Design, synthesis, characterization, and anticancer activity of a novel series of O-substituted chalcone derivatives

Article abstract of DOI:10.1016/j.bmcl.2021.127827

A new series of O-substituted chalcone derivatives bearing an/a allyl-, prenyl- or propargyl-substituent at different positions of rings A and B and their derivatives as drug leads, was designed, synthesized, and characterized. The chalcone derivatives we

Full text of DOI:10.1016/j.bmcl.2021.127827

Bioorg. Med. Chem. Lett. 35 (2021) 127827
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design, synthesis, characterization, and anticancer activity of a novel series
of O-substituted chalcone derivatives
Bath ´e l ´e my Ngamenia, , Kamdoum Cedric , Armelle T. Mbaveng , Musa Erdo g˘ an
f
,
*
b
c
d,*
,
e
c
f
Ingrid Simo , Victor Kuete , Arif Da s¸ tan
a
Department of Pharmacognosy and Pharmaceutical Chemistry, Faculty of Medicine and Biomedical Sciences, University of Yaound ´e I, P.O. Box. 1364, Yaound ´e ,
Cameroon
b
Department of Chemistry, Faculty of Science, University of Yaounde I, Yaounde, Cameroon
c
Department of Biochemistry, Faculty of Science, University of Dschang, Dschang, Cameroon
d
Department of Food Engineering, Faculty of Engineering and Architecture, Kafkas University, Kars 36100, Turkey
e
Department of Chemistry, Faculty of Science, University of Dschang, Dschang, Cameroon
f
Department of Chemistry, Faculty of Sciences, Atatürk University, Erzurum 25240, Turkey
A R T I C L E I N F O
A B S T R A C T
Keywords:
A new series of O-substituted chalcone derivatives bearing an/a allyl-, prenyl- or propargyl-substituent at
different positions of rings A and B and their derivatives as drug leads, was designed, synthesized, and char-
acterized. The chalcone derivatives were synthesized via base catalyzed Claisen-Schmidt condensation in MeOH
or EtOH solutions of appropriately substituted aromatic ketones with O-allyl, and O-propargylvanillin, respec-
tively. The intermediates O-substituted phenylketone derivatives were firstly synthesized by nucleophilic sub-
stitution reaction. All the newly synthesized compounds were characterized by IR, NMR spectral data and
elemental analyses. A preliminary cytotoxicity was performed with the compounds (1a, 1b, 2a, 2b, 3a, 3b, 4a,
Synthesis
Claisen-Schmidt condensation
Nucleophilic O-substitution reaction
4
4
-O-substituted phenylcarbonyls
-O-substituted chalcones
Anticancer activity
5
a-f, 6a-d, 7a-d) and the positive control, doxorubicin towards CCRF-CEM leukemia cells. Amongst them,
compounds 1a, 2a, 5b-d, 6b, 7a, 7c and doxorubicin displayed IC50 values below 20 µM while other compounds
were less or not active at up to 50 µM. Remarkably interesting cytotoxic effects, with IC50 values below 1 µM
were recorded with 5c against HCT116 p53- colon adenocarcinoma cells, 5e against CCRF-CEM cells and MDA-
/-
+/+
-/-
MB-231-BCRP breast adenocarcinoma cells, and 6b against HCT116 p53
cells and HCT116 p53 cells.
Introduction
as the precursors of a panel of biologically important heterocycles such
as isoflavonoids, flavones, flavanones, benzothiazepines, and pyrazo-
lines.1
0,11
Chemically, they consist of an
α, β-unsaturated ketone moiety
Cancer, occurring by abnormal division and spread of cells, is
recognized as the main global health problem and is one of the major
causes of death.1 There are many methods used in the current cancer
treatment such as chemotherapy, radiotherapy, surgery or their com-
12,13
with two phenyl rings, and can act as Michael acceptors (Fig. 1).
