Synthesis and anticancer activity evaluation of resveratrol-chalcone conjugates

Article abstract of DOI:10.1039/c3md00329a

A series of novel resveratrol-chalcone conjugates have been synthesized. Four compounds were evaluated for their anticancer activity against 60 human cancer cell lines. Among all the derivatives, compound 70 was found to be the most active and showed high

Full text of DOI:10.1039/c3md00329a

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CONCISE ARTICLE
Synthesis and anticancer activity evaluation of
resveratrol–chalcone conjugates†
Cite this: Med. Chem. Commun., 2014,
5, 528
a
a
b
a
*
Deepak Kumar, K. Kranthi Raj, Sanjay V. Malhotra and Diwan S. Rawat
A series of novel resveratrol–chalcone conjugates have been synthesized. Four compounds were evaluated
for their anticancer activity against 60 human cancer cell lines. Among all the derivatives, compound 70 was
found to be the most active and showed high selectivity towards certain ovarian cancer, non-small cell lung
cancer and breast cancer cell lines with GI50 values in the range of 1.28–34.1 mM. Docking studies were
performed to determine the probable binding mode of these compounds in the colchicine–tubulin
binding site. A strong H-bonding interaction (1.852 A˚) was observed with Cys-241 amino acid present in
the binding pocket. Thus we believe that compound 70 may possibly be used as a lead for the
development of new anticancer agents.
Received 29th October 2013
Accepted 30th January 2014
DOI: 10.1039/c3md00329a
www.rsc.org/medchemcomm
associated with resveratrol offer promise for its potential in the
designing of new chemotherapeutic agents. However, resvera-
Introduction
trol is not a very potent cytotoxic compound when compared
with other chemotherapeutic drugs and requires a high dose to
induce apoptosis in cancer cells.28–30 Moreover, the therapeutic
value of resveratrol is also limited because of its poor bioavail-
ability, photosensitivity and metabolic instability.31,32 Therefore
efforts have been made to improve the pharmacokinetic prop-
erties of resveratrol and to extend its anticancer activity. To
achieve this goal, several synthetic analogues (Fig. 1) such as
3,5,40-trimethoxy-trans-stilbene (MR-3), 3,4,40,5-tetramethoxy
derivative of resveratrol (MR-4, DMU-212), 3,5,30,40,50-pentam-
ethoxy-trans-stilbene (MR-5), and 2,30,4,40,50-pentamethoxy-
trans-stilbene (PMS) have been synthesized and tested against a
variety of cancer cell lines in vitro and in vivo.33–37 It has been
observed that methoxy derivatives of resveratrol exhibit better
antiproliferative activity on cancer cell lines than their hydroxy-
lated counterparts.38–40
Cancer is one of the leading causes of death both in the devel-
oped and developing countries. The World Health Organisation
(WHO) reported approximately 12.7 million new cases and 7.6
million deaths due to cancer worldwide in 2008.1 In 2010, about
556 400 people died due to cancer in India and accounted for
8% of the 2.5 million total male deaths and 12% of the 1.6
million total female deaths in the age group of 30 to 69 years.2
Nature has been an important source of medicines since
ancient times and more than 60% of the anticancer drugs
approved are either natural products or natural product
analogues.3–5 Thus natural products represent a signicant
source of inspiration for the designing of new biologically
important molecules with improved pharmacological prole.
Phytochemicals such as resveratrol have received great
interest in drug discovery mainly due to its potent activity for
the treatment of various types of cancer and good safety prole.
Resveratrol (3,4,50-trihydroxy-trans-stilbene, Fig. 1) is found in a
wide variety of dietary sources such as grapes, plums, peanuts
and red wine.6,7 It has been shown to possess various biological
activities such as antileukemic, antibacterial, antifungal, anti-
inammatory, antioxidant, antiplatelet aggregation, antitumor
and antiaging.8–20 It affects all the three stages of carcinogenesis
(initiation, promotion and progression) by modulating signal
transduction pathways that control cell division and growth,
apoptosis, inammation, angiogenesis and metastasis.21–27 The
interesting chemopreventive and chemotherapeutic properties
Chalcones (1,3-diaryl-2-propen-1-ones) constitute another
important class of phytochemicals which have received much
attention due to their wide range of biological activities such as
anti-inammatory, antibacterial, antioxidant, antimalarial and
anticancer.41–48
aDepartment of Chemistry, University of Delhi, Delhi, 110007, India. E-mail:
dsrawat@chemistry.du.ac.in; Tel: +91-11-27667465
bLaboratory of Synthetic Chemistry, SAIC-Frederick Inc., National Cancer Institute at
Frederick, 1050 Boyles Street, Frederick, MD 21702, USA. Tel: +1-301-846-5141
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c3md00329a
Fig. 1 Resveratrol and its synthetic analogues as anticancer agents.
