁC with 5% CO2. A549 and MCF-7 cells were
cultivated at the same conditions in DMEM þ GlutaMAX medium
(Gibco, Grand Island, NY, USA) with indicated supplements. For
chemosensitivity testing, exponentially growing cells were seeded
to 96 well plates at a density of 1.5∙104 (NB4) and 1.0 104 (A549 and
MCF-7) cells per well. For cell cycle and apoptosis analysis cells
were seeded in 6 well plates at a density of 1∙106 (NB4) and
0.45∙106 (A549 and MCF-7) cells per well. For evaluation of 3gh
effect on cell proliferation and viability, logarithmically growing
NB4 cells were seeded at a density of 0.5 ꢂ 106 cells/ml in 5 ml of
RPMI medium.
7. Conclusions
A series of a,b-unsaturated ketones with various a- and b-sub-
stituents were synthesized, and their in vitro antiproliferative ac-
tivities and selectivities against human hematological and solid
cancer cell lines were examined. (E)-1-(4-Methoxyphenyl)-4-
methyl-2-(4-nitrobenzylidene)pentan-1-one 3gh was found to be
the most potent and selective agent towards the NB4 hematological
cell line; it was shown that this compound did not induce apoptosis
but blocked cell cycle in the G0/G1 phase. It was also demonstrated
that the anti-NB4 activity of 3gh may be associated with a pro-
motion of leukemia cells to differentiation. Compounds 3 ab, 3 dl,
7a and 7c exhibited marked growth inhibition of the NB4 and MCF-
7 cancer cells with a marked apoptotic effect.
Using QSAR computational techniques, we have successfully
developed and validated models that provide foundation for the
design of new molecules with improved cancer cell growth inhib-
itory activities.
Our results revealed a set of compounds-promising candidates
for further biological evaluations.
8.1.2. Chemosensitivity testing
Compounds were dissolved in DMSO at 200 times the final
maximum concentration used in the test. For negative control, cells
were treated with an equivalent concentration of DMSO (0.5% v/v).
Each agent was tested in triplicate at different concentrations in the
range of 0.1e100 mM. For adherent cells (A549 and MCF-7) drug
treatment was started 24 h after plating, whereas NB4 cells were
treated shortly after plating. Cells were incubated with drugs for
48 h, then XTT reagent (Sigma, St. Louis, USA) was added to the
medium (20% of the culture medium volume) and cells were
further incubated for 2 h. The absorbance of each well was
measured at 450 nm and 690 nm (for background evaluation) using
Infinite M200 PRO (Tecan, Mannedorf, Switzerland). Measurements
were corrected for background by subtracting 690 nm value from
the 450 nm value. Data was expressed as GI50 values with SE.
Fig. 7. Effects of 3gh, RA and their combined treatment on NB4 cell granulocytic differentiation. Control and NB4 cells treated with 1
m
M 3gh, 1
m
M RA and with 1
m
M 3gh þ 1
mM RA
were subjected to granulocytic differentiation analysis, using NBT test (at 24e96 h time points; a) and CD11b assay (at 48 h; b). NBT test results are given as mean ( SD, n ¼ 3),
whereas CD11b assay results are representative of two independent experiments.

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42
8.1.3. NB4 cell proliferation, viability and differentiation assays
NB4 cells were exposed to 1 M RA (Sigma, St. Louis, USA), 1
3gh alone or in combination with 1 M RA for 24, 48, 72 and 96 h.
the unstable compounds 7b, 7d, 7e and 7g are presented in sup-
porting information.
m
mM
m
Cell proliferation was evaluated using the trypan blue exclusion
test. Viable and dead (blue colored) cell count was determined
using a hematocytometer. The degree of granulocytic NB4 cell
differentiation was evaluated by cells' ability to reduce soluble nitro
blue tetrazolium (NBT) to insoluble blue-black formazan after
stimulation with phorbolmyristate acetate (PMA). NBT stained cells
were counted in 5 consecutive non-overlapping microscopic fields
at a magnification of 400. The average percent of NBT positive cells
per high power field was calculated. Three independent experi-
ments were performed and their results were averaged.
8.2.4.1. (E)-3-(2-Fluorophenyl)-2-(4-methoxybenzoyl)allyl
(3ba). Yellowish oil. Yield 34%. IR (KBr): nmax ¼ 1737, 1650 (C]O)
cmꢀ1. 1H NMR (400 MHz, CDCl3)
: 1.98 (3H, s, OCOCH3), 3.87 (3H, s,
acetate
d
3
OCH3), 5.07 (2H, s, CH2OCOMe), 6.97 (2H, d, 6.18 JH,H ¼ 9.2 Hz,
3
ArH), 7.07e7.12 (1H, m, ArH), 7.19 (1H, td, JH,H ¼ 7.6 Hz,
4JH,H ¼ 0.8 Hz, ArH), 7.27 (1H, s, ¼CH), 7.33e7.43 (2H, m, ArH), 7.89
(2H, d, 3JH,H ¼ 8.8 Hz, ArH) ppm. 13C NMR (100 MHz, CDCl3)
d: 20.67,
21.4 Hz), 122.32 (d,
2
55.43, 60.46, 113.69, 115.68 (d, JC,F
¼
3
2JC,F ¼ 14.0 Hz), 124.21 (d, JC,F ¼ 3.7 Hz), 129.76, 130.20 (d,
4
3JC,F ¼ 2.4 Hz), 131.02 (d, JC,F ¼ 8.4 Hz), 132.15, 134.62 (d,
1
3JC,F ¼ 3.6 Hz), 137.26, 160.20 (d, JC,F ¼ 248.3 Hz), 163.42, 170.57,
8.1.4. Flow cytometric analysis of the cell cycle distribution,
apoptosis and CD11b surface biomarker
195.06 ppm. HRMS (ES): M þ Naþ, found 351.1007. C19H17FNaO4
requires 351.1003.
Cell cycle distribution and assessment of apoptosis and CD11b
surface marker of treated cells was analysed as described by
Savickiene et al. (2014) [19c].
8.2.4.2. (E)-4-Ethyl-2-(4-methoxybenzoyl)hex-2-en-1-yl
acetate
(3be). Yellowish oil. Yield 22%. IR (KBr): nmax ¼ 1737, 1647 (C]O)
cmꢀ1
.
1H NMR (400 MHz, CDCl3)
d:
0.88 (6H, t,
8.2. Chemistry
3JH,H ¼ 7.6 Hz,CH(CH2CH3)2), 1.21e1.32 (2H, m, CH2CH3), 1.48e1.59
(2H, m, CH2CH3), 2.00 (3H, s, OCOCH3), 2.38e2.48 (1H, m,
CH(CH2CH3)2), 3.85 (3H, s, OCH3), 4.97 (2H, s, CH2OCOMe), 6.07
8.2.1. General information
3
IR spectra were run in KBr discs on a PerkineElmer FT spec-
trophotometer Spectrum BX II. 1H and 13C NMR spectra were
recorded with a Varian Unity INOVA spectrometer (300 MHz) or
Brucker (400 MHz) in chloroform-d, using residual solvent signal as
internal standard. HRMS spectra were obtained on a mass spec-
trometer Dual-ESI Q-TOF 6520 (Agilent Technologies). All reactions
and the purity of the synthesized compounds were monitored by
TLC using Silica gel 60 F254 aluminium plates (Merck). Visualization
was accomplished by UV light. Final purification of synthesized
compounds was performed on Flash Chromatography system
CombiFlash (Teledyne Isco), using hexane e ethyl acetate mixtures.
Starting alkyne 1a was prepared according to literature proce-
dure [24] and alkynes 1b-i were prepared via Sonogashira coupling
reaction as described in our previously published protocol [9b].
(1H, d, 3JH,H ¼ 10.8 Hz, ¼CH), 6.93 (2H, d, JH,H ¼ 8.8 Hz, ArH) 7.73
(2H, d, 3JH,H ¼ 8.8 Hz, ArH) ppm. 13C NMR (100 MHz, CDCl3)
d: 11.92,
20.85, 27.66, 42.63, 55.40, 59.32, 113.45, 130.35, 131.81, 135.53,
152.29, 162.92, 170.85, 195.69 ppm. HRMS (ES): M þ Naþ, found
327.1571. C18H24NaO4 requires 327.1567.
8.2.4.3. (E)-3-Cyclohexyl-2-(4-methoxybenzoyl)allyl acetate (3bf).
Colorless oil. Yield 37%. IR (KBr): nmax ¼ 1738, 1650 (C]O) cmꢀ1. 1H
NMR (400 MHz, CDCl3) d: 1.07e1.19 (3H, m, cHex), 1.27e1.38 (2H,
m, cHex), 1.65e1.74 (5H, m, cHex), 1.99 (3H, s, OCOCH3), 2.49e2.59
(1H, m, cHex), 3.84 (3H, s, OCH3), 4.97 (2H, s, CH2OCOMe), 6.18 (1H,
d, 3JH,H ¼ 10.0 Hz, ¼CH), 6.90 (2H, d, 3JH,H ¼ 8.8 Hz, ArH), 7.70 (2H, d,
3JH,H ¼ 8.8 Hz, ArH) ppm. 13C NMR (100 MHz, CDCl3)
d: 20.80, 25.20,
25.59, 32.24, 38.05, 55.34, 59.24, 113.40, 130.30, 131.86, 133.00,
152.61, 162.91, 170.82, 195.73 ppm. HRMS (ES): M þ Naþ, found
339.1576. C19H24NaO4 requires 339.1567.
8.2.2. General method for the preparation of compounds 3e6
To a stirred solution of alkyne 1 (0.5 mmol) and aldehyde 2
(0.5 mmol) in dry dichloromethane (3 mL), boron trifluoride diethyl
etherate (0.071 g, 0.065 mL, 0.5 mmol) was added. Stirring was
continued at room temperature till the reaction was completed
(monitored by TLC). The mixture was then quenched with sodium
bicarbonate solution, and the organic layer was separated, washed
with water (2*20 mL) and dried over anhydrous Na2SO4. After
evaporation of the solvent under reduced pressure, the residue was
purified by Flash Column chromatography eluting with hex-
aneeethyl acetate mixtures.
