Curcumin inspired 2-chloro/phenoxy quinoline analogues: Synthesis and biological evaluation as potential anticancer agents

Article abstract of DOI:10.1016/j.bmcl.2018.01.070

Synthesis of twenty new curcumin inspired 2-chloro/phenoxy quinoline derivatives is outlined in this study. The obtained new chemical entities were screened in vitro for their cytotoxic activity towards various tumor cell lines. Of the compounds screened, 6c and 9d exhibited significant activity and the most active analogue 6c displayed promising cytotoxicity against PC-3 (IC₅₀ of 3.12 ± 0.11 μM), DU-145, NCI-H460 and 4 T1 cell lines. Further, 6c and 9d have 2.1 and 1.4 times more aqueous solubility, respectively, than curcumin. Additionally, the promising candidate 6c could induce G2/M cell cycle arrest and apoptosis in PC-3 cells, as determined by AO-EB staining, DAPI staining, analysis of ROS levels as well as annexin binding assay.

Full text of DOI:10.1016/j.bmcl.2018.01.070

Accepted Manuscript
Curcumin inspired 2-chloro/phenoxy quinoline analogues: Synthesis and bio-
logical evaluation as potential anticancer agents
P.V. Sri Ramya, Lalita Guntuku, Srinivas Angapelly, Shailaja Karri, Chander
Singh Digwal, Bathini Nagendra Babu, V.G.M. Naidu, Ahmed Kamal
PII:
S0960-894X(18)30081-7
https://doi.org/10.1016/j.bmcl.2018.01.070
BMCL 25596
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
19 December 2017
29 January 2018
31 January 2018
Please cite this article as: Sri Ramya, P.V., Guntuku, L., Angapelly, S., Karri, S., Singh Digwal, C., Nagendra Babu,
B., Naidu, V.G.M., Kamal, A., Curcumin inspired 2-chloro/phenoxy quinoline analogues: Synthesis and biological
evaluation as potential anticancer agents, Bioorganic & Medicinal Chemistry Letters (2018), doi: https://doi.org/
10.1016/j.bmcl.2018.01.070
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Curcumin inspired 2-chloro/phenoxy quinoline analogues: Synthesis and biological
evaluation as potential anticancer agents
P. V. Sri Ramya,a Lalita Guntuku,b Srinivas Angapelly,a Shailaja Karri,b Chander Singh Digwal,a Bathini
Nagendra Babu,a V.G.M. Naidu,b Ahmed Kamala,c*
1

Bioorganic & Medicinal Chemistry Letters
journal homepage: www.els evier.com
Curcumin inspired 2-chloro/phenoxy quinoline analogues: Synthesis and
biological evaluation as potential anticancer agents
P. V. Sri Ramya,a Lalita Guntuku,b Srinivas Angapelly,a Shailaja Karri,b Chander Singh Digwal,a Bathini
Nagendra Babu,a V.G.M. Naidu,b Ahmed Kamala,c*
aDepartment of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India.
bDepartment of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India.
cSchool of Pharmaceutical Education and Research (SPER), Jamia Hamdard University, New Delhi 110062, India.
ARTICLE INFO
ABSTRACT
Article history:
Received
Synthesis of twenty new curcumin inspired 2-chloro/phenoxy quinoline derivatives is outlined in
this study. The obtained new chemical entities were screened in vitro for their cytotoxic activity
towards various tumor cell lines. Of the compounds screened, 6c and 9d exhibited significant
activity and the most active analogue 6c displayed promising cytotoxicity against PC-3 (IC50 of
3.12 0.11 µM), DU-145, NCI-H460 and 4T1 cell lines. Further, 6c and 9d have 2.1 and 1.4
times more aqueous solubility, respectively, than curcumin. Additionally, the promising
candidate 6c could induce G2/M cell cycle arrest and apoptosis in PC-3 cells, as determined by
AO-EB staining, DAPI staining, analysis of ROS levels as well as annexin binding assay.
Revised
Accepted
Available online
Keywords:
Curcumin mimics
2-substituted quinolines
Anticancer
2009 Elsevier Ltd. All rights reserved
.