528 | Med. Chem. Commun., 2014, 5, 528–535
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Table 1 Single dose screening of the four selected compounds (49,
54, 56 and 70)
In recent years, the concept of hybrid drugs has gained more
attention in which two or more pharmacophores are linked
covalently resulting in one molecule. It is anticipated that such
an approach may solve the problem of drug resistance by
showing dual drug action.49 Using this approach, several
research groups have recently reported hybrid molecules by
coupling resveratrol with other biologically active molecules
such as coumarins, chalcones, curcumin, etc.50–52 In continua-
tion of our research program towards the synthesis of novel
bioactive molecules,53–64 we designed and synthesized a series of
resveratrol–chalcone conjugates and evaluated their anticancer
activity. Herein, we present the results of our investigation.
Growth percentage of cell lines in NCI 60
Cancer cell lines
49
54
56
70
Leukemia
CCRF-CEM
HL-60(TB)
K-562
MOLT-4
RPMI-8226
SR
97.18
103.56
100.55
86.26
96.17
104.02
91.01
97.67
19.59
92.19
87.30
92.54
99.17
82.37
94.37
87.83
92.57
102.29
85.57
21.46
14.43
9.62
ꢀ0.63
9.61
Non-small cell lung cancer
A549/ATCC
HOP-62
HOP-92
NCI-H226
NCI-H23
NCI-H322M
NCI-H460
NCI-H522
91.80
105.09
98.55
112.50
100.07
97.00
101.32
105.83
94.93
119.98
108.44
108.61
98.12
99.60
103.56
83.98
100.39
101.26
101.55
101.18
103.02
76.64
36.35
70.99
51.89
72.41
43.53
64.79
59.58
5.55
Chemistry
The synthetic route used for the preparation of resveratrol–
chalcone conjugates (14–70) is outlined in Schemes 1 and 2.
First, different substituted acetophenones (2–4) were
condensed with p-methyl benzaldehyde (1) in the presence of
40% NaOH to form a,b-unsaturated carbonyl compounds (5–7).
The methyl group was converted to CH2Br (8–10) by the reaction
of compounds 5–7 with N-bromosuccinimide (NBS) in the
presence of benzoyl peroxide using CCl4 as the solvent
(Scheme 1). Then the CH2Br group was reacted with PPh3 in
benzene to form Wittig salts (11–13), which were then treated
with different substituted benzaldehydes in the presence of 5%
aqueous NaOH in dichloromethane as the solvent to give
101.63
124.97
Colon cancer
COLO 205
HCC-2998
HCT-116
HCT-15
HT29
KM12
SW-620
111.35
99.90
93.31
101.43
93.04
96.26
102.41
107.01
94.08
95.83
102.43
103.77
104.19
104.07
107.25
105.46
97.48
68.15
94.11
17.54
33.62
36.23
29.24
39.27
90.07
104.11
100.46
99.83
CNS cancer
SF-268
SF-295
SF-539
SNB-19
SNB-75
U251
96.45
87.00
108.53
97.49
100.14
99.67
113.19
94.88
107.92
100.46
104.27
100.37
96.54
96.50
99.93
97.60
97.20
101.31
66.24
57.91
86.27
74.43
59.80
36.26
Melanoma
LOX IMVI
MALME-3M
M14
MDA-MB-435
SK-MEL-2
SK-MEL-28
SK-MEL-5
UACC-257
UACC-62
95.00
102.59
104.36
95.26
100.74
111.93
106.85
101.36
104.80
97.44
99.87
95.15
98.90
96.25
112.46
103.67
101.36
103.78
104.96
87.43
24.71
66.77
67.00
40.97
65.13
84.70
61.95
72.48
53.65
100.96
103.42
106.17
104.24
105.96
100.19
92.74
Scheme 1
Ovarian cancer
IGROV1
OVCAR-3
OVCAR-4
OVCAR-5
OVCAR-8
NCI/ADR-RES
SK-OV-3
NT
112.45
112.27
115.39
102.14
105.78
96.08
95.74
101.10
106.65
96.56
104.21
111.35
99.26
6.66
41.39
65.65
116.54
28.44
50.04
102.38
100.61
101.59
102.04
109.30
109.22
102.44
99.14
Renal cancer
786-0
A498
ACHN
CAKI-1
90.97
75.95
110.22
92.41
95.28
87.54
101.55
91.22
93.97
78.06
94.64
93.90
67.75
79.97
68.13
74.43
Scheme 2
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Table 1 (Contd.)