8.2.4.4. (E)-4-Ethyl-2-(4-methoxybenzoyl)hex-2-en-1-yl
benzoate
(3de). Yellowish oil. Yield 4%. IR (KBr): nmax ¼ 1717, 1647 (C]O)
cmꢀ1
.
1H NMR (400 MHz, CDCl3)
d:
0.89 (6H, t,
3JH,H ¼ 7.6 Hz,CH(CH2CH3)2), 1.26e1.34 (2H, m, CH2CH3), 1.52e1.58
(2H, m, CH2CH3), 2.50e2.59 (1H, m, CH(CH2CH3)2), 3.87 (3H, s,
3
OCH3), 5.24 (2H, s, CH2OCOMe), 6.13 (1H, d, JH,H ¼ 10.4 Hz, ¼CH),
6.94 (2H, d, 3JH,H ¼ 8.8 Hz, ArH), 7.38 (2H, t, 3JH,H ¼ 7.2 Hz, ArH), 7.52
3
3
(1H, t, JH,H ¼ 7.2 Hz, ArH), 7.78 (2H, d, JH,H ¼ 8.8 Hz, ArH),
7.96e7.98 (2H, m, ArH) ppm. 13C NMR (100 MHz, CDCl3)
d: 11.99,
27.72, 42.71, 55.45, 59.86, 113.54, 128.28, 129.61, 130.07, 130.50,
131.87, 132.87, 135.64, 152.27, 162.98, 166.34, 195.80 ppm. HRMS
(ES): M þ Naþ, found 389.1730. C23H26NaO4 requires 389.1723.
8.2.3. General method for the preparation of compounds 7
A solution of the MBH adduct 5bb or 5bh (0.14 mmol) and
appropriate amine (0.168 mmol) in dimethylformamide (2 mL) was
stirred at room temperature till the reaction was completed
(monitored by TLC). The mixture was then quenched with ethyl
acetate (10 mL), and the organic solution was washed with water
(2 x 20 mL) and dried over anhydrous Na2SO4. After evaporation of
the solvent under reduced pressure, the residue was purified by
Flash Column chromatography eluting with hexaneeethyl acetate
mixtures.
8.2.4.5. (E)-3-Cyclohexyl-2-(4-methoxybenzoyl)allyl benzoate (3df).
Yellowish oil. Yield 8%. IR (KBr): nmax ¼ 1717, 1646 (C]O) cmꢀ1. 1H
NMR (400 MHz, CDCl3) d: 1.14e1.20 (3H, m, cHex), 1.29e1.35 (2H,
m, cHex), 1.66e1.75 (5H, m, cHex), 2.61e2.71 (1H, m, cHex), 3.86
(3H, s, OCH3), 5.24 (2H, s, CH2OCOPh), 6.24 (1H, d,
3
3JH,H ¼ 10.0 Hz, ¼CH), 6.93 (2H, d, JH,H ¼ 7.6 Hz, ArH), 7.39 (2H, t,
3
3JH,H ¼ 8.8 Hz, ArH), 7.52 (1H, t, JH,H ¼ 7.6 Hz, ArH), 7.76 (2H, d,
3JH,H ¼ 8.8 Hz, ArH), 7.97 (2H, d, 3JH,H ¼ 7.6 Hz, ArH) ppm. 13C NMR
8.2.4. Spectral and physical data of compounds 3e7
(100 MHz, CDCl3) d: 25.25, 25.64, 32.35, 38.20, 55.43, 59.82, 113.49,
Compounds 3 ab, 4 ab, 6ac, 5bb, 5bh, 5bi, 5ch, 5cj, 5 db, 5dh,
5di, 5 dl and 5 dm [9a] and compounds 3aa, 3eb, 4aa and 5'dh [9b]
have been described in our previous publications. The NMR data of
128.28, 129.58, 130.05, 130.43, 131.96, 132.89, 133.12, 152.71, 162.97,
166.40, 195.93 ppm. HRMS (ES): M þ Naþ, found 401.1730.
C24H26NaO4 requires 401.1723.

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I. Karpaviciene et al. / European Journal of Medicinal Chemistry 98 (2015) 30e48
43
3
8.2.4.6. (E)-2-Benzoylbut-2-en-1-yl benzoate (3dk). Colorless oil.
OCH3), 4.26 (2H, t, JH,H ¼ 6.6 Hz, CH2OCOMe), 6.94e7.00 (2H, m,
ArH), 7.12 (1H, s, ¼CH), 7.56e7.62 (2H, m, ArH), 7.81e7.87 (2H, m,
Yield 22%. IR (KBr): nmax ¼ 1715, 1644 (C]O) cmꢀ1
.
1H NMR
3
(400 MHz, CDCl3)
d
: 2.05 (3H, d, JH,H ¼ 7.2 Hz, CH3), 3.85 (3H, s,
ArH), 8.22e8.28 (2H, m, ArH) ppm. 13C NMR (100 MHz, CDCl3)
d:
3
OCH3), 5.26 (2H, s, CH2OCOPh), 6.54 (1H, q, JH,H ¼ 7.2 Hz, ¼CH),
20.76, 27.94, 55.53, 62.39, 113.78, 123.84, 129.69, 129.76, 132.16,
137.54, 140.88, 141.84, 147.35, 163.49, 170.68, 196.39 ppm. HRMS
(ESIþ): M þ Naþ, found 392.1105. C20H19NNaO6 requires 392.1107.
6.92 (2H, d, 3JH,H ¼ 8.8 Hz, ArH), 7.39 (2H, t, 3JH,H ¼ 7.6 Hz, ArH), 7.52
3
3
(1H, t, JH,H ¼ 7.6 Hz, ArH), 7.75 (2H, d, JH,H ¼ 8.8 Hz, ArH),
7.97e7.99 (2H, m, ArH) ppm. 13C NMR (100 MHz, CDCl3)
d: 14.63,
55.43, 59.28, 113.49, 129.62, 129.98, 130.35, 131.86, 132.92, 136.56,
142.72, 162.95, 166.43, 195.59 ppm. HRMS (ES): M þ Naþ, found
333.1100. C19H18NaO4 requires 333.1097.
8.2.4.12. (E)-3-(4-Methoxybenzoyl)-4-(2,3,4,5,6-pentafluorophenyl)
but-3-enyl acetate (3ei). Yellowish oil. Yield 21%. IR (KBr):
nmax ¼ 1654, 1741 (C]O) cmꢀ1. 1H NMR (400 MHz, CDCl3)
d: 1.89
(3H, s, OCOCH3), 2.80 (2H, m, ¼CCH2), 3.91 (3H, s, OCH3), 4.17 (2H, t,
8.2.4.7. (E)-3-(2-Chlorophenyl)-2-(4-methoxybenzoyl)allyl benzoate
3JH,H ¼ 6.4 Hz, CH2OCOMe), 6.62 (1H, m, ¼CH), 6.97e7.04 (2H, m,
(3 dl). Colorless solid m. p. ¼ 94e96 ꢁC. Yield 33%. IR (KBr):
ArH), 7.89e7.95 (2H, m, AreH) ppm. 13C NMR (100 MHz, CDCl3)
d:
nmax ¼ 1715, 1651 (C]O) cmꢀ1. 1H NMR (400 MHz, CDCl3)
d
: 3.88
20.53, 29.50, 55.51, 61.74, 110.14 (m), 113.82, 122.05, 129.15, 132.26,
136.45 (m), 138.97 (m), 139.74 (m), 142.34 (m), 144.85 (m), 145.59,
163.77, 170.56,195.08 ppm. HRMS (ESIþ): M þ Naþ, found 437.0783.
4
(3H, s, OCH3), 5.29 (2H, d, JH,H ¼ 0.8 Hz, CH2OCOPh), 6.99 (2H, d,
3JH,H ¼ 8.8 Hz, ArH), 7.29e7.32 (2H, m, ArH), 7.33e7.38 (3H, m,
ArH, ¼CH), 7.42e7.46 (2H, m, ArH), 7.50 (1H, t, 3JH,H ¼ 7.6 Hz, ArH),
C20H15F5NaO4 requires 437.0790.