Apoptosis
Claisen-Schmidt condensation
structures of some of the bioactive 2-phenoxy/methoxy quinoline
derivatives.
Quinoline is one of the omnipresent structural motifs that
occur in several natural compounds especially alkaloids
(Cinchona and Camptotheca alkaloids) and pharmacologically
active substances.1 It constitutes an interesting and important
class of compounds, with widespread biological activities
including antimalarial,2 anti-bacterial,3 anthelmintic,4 anticancer,5
antifungal,6 antihypertensive,7 anti-inflammatory,8 analgesic,9
antiviral10 and hypoglycemic11 etc., ultimately making quinoline
as “privileged substructure” for drug design. Quinoline or its
derivatives have been incorporated extensively into a diverse set
of therapeutically interesting drugs and drug candidates; for
example (i, Fig. 1), antimalarials (Quinine and Chloroquine etc),
anticancer (Topotecan and Bosutinib etc), antibacterial
(fluoroquinolones like Ciprofloxacin), antiglaucoma (Carteolol),
antiasthmatic, antiviral, antifungal-antiprotozoal, anthelmintic,
cardiotonic and local anesthetic.1d,12
N
(i)
HO
HO
N
O
N
HN
N
H
O
N
O
N
Cl
N
OH
O
Quinine
Chloroquine
Cl
Topotecan
Cl
O
N
HN
O
F
COOH
N
H
O
O
CN
OH
N
N
O
N
HN
N
H
O
N
Bosutinib(SKI-606)
Ciprofloxacin
Carteolol
H
N
H
N
O
COOH
(ii)
F
O
Additionally, 2-substituted quinoline moiety is ubiquitous
among bioactive derivatives, like anticancer agents,13
antileishmanial agents,14 CysLT (LTD4) receptor antagonists,15
HIV-1 replication inhibitors16 and PDE4 inhibitors.17 In
particular, 2-alkoxy(aroxy)quinolines exist as substructures in
numerous medicinally interesting compounds displaying a broad
Br
N
O
N
O
NO2
SH80
anticancer
HO
anti-mycobacterial
NH
NH2
COONa
F3C
O
F
O
Br
N
O
N
O
spectrum of biological activities, such as anticancer (SH80)18a
anti-mycobacterial, antithrombin, antimalarial,
immunosuppressive and many others.18 Fig. 1 (ii) shows the
,
N
O
antithrombin
antimalarial
immunosuppressive
HN
NH2
Fig. 1. (i) Some of the representative examples of quinoline drugs and drug
candidates. (ii) Structures of 2-phenoxy/methoxy quinoline derivatives of
biological interest.
*Corresponding author: Dr. Ahmed Kamal, Tel: +91 40 27193157;
Fax: (+91) 40 27193189; E-mail: ahmedkamal@iict.res.in;
2

Curcumin (a, Fig. 2), is a phytochemical, gained from the
dried rhizomes of Turmeric plant (Curcuma longa).19 Despite the
fact that curcumin possess versatile biological properties such as
antioxidant, anti-inflammatory, anti-HIV as well as antitumor
activities,20 its utility is limited because of its poor water
solubility and poor in vivo bioavailability.21 The multiple
therapeutic properties as well as the minimal bioavailability
directed the route for the synthesis of a “super curcumin” without
these problems. Preliminary structure activity relationship
analysis of curcumin demonstrated that the lack of stability of
curcumin under biological conditions is because of the β-
diketone moiety and the active methylene group, hence the
removal of β-diketone moiety may improve the stability of
curcumin derivatives.22 Based on this knowledge, significant
efforts have been devoted for the synthesis of different
biologically interesting heterocyclic curcumin analogues (b-h,
Fig. 2).23-29 As a part of our venture towards the development of
potent curcumin congeners,28,29 herein we have tried to probe the
scope of curcumin based 2-chloro/phenoxy quinolines (Fig. 3) as
anticancer and apoptosis inducing agents.