,2
This was recognized as the main and important pharmacophore for
chalcones regarding their biological profiles, as removal of this func-
3
5
binations. Among these treatments, chemotherapy method is one of the
tionality made them mostly inactive. Over the last decades, chalcones
most common and effective treatments used in many types of cancer.
But, most antitumor agents used in chemotherapy suffer from serious
have captured the interest of chemical and pharmacological researchers
because of their simple chemical structure and various biological ac-
4
10
side effects. Therefore, the design, synthesis, and discovery of chemo-
tivities. Attractively, chalcones are synthesized with good yields by
therapeutic agents with high anticancer potential and selectivity is still a
crucial need.
Claisen-Schmidt acid- or base-catalyzed condensation.14 Due to their
simple chemistry and widespread applications in the medicinal, syn-
thetic and material sciences, chalcones have incessantly been paid a
Chalcones and their derivatives are a major class of natural sources
belonging to the flavonoid family.5–8 Chalcones are usually found in
15
huge attention. Chalcone derivatives exhibited significantly photo-
9
16
fruits, vegetables, teas, and other plants. Chalcones are also considered
physical and photochemical properties. Chalconoids are widely used
*
Corresponding authors.
E-mail addresses: bath_ngameni@yahoo.fr (B. Ngameni), musaerdogan0@gmail.com (M. Erdo g˘ an).
https://doi.org/10.1016/j.bmcl.2021.127827
Received 25 November 2020; Received in revised form 28 December 2020; Accepted 18 January 2021
Available online 26 January 2021
0
960-894X/© 2021 Elsevier Ltd. All rights reserved.

B. Ngameni et al.
Bioorganic & Medicinal Chemistry Letters 35 (2021) 127827
in optoelectronic fields such as nonlinear materials, chromophore sen-
the key intermediate in the synthesis of various biologically important
heterocyclic compounds. The acetylenic chalcones and their analogues
are relatively rare as drug molecule models. However, the appearance of
acetylenic groups in drugs is increasing, given the frequency of use and
1
6
sors and DNA biosensor. Therefore, chalcones as well as their synthetic
analogues possess a remarkably wide spectrum of useful biological and
1
7
18
pharmacological properties, including antioxidant, antimicrobial,
antimalarial, antibacterial, anti-HIV, anti-inflammatory,22 anti-
1
9
20
21
ease of the Sonogashira coupling reaction that provides for a facile
43
2
3
24
Alzheimer’s,
antiulcer
properties. In addition, chalcones have
coupling of terminal alkynes to various aromatic systems. Otherwise,
prenylation is a very interesting reaction because it increases the lipo-
philic character and biological activity compared to the unsubstituted
exhibited excellent anticancer activity and attracted much attention in
2
5,26
27
28
29
anticancer studies.
Isoliquiritigenin, Butein, Xanthohumol,
3
0
Isobavachalcone,31 Licochalcone
32
44
Xanthoangelol,
A
and Mil-
chalcones. However, synthetic chalcone derivatives containing O-
lepachine33 isolated from natural products, have been reported to
display potent cytotoxicity against a variety of human cancer cells
propargyl and O-prenyl groups are less common and less attention has
been focused on these compounds.45
(
Figure 1). A good safety profile and possibility of oral administration34
In the present study, we reported on the synthesis and structural
characterization of a new series of O-allylic, O-prenylic and O-prop-
argylic chalcones and their derivatives as drug leads via two-steps re-
action, and investigated their anticancer activities.
are the major factors contributing to the increasing interest of many
researchers to isolate and elucidate them from nature and to develop
efficient synthetic methods. Also, synthesized chalcones bearing prop-
argylic substitutions were recently reported as potent antimalarial and
4-O-substituted phenylcarbonyl derivatives 1a-b and 2a-b were
synthesized by nucleophilic substitution reaction of vanillin (1) or 4-
3
5
antitubercular agents. In addition, the substitution of ring B with
electron-donating groups like methoxy or hydroxy group improves the
antiproliferative activity against human colon HT-29 cancer cell line.36
In this line, our research group has demonstrated that the substitution of
the hydroxy group of ring B of chalcone with allyloxy substituent
enhanced the in vitro cytotoxic activities with IC50 values below 100 µM
against the five human cancer cell lines (THP-1 (4.76 µM), DU-145 (5.21
acetyl-2-allylphenol (2) with the allyl-, prenyl- or propargyl bromide
◦
in the presence of K
2
CO
3
in dry acetone at reflux (62–65 C) under a
3
7,46,47
nitrogen atmosphere.