3
7.88e7.90 (2H, m, ArH), 8.01 (2H, d, JH,H ¼ 9.2 Hz, ArH) ppm. 13
C
NMR (100 MHz, CDCl3)
d: 55.46, 60.78, 113.76, 126.90, 128.24,
8.2.4.13. (E)-4-(2-Chlorophenyl)-3-(4-methoxybenzoyl)but-3-enyl
129.56, 129.65, 129.73, 129.76, 130.18, 130.21, 132.28, 132.92, 133.11,
133.94, 136.94, 138.68, 163.53, 166.03, 195.14 ppm. HRMS (ES):
M þ Naþ, found 429.0859. C24H19ClNaO4 requires 429.0864.
acetate (3el). Yellow oil. Yield 55%. IR (KBr): nmax ¼ 1645, 1739 (C]
O) cmꢀ1 1H NMR (400 MHz, CDCl3)
. d: 1.92 (3H, s, OCOCH3), 2.96
3
(2H, t, JH,H ¼ 6.5 Hz, ¼CCH2), 3.89 (3H, s, OCH3), 4.19 (2H, t,
3JH,H ¼ 6.5 Hz, CH2OCOMe), 6.96e7.01 (2H, m, ArH), 7.19 (1H,
s, ¼CH), 7.28e7.35 (2H, m, ArH), 7.40e7.47 (2H, m, ArH), 7.93e7.99
8.2.4.8. (E)-4-(2-Fluorophenyl)-3-(4-methoxybenzoyl)but-3-enyl ac-
etate (3ea). Bright yellow oil. Yield 50%. IR (KBr): nmax ¼ 1650,
(2H, m, ArH) ppm. 13C NMR (100 MHz, CDCl3)
d: 20.80, 27.53, 55.50,
1738(C]O) cmꢀ1
.
1H NMR (400 MHz, CDCl3)
d: 1.92 (3H, s,
62.55, 113.65, 126.80, 129.61, 130.01, 130.06, 132.30, 132.56, 133.82,
134.17, 137.77, 139.17, 163.35, 170.76, 196.84 ppm. HRMS (ESIþ):
M þ Naþ, found 381.0864. C20H19ClNaO4 requires 381.0868.
OCOCH3), 3.01 (2H, t, 3JH,H ¼ 6.6 Hz, ¼CCH2), 3.87 (3H, s, OCH3), 4.25
3
(2H, t, JH,H ¼ 6.6 Hz, CH2OCOMe), 6.94e7.00 (2H, m, ArH),
7.07e7.24 (3H, m, ¼CH, ArH), 7.30e7.38 (1H, m, ArH), 7.43e7.51
(1H, m, ArH), 7.86e7.91 (2H, m, ArH) ppm. 13C NMR (100 MHz,
8.2.4.14. (E)-4-(4-Chlorophenyl)-3-(4-methoxybenzoyl)but-3-enyl
CDCl3)
d
20.62, 27.82, 55.34, 62.43, 113.49, 115.59 (d, 2JC,F ¼ 21.7 Hz),
acetate (3en). Yellow solid; m.p. ¼ 64e65 ꢁC. Yield 25%. IR (KBr):
2
3
123.12 (d, JC,F ¼ 14.3 Hz), 124.03 (d, JC,F ¼ 3.6 Hz), 129.87 (d,
nmax ¼ 1643, 1739 (C]O) cmꢀ1. 1H NMR (400 MHz, CDCl3)
d: 1.97
3JC,F ¼ 2.8 Hz), 129.99, 130.23 (d, JC,F ¼ 8.3 Hz), 132.08, 133.40 (d,
(3H, s, OCOCH3), 3.08 (2H, t, JH,H ¼ 6.7 Hz, ¼CCH2), 3.90 (3H, s,
4
3
3JC,F ¼ 3.2 Hz), 139.59, 159.97 (d, JC,F ¼ 247.1 Hz), 163.13, 170.65,
OCH3), 4.29 (2H, t, JH,H ¼ 6.7 Hz, CH2OCOMe), 6.95e7.01 (2H, m,
1
3
196.65 ppm. HRMS (ESIþ): M þ Naþ, found 365.1160. C20H19FNaO4
ArH), 7.11 (1H, s, ¼CH), 7.36e7.43 (4H, m, ArH), 7.81e7.85 (2H, m,
requires 365.1166.
ArH) ppm. 13C NMR (100 MHz, CDCl3)
d: 20.83, 27.66, 55.50, 62.66,
113.64, 128.90, 130.33, 130.35, 132.09, 133.67, 134.58, 138.24, 139.90,
8.2.4.9. (E)-5-Ethyl-3-(4-methoxybenzoyl)hept-3-enyl acetate (3ee).
163.16, 170.84, 197.08 ppm. HRMS (ESIþ): M þ Naþ, found 381.0864.
Bright yellow oil. Yield 21%. IR (KBr): nmax ¼ 1639, 1736 (C]O)
C20H19ClNaO4 requires 381.0864.
3
cmꢀ1
.
1H NMR (400 MHz, CDCl3)
d
: 0.92 (6H, t, JH,H ¼ 7.5 Hz,
CH(CH2CH3)2), 1.22e1.35 (2H, m, CH(CH2CH3)2), 1.48e1.61 (2H, m,
8.2.4.15. (E)-5-(2,4-Dichlorophenyl)-4-(4-methoxybenzoyl)pent-4-
CH(CH2CH3)2), 1.98 (3H, s, OCOCH3), 2.40 (1H, m, CH(CH2CH3)2),
en-2-yl acetate (3 fb). Yellowish oil. Yield 70%. IR (KBr):
3
2.86 (2H, t, JH,H ¼ 6.9 Hz, ¼CCH2), 3.87 (3H, s, OCH3), 4.18 (2H, t,
nmax ¼ 1650, 1738 (C]O) cmꢀ1. 1H NMR (400 MHz, CDCl3)
d: 1.18
3
3JH,H ¼ 6.9 Hz, CH2OCOMe), 5.97 (1H, d, JH,H ¼ 10.4 Hz, ¼CH),
(3H, d, 3JH,H ¼ 6.2 Hz, CH2CHCH3), 1.80 (3H, s, OCOCH3), 2.88 (2H, d,
6.91e6.97 (2H, m, ArH), 7.66e7.74 (2H, m, ArH) ppm. 13C NMR
3JH,H
¼ 6.5 Hz, ¼CCH2), 3.87 (3H, s, OCH3), 5.02 (1H, tq,
(100 MHz, CDCl3)
d:12.02, 20.93, 26.99, 27.73, 42.45, 55.43, 63.26,
3JH,H ¼ 6.5 Hz, 3JH,H ¼ 6.2 Hz, CH2CHCH3), 6.94e6.99 (2H, m, ArH),
7.04 (1H, s, ¼CH), 7.31 (1H, dd, 3JH,H ¼ 8.31 Hz, 4JH,H ¼ 1.96 Hz, ArH),
7.38 (1H, d, 3JH,H ¼ 8.31 Hz, ArH), 7.45 (1H, d, 4JH,H ¼ 2.08 Hz, ArH),
113.40, 130.92, 131.78, 136.90, 150.33, 162.71, 170.97, 197.32 ppm.
HRMS (ESIþ): M þ Naþ, found 341.1723. C19H26NaO4 requires
341.1723.
7.90e7.95 (2H, m, ArH) ppm. 13C NMR (100 MHz, CDCl3)
d: 20.26,
21.04, 34.12, 55.47, 69.64, 113.69, 127.18, 129.49, 129.54, 130.83,
132.28, 132.87, 134.62, 134.66, 135.67, 140.02, 163.40, 170.14,
8.2.4.10. (E)-4-Cyclohexyl-3-(4-methoxybenzoyl)but-3-enyl acetate
(3ef). Bright yellow oil. Yield 40%. IR (KBr): nmax ¼ 1640, 1736 (C]
196.25 ppm. HRMS (ESIþ):
M
þ
Naþ, found 429.0631.
O) cmꢀ1. 1H NMR (400 MHz, CDCl3)
d
: 1.07e1.79 (11H, m, cHex) 1.98
C21H20Cl2NaO4 requires 429.0632.
3
(3H, s, OCOCH3), 2.83 (2H, t, JH,H ¼ 6.7 Hz, ¼CCH2), 3.85 (3H, s,
3
OCH3), 4.17 (2H, t, JH,H ¼ 6.7 Hz, CH2OCOMe), 6.09 (1H, d,
8.2.4.16. (E)-5-Cyclohexyl-4-(4-methoxybenzoyl)pent-4-en-2-yl ace-
3JH,H ¼ 10.0 Hz, ¼CH), 6.89e6.93 (2H, m, ArH), 7.65e7.69 (2H, m,
tate (3ff). Yellowish oil. Yield 30%. IR (KBr): nmax ¼ 1644, 1736 (C]
ArH) ppm. 13C NMR (100 MHz, CDCl3)
d: 20.87, 25.42, 25.74, 26.82,
O) cmꢀ1
.
1H NMR (400 MHz, CDCl3)
d
: 1.06e1.81 (10H, m, cHex),
3
32.40, 38.12, 55.38, 63.46, 113.34, 130.90, 131.83, 134.33, 151.08,
1.26 (3H, d, JH,H ¼ 6.2 Hz, CH2CHCH3), 1.88 (3H, s, OCOCH3)
2.45e2.57 (1H, m, ¼CHCH), 2.81 (2H, d, 3JH,H ¼ 6.2 Hz, ¼CCH2), 3.87
(3H, s, OCH3), 5.03 (1H, sext, 3JH,H ¼ 6.2 Hz, CH2CHCH3) 6.04 (1H, d,
3JH,H ¼ 10.0 Hz, ¼CH) 6.90e6.95 (2H, m, ArH), 7.67e7.73 (2H, m,
162.68, 170.89, 197.45 ppm. HRMS (ESIþ): M þ Naþ, found 353.1723.
C
20H26NaO4 requires 353.1718.