Table 2 Five dose screening results of compound 70
Growth percentage of cell lines in NCI 60
Cancer cell lines
GI50 (mM)
TGI (mM)
LC50 (mM)
Cancer cell lines
49
54
56
70
Leukemia
CCRF-CEM
HL-60(TB)
K-562
MOLT-4
RPMI-8226
SR
RXF 393
SN12C
UO-31
114.78
99.85
80.66
116.82
102.49
94.44
115.82
97.37
102.07
71.35
56.66
40.55
4.15
4.49
3.03
3.49
2.57
1.98
>100
>100
>100
>100
8.54
>100
>100
>100
>100
>100
>100
Prostate cancer
PC-3
DU-145
107.85
102.73
105.93
109.38
98.73
107.82
52.19
68.44
>100
Non-small cell lung cancer
A549/ATCC
HOP-62
NCI-H226
NCI-H23
NCI-H322M
NCI-H460
NCI-H522
Breast cancer
MCF7
MDA-MB-231/ATCC
BT-549
T-47D
MDA-MB-468
4.67
1.28
3.57
5.39
1.98
8.65
3.30
80.9
63.8
22.8
65.9
>100
>100
30.7
>100
>100
>100
>100
>100
>100
>100
89.51
117.45
93.37
83.42
112.99
93.87
116.15
101.12
93.84
93.02
103.34
102.70
81.59
30.55
76.77
41.56
43.35
51.90
112.38
110.49
Colon cancer
COLO 205
HCC-2998
HCT-116
HCT-15
HT29
KM12
SW-620
13.7
38.4
2.62
2.42
4.17
3.75
4.50
>100
>100
>100
>100
>100
83.9
>100
>100
>100
>100
>100
>100
>100
primarily trans-stilbenes (Scheme 2). The crude compounds
were puried by column chromatography using EtOAc/hexane
as an eluent to obtain pure trans-stilbenes (14–70).
>100
Experimental section
In vitro anticancer activity
CNS cancer
SF-268
SF-295
SF-539
SNB-19
SNB-75
U251
6.08
9.01
12.2
21.1
5.50
5.09
88.3
>100
78.3
>100
47.7
54.7
>100
>100
>100
>100
>100
>100
Out of all the synthesized compounds (14–70), four compounds
49, 54, 56 and 70 were selected by the National Cancer Institute
(NCI). The anticancer activity of the selected compounds was
evaluated using the NCI 60 human cancer cell line panel, which
consists of nine different cancer types: leukemia, lung, colon,
central nervous system, melanoma, ovary, kidney, prostate and
breast cancer (Table 1).
Melanoma
LOX IMVI
MALME-3M
M14
3.76
13.2
9.61
4.28
1.89
1.69
3.39
9.00
7.13
60.9
>100
>100
47.7
>100
>100
19.2
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
Details of the methodology for the NCI 60 cell line screening
are
available
at
http://dtp.nci.nih.gov/branches/btb/
MDA-MB-435
SK-MEL-2
SK-MEL-28
SK-MEL-5
UACC-257
UACC-62
ivclsp.html. Briey, the cells were grown in supplemented
RPM1 1640 medium for 24 h. The test compound was dissolved
in DMSO and incubated with cells at desired concentrations. In
the case of the ve dose study, the compound was dissolved in
ve concentrations with 10-fold dilutions, the highest being
10ꢀ4 M and the others being 10ꢀ5, 10ꢀ6, 10ꢀ7, and 10ꢀ8 M. The
assay was terminated by addition of cold trichloroacetic acid,
and the cells were xed and stained with sulforhodamine B.