Scheme 1. (i) 15% NaOH, ethanol, 0 °C–rt, 2-3 h, 70–85%; (ii) POCl3, DMF,
65–70 °C, 17 h, 89%; (iii) K2CO3, DMF, 70–80 °C, 2-3 h, 68–74%; (iv) 15%
CH3ONa, ethanol, 0 °C–rt, 2-3 h, 65–92%.
All the synthesized compounds (6a–d and 9a–p) were
1
explicitly characterized by means of FT-IR, HRMS, H and 13C
1
NMR spectroscopic techniques. The H NMR spectrum of 6a
showed a sharp singlet of C-4 proton of quinoline at 8.47, which
is highly deshielded, another sharp singlet of methoxy protons at
3.86 and remaining protons were seen between 8.13-6.96 ppm. In
13C NMR spectrum, peaks at 188.1 and 55.4 affirmed the
presence of ketone functionality and methoxy carbon in
compound 6a, respectively and the other carbons were observed
in between 161.9-114.5 ppm. The stretching band of ketone
appeared at 1663.3 cm-1 in FT-IR spectrum of 6a. Almost similar
Fig. 2. Structures of curcumin and its congeners.
1
patterns were noted in H and 13C NMR spectra of the other
analogues 6b–d and 9a–p.
The newly synthesized curcumin inspired quinoline
analogues (6a–d and 9a–p) bearing different methoxy
substituents on the chalcone were examined for their cytotoxic
activity against some cancer cell lines viz. cervical (HeLa),
gastric (HGC-27), lung (NCI-H460), prostate (DU145 and PC-3)
and breast (4T1), using MTT assay.34 The activity results of test
compounds 6a–d, 9a–p and reference standard curcumin are
shown in Table 1.
Fig. 3. Design strategy to achieve title compounds.
The desired compounds (1E,4E)-1-(2-chloroquinolin-3-yl)-
5-phenylpenta-1,4-dien-3-ones (6a–d) and (1E,4E)-1-(2-
phenoxyquinolin-3-yl)-5-phenylpenta-1,4-dien-3-ones
were synthesized from chalcones (3a–f) and 2-chloroquinoline-3-
carbaldehyde (5) or 2-phenoxyquinoline-3-carbaldehyde
(9a–p)
We diversified the substitutions on quinoline and chalcone
in an attempt to analyze their structure-activity relationship
(SAR). The selection of substituent (such as varied number of
methoxy groups at different positions) on the chalcone was based
28-29
on the previous reports, with respect to biological activity.
derivatives (8a–d) as shown in Scheme 1. The aldehydes (1a–f)
were converted into chalcones (3a–f) via Claisen-Schmidt
condensation reaction with acetone using 15% NaOH.30 Next,
acetanilide was cyclized with POCl3 by the versatile Vilsmeier-
Haack reaction and the resulting 2-chloroquinoline-3-
carbaldehyde (5)31 was treated with various substituted phenols in
the presence of K2CO3 to give 2-phenoxyquinoline-3-
carbaldehyde derivatives (8a–d).32 Lastly, CH3ONa-catalysed
Claisen-Schmidt condensation reaction of chalcones (3a–f) and
2-chloroquinoline-3-carbaldehyde (5) or 2-phenoxyquinoline-3-
carbaldehyde derivatives (8a–d) furnished the desired
compounds (6a–d and 9a–p, respectively) in moderate to
excellent yields.33
From the initial results, it is evident that the compounds 6c and
9d displayed considerable cytotoxicity towards every cell line
examined, having IC50 ranging from 1.81
– 12.40 µM.
Compounds 6c and 9d are significantly cytotoxic on PC-3 having
IC50 of 3.12 0.11 µM and 7.29 0.22 µM, respectively and on
NCI-H460 with IC50 of 3.96 0.07 µM and 8.03 0.06 µM,
respectively. Compounds 6a, 6b and 6d with chloro substitution
on the quinoline and mono, di and trimethoxy substitutions,
respectively on the phenyl ring of the chalcone were noted non-
3

cytotoxic on every cell line tesed at the concentration of 10 µM
(IC50 > 10 µM). In contrast, 6c with chloro substitution on the
quinoline and 2,4,5-trimethoxy substitution on the chalcone
exhibited excellent cytotoxicity on all the cell lines tested.