8.2.4.11. (E)-3-(4-Methoxybenzoyl)-4-(4-nitrophenyl)but-3-enyl ac-
ArH) ppm. 13C NMR (100 MHz, CDCl3)
d: 20.20, 21.23, 25.43, 25.48,
etate (3eh). Brownish solid; m.p. ¼ 121e122 ꢁC. Yield 53%. IR (KBr):
25.78, 32.27, 32.39, 33.21, 38.14, 55.41, 70.56, 113.37, 130.71, 131.94,
134.53, 150.30, 162.70, 170.49, 197.37 ppm. HRMS (ESIþ): M þ Naþ,
found 367.1880. C21H28NaO4 requires 367.1882.
nmax ¼ 1636, 1734 (C]O) cmꢀ1. 1H NMR (400 MHz, CDCl3)
d: 1.94
3
(3H, s, OCOCH3), 3.05 (2H, t, JH,H ¼ 6.6 Hz, ¼CCH2), 3.88 (3H, s,

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44
8.2.4.17. (E)-4-(4-Methoxybenzoyl)-5-(2,3,4,5,6-pentafluorophenyl)
pent-4-en-2-yl acetate (3fi). Greenish oil. Yield 8%. IR (KBr):
IR (KBr): nmax ¼ 1647 (C]O) cmꢀ1
. d:
1H NMR (400 MHz, CDCl3)
0.92 (6H, d, 3JH,H ¼ 6.4 Hz, CH(CH3)2), 1.86 (1H, sept, 3JH,H ¼ 6.8 Hz,
CH(CH3)2), 2.63 (2H, d, 3JH,H ¼ 6.8 Hz, CH2), 3.87 (3H, s, OCH3), 6.97
nmax ¼ 1651, 1738 cm-1. 1H NMR (400 MHz, CDCl3)
d: 1.20 (3H, d,
3
J ¼ 6.4 Hz, CH2CHCH3), 1.77 (3H, s, OCOCH3), 2.72 (1H, dd,
2JH,H ¼ 14.1 Hz, 3JH,H ¼ 8.4 Hz, ¼CCH2), 2.76 (1H, dd, 2JH,H ¼ 14.1 Hz,
3JH,H ¼ 4.4 Hz, ¼CCH2), 3.90 (3H, s, OCH3), 5.01 (1H, dqd,
(2H, d, JH,H ¼ 9.2 Hz, ArH), 7.01 (1H, br. s, ¼CH), 7.47 (2H, d,
3
3JH,H ¼ 8.4 Hz, ArH), 7.64 (2H, d, JH,H ¼ 8.4 Hz, ArH), 7.91 (2H, d,
3JH,H ¼ 8.8 Hz, ArH) ppm. 13C NMR (100 MHz, CDCl3)
d: 22.73, 28.08,
3
3
1
3
3JH,H ¼ 8.4 Hz, JH,H ¼ 6.4 Hz, JH,H ¼ 4.4 Hz, CH2CHCH3), 6.59 (1H,
36.90, 55.38, 113.63, 123.99 (q, JC-F ¼ 270.5 Hz), 125.31 (q, JC-
s, ¼CH), 6.96e7.02 (2H, m, ArH), 7.88e7.93 (2H, m, ArH) ppm. 13
C
¼ 3.8 Hz), 129.18, 129.73 (q, 2JC-F ¼ 32.4 Hz), 130.02, 132.13, 136.52,
F
NMR (100 MHz, CDCl3)
d
: 20.23, 20.77, 36.18, 55.48, 69.09, 110.28
139.58, 143.92, 163.24, 197.40 ppm. HRMS (ES): M þ Naþ, found
(m), 113.83, 121.61, 128.89, 132.24, 136.46 (m), 138.99 (m), 139.71
(m), 142.32 (m), 144.83 (m), 145.74, 163.72, 170.09, 194.92 ppm.
HRMS (ESIþ): M þ Naþ, found 451.0939. C21H17F5NaO4 requires
451.0944.
385.1390. C21H21F3NaO2 requires 385.1386.
8.2.4.23. (E)-2-(Cyclohexylmethyl)-3-(2,4-dichlorophenyl)-1-(4-
methoxyphenyl)prop-2-en-1-one (3 hb). Yellow oil. Yield 50%. IR
(KBr): nmax ¼ 1651 (C]O) cmꢀ1
. d:
1H NMR (400 MHz, CDCl3)
0.75e0.84 (2H, m, cHex), 1.01e1.16 (3H, m, cHex), 1.35e1.44 (1H, m,
8.2.4.18. (E)-5-(4-Chlorophenyl)-4-(4-methoxybenzoyl)pent-4-en-2-
3
yl acetate (3fn). Yellowish oil. Yield 21%. IR (KBr): nmax ¼ 1644,1736
cHex), 1.53e1.66 (5H, m, cHex), 2.49 (2H, d, JH,H ¼ 6.8 Hz,
(C]O) cmꢀ1. 1H NMR (400 MHz, CDCl3)
d
: 1.31 (3H, d, 3JH,H ¼ 6.2 Hz,
CH2cHex), 3.87 (3H, s, OCH3), 6.96e6.98 (3H, m, ArH, ¼CH),
2
CH2CHCH3), 1.85 (3H, s, OCOCH3), 2.99 (1H, dd, JH,H ¼ 13.9 Hz,
7.27e7.28 (2H, m, ArH), 7.44 (1H, d, 4JH,H ¼ 1.2 Hz, ArH), 7.99 (2H, d,
3JH,H
¼
5.0 Hz, ¼CCH2), 3.04 (1H, dd, JH,H
¼
13.9 Hz,
3JH,H ¼ 8.8 Hz, ArH) ppm. 13C NMR (100 MHz, CDCl3)
d: 26.05, 26.19,
2
3JH,H ¼ 8.7 Hz, ¼CCH2), 3.90 (3H, s, OCH3), 5.18 (1H, dqd,
3JH,H ¼ 8.7 Hz, 3JH,H ¼ 6.2 Hz, 3JH,H ¼ 5.0 Hz, CH2CHCH3), 6.95e6.99
(2H, m, ArH), 7.05 (1H, s, ¼CH), 7.39e7.41 (4H, m, ArH), 7.81e7.85
33.30, 35.41, 36.80, 55.41, 113.62, 126.91, 129.30, 129.93, 130.95,
132.25, 133.43, 134.16, 134.39, 134.55, 143.30, 163.28, 197.06 ppm.
HRMS (ES): M þ Naþ, found 425.1041. C24H25Cl2NaO2 requires
425.1046.
(2H, m, ArH) ppm. 13C NMR (100 MHz, CDCl3)
d: 20.58, 21.12, 34.42,
55.50, 70.14, 113.63, 128.85, 130.07, 130.36, 132.16, 133.80, 134.45,
138.74, 139.18, 163.15, 170.36, 196.98 ppm. HRMS (ESIþ): M þ Naþ,
found 395.1021. C21H21ClNaO4 requires 395.1024.
8.2.4.24. (E)-2-(Cyclohexylmethyl)-3-(4-trifluoromethylphenyl)-1-
(4-methoxyphenyl)prop-2-en-1-one (3ho). Bright yellow oil. Yield
54%. IR (KBr): nmax ¼ 1646 (C]O) cmꢀ1. 1H NMR (400 MHz, CDCl3)
8.2.4.19. (E)-2-(2,4-Dichlorobenzylidene)-1-(4-methoxyphenyl)-4-
methylpentan-1-one (3gb). Yellow oil. Yield 70%. IR (KBr):
d: 0.89e0.98 (2H, m, cHex), 1.10e1.22 (3H, m, cHex), 1.49e1.73 (6H,
m, cHex), 2.63 (2H, d, 3JH,H ¼ 6.8 Hz, CH2cHex), 3.88 (3H, s, OCH3),
nmax ¼ 1650 (C]O) cmꢀ1. 1H NMR (400 MHz, CDCl3)
d: 0.82 (6H, d,
6.97 (2H, d, JH,H ¼ 8.8 Hz, ArH), 7.01 (1H, s, ¼CH), 7.46 (2H, d,
3
3JH,H ¼ 6.8 Hz, CH(CH3)2), 1.72 (1H, sept, 3JH,H ¼ 6.8 Hz, CH(CH3)2),
2.49 (2H, dd, 3JH,H ¼ 6.8 Hz, 4JH,H ¼ 0.4 Hz, CH2), 3.86 (3H, s, OCH3),
6.95e6.98 (3H, m, ArH, ¼CH), 7.26e7.27 (2H, m, ArH), 7.42e7.43
3JH,H ¼ 8.0 Hz, ArH), 7.64 (2H, d, JH,H ¼ 8.4 Hz, ArH), 7.89 (2H, d,
3
3JH,H ¼ 8.8 Hz, ArH) ppm. 13C NMR (100 MHz, CDCl3)
d: 26.16, 26.21,
33.54, 35.66, 37.58, 55.42, 113.64, 124.00 (q, 1JC-F ¼ 270.4 Hz), 125.33
(q, 3JC-F ¼ 3.8 Hz), 129.20, 129.74 (q, 2JC-F ¼ 32.4 Hz), 130.06, 130.22,
132.16, 136.69, 139.59, 143.68, 163.22, 197.46 ppm. HRMS (ES):
M þ Naþ, found 425.1690. C24H25F3NaO2 requires 425.1699.
3
(1H, m, ArH), 7.99 (2H, d, JH,H ¼ 9.2 Hz, ArH) ppm. 13C NMR
(100 MHz, CDCl3)
d: 22.55, 27.40, 36.69, 55.35, 113.58, 126.88,
129.26, 129.82, 130.89, 132.21, 133.36, 134.14, 134.18, 134.51, 143.53,
163.26, 196.93 ppm. HRMS (ES): M þ Naþ, found 385.0727.
C
20H20Cl2NaO2 requires 385.0733.