The bound stain was solubilized, and the absorbance was read
on an automated plate reader. The cytostatic parameter, that is,
50% growth inhibition (GI50), was calculated from time zero,
control growth, and the absorbance of the ve concentration
levels. The cytotoxic parameter, that is, inhibitory concentra-
tions (LC50), represents the average of two independent
experiments. The in vitro screening is a two-stage process
starting with the evaluation of the compound against the 60
human tumor cell lines with a single dose of 10.0 mM, which is
done by following the same protocol as that used for the ve
dose screening. Only the compounds which show more than
60% of growth inhibition in at least 8 tumor cell lines are
selected for the ve dose testing.
Ovarian cancer
IGROV1
OVCAR-3
OVCAR-4
OVCAR-5
OVCAR-8
NCI/ADR-RES
SK-OV-3
9.24
3.92
6.31
34.1
3.76
5.46
15.6
76.4
14.3
47.3
>100
61.1
>100
64.5
>100
74.4
>100
>100
>100
>100
>100
Renal cancer
786-0
A498
10.4
18.6
11.6
14.6
8.01
9.61
4.64
71.1
>100
>100
>100
43.6
>100
>100
>100
>100
>100
>100
>100
>100
>100
ACHN
CAKI-1
RXF 393
SN12C
UO-31
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Table 2 (Contd.)
obtain ligand binding conformation and binding pattern
discernment. The protein retrieved was prepared with the
addition of hydrogen atoms and suitable corrections by
removing water molecules coupled with the changes regarding
tautomeric states of residues, orientations of hydroxyl groups,
and protonation states of basic and acidic residues. The
complex while constraining all the heavy atoms (non-hydrogen)
to their original positions with optimized hydrogen coordi-
nates was nally minimized using an OPLS_2005 force eld.
The protein with optimized hydrogen coordinates was nally
saved as a separate le to be used for docking. The binding
Cancer cell lines
GI50 (mM)
TGI (mM)
LC50 (mM)
Prostate cancer
PC-3
DU-145
5.65
10.2
>100
>100
>100
>100
Breast cancer
MCF7
MDA-MB-231/ATCC
BT-549
T-47D
MDA-MB-468
2.18
10.2
3.36
6.19
3.39
36.6
>100
16.8
>100
48.7
>100
>100
>100
>100
>100
˚
˚
˚
region was dened by a 20 A_20 A_20 A box centred on the
centroid of the colchicine to restrict the centroid of the docked
ligand. No scaling factors were applied to the van der Waals
radii. All the four active compounds prepared by using the
LigPrep module67 were used to dock at the active site of the
target.
Docking studies
The docking studies were conducted using a GLIDE version 3.0
(Schrodinger, Inc.) in ‘Extra Precision’ mode (Glide XP)65,66
which covers the complete conformational, orientational and
positional space by performing a complete systematic search
and using scores it even eliminates the unwanted conformers
followed by optimisation. Monte Carlo sampling of pose
conformation further renes the conformation. PDB-ID 1SA0
Results and discussion
Compounds 49, 54 and 56 having a methoxy group in one
aromatic ring and a halogen atom (uoro or chloro) in the
other were totally inactive against most of the cancer cell lines,
however less activity was observed against few cell lines
˚
with a resolution of 3.58 A is considered in the studies to
Fig. 2 Five dose assay graph of compound 70 against the nine panel cancer cell lines at NCI.
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Fig. 3 Schematic 2D representation of the most active compound 70
in the colchicine binding pocket of tubulin.
(Table 1). Interestingly, compound 70 having three methoxy
groups at 3,4,5-positions in one ring and 4-methoxy group in
another ring displayed considerable antiproliferative activity.
In single dose testing, it exhibited high selectivity against
CCRF-CEM, HL-60(TB), K-562, MOLT-4, RPMI-8226 and
SR (leukemia cancer cell lines) and NCI-H522 lung cancer cell
line, IGROV1 (ovarian cancer cell line) compared to the other
cell lines. It showed excellent activity against leukemia cell
lines CCRF-CEM, HL-60(TB), K-562, MOLT-4, RPMI-8226 and
SR with 80.41, 78.54, 85.57, 90.38, 100, and 90.39% inhibition
in tumor cell growth, respectively. It also inhibited the growth
of lung cancer cell lines with 27.59 to 94.45% inhibition
showing the best activity against the NCI-H522 cell line.
