Synthesis, DNA binding, docking and photocleavage studies of quinolinyl chalcones

Article abstract of DOI:10.1039/c4md00185k

A series of simple quinoline-chalcone conjugates have been synthesized by Claisen-Schmidt condensation reactions of substituted acetophenones with 2-chloro-3-formyl-quinoline and evaluated for their nucleolytic activity. The structures of the synthesized

Full text of DOI:10.1039/c4md00185k

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Synthesis, DNA binding, docking and
photocleavage studies of quinolinyl chalcones†
Cite this: Med. Chem. Commun., 2014,
5, 1708
a
P. J. Bindu, K. M. Mahadevan,a T. R. Ravikumar Naikb and B. G. Harishc
*
A
series of simple quinoline–chalcone conjugates have been synthesized by Claisen–Schmidt
condensation reactions of substituted acetophenones with 2-chloro-3-formyl-quinoline and evaluated
for their nucleolytic activity. The structures of the synthesized quinoline–chalcone conjugates were
confirmed by IR, 1H NMR, 13C NMR and mass spectral analyses. Most of the prepared compounds
showed significant DNA binding and photocleavage activities. The incorporation of an electron-donating
group into ring A caused a moderate increase in the DNA binding and photocleavage activities.
Compounds 3c and 3d exhibited promising DNA photocleavage against pUC 19 DNA with 85% inhibition
at 100 mM concentration. A structure–activity relationship analysis of these compounds was performed;
compounds 3c and 3d are potential candidates for future drug discovery and development.
Received 29th April 2014
Accepted 17th August 2014
DOI: 10.1039/c4md00185k
www.rsc.org/medchemcomm
melanoma, ovarian, prostate, renal cell, cervix, pancreas, and
bone carcinomas.3–5
Introduction
On the other hand, photodynamic therapy (PDT) and
vascular disrupting agents (VDAs) have their advantages in the
treatment of solid tumors. Among the different types of
photosensitizers being used in PDT, chalcones are the most
extensively studied, due to their photophysical and biological
properties.6 Recently, chalcones act as vascular disrupting
agents and destroy tumour neovasculature.7 However, it was
noticed that during VDAs, the non-targeted (unvascularised)
cells lead the tumour to regrow at viable rim of tumor vascu-
lature aer VDA treatment. During this period the viable cells
rapidly proliferate and recover their blood supply within 24 h. It
is hence necessary to associate the VDAs with other therapies to
block the blood supply to the tumor vasculature.8
There is presently interest in low molecular weight ligands that
can interact with nucleic acids in a sequence-selective manner.
The development of therapies which are selective for tumour
tissues is one of the most important goals in anticancer
research, within this framework photodynamic therapy (PDT)
can be considered as a very promising approach. Photodynamic
therapy (PDT) is a minimally invasive treatment that destroys
target cells in the presence of oxygen when light irradiates a
photosensitizer, generating highly reactive singlet oxygen.1
Singlet oxygen then attacks cellular targets, causing destruction
through direct cellular damage, vascular shutdown, and acti-
vation of an immune response against targeted cells. PDT has
several advantages over conventional therapies because of its
noninvasive nature, its selectivity, the ability to treat patients
with repeated doses without initiating resistance or exceeding
total dose limitations (as associated with radiotherapy), the fast
healing process resulting in little or no scarring, the ability to
treat patients in an outpatient setting, and the lack of associated
side effects.2 Current clinical applications of PDT include the
treatment of solid tumors in the skin (basal cell carcinomas),
lung, esophagus, bladder, head and neck, brain, ocular
The functionalized chalcone framework continues to occupy
an important place in medicinal chemistry, due to the presence
of a reactive ketovinyl moiety in the molecule and associated
with the avonoid family. These functionalized chalcones are
one of the major classes of natural products with widespread
distribution in fruits, vegetables and soy bean based foodstuff
and have been recently subjects of great interest due to their
interesting pharmacological activities.9 Chalcones have been
reported to possess many useful properties, including antibac-
terial,10 antifungal,11 anticancer,12 anti-inammatory,13 antitu-
aDepartment of Studies and Research in Chemistry, Kuvempu University,
Shankaraghatta-577 451, India. E-mail: bindu12_naik@rediffmail.com; Tel: +91
9900792675
bercular,14
antihyperglycemic,15
antimalarial
agents,16
modulation of nitric oxide production17 and so on. These
compounds are important synthons for the preparation of ve
and six membered ring systems18a as well as intermediates in
the synthesis of many pharmaceuticals.18b Having such varied
pharmacological activities and synthetic utilities, chalcones
have attracted the chemists to develop newer molecules for
their biological activity.
bDepartment of Center of Nano Science and Engineering, Indian Institute of Science,
Bangalore 560 012, India
cDepartment of Biotechnology, M.S. Ramaiah Institute of Technology, MSR Nagar,
Bengaluru, Karnataka, India
† Electronic supplementary information (ESI) available: Experimental procedures,
characterization data, and 1H-NMR, 13C-NMR and mass spectra of CQCs. See DOI:
10.1039/c4md00185k
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We found that most of the naturally occurring chalcones are (d, 1H), d 7.89–7.85 (t, 1H) and d 7.66–7.62 (t, 1H) for aromatic
hydroxylated in their aryl ring A and therefore such compounds protons. The 13C NMR spectra of 2-chloro-3-formyl-quinoline
have mainly been objects of anticancer studies.19 Little is known showed a signal at d ¼ 189.07 (C]O), 150.03, 149.51, 140.22,
about the position effect of a phenolic group located in aryl ring 133.54, 129.66, 128.54, 128.08, 126.47, and 126.31 ppm,