8.2.4.25. (E)-N-(3-(2,4-Dichlorophenyl)-2-(4-methoxybenzoyl)allyl)-
N-methylbenzamide (3ib). Yellowish oil. Yield 51%. IR (KBr):
8.2.4.20. (E)-2-(4-Nitrobenzylidene)-1-(4-methoxyphenyl)-4-
methylpentan-1-one (3gh). Yellow oil. Yield 76%. IR (KBr):
nmax ¼ 1643, 1633 (C]O) cmꢀ1. 1H NMR (400 MHz, CDCl3)
d: 2.91
(3H, s, NCH3), 3.85 (3H, s, OCH3), 4.59 (2H, br. s, CH2NMeCOPh), 6.95
nmax ¼ 1646 (C]O) cmꢀ1. 1H NMR (400 MHz, CDCl3)
d: 0.89 (6H, d,
(2H, d, 3JH,H ¼ 8.8 Hz, ArH), 7.04e7.08 (2H, m, ArH, ¼CH), 7.20e7.37
3JH,H ¼ 6.8 Hz, CH(CH3)2), 1.82 (1H, sept, 3JH,H ¼ 6.8 Hz, CH(CH3)2),
(5H, m, ArH), 7.43 (1H, d, JH,H ¼ 1.6 Hz, ArH), 7.61e7.74 (1H, m,
4
3
3
2.60 (2H, d, JH,H ¼ 7.2 Hz, CH2), 3.85 (3H, s, OCH3), 6.95 (2H, d,
ArH), 7.99 (2H, d, JH,H ¼ 7.6 Hz, ArH) ppm. 13C NMR (100 MHz,
3
3JH,H ¼ 8.8 Hz, ArH), 6.99 (1H, s, ¼CH), 7.49 (2H, d, JH,H ¼ 8.8 Hz,
CDCl3) d: 39.39, 46.54, 55.40, 113.75, 113.87, 126.67, 127.08, 128.14,
3
3
ArH), 7.88 (2H, d, JH,H ¼ 8.8 Hz, ArH), 8.21 (2H, d, JH,H ¼ 8.8 Hz,
129.29, 129.41, 129.81, 131.25, 132.12, 132.34, 134.38, 134.76, 135.80,
139.59, 163.65, 171.72, 196.32 ppm. HRMS (ES): M þ Naþ, found
476.0787. C25H21Cl2NNaO3 requires 476.0791.
ArH) ppm. 13C NMR (100 MHz, CDCl3)
d: 22.66, 27.98, 37.02, 55.35,
113.62, 123.55, 129.56, 129.60, 132.04, 135.11, 142.55, 145.06, 146.89,
163.28, 196.89 ppm. HRMS (ES): M þ Naþ, found 362.1357.
C
20H21NNaO4 requires 362.1363.
8.2.4.26. (E)-N-(3-cyclohexyl-2-(4-methoxybenzoyl)allyl)-N-methyl-
benzamide (3if). Yellow oil. Yield 49%. IR (KBr): nmax ¼ 1640, 1632
8.2.4.21. (E)-2-(4-Chlorobenzylidene)-1-(4-methoxyphenyl)-4-
(C]O) cmꢀ1. 1H NMR (400 MHz, CDCl3)
d: 1.06e1.17 (4H, m, cHex),
methylpentan-1-one (3gn). Yellow oil. Yield 46%. IR (KBr):
1.54e1.87 (6H, m, cHex), 2.80 (1H, br. s, cHex), 2.95 (3H, br. s, NCH3),
3.83 (3H, s, OCH3), 4.43e4.57 (2H, m, CH2NMeCOPh), 6.11 (1H, d,
4JH,H ¼ 9.6 Hz, ¼CH), 6.90 (2H, d, 3JH,H ¼ 8.8 Hz, ArH), 7.27e7.35 (5H,
nmax ¼ 1644 (C]O) cmꢀ1. 1H NMR (400 MHz, CDCl3)
d: 0.92 (6H, d,
3JH,H ¼ 6.8 Hz, CH(CH3)2), 1.86 (1H, sept, 3JH,H ¼ 6.8 Hz, CH(CH3)2),
2.63 (2H, d, 3JH,H ¼ 7.2 Hz, CH2), 3.87 (3H, s, OCH3), 6.94e6.97 (3H,
m, ArH), 7.64e7.80 (2H, m, ArH) ppm. 13C NMR (100 MHz, CDCl3)
d:
3
m, ArH, ¼CH), 7.29 (2H, d, JH,H ¼ 8.4 Hz, ArH), 7.35 (2H, d,
25.19, 25.65, 32.16, 37.75, 38.68, 44.27, 55.34, 113.45, 113.81, 126.66,
128.23, 129.34, 130.57, 131.90, 136.36, 151.65, 162.96, 171.69,
197.38 ppm. HRMS (ES): M þ Naþ, found 414.2043. C25H29NNaO3
requires 414.2040.
3JH,H ¼ 8.4 Hz, ArH), 7.87 (2H, d, 3JH,H ¼ 9.2 Hz, ArH) ppm. 13C NMR
(100 MHz, CDCl3)
d: 22.76, 28.10, 36.72, 55.39, 113.54, 128.61,
130.28, 130.31, 132.08, 133.85, 134.32, 137.38, 142.60, 163.04,
197.66 ppm. HRMS (ES): M þ Naþ, found 351.1117. C20H21ClNaO2
requires 351.1122.
8.2.4.27. (Z)-3-(2-Chlorophenyl)-2-(4-methoxybenzoyl)allyl benzo-
ate (4 dl). Colorless oil. Yield 20%. IR (KBr): nmax ¼ 1715, 1651 (C]
8. 2 . 4. 22. (E)-2-(4-Tri flu orom ethylbenzylidene)-1-(4-
methoxyphenyl)-4-methylpentan-1-one (3go). Yellow oil. Yield 71%.
O) cmꢀ1. 1H NMR (400 MHz, CDCl3)
d: 3.76 (3H, s, OCH3), 5.26 (2H,
d, 3JH,H ¼ 1.2 Hz, CH2OCOPh), 6.74 (2H, d, 3JH,H ¼ 8.8 Hz, ArH), 6.93

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_
I. Karpaviciene et al. / European Journal of Medicinal Chemistry 98 (2015) 30e48
45
3
4
(1H, td, JH,H ¼ 7.6 Hz, JH,H ¼ 0.8 Hz, ArH), 7.04 (1H, td,
5.70 (1H, s, CHOH),5.89 (1H, br. s, ¼CH), 5.93 (1H, d,
3JH,H ¼ 5.2 Hz, ¼CH), 6.90 (2H, d, 3JH,H ¼ 8.8 Hz, ArH), 6.99e7.04 (1H,
m, ArH), 7.15 (1H, td, 3JH,H ¼ 7.6 Hz, 4JH,H ¼ 0.8 Hz, ArH), 7.22e7.28
3JH,H ¼ 7.6 Hz, JH,H ¼ 1.6 Hz, ArH), 7.13 (1H, dd, JH,H ¼ 7.6 Hz,
4JH,H ¼ 1.6 Hz, ArH), 7.24 (1H, dd, 3JH,H ¼ 8.0 Hz, 4JH,H ¼ 0.8 Hz, ArH),
7.30 (1H, br. s, ¼CH), 7.34e7.38 (2H, m, ArH), 7.51 (1H, t,
3JH,H ¼ 7.6 Hz, ArH), 7.82 (2H, d, 3JH,H ¼ 8.8 Hz, ArH), 7.89e7.92 (2H,
m, ArH) ppm. HRMS (ES): M þ Naþ, found 429.0870. C24H19ClNaO4
requires 429.0864.
4
3
3
4
(1H, m, ArH), 7.57 (1H, td, JH,H ¼ 7.6 Hz, JH,H ¼ 1.6 Hz, ArH), 7.75
(2H, d, 3JH,H ¼ 8.8 Hz, ArH) ppm. 13C NMR (100 MHz, CDCl3)
d: 55.47,
69.42 (d, 3JC,F ¼ 3.2 Hz), 113.62, 115.18 (d, 2JC,F ¼ 21.2 Hz), 124.30 (d,
3
3JC,F ¼ 3.5 Hz), 125.63, 128.09 (d, JC,F ¼ 3.9 Hz), 128.27 (d,
4
2JC,F ¼ 13.0 Hz), 129.29 (d, JC,F ¼ 8.2 Hz), 129.62, 132.16, 147.12,
1
8.2.4.28. 1-(2-Fluorophenyl)-2-(4-methoxybenzoy)lallyl
acetate
159.82 (d, JC,F ¼ 244.9 Hz), 163.68, 197.52 ppm. HRMS (ES):
(5ba). Colorless oil. Yield 31%. IR (KBr): nmax ¼ 1744, 1651 (C]O)
M þ Naþ, found 309.0896. C17H15FNaO3 requires 309.0897.
cmꢀ1. 1H NMR (400 MHz, CDCl3)
d
¼
: 2.09 (3H, s, OCOCH3), 3.84 (3H, s,
0.8 Hz, ¼CH), 5.87 (1H, d,
4
OCH3), 5.76 (1H, d, JH,H
8.2.4.33. 2-((2,4-Dichlorophenyl) (hydroxy)methyl)-1-(4-
methoxyphenyl)prop-2-en-1-one (5'db). Orange oil. Yield 32%. IR
4JH,H ¼ 1.2 Hz, ¼CH), 6.91 (2H, d, 3JH,H ¼ 8.8 Hz, ArH), 7.01e7.06 (2H,
m, CHOCOMe, ArH), 7.13 (1H, td, 3JH,H ¼ 7.6 Hz, 4JH,H ¼ 0.8 Hz, ArH),
(KBr): nmax ¼ 3431 (OH), 1645 (C]O) cmꢀ1
.