The vanillin (1) and 4-acetyl-2-allylphenol
(2), which were commercially available, became the key structures that
allowed us to prepare 4-O-substituted phenylcarbonyl derivatives 1a-b
and 2a-b.
3
7
µM), HL60 (7.90 µM), Hep-G2 (10.12 µM) and MCF-7 (10.32 µM)). All
our synthesized allyloxychalcone derivatives have shown their ability to
kill tumor cells in vitro.37
Synthesis of key intermediates 2a-b were reported here for the first
time while the compounds 1a-b were synthesized via a previously re-
37,46
ported method (Schemes 1).
The synthetic methods of allylated,
On the other hand, aromatic compounds containing the propargyl
functional group are of considerable interest in the medicinal and
analytical fields, and have long been recognized as mechanism-based
inhibitors of CYPs.38 Then, both Tremorine and Oxotremorine com-
pounds have been reported to have potential value in Parkinson’s dis-
prenylated or propargylated chalcones 3a-b, 4a, 5a-f, 6a-d and 7a-d are
illustrated and summarized in Schemes 2–5. In order to obtain both 4-O-
′
′
allyl-4 -O-prenyl and 4-O-allyl-4 -O-propargylchalcone derivatives 3a-b
and 4a, respectively; we examined Claisen-Schmidt condensation re-
actions between 4-allyloxy-3-methoxybenzaldehyde (1a) and the O-
3
9
48,49
ease. Acetylenic derivatives are an important class of compounds due
to their ability to exhibit anticancer properties.40 They also function as a
key pharmacophoric unit in acetylenic antibiotics, and these functional
groups have been reported to contribute to enhancing lipophilicity.35
This group is found in the structure of synthetic drugs as well as natu-
rally occurring antitumor and anticancer drugs such as calicheamicin,
esperamicin, dynemicin, and namenamicin which are the most potent
anticancer agents identified up to the present.40 The presence of the
nucleophilic triple bond, coupled with fairly acidic terminal acetylenic
hydrogen in many cases, make these propargylic compounds highly
potential for a wide useful chemical transformations.41 Altogether, al-
kynes are versatile building blocks for the synthesis of natural products
and also hybrid structures with interesting biological activities. Most
important of all of its applications is to use them as triazole intermedi-
substituted ketones 2a-b.
As a result of these reactions, we obtained
from the first reaction two chalcone isomers, the major E isomer 3a with
good yield (80%) and its minor Z isomer 3b (20%) while the second
reaction provides only a major E isomer 4a with excellent yield (90%)
(Scheme 2).
Similarly, chalcones 5a-f were synthesized via the Claisen-Schimidt
condensation of various appropriate substituted aromatic ketones 8a-f
with O-propargylvanillin (1b). The newly synthesized O-prop-
argylchalcones 5a-f were obtained in good yields of up to 96% (Schemes
3).
In order to further explore a biological profile of some chalcones
containing a substituted heterocyclic moiety, we synthesized the novel
compounds 6a-d via the Claisen-Schimidt condensation from O-prop-
argylvanillin 1b (Scheme 4).