B. The electron donating groups are considered to play a respectively.
signicant role in the anticancer activity of chalcones.19 And
In general, we observed that chalcones bearing electron-
also the SAR analysis of the chalcones shows that the presence donating or electronically neutral groups were formed in better
and the position of alkoxy groups on both ring A and ring B yields when compared to the chalcones bearing electron-with-
favour the biological activity. In particular the hydroxy and drawing groups (Table 1). The desired products were obtained
methoxy substitution at 20 and 40 positions of ring A are more on an average yield of 84% aer purication and their struc-
favourable for the anticancer activity.20
tures were conrmed by IR, 1H NMR, 13C NMR and
Recently, quinolines and their derivatives have been exten- mass spectrometry. The IR frequency of 3c was observed at 1656
sively explored for their biological, antimalarial, antimicrobial (C]O), 1570, and 1511 (C]C) cmꢀ1. The 1H NMR spectrum
and antitumor activities.21 Quinolines have attracted signicant showed the presence of the methoxy functional group at d ¼
interest, mainly due to their aromaticity, chemical stability, and 3.90 and this was also conrmed by 13C NMR at d ¼ 55.3.2. The
low toxicity, and they have been used as the most attractive protons, Ha and Hb appeared at d ¼ 7.75 and d ¼ 8.15,
pharmacophores for drug design and discovery. On the other respectively.
hand, experimental evidence has proved the ability of quino-
lines as potential antitumor agents.22
Nucleolytic activity
Thus, in continuation of our research on the synthesis of
The choice of the rational screening strategy for new chemical
substituted quinoline derivatives,23 herein we report the
entities constitutes a signicant challenge for small academic
synthesis of quinolinyl chalcones with diverse substituents in
organizations. The presently preferred target-oriented
the aromatic rings, mainly on ring A and probed for the
screening as a primary tool for evaluation of new compounds
nucleolytic activity. Our objective was to nd the DNA cleavers
seems to be justied only if applied to dozens of different
for developing new anticancer drugs based on the quinoline–
targets, as testing against a single target could result in a waste
chalcone skeleton.
of precious potential of new chemical entities with potentially
important biological properties.
Results and discussion
Synthesis
Drug development has, for the most part, been based on the
non-covalent interaction of small organic molecules (agonists
and antagonists) with specic protein targets to elicit a desired
pharmacological response. In many instances however, func-
tionally orthogonal proteins can share structural features and/
or mechanisms of action. This can result in unwanted side-
effects if a drug binds indiscriminately to proteins other than
By far the most popular way of synthesising chalcones consists
of base-catalyzed Claisen–Schmidt condensation of an appro-
priate acetophenone with benzaldehydes.24 A number of reports
have been published on the comparative studies of chalcone
synthesis under both acidic and alkaline conditions.25 In an
the one for which it was intended.27
ongoing project on the synthesis of a quinoline anticancer drug,
we have selected 2-chloro-3-formyl-quinoline as the starting
DNA-binding studies of 3-(2-chloroquinolin-3-yl)-1-
material in the present investigation (Scheme 1).26 2-Chloro-3-
phenylprop-2-en-1-ones
formyl-quinoline thus obtained was conrmed by 1H NMR and
13C NMR spectral data. 2-Chloro-3-formyl-quinoline shows a
The DNA-binding modes of these QCs were investigated by
absorption spectroscopy, uorescence and viscosity measure-
ments. Electronic absorption spectroscopy has been widely
singlet at d 10.54 ppm for an aldehydic (HC]O) proton, a
singlet at d 8.73 ppm for a proton C-4 position of the quinoline
moiety, a set of doublets at d 8.06–8.04 (d, 1H), d 7.98–7.96
Table 1 Scope of 3-(2-chloroquinolin-3-yl)-1-phenylprop-2-en-1-
one
Productsa
R
Time (min)
Yieldb (%)
M.P. (ꢁC)
3a
3b
3c
3d
3e
3f
H
60–120
60–120
60–120
60–120
60–120
60–120
60–120
60–120
85
87
80
82
85
88
80
73
180–182 (ref. 29)
151–153
226–228
178–181
170–173
187–189
165–167
172–175
p-CH3
p-OCH3
p-OH
p-Cl
p-Br
p-NO2
p-NHMe
3g
3h
a
All the products were characterized by elemental analysis, 1H NMR 13
NMR and mass spectral studies. b Yields of isolated products.
C
Scheme 1
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employed to determine the binding characteristics of small Further, Fig. 1(b) shows the interaction of 3d with CT-DNA at
molecules with DNA. The DNA concentration per nucleotide 410 nm. The intrinsic binding constants Kb of 2-chloro-3-qui-
was determined by absorption spectroscopy using the molar nolinyl-3-phenylpropen-2-ones with CT-DNA were determined
absorption coefficient (6600 Mꢀ1 cmꢀ1) at 260 nm.28 Relative and are presented in Table 2 (eqn 1, cf. ESI†).
binding of the QC to calf-thymus (CT-DNA) was studied by
When CT-DNA was added to the complex solutions, the
uorescence and viscosity measurements with CT-DNA solution electronic absorption spectra of QCs exhibited detectable
in Tris–HCl/NaCl buffer (pH 7.2) at room temperature.29
hypochromism in the absorption intensities in all the chalcones
studied. The percentage hypochromism of 3c and 3d was found
to be 20.5 and 23.7%, respectively. The intrinsic binding
constants of 3c and 3d were found to be 2.8 ꢂ 104 Mꢀ1 and 1.9
ꢂ 104 Mꢀ1, respectively. The observed Kb values of QCs were
compared with classical intercalators (Fig. 1 and Table 2).29c,30
The resulting values suggested that the stacking interaction
between the QCs and the base pairs of DNA has intercalative
binding.
Absorption spectral studies
Electronic absorption spectroscopy is an effective method for
examining the binding mode of DNA with organic molecules.28
If the binding mode was intercalation, the p* orbital of the
intercalated ligand can couple with the p orbital of the base
pairs, thus decreasing the p–p* transition energy and resulting
in bathochromism. On the other hand, the coupling p orbital
was partially lled by electrons, thus decreasing the transition
probabilities and concomitantly resulting in hypochromism.28a
The interaction of 3c with CT-DNA was monitored by the blue
shi in UV-visible spectra. The maximum wavelength of 3c was
observed at 390 nm when it was mixed with CT-DNA [Fig. 1(a)].