1H NMR (300 MHz,
: 3.85 (3H, s, OCH3), 5.70 (1H, s, ¼CH),5.73 (1H, d,
3
3
7.25e7.29 (1H, m, ArH), 7.43 (1H, td, JH,H ¼ 7.6 Hz, JH,H ¼ 1.6 Hz,
CDCl3)
d
ArH), 7.79 (2H, d, JH,H ¼ 8.8 Hz, ArH) ppm. 13C NMR (100 MHz,
4JH,H ¼ 0.9 Hz, ¼CH), 5.91 (1H, s, CHOH), 6.91 (2H, d, 3JH,H ¼ 9.0 Hz,
3
3
3
4
CDCl3)
d
: 20.85, 55.40, 69.29 (d, JC,F ¼ 2.8 Hz), 113.56, 115.74 (d,
ArH), 7.29 (1H, dd, JH,H ¼ 8.4 Hz, JH,H ¼ 2.1 Hz, ArH), 7.36 (1H, d,
2JC,F ¼ 21.2 Hz), 124.13 (d, JC,F ¼ 3.6 Hz), 124.19, 125.00 (d,
4JH,H ¼ 2.1 Hz, ArH), 7.63 (1H, d, JH,H ¼ 8.4 Hz, ArH), 7.77 (2H, d,
3
3
2JC,F ¼ 13.1 Hz), 129.27 (d, JC,F ¼ 3.6 Hz), 129.72, 130.13 (d,
3JH,H ¼ 9.0 Hz, ArH) ppm. 13C NMR (75 MHz, CDCl3)
d: 55.49, 71.11,
3
4JC,F ¼ 8.3 Hz), 131.90, 145.57, 160.39 (d, JC,F ¼ 248.1 Hz), 143.41,
113.72, 126.56, 127.36, 129.13, 129.15, 129.35, 132.24, 132.83, 133.92,
137.13, 146.43, 163.83, 197.60 ppm. HRMS (ES): M þ Naþ, found
359.0220. C17H14Cl2NaO3 requires 359.0212.
1
169.33, 194.06 ppm. HRMS (ES): M þ Naþ, found 351.1005.
C
19H17FNaO4 requires 351.1003.
8.2.4.29. 4-Ethyl-2-(4-methoxybenzoyl)hex-1-en-3-yl acetate (5be).
Yellowish oil. Yield 36%. IR (KBr): nmax ¼ 1741, 1650 (C]O) cmꢀ1. 1H
8.2.4.34. 4-Ethyl-2-(4-methoxybenzoyl)hex-1-en-3-yl
(5de). Yellowish oil. Yield 37%. IR (KBr): nmax ¼ 1718, 1650 (C]O)
cmꢀ1 1H NMR (400 MHz, CDCl3)
0.92e0.98 (6H, m,
benzoate
NMR (400 MHz, CDCl3)
d
: 0.85 (3H, t, 3JH,H ¼ 7.2 Hz,CH(CH2CH3)2),
.
d:
0.89 (3H, t, 3JH,H ¼ 7.2 Hz,CH(CH2CH3)2), 1.23e1.34 (2H, m, CH2CH3),
1.37e1.44 (1H, m, CH2CH3), 1.46e1.53 (1H, m, CH2CH3), 1.56e1.63
(1H, m, CH(CH2CH3)2), 2.07 (3H, s, OCOCH3), 3.84 (3H, s, OCH3), 5.64
CH(CH2CH3)2), 1.36e1.53 (3H, m, CH2CH3), 1.64e1.77 (2H, m,
CH2CH3, CH(CH2CH3)2), 3.85 (3H, s, OCH3), 5.69 (1H, s, ¼CH), 5.86
(1H, d, 4JH,H ¼ 0.8 Hz, ¼CH), 6.14 (1H, d, 3JH,H ¼ 4.4 Hz, CHOCOPh),
6.93 (2H, d, 3JH,H ¼ 8.8 Hz, ArH), 7.45 (2H, t, 3JH,H ¼ 7.2 Hz, ArH), 7.57
3
(1H, s, ¼CH), 5.78 (1H, s, ¼CH), 5.83 (1H, d, JH,H ¼ 4.8 Hz, CHOC-
3
3
3
3
OMe), 6.91 (2H, d, JH,H ¼ 8.8 Hz, ArH) 7.79 (2H, d, JH,H ¼ 8.8 Hz,
(1H, t, JH,H ¼ 7.2 Hz, ArH), 7.85 (2H, d, JH,H ¼ 8.8 Hz, ArH),
ArH) ppm. 13C NMR (100 MHz, CDCl3)
d
: 11.28, 11.33, 20.92, 20.93,
8.08e8.10 (2H, m, ArH) ppm. 13C NMR (100 MHz, CDCl3)
d: 11.44,
22.12, 43.44, 55.38, 74.47, 113.51, 123.24, 129.87, 131.92, 146.36,
11.55, 21.16, 22.43, 43.77, 55.39, 74.89,113.56,128.41,129.58,129.93,
130.14, 131.96, 133.02, 146.44, 163.30, 165.49, 194.84 ppm. HRMS
(ES): M þ Naþ, found 389.1722. C23H26NaO4 requires 389.1723.
163.28, 170.07, 194.81 ppm. HRMS (ES): M þ Naþ, found 327.1567.
C
18H24NaO4 requires 327.1567.
8.2.4.30. 1-Cyclohexyl-2-(4-methoxybenzoyl)allyl acetate (5bf).
Yellowish oil. Yield 29%. IR (KBr): nmax ¼ 1732, 1651 (C]O) cmꢀ1. 1H
8.2.4.35. 1-Cyclohexyl-2-(4-methoxybenzoyl)allyl benzoate (5df).
White solid, m. p. ¼ 87e89 ꢁC. Yield 55%. IR (KBr): nmax ¼ 1702,
NMR (400 MHz, CDCl3)
d
: 1.03e1.24 (5H, m, cHex), 1.62e1.81 (6H,
1649 (C]O) cmꢀ1. 1H NMR (400 MHz, CDCl3)
d: 1.13e1.28 (5H, m,
m, cHex), 2.05 (3H, s, OCOCH3), 3.85 (3H, s, OCH3), 5.52 (1H, d,
cHex),1.65e1.93 (6H, m, cHex), 3.84 (3H, s, OCH3), 5.68 (1H, s, ¼CH),
3JH,H ¼ 6.0 Hz, CHOCOMe), 5.63 (1H, s, ¼CH), 5.80 (1H, s, ¼CH), 6.91
5.82 (1H, d, 3JH,H ¼ 5.6 Hz, CHOCOPh), 5.90 (1H, s, ¼CH), 6.91 (2H, d,
(2H, d, 3JH,H ¼ 8.8 Hz, ArH), 7.79 (2H, d, 3JH,H ¼ 8.8 Hz, ArH) ppm. 13
C
3JH,H ¼ 8.8 Hz, ArH), 7.45 (2H, t, JH,H ¼ 7.2 Hz, ArH), 7.56 (1H, t,
3
NMR (100 MHz, CDCl3)
d
: 20.93, 25.85, 25.96, 26.21, 27.97, 29.27,
3JH,H ¼ 7.2 Hz, ArH), 7.83 (2H, d, 3JH,H ¼ 8.8 Hz, ArH), 8.07e8.09 (2H,
40.70, 55.39, 77.42, 113.51, 123.75, 129.93, 131.98, 145.95, 163.28,
m, ArH) ppm. 13C NMR (100 MHz, CDCl3)
d: 25.91, 25.99, 26.23,
170.18, 194.85 ppm. HRMS (ES): M þ Naþ, found 339.1571.
27.86, 29.48, 40.95, 55.36, 77.65, 113.50, 123.92, 128.35, 129.53,
129.87, 130.18, 131.99, 132.95, 145.95, 163.22, 165.54, 194.86 ppm.
HRMS (ES): M þ Naþ, found 401.1718. C24H26NaO4 requires
401.1723.
C
19H24NaO4 requires 339.1567.
8.2.4.31. 1-(2-Fluorophenyl)-2-(4-methoxybenzoyl)allyl
benzoate
(5da). Yellowish oil. Yield 42%. IR (KBr): nmax ¼ 1721, 1650 (C]O)
cmꢀ1. 1H NMR (400 MHz, CDCl3)
d: 3.84 (3H, s, OCH3), 5.82 (1H, d,
8.2.4.36. 2-((2,3,4,5,6-Pentafluorophenyl) (hydroxy)methyl)-1-(4-
methoxyphenyl)prop-2-en-1-one (5'di). Yellow oil. Yield 38%. IR
4
4JH,H ¼ 1.2 Hz, ¼CH), 6.01 (1H, d, JH,H ¼ 1.2 Hz, ¼CH), 6.92 (2H, d,
3JH,H ¼ 8.8 Hz, ArH), 7.04e7.09 (1H, m, ArH), 7.14 (1H, td,
3JH,H ¼ 7.6 Hz, 3JH,H ¼ 0.8 Hz, ArH), 7.31 (1H, br. s., CHOCOPh), 7.41
(KBr): nmax ¼ 3431 (OH), 1654 (C]O) cmꢀ1
.