4
2
ate. Furthermore, chalcones holding a propargyl group are known as
Surprisingly, during the Claisen-Schimidt condensation of O-
O
OH
O
O
R
G
A
B
HO
OH
OH
HO
R
OH
Chalcone
Xanthhumol R: OMe, G: CH3
Isoliquiritigenin R: H
Butein R: OH
Xanthoangelol R: H, G:
OH
O
O
O
O
HO
OH
HO
O
OH
O
O
Isobavachalcone
Licochalcone A
Millepachine
Fig. 1. Structures of simple chalcone, and some isolated natural chalcones.
2

B. Ngameni et al.
Bioorganic & Medicinal Chemistry Letters 35 (2021) 127827
O
O
OH
O
O
O
O
K CO
2
K2CO3
Br
3
O
O
1
1b
1a
Br
92%
81%
O
O
O
K CO
2
K CO
2 3
3
O
O
HO
Br
Br
2a
2
2b
73%
84%
Scheme 1. Synthesis of the key intermediate 4-O-substituted phenylcarbonyl derivatives 1a-b and 2a-b.
O
H
O
O
O
O
O
O
+
H
O
2a
3b
3
a
KOH/EtOH
O
O
O
O
O
O
1a
KOH/EtOH
O
O
O
O
4a
O
2b
Scheme 2. Synthesis of novel O-allyl, O-prenyl and O-propargylchalcone derivatives 3a-b and 4a from 1a and 2a-b.
O
O
O
O
R2
R1
R2
R1
O
KOH 50%
MeOH
O
O
+
R3
R3
1b
8a-f
5a-f
1
2
3
1
2
3
5
a R : Prenyl, R : H, R : H (59%)
5d R : H, R : OMe, R : H (56%)
1
2
3
1
2
3
5
b R : Isopropyl, R : H, R : H (68%)
5e R : H, R : H, R : Me (85%)
1
2
3
1
2
3
5
c R : OMe, R : OMe, R : H (76%)
5f R : Me, R : H, R : H (96%)
Scheme 3. Synthesis of novel O-propargylchalcone derivatives 5a-f from O-propargylvanillin 1b.
propargylvanillin (1b) with m-bromo or m-methylacetophenone in the
presence of KOH 50% in methanol, the prochiral monohydrochalcone
derivatives 7b, and 7d are obtained from moderate (19%) to good yield
7c (17%). The difference observed in the formation of compounds 7c
and 7d regarding their yields is more crucial for these reaction condi-
tions and can also help on further to oriente the synthesis of major
product.
(
50%) in both cases, respectively (Scheme 5). Otherwise, the lower
temperature of reaction conditions of m-bromoacetophenone between
Furthermore, the mechanism of formation of the newly synthesized
compounds 7b and 7d can be explained via a Michael reaction which
◦
3
0 and 34 C for 21 h under N
2
atm. is provided two products: 7c (24%)
◦
and 7d (43%) while at the high temperature (44–46 C), the formation
occurred 1,4-addition or a conjugate addition between the
α, β-unsatu-
of prochiral product is more increased (50%) compared to the chalcone
rated ketones and nucleophiles (aromatic enolate ion) (Scheme 6). The
3

B. Ngameni et al.
Bioorganic & Medicinal Chemistry Letters 35 (2021) 127827
O
O
O
O
KOH 50%
MeOH
O
O
O
G2
+
G2
1b
6a-d
G2
N
N
6c (84%)
O
O
6d (86%)
N
6a (85%)
N
b (66%)
6
Scheme 4. Synthesis of novel O-propargylated chalcones (6a-d) containing a substituted heterocyclic moiety from O-propargylvanillin 1b.
O
R
O
O
7a, R: Me (21%); 7c, R: Br (17%)
O
O
O
O
R
KOH 50%
MeOH
+
+
O
O
1b
R: CH , Br
3
R
O
O
R
Prochiral monohydrochalcone
7
b, R: CH (19%); 7d, R: Br (50%)
3
Scheme 5. Synthesis of novel O-propargylchalcone derivatives 7a-d from O-propargylvanillin 1b with formation of unusually prochiral monohydrochalcones 7b and
d, respectively. Repeated reaction at low temperature: 7c 24%, 7d 43%.