Compound 70 showed moderate to good activity against
CNS cancer, melanoma cancer, colon cancer, renal cancer,
prostate cancer and breast cancer cell lines. Compound 70
was also active in all the ovarian cancer cell lines with the
highest activity towards the IGROV1 cell line (93.34%
inhibition).
Based on the promising results in single dose testing,
compound 70 was further evaluated for an advanced assay
against 60 human cancer cell lines at ve different concentra-
tions (100, 10, 1, 0.1 and 0.001 mM). The anticancer activity was
measured by three parameters for each cell line: log GI50 value
(GI50 ¼ molar concentration of the compound that inhibits 50%
net cell growth), log TGI value (TGI ¼ molar concentration of
the compound leading to total inhibition) and log LC50 value
(LC50 ¼ molar concentration of the compound leading to 50%
net cell death). Furthermore,
a mean graph midpoint
(MG_MID) is calculated for each of the mentioned parameters,
giving an averaged activity parameter over all cell lines. For the
calculation of the MG_MID, insensitive cell lines are included
with the highest concentration tested. The 5-dose assay results
are shown in Table 2. The results are also represented graphi-
cally in Fig. 2 as dose response curves against 9 different cancer
panels.
Compound 70 showed remarkable anticancer activity
against most of the tested cancer cell lines with GI50 values in
the range 1.2–38.4 mM. It was found to be highly sensitive
towards the leukemia SR cell line (GI50 ¼ 1.98 mM), RPMI-8226
Fig. 4 (A–E): Compounds 70, 56, 54, 49 and resveratrol in the tubulin
binding pocket. (A) Compound 70 showed strong hydrogen bonding
with Cys 241 [O/HS: 1.852 A˚]. (B) Compound 56 showed hydrogen
bonding with Cys 241 [O/HS: 2.074 A˚]. (C) Compound 54 showed
hydrogen bonding with Cys 241 [O/HS: 2.327 A˚]. (D) Compound 49
showed hydrogen bonding with Cys 241 [O/HS: 2.346 A˚]. (E)
Resveratrol showed no hydrogen bonding with any amino acid.
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(GI50 ¼ 2.57 mM), non-small cell lung cancer HOP-62 (GI50
¼
variations of active compounds has given a clear picture of
1.28 mM) and NCI-H322M cell line (GI50 ¼ 1.98 mM), melanoma the information needed. All the compounds in the active site
cancer SK-MEL-2 (GI50 ¼ 1.89 mM) and SK-MEL-28 (GI50 ¼ 1.69 were in the same orientation and the conformations were
mM) cell line, breast cancer MCF7 (GI50 ¼ 2.18 mM), BT549 (GI50 quite comparable with the standard compound resveratrol.
¼ 3.36 mM) and MDA-MB-468 cell line (GI50 ¼ 3.39 mM). The colchicine binding site of the tubulin was mainly
Furthermore, it showed 100% inhibition towards most of the hydrophobic due to the presence of amino acids Val, Cys,
ovarian cancer, non-small cell lung cancer and breast cancer Leu, Ala, Met, Pro, and Ile. Amino acids like Asn and Thr
cell lines. Moreover, compound 70 exhibited some killing make the binding pocket polar and Lys makes it positively
activity also against the ovarian cancer OVCAR-3 cell line with charged (Fig. 3). The most active compound has shown the
an LC50 value of 74.4 mM. Thus OVCAR-3 was the most affected highest glide score of ꢀ6.25, when compared with other
cell line with GI50 ¼ 3.92 mM, TGI ¼ 14.3 mM, and LC50
¼
active compounds (Table 3). The carbonyl group of all the
four compounds has shown hydrogen bonding with Cys 241
74.4 mM.