1H NMR (400 MHz,
4
CDCl3)
d
: 3.86 (3H, s, CH3O), 5.89 (1H, d, JH,H ¼ 1.6 Hz, ¼CH), 6.15
3
4
(2H, t, JH,H ¼ 7.6 Hz, ArH), 7.52e7.57 (2H, m, ArH), 7.84 (2H, d,
(1H, br. s, CHOH), 6.20 (1H, d, JH,H ¼ 1.6 Hz, ¼CH), 6.92 (2H, d,
3JH,H ¼ 8.8 Hz, ArH), 8.05e8.08 (2H, m, ArH) ppm. 13C NMR
3JH,H ¼ 8.8 Hz, ArH), 7.75 (2H, d, 3JH,H ¼ 9.2 Hz, ArH) ppm. 13C NMR
(100 MHz, CDCl3)
d
: 55.38, 70.04 (d, 3JC,F ¼ 2.5 Hz), 113.57, 115.81 (d,
(100 MHz, CDCl3) d: 55.48, 65.07, 113.74, 114.90 (m), 125.31, 128.43,
3
2JC,F ¼ 21.2 Hz), 124.12, 124.17 (d, JC,F ¼ 3.6 Hz), 124.95 (d,
129.37, 130.11, 131.99, 136.24, 138.76, 139.66, 143.83, 146.01, 146.28,
2JC,F ¼ 13.0 Hz), 128.36, 129.39 (d, JC,F ¼ 3.5 Hz), 129.53, 129.68,
163.75, 195.52 ppm. HRMS (ES): M þ Hþ, found 381.0524.
3
4
129.70, 130.20 (d, JC,F ¼ 8.2 Hz), 131.90, 133.15, 145.54, 160.50 (d,
C17H11F5NaO3 requires 381.0521.
3JC,F ¼ 248.2 Hz), 163.40, 164.88, 194.09 ppm. HRMS (ES): M þ Naþ,
found 413.1162. C24H19FNaO4 requires 413.1160.
8.2.4.37. 1-(2-Nitrophenyl)-2-(4-methoxybenzoyl)allyl
benzoate
(5dj). Yellowish solid; m.p. ¼ 120e122 ꢁC. Yield 22%. IR (KBr):
8.2.4.32. 2-((2-Fluorophenyl) (hydroxy)methyl)-1-phenylprop-2-en-
nmax ¼ 1726, 1651 (C]O) cmꢀ1.1H NMR (400 MHz, CDCl3)
d: 3.85
4
1-one (5'da). Yellowish oil. Yield 9%. IR (KBr): nmax ¼ 3433 (OH),
(3H, s, OCH3), 5.81 (1H, d, JH,H ¼ 1.2 Hz, ¼CH), 5.86 (1H, d,
1643 (C]O) cmꢀ1. 1H NMR (400 MHz, CDCl3)
d: 3.85 (3H, s, OCH3),
4JH,H ¼ 0.4 Hz, ¼CH), 6.93 (2H, d, JH,H ¼ 8.8 Hz, ArH), 7.42 (2H, t,
3

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I. Karpaviciene et al. / European Journal of Medicinal Chemistry 98 (2015) 30e48
46
3JH,H
¼
7.6 Hz, ArH), 7.46e7.51 (1H, m, ArH), 7.56 (1H, t,
123.94, 128.59, 129.28, 129.77, 130.17, 130.49, 130.55, 132.07, 132.10,
132.84, 133.71, 137.94, 141.22, 145.30, 151.19, 162.96, 163.21, 164.92,
196.00, 196.98 ppm. HRMS (ES): M þ Naþ, found 555.1776.
3JH,H ¼ 7.6 Hz, ArH), 7.60 (1H, br. s, CHOCOPh), 7.63 (1H, td,
3JH,H ¼ 7.6 Hz, JH,H ¼ 1.2 Hz, ArH), 7.77 (1H, dd, JH,H ¼ 8.0 Hz,
4
3
4JH,H ¼ 1.2 Hz, ArH), 7.84 (2H, d, 3JH,H ¼ 8.8 Hz, ArH), 8.01e8.04 (3H,
C34H28NaO6 requires 555.1778.
m, ArH) ppm. 13C NMR (100 MHz, CDCl3)
d: 55.44, 71.10, 113.67,
124.94, 126.01, 128.46, 129.14, 129.21, 129.33, 129.58, 129.76, 131.95,
133.36, 133.43, 145.59, 148.23, 163.49, 164.88, 193.97 ppm. HRMS
(ES): M þ Naþ, found 440.1089. C24H19NNaO6 requires 440.1105.
8.2.4.43. (E)-2-(4-Methylbenzylidene)-4-methylene-1,5-
diphenylpentane-1,5-dione (6bg). Yellow oil. Yield 17%. IR (KBr):
nmax ¼ 1651 (C]O) cmꢀ1. 1H NMR (300 MHz, CDCl3)
d: 3.85 (3H, s,
OCH3), 3.87e3.88 (5H, m, ¼CCH2C ¼ , OCH3), 5.57 (1H, br. s, ¼CHH),
5.78 (1H, br. s, ¼CHH), 6.88 (2H, d, 3JH,H ¼ 9.2 Hz, ArH), 6.95 (2H, d,
3JH,H ¼ 8.8 Hz, ArH), 7.30 (1H, s, ¼CH), 7.34e7.41 (3H, m, ArH),
7.44e7.46 (2H, m, ArH), 7.78 (2H, d, 3JH,H ¼ 8.8 Hz, ArH), 7.85 (2H, d,
8.2.4.38. 3-Benzoylbut-3-en-2-yl benzoate (5dk). Colorless oil.
Yield 23%. IR (KBr): nmax ¼ 1715, 1649 (C]O) cmꢀ1
.
1H NMR
3
(400 MHz, CDCl3)
d
: 1.60 (3H, d, JH,H ¼ 6.4 Hz, CH3), 3.86 (3H, s,
OCH3), 5.63 (1H, s, ¼CH), 5.99 (1H, d, 4JH,H ¼ 1.2 Hz, ¼CH), 6.02 (1H,
3JH,H ¼ 9.2 Hz, ArH) ppm. 13C NMR (75 MHz, CDCl3)
d: 31.40, 55.42,
3
3
q, JH,H ¼ 6.4 Hz, CHOCOPh), 6.93 (2H, d, JH,H ¼ 8.8 Hz, ArH), 7.42
(2H, t, 3JH,H ¼ 7.6 Hz, ArH), 7.55 (1H, t, 3JH,H ¼ 7.6 Hz, ArH), 7.84 (2H,
55.46, 113.46, 113.57, 123.77, 128.65, 128.83, 129.21, 130.60, 132.07,
132.11, 135.16, 137.81, 142.42, 145.57, 162.92, 163.20, 196.69,
197.09 ppm. HRMS (ES): M þ Hþ, found 413.1743. C27H25O4 requires
413.1747.
3
d, JH,H ¼ 8.8 Hz, ArH), 8.03e8.05 (2H, m, ArH) ppm. 13C NMR
(100 MHz, CDCl3) d: 20.29, 55.43, 70.19, 113.55, 122.04, 128.33,
129.56, 129.90, 130.19, 132.00, 132.97, 148.46, 163.38, 165.41,
195.14 ppm. HRMS (ES): M þ Naþ, found 333.1094. C19H18NaO4
requires 333.1097.
8.2.4.44. (E)-2-(4-Methylbenzylidene)-4-methylene-1,5-di(4-
methoxyphenyl)pentane-1,5-dione (6dc). Yellowish oil. Yield 26%. IR
(KBr): nmax ¼ 1715, 1644 (C]O) cmꢀ1. 1H NMR (300 MHz, CDCl3)
d:
8.2.4.39. 2-((2-Chlorophenyl) (hydroxy)methyl)-1-(4-
methoxyphenyl)prop-2-en-1-one (5'dl). Yellow oil. Yield 13%. IR
2.36 (3H, s, CH3C6H4), 3.85 (3H, s, OCH3), 3.87e3.88 (5H,
m, ¼CCH2C ¼ and OCH3), 5.56 (1H, br. s, ¼CHH), 5.76 (1H, br.
s, ¼CHH), 6.89 (2H, d, 3JH,H ¼ 8.7 Hz, ArH), 6.94 (2H, d, 3JH,H ¼ 8.7 Hz,
ArH), 7.20 (2H, d, 3JH,H ¼ 8.1 Hz, ArH), 7.30 (1H, s, ¼CH), 7.35 (2H, d,
3JH,H ¼ 8.1 Hz, ArH), 7.78e7.84 (4H, m, ArH) ppm. HRMS (ES):
M þ Naþ, found 449.1416. C28H26NaO4 requires 449.1723.
(KBr): nmax ¼ 3435 (OH), 1645 (C]O) cmꢀ1
.
1H NMR (300 MHz,
: 3.86 (3H, s, OCH3), 5.69 (1H, s, ¼CH),5.73 (1H, s, ¼CH),
CDCl3)
d
5.98 (1H, s, CHOH), 6.91 (2H, d, 3JH,H ¼ 8.7 Hz, ArH), 7.20e7.25 (1H,
3
m, ArH), 7.29e7.37 (2H, m, ArH), 7.70 (1H, dd, JH,H ¼ 7.5 Hz,
3
4JH,H ¼ 1.5 Hz, ArH), 7.79 (2H, d, JH,H ¼ 8.7 Hz, ArH) ppm. HRMS
(ES): M þ Naþ, found 325.0606. C17H15ClNaO3 requires 325.0602.
8.2.4.45. (E)-2-((Diethylamino)methyl)-1-(4-methoxyphenyl)-3-(4-
ꢁ
nitrophenyl)prop-2-en-1-one (7a). Yellow solid, m. p. ¼ 69e71 C.