Furthermore, 9a with 2-phenoxy quinoline as well as 4-methoxy
phenyl moiety and compounds 9b and 9c having 2-phenoxy
quinoline and dimethoxy substitutions on the chalcone were not
active (IC50 > 10 µM), whereas 9d possessing 2-phenoxy
quinoline and 2,4,5-trimethoxy substitution on the chalcone
exhibited appreciable cytotoxicity on most of the cell lines tested.
While, 9e with 2-phenoxy quinoline and 2,4,6-trimethoxy
substitution on the chalcone was observed to be inactive.
Notably,
9f-j with 2-(4-bromophenoxy)quinoline and
monomethoxy/dimethoxy/trimethoxy substituted chalcone were
also found non-cytotoxic. Likewise, compounds 9k–o possessing
2-(3-chlorophenoxy)quinoline and di or trimethoxy phenyl motif
were not active. In addition, compound 9p with 2-(2-
isopropylphenoxy)quinoline and 2,4,6- trimethoxy substitution
on the chalcone did not show any cytotoxicity.
Table 1. IC50 valuesa,g (µM) of analogues 6c and 9d against selected cancer cell lines.
Compound
HeLab
HGC-27c
NCI-H460d
DU-145e
PC-3e
4T1f
3.12 0.11
6c
5.41 0.75
12.40 0.37
N. D.
8.73 0.11
10.53 0.61
N. D.
3.96 0.07
8.03 0.06
17.11 0.68
3.99 0.11
9.22 0.07
33.15 1.96
1.81 0.03
7.63 0.23
N. D.
9d
7.29 0.22
Curcumin
18.65 1.11
a50% inhibitory concentration after 48 h of drug treatment and mean standard error of mean of three independent experiments performed in triplicate.
bHuman cervical cancer cell line.
cHuman gastric cancer cell line.
dHuman lung cancer cell line.
eHuman prostate cancer cell line.
fMouse breast cancer cell line.
gAll the other compounds (6a-b, 6d, 9a-c and 9e-p) showed IC50 of > 10 µM against all the tested cancer cell lines.
N. D. – Not determined.
The structure-activity relationship (SAR) analysis of
compounds 6a–d and 9a–p based on their IC50 values revealed
that the impact of substitution on the chalcone and quinoline is
interesting based on the following conclusions drawn (Fig. 4):
Table 2. Relative potency of curcumin mimics.
IC50 of curcumin/IC50 of compounda
Compound
NCI-H460d
DU-145e
PC-3e
Curcumin
6c
1
4.3
2.1
1
8.3
3.6
1
6.0
2.6
a. In general, it is notable that the presence of 2-(4-
9d
bromophenoxy)
or
2-(3-chlorophenoxy)
or
2-(2-
isopropylphenoxy) substitution on the quinoline did not
aThe relative potency of curcumin mimics was calculated by dividing the IC50
value of curcumin by that of each curcumin mimic.
dHuman lung cancer cell line.
produce the bioactive compounds (9f–j, 9k–o and 9p
respectively): the order may be neutral
withdrawing = electron donating.
> electron
eHuman prostate cancer cell line.
The solubility of the most active curcumin inspired
analogues 6c and 9d in water was measured in comparison to
curcumin by preparing their saturated aqueous solutions in milli-
Q water.35 The amount of curcumin/compound solubilized was
measured spectrophotometrically by scanning at 200‒600 nm.
UV-visible spectra were recorded for compounds 6c and 9d (Fig.
5, see suppoting information) and the results indicate that 6c and
9d have 2.1 and 1.4 times more aqueous solubility, respectively,
than curcumin.
b. Compounds possessing 2-chloro or 2-phenoxy substitution
on the quinoline and 2,4,5-trimethoxy substitution on the
chalcone (6c and 9d respectively) were the most active
compounds, whereas the similar compounds with 2,4,6-
trimethoxy substitution (6d and 9e, respectively) did not
show cytotoxicity.
c. Compounds containing trimethoxy group, particularly 2,4,5-
trimethoxy moiety (6c and 9d) on the chalcone showed
improved cytotoxicity than the mono or dimethoxy
compounds.