To gain insight into the mechanism of action of our which was a crucial amino acid involved in hydrogen
compounds, we rst performed the NCI's bioinformatics tool bonding with colchicine in the protein, but the most active
COMPARE analysis68 for the most active compound 70. When compound 70 has shown hydrogen bonding with Cys 241
˚
tested as a seed against the NCI “standard agents” database, (O/HS: 1.825 A) along with the highest protein ligand van
the compound showed Pearson Correlation Coefficients der Waals energy of ꢀ5.6. Almost all other features like
(PCCs) of >0.482 at the GI50 level and higher values, 0.671, electrostatic rewards, hydrophobic enclosure rewards, ligand
0.610, and 0.592, at the TGI level. In all cases the receptor non-hydrogen bond complementary terms are the
highest PCCs were obtained for compounds NSC 332598 same, but in terms of penalty for the exposed hydrophobic
(rhizoxin), NSC 125973 (paclitaxel), and NSC 153858 (may- ligand groups, compound 70 has the least value when
tansine), which are all antimitotic agents directed against compared with the remaining active compounds. Based on
tubulin.
these factors all the active molecules bind in a similar
Furthermore, we also decided to perform in silico docking manner but compound 70 has an added advantage of non-
studies against tubulin. Tubulin has three different binding exposed hydrophobic ligand groups which makes it more
sites: vinca binding sites, colchicine binding sites and taxane active. The chalcone part of compound 70 was completely
binding sites. Many of the anticancer agents both natural as inside the hydrophobic pocket which gave out positive
well as synthetic are believed to act by binding to the signals of stability. The methoxy group attached to it was
colchicine site on tubulin.69–71 In the present study, we deep inside the pocket making the carbonyl group of the
docked representative compounds (70, 56, 54, and 49) and compound to move towards Cys 241 and attributed to the
resveratrol in the colchicine binding pocket of tubulin for formation of a strong hydrogen bond. The trimethoxy phenyl
identifying its orientational and conformational information group was exactly in between the polar and positively charged
(Fig. 4A–E). The exible docking program of Schrodinger regions which further stabilized the compound in the
soware which was used to nd the conformational binding pocket of tubulin.
Table 3 Docking results of compounds 70, 56, 54, 49 and resveratrol
H-bond
interaction
Glide
score
Total protein–
ligand vdW
Electrostatic
reward
˚
Comp.
Hydrophobic interaction (within 5 A)
˚
70
Val-238, Cys-241, Leu-242, Leu-248, Ala-
250, Leu-252, Leu-255, Val-257, Met-259,
Pro-261, Leu-313, Val-315, Ala-316, Val-
318, Ile-347, Pro-348, Ala-354
Val-238, Cys-241, Leu-242, Leu-248, Ala-
250, Leu-252, Leu-255, Met-259, Val-315,
Ala-316, Ala-317, Val-318, Ile-347, Pro-
348, Ala-354
Val-238, Cys-241, Leu-242, Leu-248, Ala-
250, Leu-252, Leu-255, Met-259, Val-315,
Ala-316, Ala-317, Val-318, Pro-348, Ala-
354
Val-238, Cys-241, Leu-242, Leu-248, Ala-
250, Leu-252, Leu-255, Met-259, Val-315,
Ala-316, Ala-317, Val-318, Pro-348, Ala-
354
O/HS: (1.852 A)
ꢀ6.25
ꢀ5.3
ꢀ4.5
ꢀ4.2
ꢀ4.8
ꢀ5.6
ꢀ4.6
ꢀ4.4
ꢀ4.1
ꢀ3.1
ꢀ0.1
˚
56
O/HS: (2.076 A)
0.1
˚
54
O/HS: (2.237 A)
ꢀ0.04
ꢀ0.03
ꢀ0.04
˚
49
O/HS: (2.346 A)
Resveratrol
Val-315, Met-259, Leu-284, Val-318, Ala-
316, Ala-317, Ala-354, Val-238, Leu-252,
Ala-250, Leu-255, Leu-242, Cys-241
—
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Compound
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study suggest that the a,b-unsaturated carbonyl group
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groups (polar region) are essential for antiproliferative activity.
Thus compound 70 provides
a good lead for further
development.
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Acknowledgements
D.S.R. thanks the Council of Scientic and Industrial Research
(CSIR) [no. 02(0049)/12/EMR-II] New Delhi, India and
DU-PURSE grant for nancial support. D.K. and K.K.R. are
thankful to CSIR for the award of senior research fellowship and
research associate fellowship. S.V.M. would like to acknowledge
the support from the National Cancer Institute, National Insti-
tutes of Health, under contract no. HHSN261200800001E. The
authors are also thankful to CIF-USIC, the University of Delhi,
Delhi for NMR spectral data and RSIC, CDRI, Lucknow for mass
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