8.2.4.40. 2-((2,4-Dinitrophenyl) (hydroxy)methyl)-1-(4-
methoxyphenyl)prop-2-en-1-one (5'dm). Yellow oil. Yield 59%. IR
Yield 48%. IR (KBr): nmax ¼ 1650 (C]O) cmꢀ1. 1H NMR (400 MHz,
3
CDCl3)
d
: 0.90 (6H, t, JH,H ¼ 6.4 Hz, N(CH2CH3)2), 2.48 (4H, q,
(KBr): nmax ¼ 3436 (OH), 1639 (C]O) cmꢀ1
.
1H NMR (300 MHz,
3JH,H ¼ 6.4 Hz, N(CH2CH3)2), 3.58 (2H, s, CH2NEt2), 3.88 (3H, s,
OCH3), 6.97 (2H, d, 3JH,H ¼ 8.8 Hz, ArH), 7.06 (1H, s, ¼CH), 7.73 (2H,
d, 3JH,H ¼ 8.4 Hz, ArH), 7.90 (2H, d, 3JH,H ¼ 8.4 Hz, ArH), 8.24 (2H, d,
CDCl3)
d
: 3.85 (3H, s, CH3O), 5.74 (1H, d, 4JH,H ¼ 0.6 Hz, ¼CH), 5.75
(1H, s, ¼CH), 6.31 (1H, br. s, CHOCOPh), 6.89 (2H, d, 3JH,H ¼ 9.0 Hz,
3
3
ArH), 7.70 (2H, d, JH,H ¼ 9.0 Hz, ArH), 8.24 (1H, d, JH,H ¼ 8.7 Hz,
3JH,H ¼ 8.8 Hz, ArH) ppm. 13C NMR (100 MHz, CDCl3)
d: 11.24, 46.63,
ArH), 8.48 (1H, dd, 3JH,H ¼ 8.7 Hz, 4JH,H ¼ 2.4 Hz, ArH), 8.79 (1H, d,
50.59, 55.48, 113.69, 123.47, 129.71, 130.55, 131.98, 135.97, 142.17,
144.10, 147.28, 163.34, 196.65 ppm. HRMS (ES): M þ Hþ, found
369.1806. C21H25N2O4 requires 369.1809.
4JH,H ¼ 2.4 Hz, ArH) ppm. 13C NMR (75 MHz, CDCl3)
d: 55.50, 69.75,
113.81, 120.04, 126.93, 127.37, 128.67, 130.71, 132.20, 143.15, 146.31,
147.14, 147.57, 164.00, 196.72 ppm. HRMS (ES): M þ Naþ, found
381.0698. C17H14N2NaO7 requires 381.0693.
8.2.4.46. (E)-1-(4-Methoxyphenyl)-2-(morpholinomethyl)-3-(4-
nitrophenyl)prop-2-en-1-one (7c). Yellow solid, m. p. ¼ 107e109 ꢁC.
Yield 77%. IR (KBr): nmax ¼ 1656 (C]O) cmꢀ1. 1H NMR (400 MHz,
8.2.4.41. (E)-4-(2,4-Dibenzoylpenta-1,4-dien-1-yl)phenyl benzoate
(6ad). Yellowish oil. Yield 14%. IR (KBr): nmax ¼ 1738, 1659, 1651
(C]O) cmꢀ1 1H NMR (400 MHz, CDCl3)
. d: 3.95 (2H, br.
CDCl3)
d:
2.45 (4H, br. s, N(CH2CH2)2O), 3.49 (2H, s,
CH2N(CH2CH2)2O), 3.62 (4H, br. s, N(CH2CH2)2O), 3.87 (3H, s, OCH3),
s, ¼CCH2C ¼ ), 5.71 (1H, br. s, ¼CHH), 5.91 (1H, t, br. s, ¼CHH), 7.28
(2H, d, 3JH,H ¼ 8.8 Hz, ArH), 7.40e7.44 (3H, m, ¼CH, ArH), 7.46e7.59
(8H, m, ArH), 7.63e7.67 (1H, m, ArH), 7.75e7.77 (2H, m, ArH),
7.80e7.83 (2H, m, ArH), 8.19e8.22 (2H, m, ArH) ppm. 13C NMR
3
6.96 (2H, d, JH,H ¼ 8.8 Hz, ArH), 7.17 (1H, s, ¼CH), 7.76 (2H, d,
3
3JH,H ¼ 8.4 Hz, ArH), 7.87 (2H, d, JH,H ¼ 8.8 Hz, ArH), 8.24 (2H, d,
3JH,H ¼ 8.8 Hz, ArH) ppm. 13C NMR (100 MHz, CDCl3)
d: 53.37, 55.22,
55.47, 66.82, 113.77, 123.52, 129.35, 130.57, 131.98, 138.33, 141.57,
141.79, 147.40, 163.42, 196.12 ppm. HRMS (ES): M þ Hþ, found
383.1607. C21H23N2O5 requires 383.1601.
(100 MHz, CDCl3) d: 30.55, 122.08, 126.00, 128.19, 128.32, 128.58,
129.19, 129.55, 129.61, 130.16, 130.62, 131.97, 132.32, 132.62, 133.73,
137.33, 137.77, 138.19, 143.25, 145.14, 151.39, 164.86, 197.76,
198.15 ppm. HRMS (ES): M þ Naþ, found 495.1563. C32H24NaO4
requires 495.1567.
8.2.4.47. (E)-3-(2,4-Dichlorophenyl)-1-(4-methoxyphenyl)-2-(mor-
pholinomethylꢁ)prop-2-en-1-one
(7f). Yellow
solid,
m.
8.2.4.42. (E)-4-(2,4-Bis(4-methoxybenzoyl)penta-1,4-dien-1-yl)
phenyl benzoate (6bd). Yellowish oil. Yield 12%. IR (KBr):
p. ¼ 117e118 C. Yield 53%. IR (KBr): nmax ¼ 1643 (C]O) cmꢀ1. 1H
NMR (400 MHz, CDCl3) d: 2.39 (4H, br. s, N(CH2CH2)2O), 3.44 (2H, s,
nmax ¼ 1737, 1658, 1650 (C]O) cmꢀ1. 1H NMR (400 MHz, CDCl3)
d
:
CH2N(CH2CH2)2O), 3.57 (4H, br. s, N(CH2CH2)2O), 3.88 (3H, s, OCH3),
3
3.84 (3H, s, OCH3), 3.88 (3H, m, OCH3), 3.91 (2H, br. s, ¼CCH2C ¼ ),
5.59 (1H, br. s, ¼CHH), 5.80 (1H, br. s, ¼CHH), 6.89 (2H, d,
6.97 (2H, d, JH,H ¼ 8.8 Hz, ArH), 7.14 (1H, s, ¼CH), 7.29 (1H, dd,
3JH,H ¼ 8.0 Hz, 4JH,H ¼ 2.0 Hz, ArH), 7.44 (1H, d, 4JH,H ¼ 2.0 Hz, ArH),
3
3
3
3JH,H ¼ 9.2 Hz, ArH), 6.96 (2H, d, JH,H ¼ 8.8 Hz, ArH), 7.27 (2H, d,
7.61 (1H, d, JH,H ¼ 8.0 Hz, ArH), 7.94 (2H, d, JH,H ¼ 8.8 Hz, ArH)
3JH,H ¼ 8.8 Hz, ArH),7.30 (1H, s, ¼CH), 7.52e7.55 (4H, m, ArH), 7.65
(1H, t, 3JH,H ¼ 7.6 Hz, ArH), 7.78 (2H, d, 3JH,H ¼ 8.8 Hz, ArH), 7.85 (2H,
ppm. 13C NMR (100 MHz, CDCl3)
113.70, 126.91, 129.27, 129.54, 131.91, 132.14, 132.55, 134.58, 134.89,
163.41, 196.22 ppm. HRMS (ES):
Hþ, found 406.0977.
C21H22Cl2NO3 requires 406.0971.
d: 53.33, 55.03, 55.45, 66.82,
3
d, JH,H ¼ 8.8 Hz, ArH), 8.19e8.21 (2H, m, ArH) ppm. 13C NMR
M
þ
(100 MHz, CDCl3)
d: 31.43, 55.39, 55.45, 113.48, 113.59, 122.02,

ꢀ
_
I. Karpaviciene et al. / European Journal of Medicinal Chemistry 98 (2015) 30e48
47
speciosum and their enhancement effect on TRAIL-induced apoptosis, Bioorg.
Med. Chem. 17 (2009) 6748e6754.
Acknowledgments
[6] (a) J.M. Yun, M.H. Kweon, H. Kwon, J.K.Hwang, H.Mukhtar. Induction of
apoptosis and cell cycle arrest by a chalcone panduratin A isolated from
Kaempferia pandurata in androgenindependent human prostate cancer cells
PC3 and DU145, Carcinogenesis 27 (2006) 1454e1464;
The research was funded by the European Social Fund under the
Global Grant measure (Grant No. VP1-3.1-SMM-07-K-01-002).
ꢀ
(b) Y.L. Hsu, P.L. Kuo, L.C. Chiang, C.C. Lin, Isoliquiritigenin inhibits the pro-
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Appendix A. Supplementary data
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II inhibition by the pyranonaphthoquinone derivatives -lapachone and
-lapachone, Cancer Chemother. Pharmacol. 47 (2001) 187e198;
(b) H. Nozaki, K.I. Hayashi, M. Kido, K. Kakumoto, S. Ikeda, N. Matsuura,
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(2007) 8290e8292.
Supplementary data contains notation and short description of
the QSAR molecular descriptors involved in the models and copies
of 1H and 13C NMR spectra of all synthesized compounds can be
found at http://dx.doi.org/10.1016/j.ejmech.2015.05.012.
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