7
resulting products of our approach, prochiral chalcones 7b and 7d were
reported here for the first time via base-catalyzed condensation reaction.
Then, the method used is effective since it specifically generates
more (E)-isomer. This is supported by the 1H NMR spectra which in-
dicates that chalcones 3a, 4a, 5a-f, 6a-d, 7a, and 7c were geometrically
Amongst them, compounds 1a, 2a, 5b-e, 6b, 7a, 7c and doxorubicin
displayed IC50 values below 20 µM, 2b had an IC50 value of 38.20 µM
meanwhile other compounds were not active at up to 50 µM (Table 1).
The cytotoxicity of 1a, 2a, 5b-e, 6b, 7a, 7c as well as doxorubicin were
selected and tested towards a panel of 8 other cancer cell lines and a
normal AML12 hepatocytes (Table 2). All selected compounds (1a, 2a,
5b-e, 6b, 7a, 7c) had cytotoxic effect in the 8 tested carcinoma cell lines
with below 50 µM (Table 2). The accepted IC50 values for good cytotoxic
pure and with E configuration (J –Hβ = 15.5–15.8 Hz). The configu-
H
α
50
ration is also commonly found in naturally occurring chalcones. All
the synthesized compounds present characteristic signals of the two
5
2–54
In the present study, it was noted that
vinylic protons H
α
and H
) and δ 7.66–7.75 (H
5.5–15.8 Hz) of the two doublets corresponding to protons H
ß
of the propenone chain as two doublets at δ
). The high coupling constant (J =
and H of
H
compounds are below 10 µM.
7
.14–7.41 (H
α
H
ß
compounds 1a, 5b, 5c, 5d, 5e, 6b, 7a and 7c had IC50 values below or
around 10 µM on all selected cancer cell lines including drug-sensitive
and multidrug resistant (MDR) phenotypes (Table 2). This is a clear
indication that these compounds could offer good alternative to fight
malignant diseases including refractory cancers. This hypothesis is
confirmed by the fact that in most of the cases, the D.R. was below 1 as
shown in Table 2. Collateral sensitivity (D.R. below 1) of MDR cells to
phytochemicals combined to their good cytotoxicity could be better
criteria to select substances for clinical studies, as they can be better
candidate to reverse cancer drug resistance or to tackle MDR cancer
1
α
ß
the propenone chain indicates that the synthesized chalcones were ob-
tained with E configuration.51 Herein, the newly synthesized com-
pounds offer a new template for the design and future development of
Click chemistry for the valorization of heterocyclic chemistry. Addi-
tionally, the present study potentially also paves the way for the con-
struction of novel chalcone for use of its derivatives in different
applications.
A preliminary cytotoxicity was performed with the synthetized
compounds (1a, 1b, 2a, 2b, 3a, 3b, 4a, 5a-f, 6a-d, 7a-d) and the
positive control, doxorubicin towards CCRF-CEM cells (Table 1).
cells.5
5–56
Hence, compounds 1a, 2a, 5b, 5c, 5d, 5e, 6b, 7a and 7c
appear as good drug candidates to tackle the multidrug resistance of
4

B. Ngameni et al.
Bioorganic & Medicinal Chemistry Letters 35 (2021) 127827
O
O
O
+
KOH
K
-
H O
2
R
R
R
O
O
O
O
KOH
R
O
O
+
O
1b
R
H
O
O
O
O
O
H
O
O
R
R
O
O
R
R
7b, R: Me; 7d, R: Br
Scheme 6. Proposed mechanism of the formation of prochiral monohydrochalcone derivatives 7b, and 7d.
selectivity to HepG2 hepatocarinoma cells compared to the normal
Table 1
AML12 hepatocytes (S.I. above 2), suggesting that they could be more
appropriate for cancer chemotherapy. Interestingly, all the selected
compounds had better cytotoxicity than doxorubicin towards the
doxorubicin resistant CEM/ADR5000 cells (Table 2). Furthermore,
better cytotoxic effects than that of doxorubicin (IC50 value of 1.78 µM)
Preliminary cytotoxicity of compounds on the sensitive CCRF-CEM
leukemia cells.