Progression of cell cycle and regulation of apoptosis are the
two important regulatory mechanisms required for cell division,
development, and differentiation. Cell cycle checkpoints
guarantee the conservation of genomic integrity by hampering
DNA damage and cells with incomplete DNA from further cell
division.36 Many of the cytotoxic agents alters the regulation of
cell cycle and thus elicit their cytotoxic property. To test whether
compound 6c has any effect on the cell cycle progression, we
analyzed the population of PC-3 cells treated with 6c by flow-
cytometry analysis.37 As depicted in Fig. 6, the ratio of the cells
in G2/M phase was increased from 34.4% in the control to 38.1%
and 45.7% in 6c treated cells (2 and 4 µM, respectively) in a
concentration dependent manner. The data clearly demonstrate
that compound 6c inhibits cell proliferation of PC-3 cells at
G2/M phase.
Fig. 4. SAR analysis of curcumin inspired 2-chloro/phenoxy quinolines.
With respect to potency, 6c and 9d were noted superior to
curcumin by comparing their IC50 values as shown in Table 2.
Compound 6c is 4.3, 8.3 and 6.0 times, more cytotoxic than
curcumin on NCI-H460, DU145 and PC-3 cell lines,
respectively. Further, the promising candidate 6c was considered
for detailed mechanistic studies.
Apoptosis and necrosis are the two major classes of cell
death, delineated in response to a death stimulus. Improper
regulation of apoptotic and necrosis processes can lead to the
development of several diseases including cancer.38-39 Acridine
orange-ethidium bromide (AO-EB) staining was carried out to
4

test whether the compound 6c could induce apoptosis in PC-3
cells.40 As exemplified in Fig. 7, in the control, the live cells
showed bright green nucleus which is intact, while 6c treated PC-
DAPI staining was carried out in PC-3 cells to determine the
chromatin condensation or nuclear damage induced by the
compound 6c. Fig. 8 clearly demonstrates the intact nucleus in
untreated cells as well as condensed and pyknotic nuclei in
compound 6c treated PC-3 cells. Hence, the data evidently shows
that 6c can induce apoptosis in PC-3 cells.
3
cells displayed early apoptotic characteristics like cell
membrane blebbing and condensed chromatin at 1 µM. Also,
non-uniform distribution of chromatin along with fragmentation
of chromatin were noted at 2 and 4 µM of 6c, respectively.
Fig. 6. Cell cycle analysis in PC-3 cells exposed to compound 6c for 24 h using propidium iodide cell staining method. All assays were done in triplicate.
Fig. 7. Morphological features in PC-3 cells (a) control; (b) exposure to 1 µM; (c) 2 µM; (d) 4 µM of compound 6c for 24 h and the cells were stained with
AO/EB.
Fig. 8. Nuclear morphology in PC-3 cells stained with DAPI. PC-3 cells were treated with compound 6c (a) 0.0 µM; (b) 2 µM and (c) 4 µM for 24 h and stained
with DAPI. The images were captured with fluorescence microscope.
5

It has been described that apoptosis can be triggered by
increased levels of intracellular ROS.41 To examine even if the
cytotoxicity displayed by 6c is relying on the intracellular ROS
levels, PC-3 cells were exposed to the compound 6c for 24 h and
To confirm and quantitatively estimate the apoptotic effect
of the compound 6c and to determine the percentage of apoptotic
cells, Annexin V/PI dual staining assay was conducted. It enables
the determination of live cells (Q1-LL; AV‒/PI‒), early apoptotic
cells (Q1-LR; AV+/PI‒), late apoptotic cells (Q3-UR; AV+/PI+)
and necrotic cells (Q4-UL; AV‒/PI+). PC-3 cells were exposed
to the treatment of 6c at 2 µM and 4 µM for 24 h. As displayed in
Fig. 10, the percentage of late apoptotic (Q3) cells was enhanced
to 18.5% (at 2 µM) and 29.1% (at 4 µM) in comparison to the
control (7.8%), which confirmed that 6c induced apoptosis in
PC-3 cells.