Fluorescence studies
To further clarify the binding of quinolinyl chalcone 3d with
DNA, the emission spectra were recorded in the absence and
presence of CT-DNA, as shown in Fig. 2. The emission intensity
increased apparently when CT-DNA was added to the solution
(Fig. 2), indicating that the emission of this ligand was
‘switched-on’ by the DNA solution. The quenching constants K
of QCs (3a–h) were calculated according to the classical Stern–
Volmer equation (eqn 2, cf. ESI†).31 The uorescence quenching
curves of QCs are shown in Fig. 3 (cf. ESI†). At a ratio of [DNA]/
[QC] ¼ 4.0, the emission intensity is saturated and the relative
emission intensity (r ¼ I/I0) is ca. 1.8. This behavior may be
explained by the fact that the bound cations of 3d are protected
from the anionic water-bound quencher by an array of negative
charges along the DNA phosphate backbone.31 The uorescence
indicated that QCs bind to DNA by intercalation.
Fig. 1 (a) UV absorption spectra of 3c upon addition of calf-thymus Viscosity measurements
(ds) DNA. 3c; control [DNA] ¼ 0.5 mM [
20 mM [ ]; 30 mM [ ]; 40 mM [
shows the absorbance changing upon the increase of DNA concen-
], [3c] + [DNA] ¼ 10 mM [
];
The results of the electronic absorption spectroscopy and uo-
rescence studies clearly indicate the strong binding of the QCs
] DNA, respectively. The arrow
tration. The inner plot of [DNA]/(3a ꢀ 3f) vs. [DNA] for the titration of to the DNA. The viscosity experiments, being sensitive to the
DNA with 3c. (b) UV absorption spectra of 3d upon addition of calf-
change of length of double helix DNA, were considered as one of
thymus (ds) DNA. 3d; control [DNA] ¼ 0.5 mM [
], [3d] + [DNA] ¼ 10
the most unambiguous methods to determine the binding
mode of the complex to DNA in the absence of crystal data.32,33
In general, the relative viscosity of DNA in the presence of a
ligand in an intercalation mode will be increased, because it
mM [ ]; 20 mM [ ]; 30 mM [ ]; 40 mM [
]; 50 mM [ ] DNA,
respectively. The arrow shows the absorbance changing upon the
increase of DNA concentration. The inner plot of [DNA]/(3a ꢀ 3f) vs.
[DNA] for the titration of DNA with 3d.
Table 2 The data of binding, docking energy, inhibition constants and DNA binding constant by docking and absorption spectral studies
Docking energy
Nucleotide residues
involved in H-bond
Entry
(kcal molꢀ1
)
Inhibition constant (M)
Bond length (A)
RMSD
DNA binding constant Kb
˚
3a
3b
3c
3d
3e
3f
ꢀ9.28
ꢀ9.53
ꢀ22.71
ꢀ22.72
ꢀ9.16
ꢀ9.2
5.72 ꢂ 10ꢀ7
5.4 ꢂ 10ꢀ7
DT7 DT19
DT18
CBR9
DA5
DT7 DT19
DT20
2.77 2.56
2.69
2.05
2.22
2.48 2.69
2.05
1.1
1.0
0.4
0.3
1.3
1.5
1.2
0.2
5.2 ꢂ 104 Mꢀ1
4.9 ꢂ 104 Mꢀ1
2.8 ꢂ 104 Mꢀ1
1.9 ꢂ 104 Mꢀ1
5.13 ꢂ 104 Mꢀ1
4.2 ꢂ 104 Mꢀ1
4.91 ꢂ 104 Mꢀ1
3.5 ꢂ 104 Mꢀ1
1.49 ꢂ 10ꢀ16
1.42 ꢂ 10ꢀ16
5.62 ꢂ 10ꢀ7
4.68 ꢂ 10ꢀ7
5.31 ꢂ 10ꢀ7
1.45 ꢂ 10ꢀ16
3g
3h
ꢀ9.44
ꢀ8.45
DT18
DA5
2.45
2.02
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Thus, the viscosity measurements supported the above results
that the stacking interaction of these QCs with the base pairs of
DNA lengthens the DNA helix, indicating that these QCs may
bind to calf thymus DNA in a nonclassical intercalation mode.
DNA docking studies
Molecular docking techniques are an attractive scaffold to
understand the drug–DNA interactions in rational drug design,
as well as in the mechanistic study by placing a small molecule
into the binding site of the target specic region of the DNA
mainly in a non-covalent fashion.28a
In the present study, the quinolinyl chalcones were screened
for targeted ds-DNA base pairs d(CGCGAATTCGCG)2 dodeca-
mer (PDB ID: 1BNA) and provide an energetically favorable
docked pose that is shown in Fig. 5 and Table 2. The result
shows that quinolinyl chalcones 3c and 3d showed the highest
affinity ꢀ22.71 and ꢀ22.72 kcal molꢀ1 docking energy, 1.49 ꢂ
10ꢀ16 and 1.42 ꢂ 10ꢀ16 estimated inhibition constants with an
RMSD of 0.4 and 0.3 compared to the other derivatives. Fig. 5a
and b show that the quinolinyl chalcones 3c and 3d were
completely enfolded in the entire binding pocket of ds-DNA. In
this model, it is clearly indicated that compound 3d formed a
hydrogen bond between –OH and N1 of adenine, which is DA5
Fig. 2 The emission spectra of quinolinyl chalcone (3d) in the pres-
ence and absence of CT-DNA.
with a bond length of 2.22 A (Fig. 6a).34 The molecular docking
˚
studies of QC 3h show two hydrogen bonds at N1 and N9 of
adenine, respectively (Fig. 6b) (cf. ESI†).31
Fig. 3 The fluorescence quenching curves of QC (3a–g) in the pres-
ence and absence of CT-DNA.
separates the base pairs of DNA, and thus lengthens the DNA
helix. The experiments on the relative viscosity of rod-like CT-
DNA in the presence of QC (3a–g), analyzed as a plot of the cubic
root of the relative viscosity of the solution versus the ligand-to-
DNA ratio r and compared with the results obtained with
ethidium bromide, i.e. a typical intercalator, under identical
conditions were carried out and the results are shown in Fig. 4.