Tested compounds
IC50 values (in µM)
1
1
2
2
3
3
4
5
5
5
5
5
5
6
6
6
6
7
7
7
7
a
b
a
b
a
b
a
a
b
c
14.04 ± 0.39
–
-/-
were also recorded with 5c, 5d, 5e, 6b and 7a against HCT116 p53
16.25 ± 0.44
(
IC50 value of 0.32 µM, 1.01, 1.06, 0.67 and 1.06, respectively)
Table 2).
38.20 ± 2.13
(
–
–
Regarding the structure–activity relationship, it appears that the key
–
intermediate 4-O-substituted phenylcarbonyl derivatives 1a-b and 2a-b,
as well as allylated, prenylated or propargylated chalcones 3a-b, 4a, 5a-
b, 5f, 6a-d, and 7b-d had poor or no cytotoxic effects (IC50 values above
10 µM (Table 1). In contrast, O-propargylated chalcones 5c-e without as
allyl, isopropyl or prenyl substituents, as well as the novel O-prop-
argylchalcone derivatives 7d has the best cytotoxic effect with IC50
values below 10 µM against many cancer cell lines(Tables 1 and 2). This
is an indication that allyl, isopropyl or prenyl substituents decrease the
activity of O-propargylchalcones. Within the O-propargylated chal-
cones, it was observed that the numbers and positions of both methoxy
–
11.85 ± 1.27
8.65 ± ±0.93
d
e
f
5.59 ± ±0.48
6.95 ± ±1.77
–
–
a
b
c
14.95 ± 3.63
–
–
d
a
b
c
8.82 ± ±0.77
–
(
5c and 5d) and methyl (5e and 5f) significantly influence the cytotoxic
15.16 ± 3.66
activity (Tables 1 and 2). The presence of Br substituent also signifi-
cantly increases the activity O-propargylchalcones, as 7c (with Br sub-
stituent), had good cytotoxicity contrary to 7a (with methyl substituent)
(Table 1). However, the prochiral monohydrochalcones 7d also having a
Br substituent was devoid of cytotoxic effect, suggesting that the addi-
tional aromatic cycle containing another Br rather cancelled the bio-
logical activity, probably due to the steric hindrance that might prevent
the compound to reach its biological target.
d
–
Doxorubicin
0.02 ± ±0.00
(
-): IC50 value above 50 µM; In bold: significant cytotoxic
5
2–54
effect.
cancer cells. Remarkably interesting cytotoxic effects, with IC50 values
-
/-
below 1 µM were recorded with 5c towards HCT116 p53 cells (IC50
value of 0.32 µM), 5e towards CCRF-CEM cells and MDA-MB-231-BCRP
cells (IC50 value of 0.92 µM and 0.99 µM, respectively), and 6b towards
In summary, seventeen new chalcone derivatives were designed and
synthesized via the Claisen-Schmidt condensation, in basic media, with
good yields 80–90%, and characterized. Anticancer activities of the
obtained new compounds evaluated against a panel of 10 cancer cell
lines including drug sensitive and MDR phenotypes. Compounds 1a, 5b,
+
/+
-/-
HCT116 p53
cells and HCT116 p53 cells (IC50 value of 0.78 µM and
0
.67 µM, respectively) (Table 2). It is noteworthy that contrary to other
selected compounds, 5d, 5e, 6b, 7a and doxorubicin had good
5

B. Ngameni et al.
Bioorganic & Medicinal Chemistry Letters 35 (2021) 127827
Table 2
Cytotoxicity of selected compounds and doxorubicin towards drug sensitive cell line, their resistant counterpart’s and hepatocytes as determined by RRA after 72 h
incubation.