ʹ,7ʹ
the ROS levels were determined using DCFDA (2
-
dichlorofluorescin diacetate) staining method.29 Treatment of PC-
3 cells with 6c for 24 h demonstrated considerable enhancement
in DCFDA fluorescence than that of control (Fig. 9), which
indicate that the compound 6c could induce cytotoxicity through
ROS generation.
Fig. 9. Intracellular ROS levels in PC-3 cells treated with 1 and 2 µM of compound 6c for 24 h and the DCF fluorescent intensity was determined by flow-
cytometry. Data were mean SEM of three individual experiments. * P<0.05 ** P<0.01 ***P<0.001 vs. Ctrl In comparison to control (One way ANNOVA
followed by Dunnet’s multiple comparison test).
Fig. 10. Flow-cytometry analysis of apoptotic PC-3 cells after Annexin V-FITC/propidium iodide (PI) double staining (representative result of three independent
experiments). PC-3 cells were treated with compound 6c, stained with Annexin V-FITC/PI and examined for apoptosis using flow-cytometer. The 10,000 cells
from every sample were assessed by flow cytometry. The %cells positive for Annexin V-FITC and/or Propidium iodide is reported inside the quadrants. Cells in
the lower left quadrant (Q1-LL: AV-/PI-): live cells; lower right quadrant (Q2-LR: AV+/PI-): early apoptotic cells; upper right quadrant (Q3-UR: AV+/PI+): late
apoptotic cells and upper left quadrant (Q4-UL: AV-/PI+): dead cells.
cells at G2/M phase. Additionally, 6c induced apoptosis in PC-3
In summary, a series of curcumin inspired 2-chloro/phenoxy
cells and enhanced the intracellular ROS levels. Moreover, the
quinolines (6a‒d and 9a‒p) were made and tested for their
treatment of PC-3 cells with 6c led to the enhancement of the late
antitumor activity on some cancer cell lines including cervical
apoptotic cells, which is apparent from Annexin FITC/PI dual
(HeLa), gastric (HGC-27), lung (NCI-H460), prostate (DU-145
staining assay. Collectively, these assays disclosed that the
and PC-3) and breast (4T1). Of the compounds tested, 6c and 9d
proliferation of PC-3 cells was impeded by 6c through G2/M cell
showed notable potency towards every cell line with IC50
cycle arrest along with the induction of apoptosis. This forms the
between 1.81 – 12.4 µM. The most active compound 6c exhibited
first study wherein curcumin inspired quinoline derivatives have
promising cytotoxicity against PC-3 (IC50 of 3.12 0.11 µM),
been synthesized and established as efficient inducers of
DU-145 (IC50 of 3.99 0.11 µM), NCI-H460 (IC50 of 3.96 0.07
apoptosis. Finally, the broad spectrum of cytotoxic activity along
µM) and 4T1 (IC50 of 1.81 0.03 µM) cell lines. In addition, the
with the apoptosis inducing ability of 6c would encourage further
aqueous solubility data disclosed that 6c and 9d are 2.1 and 1.4
derivatization and optimization of such scaffold to perceive more
times, respectively more soluble in water than curcumin. The cell
potent and selective lead curcumin mimics.
cycle distribution suggested that the compound 6c inhibits PC-3
6

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Acknowledgments
PVSR, LG, SA and CSD are thankful to DoP, Ministry of
Chemicals & Fertilizers, Govt. of India, New Delhi, for the
award of NIPER fellowship.
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Supplementary Material
29. Ramya PVS, Guntuku L, Angapelly S, Digwal CS, Lakshmi UJ,
Sigalapalli DK, Babu BN, Naidu VGM, Kamal A. Synthesis and
biological evaluation of curcumin inspired imidazo[1,2-a]pyridine
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2018;143:216.
1
Synthetic procedures, spectral data, copies of H and 13C
NMR spectra and experimental details for biological evaluation
are provided in the supporting information.
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