Fig. 5 View of the energy minimized docked poses of QC 3c, 3d, 3e
and 3h with DNA d(CGCGAATTCGCG)2 (PDB ID: 1BNA).
Fig. 4 Relative specific viscosity of CT-DNA in the presence of QCs Fig. 6 (a) A molecular docked model of QC 3d showing chemically
(3a–g) and ethidium bromide [—] as a function of the ligand-to-DNA significant hydrogen-bonding interactions with DNA
d(CGCGAATTCGCG)2 (PDB ID: 1BNA).
ratio, cDNA ¼ 1 mM bp in phosphate buffer.
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Moreover, the other derivatives of QC formed less H-bond 3d can almost promote about 70% conversion of DNA from
interaction with the DNA due to the orientation of the aromatic Form I to II (Fig. 7). Fig. 8 shows the DNA cleavage of pUC19
ring involved in van der Waals interactions (Wireframe model) DNA at 60 mM concentration. However, other derivatives exhibit
and at hydrophobic regions of the binding sites of DNA much lower cleaving efficiency for pUC 19 DNA. Compound 3h
(Table 2). Thus, we can conclude that there is a mutual shows a moderate binding constant compared to other deriva-
complement between spectroscopic techniques and molecular tives, but it fails in DNA cleavage studies. Even at the concen-
docking, which can provide valuable information about the tration of 80 mM, it can promote only 40% conversion of DNA
mode of interaction of the QCs with DNA and the conformation from Form I to II (Fig. 9). Compound 3c also shows similar DNA
constraints for adduct formation.34
cleavage activity compared to the other derivatives. But at
higher concentrations around 140 mM, the compounds get
precipitated and there is no movement in the DNA. This reveals
that quinolinyl chalcone nuclease is capable of accelerating the
cleavage of plasmid DNA which is purely concentration
dependent. The percentage of DNA cleavage with different
concentrations of QCs (20–100 mM) is shown in Fig. 10. At the
concentrations of 20 mM and 40 mM, QCs can almost promote 8
and 24% conversion of supercoiled DNA to nicked form DNA.
Even at 60 mM concentration, the QCs can exhibit about 50%
conversion of Form I to II. However, at the 80 mM concentration,
the QCs promoted almost 70% conversion supercoiled DNA to
nicked and 24% linear DNA. Also, the electrophoresis experi-
ment showed that the plasmid DNA cleavage depends on the
substituent of the molecule. Excited states of QCs are known to
photocleave DNA by H-abstraction mechanisms.35c,d The alkoxy
groups are highly reactive radicals, which abstract hydrogen
atoms efficiently at C-40 of 2-deoxyribose. It is of interest to note
DNA photocleavage studies
The H abstraction from C-40 is the most important process in
DNA cleavage. The gel electrophoresis was an effective method
for examining the DNA cleavage studies.35a,b When circular
plasmid DNA is subjected to electrophoresis, relatively fast
migration will be observed for the intact supercoil form (Form
I). If scission occurs on one strand (nicking), the supercoil will
relax to generate a slower-moving open circular form (Form II).
If both strands are cleaved, a linear form (Form III) that
migrates at rates between Form I and Form II will be gen-
erated.35b,c Fig. 7 shows gel electrophoresis separation of pUC19
DNA aer incubation with different concentrations of quino-
linyl chalcones and irradiated for 2 h, in 1 : 9 DMSO/Tris buffer
(20 mM, pH-7.2) at 365 nm. No DNA cleavage was observed for
the control in which quinolinyl chalcones were absent (lane 1)
(Fig. 7). With increasing concentration of these quinolinyl
chalcones (lanes 2–9), the amount of Form I of pUC 19 DNA
diminished gradually, whereas Form II increased (Fig. 7).
On the other hand, the QC (3a–g) exhibited different cleaving
efficiencies for the plasmid DNA. At 40 mM concentration, the
compound (3d) can promote only 24% conversion of DNA from
Form I to II (Fig. 7). At the concentration of 80 mM, compound
Fig. 9 Light-induced cleavage of DNA by quinolinyl chalcones at
365 nm. Supercoiled DNA runs at position I (SC), linear DNA at position
III (LC) and nicked DNA at position II (NC). Lane 1: control DNA (without
compound), Lane 2: 80 mM (3a), Lane 3: 80 mM (3b), Lane 4: 80 mM (3c),
Lane 5: 80 mM (3d), Lane 6: 80 mM (3e), Lane 7: 80 mM (3f), Lane
8: 80 mM (3g), and Lane 9 60 mM (3h).
Fig.
7 Light-induced DNA cleavage by quinolinyl chalcones at
different concentrations. 2-Chloro-3-quinolinyl-3-phenylpropen-2-
ones were irradiated with UV light at 365 nm. Lane 1: control DNA
(without compound), Lane 2: 20 mM (3d), Lane 3: 40 mM (3d), Lane 4:
60 mM (3d), and Lane 5: 80 mM (3d).
Fig. 8 Light-induced cleavage of DNA by quinolinyl chalcones at 365
nm. Lane 1: control DNA (without compound), Lane 2: 60 mM (3a), Lane Fig. 10 Plot representation of the percentage of pUC 19 DNA
3: 60 mM (3b), Lane 4: 60 mM (3c), Lane 5: 60 mM (3d), Lane 6: 60 mM cleavage with different concentrations of quinolinyl chalcones
(3e), Lane 7: 60 mM (3f), Lane 8: 60 mM (3g), and Lane 9: 60 mM (3h).