Tested compound
Cell lines, IC50 values (in µM), D.R.* or S.I.** (in bracket)
CEM/
MDA-MB-231-
MDA-MB-231
HCT116
HCT116
-/-
U87MG
U87MG.
HepG2
AML12
+
/+
ADR5000
pcDNA
-BCRP
p53
p53
ΔEGFR
1
2
5
5
5
5
6
7
7
a
a
b
c
3.48 ± ±0.17
14.99 ± 1.67
17.87 ± 2.01
4.07 ± ±0.33
13.62 ± 1.49
13.76 ± 1.18
14.78 ± 1.42
2.03 ± ±0.13
2.03 ± ±0.21
3.50 ± ±0.40
0.13 ± ±0.01
7.53 ± ±0.75
(0.50)
5.77 ± ±0.39
10.64 ± 0.94
3.70 ± ±0.27
2.01 ± ±0.33
1.92 ± ±0.17
1.66 ± ±0.18
0.78 ± ±0.05
1.38 ± ±0.11
2.90 ± ±0.38
0.48 ± ±0.06
8.02 ± ±0.67
(1.39)
7.50 ± ±0.66
12.93 ± 1.21
2.84 ± ±0.18
2.86 ± ±0.15
1.46 ± ±0.12
2.10 ± ±0.30
1.41 ± ±0.09
1.80 ± ±0.28
2.59 ± ±0.32
0.26 ± ±0.03
6.97 ± ±0.47
(0.93)
10.46 ± 1.13
14.67 ± 1.28
6.31 ± ±0.42
5.98 ± ±0.61
5.54 ± ±0.44
2.64 ± ±0.31
5.39 ± ±0.56
5.03 ± ±0.47
10.10 ± 0.88
4.56 ± ±0.48
15.27 ± 1.28
(1.46)
(
0.25)
5.25 ± ±0.89
0.32)
2.72 ± ±0.31
0.23)
1.44 ± ±0.22
0.17)
1.10 ± ±0.17
0.20)
0.92 ± ±0.06
0.13)
1.00 ± ±0.08
0.07)
1.38 ± ±0.09
0.16)
2.28 ± ±0.19
0.15)
122.96 ± 10.94
6,683.00)
11.92 ± 2.00
(0.67)
13.95 ± 0.93
(1.31)
12.20 ± 1.16
(0.94)
18.08 ± 1.17
(1.23)
(
2.93 ± ±0.24
(0.72)
3.13 ± ±0.40
(0.85)
2.12 ± ±0.11
(0.75)
9.91 ± ±0.10
(1.57)
(
1.89 ± ±0.14
(0.14)
0.32 ± ±0.28
(0.16)
1.56 ± ±0.18
(0.55)
6.75 ± ±0.39
(1.13)
(
d
e
b
a
c
1.23 ± ±0.07
(0.09)
1.01 ± ±0.19
(0.53)
1.33 ± ±0.10
(0.91)
11.38 ± 1.03
(2.05)
(
0.99 ± ±0.01
(0.07)
1.06 ± ±0.07
(0.64)
1.21 ± ±0.09
(0.58)
8.20 ± ±0.77
(3.11)
(
1.74 ± ±0.10
(0.86)
0.67 ± ±0.01
(0.86)
1.08 ± ±0.06
(0.77)
12.71 ± 1.06
(2.36)
(
1.77 ± ±0.18
(0.87)
1.06 ± ±0.06
(0.77)
1.97 ± ±0.20
(1.09)
11.27 ± 0.97
(2.24)
(
3.09 ± ±0.21
(0.88)
1.90 ± ±0.14
(0.66)
4.16 ± ±0.29
(1.61)
12.51 ± 1.12
(1.24)
(
Doxorubicin
0.79 ± ±0.08
(6.14)
1.78 ± ±0.08
(3.73)
0.98 ± ±0.07
(3.79)
52.90 ± 4.09
(11.59)
(
(
*): D.R.: the degree of resistance (D.R.) was determined as the ratio of IC50 value in the resistant divided by the IC50 in the sensitive cell line; CEM/ADR5000, MDA-MB-
-
/-
+/+
2
31-BCRP, HCT116 p53 and U87.MGΔEGFR were used as the corresponding resistant counterpart for CCRF-CEM (Table 1), MDA-MB-231-pcDNA, HCT116 p53
,
U87.MG cell lines, respectively; (**): S.I.: the selectivity index (S.I.) was determined as the ratio of IC50 value in the normal AML12 hepacytes divided by the IC50 in
5
2–54
HepG2 hepatocarcinoma cells; In bold: significant cytotoxic effect.