(20–100 mM) at 37 ꢁC.
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that the hydroxyl group has been reported to bring about oxygen the oxygen atom of the methoxy group delocalizes into the p
radical mediated DNA damage in the presence of space of the benzene ring, thereby increasing the activity.
photoirradiation.
Similarly, electron-withdrawing substituents, such as halogens,
Hence, the mechanism of cleavage of DNA by these QCs is lower the activity. Quinoline chalcones with 4-hydroxy and 4-
most probably due to oxygen radical intermediate (hydroxy methoxy A rings show the highest cytotoxicities, as expected for
radical) abstracting hydrogen from the C-40 position of the DNA photocleavage studies. Replacement of a hydrogen or
deoxyribose sugar and subsequent cleavage of the phospho- hydroxyl group by a halogen atom is a strategy widely used in
diester backbone as shown in Fig. 11. Calculations show that drug development to alter the biological function.37 However
the (40) C–H bond is the weakest in 2-deoxyribose and the most the result shows that the activity of halogen substituted QC (3e)
sterically exposed in B-DNA. The molecules having halogen and was signicantly lower. Therefore, designing chalcone deriva-
nitro groups are less active compared to others.
tives with electron-withdrawing substituents on ring A increases
the DAN binding and cleavage activity. The observed and pre-
dicted analysis results of quinolinyl chalcone derivatives are
presented in Table 3.
Structure–activity relationship by in silico analysis
The structure–activity relationship is the relationship of the
chemical structure and biological activity of a drug molecule.
The study involving the structural modication of the drugs
with the systematic fashion and determination of undesired
effects or low bioactivity. Osiris Property Explorer is one such
knowledge based activity prediction tool which predicts drug
likeliness, drug score and undesired properties such as muta-
genic, tumorigenic, irritant and reproductive effects of novel
compounds based on chemical fragment data of available drugs
and non-drugs as reported.36
Conclusion
In summary, we have synthesized substituted quinolinyl chal-
cones and evaluated their nucleolytic activity. The binding
behavior of QCs with DNA was studied by UV spectra, viscosity,
uorescence and gel retardation assay under physiological
conditions. Moreover, the DNA docking studies suggested that
samples 3c and 3d were completely enfolded in the entire
binding pocket of ds-DNA (Fig. 5a and b, respectively). Thus, an
available proton donor in the B ring, which is involved in
intramolecular hydrogen bonding with N1 of adenine, plays a
crucial role in the DNA binding studies of QCs. All the experi-
mental evidence indicates that these QCs can strongly bind to
CT DNA via an intercalation mechanism. Furthermore, we
clearly demonstrated that efficient DNA damage may be
induced on irradiation of QCs of 3c and 3d with pUC19 DNA.
Upon photoirradiation, compounds 3c and 3d are highly reac-
tive radicals which abstract hydrogen atoms efficiently at C-40 of
2-deoxyribose of B DNA. Results obtained from our present
work would be very useful to understand the mechanism of
interactions of the small molecules binding to DNA and helpful
in the development of their potential applications in biological,
pharmaceutical and physiological elds in the future.
Quinolinyl chalcones with an electron-donating substituent
like hydroxy and methoxy groups on ring A increase DNA
binding and DNA cleavage activity. A lone pair of electrons on
Fig. 11 Hydrogen abstraction from C-40 of DNA sugar.
Experimental
Materials and equipment
Table 3 Drug likeliness properties of synthesized (E)-3-(2-chlor-
oquinolin-3-yl)-1-phenylprop-2-en-1-ones (3a–3h).36
All the chemicals used in the present study were of AR grade.
Whenever analytical grade chemicals were not available, labo-
ratory grade chemicals were puried and used. Calf thymus
DNA (CT DNA) and supercoiled pUC19 DNA (cesium chloride
puried) were obtained from Bangalore Genei (India). Agarose
(low melt, 65 ꢁC, molecular biology grade for DNA gels),
ethidium bromide, bromophenol blue, Tris(hydroxymethyl)
aminomethane (Tris), sodium chloride, ethylene diamine tet-
raacetic acid disodium salt (EDTA-Na2), and sodium azide were
of molecular biology grade and were obtained from Himedia
(India).
Toxicity risksa
Mol.
Entry wt
Drug-
Drug-
C log P likeliness score
Mb
Tc
Id
Re
3a
3b
3c
3d
3e
3f
293
307
323
309
327
371
340
322
4.32
4.67
4.25
3.98
4.93
5.05
3.72
3.92
0.58
0.34
1.32
1.66
3.26
0.49
0.42
0.53
0.60
0.46
0.25
0.18
0.30
(+)
(+)
(+)
(+)
(+)
(+)
(+)
(+)
(+)
(+)
(+)
(+)
(+) (+)
(+) (+)
(+) (+)
(+) (+)
(+) (+)
(+) (+)
(+) (ꢀ)
ꢀ1.82
3g
3h
1.28
(ꢀ) (+)
0.64
(+)
(ꢀ) (+) (+)
Melting points were recorded on an open capillary tube with
a
Ranking as (+) no bad effect, (+/ꢀ) medium bad effect, and (ꢀ) bad
a
Buchi melting point apparatus and are uncorrected.
Elemental analyses were carried out using a Perkin-Elmer 240C
CHN-analyzer. IR spectra were recorded on FT-IR
b
c
d
effect. M (mutagenic effect). T (tumorigenic effect). I (irritant
effect). e R (reproductive effect).
a
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spectrophotometer. 1H-NMR spectra were obtained at 300 MHz
C
19H14ClNO2: C, 70.48; H, 4.36; N, 4.33. Found: C, 70.46; H,
and 400 MHz on a Bruker spectrometer (chemical shis in d 4.34; N, 4.31.
ppm). Mass spectra were recorded using a microspray Q-TOF
MS ES Mass spectrometer.
(E)-3-(2-Chloroquinolin-3-yl)-1-(4-hydroxyphenyl)prop-2-en-1-
one (3d)
General procedure for the preparation of 3-(2-chloroquinolin-
3-yl)-1-phenylprop-2-en-1-ones
M.p.: 178–181 ꢁC; IR (Neat): 1653 (C]O), 1459 (C]C) cmꢀ1; 1H
NMR (400 MHz, CDCl3): d ¼ 6.92–6.94 (d, 2H, J ¼ 8.0, Ar-H),
6.96–7.00 (d, 1H, Ha, J ¼ 16.0), 7.05–7.07 (d, 1H, J ¼ 8.0, Ar-H),
7.49–7.51 (d, 1H, J ¼ 8.0), 7.51–7.53 (d, 1H, J ¼ 8.0), 7.71–7.88 (t,
1H, J ¼ 8.0), 7.92–7.96 (d, 1H, Ha, J ¼ 16.0), 8.00–8.17 (t, 1H, J ¼
8.0), 8.31–8.35 (d, 1H, Hb, J ¼ 16.0), 8.79 (s, 1H), 10.45 (OH, 1H)
ppm; 13C NMR (400 MHz, CDCl3): d ¼ 113.8, 126.1, 126.8, 127.5,
127.8, 128.1, 128.3(Cq), 130.3(Cq), 130.9(Cq), 131.3(Cq), 135.9,
138.3(Cq), 147.6(Cq), 150.2(Cq), 163.6(Ar-O), 187.8 (C]O) ppm;
MS (m/z) 332 (M + 23), calcd (309), found (332); anal. calcd (%)
for C18H12ClNO2: C, 69.80; H, 3.90; N, 4.52. Found: C, 69.78; H,
3.88; N, 4.53.
A stirred solution of acetophenone (0.6 g, 5.2 mmol) and (1.0 g,
5.2 mmol) 2-chloro-3-formylquinoline was dissolved in 10 mL
95% ethanol containing 2 mL 2.5 M NaOH (aq). The resulting
solution was stirred at room temperature and within ve
minutes the mixture was precipitated. Aer one hour, the
ꢁ
reaction mixture was kept overnight at 0–5 C and then it was
poured into cold water, and ltered, and the solid was rinsed
with water and cold ethanol. The crude product thus obtained
was recrystallized from MeOH to obtain the desired product
(Scheme 1 and Table 1).
(E)-3-(2-Chloroquinolin-3-yl)-1-phenylprop-2-en-1-one (3a)38
(E)-3-(2-Chloroquinolin-3-yl)-1-(4-chlorophenyl)prop-2-en-1-
one (3e)
M.p.: 180–182 ꢁC; IR (Neat): 1680 (C]O), 1559 (C]C) cmꢀ1; 1H
NMR (400 MHz, CDCl3): d ¼ 7.45–7.56 (d, 2H, J ¼ 8.0, Ar-H),
7.61–7.64 (t, 1H, J ¼ 8.0), 7.76–7.77, (d, 1H, J ¼ 8.0), 7.78–7.79 (d, M.p.: 170–173 ꢁC; IR (Neat): 1604 (C]O), 1459 (C]C) cmꢀ1; 1H
1H, J ¼ 8.0, Ar-H), 7.86–7.90 (d, 1H, Ha, J ¼ 16.0), 7.96–7.98 (d, NMR (400 MHz, CDCl3): d ¼ 7.24–7.28 (d, 1H, J ¼ 8.0), 7.40–7.42
1H, J ¼ 8.0), 8.07–8.17 (d, 1H, J ¼ 8.0), 8.19–8.23 (d, 1H, Hb, J ¼ (d, 2H, J ¼ 8.0), 7.59–7.63 (t, 1H, J ¼ 8.0), 7.78–7.82 (d, 1H, Ha, J
16.0), 8.53 (s, 1H) ppm; MS (m/z) 316 (M + 23), calcd (293), found ¼ 16.0), 7.94–7.97 (d, 2H, J ¼ 8.0, Ar-H), 8.04–8.06 (d, 1H, J ¼
(316); anal. calcd (%) for C18H12ClNO: C, 73.60; H, 4.12; N, 4.77. 8.0), 8.17–8.19 (d, 2H, J ¼ 8.0, Ar-H), 8.32–8.36 (d, 1H, Hb, J ¼
Found: C, 73.58; H, 4.10; N, 4.75.
16.0), 8.62 (s, 1H) ppm; 13C NMR (400 MHz, CDCl3): d ¼ 119.6,
119.7, 127.0, 127.1, 128.0, 128.9, 128.9, 129.9(Cq), 130.1(Cq),
134.4(Cq), 136.2(Cq), 137.0, 139.8(Cq), 146.3(Cq), 150.3(Cq–Cl),
196.5 (C]O) ppm; MS (m/z) 350 (M + 23), calcd (327), found
(350); anal. calcd (%) for C18H11Cl2NO: C, 65.87; H, 3.38; N, 4.27.
Found: C, 65.85; H, 3.36; N, 4.25.