5
d, 5e, 6b, 7a and 7c had good cytotoxic potential, with IC50 values
3 Riaz S, Iqbal M, Ullah R, et al. Synthesis and evaluation of novel -substituted
α
chalcones with potent anti-cancer activities and ability to overcome multidrug
resistance. Bioorg Chem. 2019;87:123–135.
below or around 10 µM on all selected cancer cell lines. The present
study clearly shows that compounds 1a, 5b, 5d, 5e, 6b, 7a and 7c have
a promising potential for the future development of active anticancer
agents. These results make the newly synthesized chalcones and their
derivatives interesting lead molecules for further intermediated syn-
thetic and biological evaluation.
4
5
6
7
Farghaly TA, Masaret GS, Muhammad ZA, Harras MF. Discovery of thiazole-based-
chalcones and 4-hetarylthiazoles as potent anticancer agents: Synthesis, docking
study and anticancer activity. Bioorg Chem. 2020;98, 103761.
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characterization and anticancer activity of new thiazole ortho-hydroxychalcones.
Med Chem Res. 2018;27:1396–1407.
Thirumurugan C, Vadivel P, Lalitha A, Lakshmanan S. Synthesis, characterization of
novel quinoline-2-carboxamide based chalcone derivatives and their molecular
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Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
8 Sabina XJ, Karthikeyan J, Velmurugan G, Tamizh MM, Shetty AN. Design and in
vitro biological evaluation of substituted chalcones synthesized from nitrogen
mustards as potent microtubule targeted anticancer agents. New J Chem. 2017;41:
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096–4109.
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Zhuang C, Zhang W, Sheng C, Zhang W, Xing C, Miao Z. Chalcone: a privileged
˙
structure in medicinal chemistry. Chem Rev. 2017;117:7762–7810.
The authors are grateful for the financial support from TÜBITAK-
1
0 Mansour E, Aboelnaga A, Nassar EM, Elewa SI. A new series of thiazolyl pyrazoline
derivatives linked to benzo [1,3] dioxole moiety: Synthesis and evaluation of
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1 Xue Y, Liu Y, Luo Q, et al. Antiradical activity and mechanism of coumarin-chalcone
hybrids: Theoretical insights. J Phys Chem A. 2018;122:8520–8529.
˙
BIDEB 2221-Funding of Visiting Scientists on Sabbatical Leave Fellow-
ship Program to the Department of Chemistry, Ataturk University,
Erzurum, Turkey. Thanks are also due to the Department of Chemistry,
Ataturk University for the important support with the experimental
equipment. Authors are thankful to Prof. Dr. Thomas Efferth for
providing facilities for biological studies. Authors are grateful to Alex-
ander von Humboldt Foundation for the Equipment grants 3.4 - 8151/
Kuete (GA-Nr.19014) to VK and 3.4 - 8151 / 18026 to ATM.
1
1
1
1
2 Choi D, Park JC, Lee HN, et al. In Vitro Osteogenic Differentiation and Antibacterial
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5 Vinoth R, Rangarajan TM, Singh RP, Singh M. Synthesis of novel chalcones through
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Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.bmcl.2021.127827.
1
1
1
6 Kumari R, Varghese A, George L, Sudhakar YN. Effect of solvent polarity on the
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