(E)-3-(2-Chloroquinolin-3-yl)-1-(4-methylphenyl)prop-2-en-1-
one (3b)
M.p.: 151–153 ꢁC; IR (Neat): 1662 (C]O), 1487 (C]C) cmꢀ1; 1H
NMR (400 MHz, CDCl3): d ¼ 2.43 (s, 3H, CH3), 7.30–7.32 (d, 2H, J
¼ 8.0, Ar-H), 7.35 (d, 1H, J ¼ 8.0, Ar-H), 7.57–7.58 (d, 1H, J ¼ 8.0),
7.59–7.64 (d, 1H, Ha, J ¼ 16.0), 7.73–7.77 (t, 1H, J ¼ 8.0), 7.85–
7.88 (t, 1H, J ¼ 8.0), 7.95–7.97 (d, 1H, J ¼ 8.0), 7.99–8.01 (d, 1H, J
¼ 8.0), 8.14–8.18 (d, 1H, Hb, J ¼ 16.0), 8.50 (s, 1H) ppm; 13C NMR
(400 MHz, CDCl3): d ¼ 42.3 (CH3), 126.2, 126.9, 127.2, 127.9,
128.5, 128.6(Cq), 131.5, 133.2, 134.8(Cq), 137.4(Cq), 139.2(Cq),
146.2(Cq), 147.7(Cq), 150.3(Cq), 150.5(Cq), 189.7 ppm; MS (m/z)
330 (M + 23), calcd (307), found (330); anal. calcd (%) for
(E)-3-(2-Chloroquinolin-3-yl)-1-(4-bromophenyl)prop-2-en-1-
one (3f)
M.p.: 187–189 ꢁC; IR (Neat): 1607 (C]O), 1511 (C]C) cmꢀ1; 1H
NMR (400 MHz, CDCl3): d ¼ 7.37–7.39 (d, 1H, J ¼ 8.0, Ar-H),
7.57–7.60 (t, 1H, J ¼ 8.0), 7.74–7.76 (d, 1H, J ¼ 8.0), 7.79–7.81 (d,
2H, J ¼ 8.0, Ar-H), 7.82–7.86 (d, 1H, Ha, J ¼ 16.0), 7.98–7.80 (d,
1H, J ¼ 8.0), 8.14–8.16 (d, 1H, J ¼ 8.0), 8.29–8.33 (d, 1H, Hb, J ¼
16.0), 8.51 (s, 1H) ppm; MS (m/z) 395 (M + 23), calcd (372), found
(395); anal. calcd (%) for C18H11BrClNO: C, 58.02; H, 2.98; N,
3.76. Found: C, 58.00; H, 2.96; N, 3.74.
C
19H14ClNO: C, 74.15; H, 4.58; N, 4.55. Found: C, 74.13; H, 4.56;
N, 4.53.
(E)-3-(2-Chloroquinolin-3-yl)-1-(4-methoxyphenyl)prop-2-en-1-
one (3c)
(E)-3-(2-Chloroquinolin-3-yl)-1-(4-nitrophenyl)prop-2-en-
1one (3g)
M.p.: 226–228 ꢁC; IR (Neat): 1656 (C]O), 1570, 1511 (C]C)
cmꢀ1; 1H NMR (400 MHz, CDCl3): d ¼ 3.90 (s, 3H, OCH3), 6.99–
7.01 (d, 2H, J ¼ 8.0, Ar-H), 7.60–7.64 (2d, 2H, J ¼ 8.0, Ar-H), 7.75– M.p.: 165–167 ꢁC; IR (Neat): 1658 (C]O), 1523 (C]C) cmꢀ1; 1H
7.79 (t, 1H, Ha, J ¼ 16.0), 7.87–7.89 (d, 1H, J ¼ 8.0), 8.01–8.03 (d, NMR (400 MHz, CDCl3): d ¼ 7.25–7.28 (t, 1H, J ¼ 8.0), 7.35–7.37
1H, J ¼ 8.0), 8.06–8.08 (d, 1H, J ¼ 8.0), 8.15–8.19 (d, 1H, Hb, J ¼ (d, 1H, J ¼ 8.0), 7.58–7.61 (t, 1H, J ¼ 8.0), 7.73–7.75 (d, 1H, J ¼
16.0), 8.50 (s, 1H), ppm; 13C NMR (400 MHz, CDCl3): d ¼ 52.32 8.0, Ar-H), 7.81–7.83 (d, 1H, J ¼ 8.0, Ar-H), 7.85–7.89 (d, 1H, Ha, J
(OCH3), 110.7, 123.0, 123.7, 124.4, 124.7, 125.0, 125.2(Cq), ¼ 16.0), 8.03–8.05 (d, 1H, J ¼ 8.0), 8.19–8.23 (d, 1H, Hb, J ¼ 16.0),
127.2(Cq), 127.8(Cq), 128.2(Cq), 132.8, 135.2(Cq), 144.5(Cq), 8.60 (s, 1H) ppm; MS (m/z) 361 (M + 23), calcd (338), found (361);
147.1(Cq), 160.5(Ar-O), 184.7 (C]O) ppm; MS (m/z) 346 anal. calcd (%) for C18H11ClN2O3: C, 63.82; H, 3.27; N, 8.27.
(M + 23), calcd (323), found (346); anal. calcd (%) for Found: C, 63.80; H, 3.25; N, 8.25.
1714 | Med. Chem. Commun., 2014, 5, 1708–1717
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CT-DNA solution (1 mM base pair in the Tris–HCl buffer). Flow
times were measured aer a thermal equilibration period of 5
min. Each ow time was measured three times and an average
ow time value was calculated. As a reference, ethidium
bromide was employed under identical conditions. The relative
(E)-3-(2-Chloroquinolin-3-yl)-1-(4-(methylamino)phenyl)prop-
2-en-1-one (3h)
M.p.: 165–167 ꢁC; IR (Neat): 1647 (C]O), 1590, 1552 (C]C)
cmꢀ1; 1H NMR (400 MHz, CDCl3): d ¼ 4.875 (S, NHCH3), 7.33–
7.35 (d, 1H, J ¼ 8.0), 7.38–7.40 (d, 1H, J ¼ 8.0), 7.41–7.42 (d, 2H, J
¼ 8.0, Ar-H), 7.58–7.63 (t, 1H, J ¼ 8.0), 7.75–7.79 (t, 1H, J ¼ 8.0),
7.95 (d, 1H, Ha, J ¼ 16.0), 8.03–8.05 (d, 1H, J ¼ 8.0, Ar-H), 8.06–
8.10 (d, 1H, Hb, J ¼ 16.0), 8.61 (s, 1H) ppm; 13C NMR (400 MHz,
CDCl3): 13C NMR (400 MHz, CDCl3): d ¼ 33.1 (CH3), 117, 120.0,
123.4, 124.5, 127.0, 127.4, 127.6, 128.2(Cq), 128.3, 130.0(Cq),
131.2(Cq), 136.8(Cq), 138.1(Cq), 147.1(Cq), 149.9(Cq),
186.1 ppm.
viscosity was presented as (h/h0)1/3
.
Molecular docking28
The quinolinyl chalcones were designed and the structures were
analyzed using Chem-Draw Ultra 6.0 and they were subjected to
geometrical optimization using MM2 and the energy was
minimized by the steepest gradient method in Chem3D ultra
6.0. The nal selected conformation of quinolinyl chalcones
was tested for Lipinski's rule, drug toxicity and other properties
through a preADMET server. The small-molecule topology
generator prodrug server automatically generates the coordi-
nates for all the quinolinyl chalcones. Automated docking was
used to determine the orientation of inhibitors that bind to the
ds-DNA. A genetic algorithm method, implemented in the
program Auto-Dock 3.0, was employed. The crystal structure of
the B-DNA dodecamer, d(CGCGAATTCGCG)2 (NBD code
GDLB05), was obtained from the protein data bank. The coor-
dinates for the heteroatom including water and other small
molecules were removed. This structure was later added with
polar hydrogen and Kollman charges to remove nonintegral
charges. For docking calculations, Gasteiger Marsili partial
charges were assigned to the quinolinyl chalcones and nonpolar
hydrogen atoms were merged. All torsions were allowed to
rotate during docking. Lennard-Jones parameters 12-10 and 12-
6, supplied with the program, were used for modelling H-bonds
and van der Waals interactions, respectively. The distance-
dependent dielectric permittivity of Mehler and Solmajer was
used to calculate the electrostatic grid maps. Random starting
points, random orientation, and torsions were used for all
ligands. The translation, quaternion, and torsion steps were
taken from default values using Auto-Dock. The Lamarckian
genetic algorithm and the pseudo-Solis and Wets methods were
applied for minimization, using default parameters. The
number of docking runs was 50, the population in the genetic
algorithm was 250, the number of energy evaluations was
100 000, and the maximum number of iterations was 10 000.
UV-visible absorbance spectral studies28
All the experiments involving the interaction of the quinolinyl
chalcones with CT-DNA were carried out in doubly distilled H2O
buffer containing 5 mM Tris and 50 mM NaCl and adjusted to
pH-7.2 with Tris–HCl buffer. A solution of CT-DNA gave a ratio
of UV absorbance at 260 and 280 nm of about 1.8–1.9, indi-
cating that the CT-DNA was sufficiently free of protein. The CT-
DNA concentration per nucleotide was determined spectro-
photometrically by employing an extinction coefficient of 6600
Mꢀ1 cmꢀ1 at 260 nm. The quinolinyl chalcones were dissolved
in a solvent mixture of 10% DMSO and 90% Tris–HCl buffer
(5 mM Tris–HCl, 50 mM NaCl, pH-7.2) at a concentration of
10.0 ꢂ 10ꢀ6 M. An absorption titration experiment was per-
formed by maintaining the 10 mM compounds and varying the
concentration of nucleic acid. While recording the absorption
spectra, an equal amount of CT-DNA was added to both the
compound solution and the reference solution to eliminate the
absorbance of CT-DNA itself. The absorption data were analyzed
for an evaluation of the intrinsic binding constant Kb. The
observed values for the quinolinyl chalcones were then calcu-
lated by eqn (1) to obtain the intrinsic binding constant Kb.
Fluorescence spectra31
Fluorescence spectra were recorded on a Varian Cary Eclipse
Fluorescence
Spectrophotometer.
Spectrophotometric
measurements were performed in thermostatted quartz sample
cells of 10 mm path length at 20 ꢁC. The CT-DNA concentration
per nucleotide was determined spectrophotometrically by
employing an extinction coefficient of 6600 Mꢀ1 cmꢀ1 at
260 nm. The quinolinyl chalcones were dissolved in a solvent
mixture of 10% DMSO and 90% Tris–HCl buffer (5 mM Tris–
HCl, 50 mM NaCl, pH-7.2) at a concentration of 10.0 ꢂ 10ꢀ6 M.
The prepared solutions were placed into quartz cells and
titrated with the titrant solutions at intervals of 0.5–2 equivalent
and absorption spectra were recorded. All spectrophotometric
titrations were performed at least 2–3 times to ensure the
reproducibility.
DNA photocleavage by gel electrophoresis21a,28
For the gel electrophoresis experiments, supercoiled
pUC19DNA (0.5 mg) in Tris–HCl buffer (50 mM) with 50 mM
NaCl (pH 7.2) was treated with quinolinyl chalcones (40 and 80
mM) and the solution was irradiated for 2 h, in 1 : 9 DMSO: Tris
buffer (20 mM, pH 7.2) at 365 ꢁnm (10 W). Aer irradiation, the
solution was incubated at 37 C for 1 h. A loading buffer con-
taining 25% bromophenol blue, 0.25% xylene cyanol and 30%
glycerol was used. Electrophoresis was carried out for 3 h at 50 V
on a 0.8% agarose gel in Tris–boracic–EDTA buffer. The gel was
Viscometric titration
Viscosity measurements were carried out using a semimicro- stained with 1.0 mg mlꢀ1 ethidium bromide. Bands were visu-
dilution capillary viscometer at room temperature. Aliquots of alized using UV light and photographed. The cleavage efficiency
the solution of the ligand in Tris–HCl buffer were added to the was measured by determining the ability of the quinolinyl
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chalcones to convert the supercoiled DNA (SC) to nicked
circular form (NC) and linear form (LC).
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Acknowledgements
We thank Prof. H. S. Bhojya Naik, Kuvempu University for
providing lab facilities and we are grateful to the Indian Insti-
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