Synthesis, antimalarial activity and cytotoxic potential of new monocarbonyl analogues of curcumin

Article abstract of DOI:10.1016/j.bmcl.2012.11.004

A series of novel monocarbonyl analogues of curcumin have been designed, synthesized and tested for their activity against Molt4, HeLa, PC3, DU145 and KB cancer cell lines. Six of the analogues showed potent cytotoxicity towards these cell lines with IC₅₀ values below 1 μM, which is better than doxorubicin, a US FDA approved drug. Several analogues were also found to be active against both CQ-resistant (W2 clone) and CQ-sensitive (D6) strains of Plasmodium falciparum in an in-vitro antimalarial screening. This level of activity warrants further investigation of the compounds for development as anticancer and antimalarial agents.

Full text of DOI:10.1016/j.bmcl.2012.11.004

Bioorganic & Medicinal Chemistry Letters 23 (2013) 112–116
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis, antimalarial activity and cytotoxic potential of new
monocarbonyl analogues of curcumin
Sunny Manohar a, Shabana I. Khan b, Shamseer Kulangara Kandi a, Kranthi Raj a, Guojing Sun c,
a,
Xiaochuan Yang c, Angie D. Calderon Molina c, Nanting Ni c, Binghe Wang c, , Diwan S. Rawat
⇑
⇑
a Department of Chemistry, University of Delhi, Delhi 110007, India
b National Centre for Natural Products Research, University of Mississippi, MS 38677, USA
c Department of Chemistry, Center for Diagnostics and Therapeutics, and Center for Drug Design and Biotechnology, Georgia State University, Atlanta, GA 30302-4089, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 July 2012
Revised 13 October 2012
Accepted 2 November 2012
Available online 10 November 2012
A series of novel monocarbonyl analogues of curcumin have been designed, synthesized and tested for
their activity against Molt4, HeLa, PC3, DU145 and KB cancer cell lines. Six of the analogues showed
potent cytotoxicity towards these cell lines with IC50 values below 1 lM, which is better than doxorubi-
cin, a US FDA approved drug. Several analogues were also found to be active against both CQ-resistant
(W2 clone) and CQ-sensitive (D6) strains of Plasmodium falciparum in an in-vitro antimalarial screening.
This level of activity warrants further investigation of the compounds for development as anticancer and
antimalarial agents.
Keywords:
Curcumin
Anticancer
Cytotoxicity
HeLa cell line
Antimalarial
Ó 2012 Elsevier Ltd. All rights reserved.
Natural products have played a vital role in the drug discovery
process and approximately 67% of the drugs in the clinical market
today are inspired by or derived from natural sources.1 Curcumin
(diferuloylmethane, Fig. 1), isolated from the rhizome of turmeric
(Curcuma longa Linn.), is one of such natural compounds, which
has been a subject of intense study for many decades.2 Turmeric
has been used since ancient time in South Asian subcontinents par-
ticularly in India and China as a dietary pigment, essential spice, and
it has also been used in the traditional medicine as an antiseptic,
anti-inflammatory and wound-healing agent.3 Curcumin is also
known for its anti-inflammatory, antioxidant, antimicrobial, antivi-
ral, antiangiogenic, chemopreventative, chemotherapeutic and anti-
cancer activities.4 Recently, curcumin was also explored for its
antimalarial activity against both chloroquine (CQ)-sensitive and
chloroquine (CQ)-resistance strains of Plasmodium falciparum.5 It
has also shown hepato-protective and nephro-protective,6 throm-
bosis suppressing,7 myocardial infarction protective,8 anti-hypogly-
cemic,9 and anti-rheumatic10 activities, and exhibited decreased
tumorigenesis in many organs when tested in vivo.2,11
cancer cells.16 However, limited clinical efficacy such as poor solu-
bility, bioavailability and absorption as well as rapid metabolism
have been major problems associated with curcumin.17
Detailed pharmacological studies conducted on curcumin dem-
onstrates that the b-diketone functionality of curcumin is a sub-
strate for liver aldoketo reductases and this may be one of the
reasons for the rapid metabolism of curcumin in vivo.18 The mono
carbonyl analogues of the curcumin have been designed and syn-
thesized in anticipation that the in vivo metabolic stability of these
analogues can be improved and some of these compounds have
shown very good anticancer activity.19 Structure–activity relation-
ship studies conducted on these compounds revealed that the
heteroaromatic core in these compounds correlated with high
anti-proliferative and anti-inflammatory activities.20 Therefore, as
a part of our ongoing programme towards the development of
medicinally important molecules,21 we became interested in
modifying the structure of the curcumin by changing the b-dike-
tone structure to mono carbonyl with rigid ring, while retaining
In vitro studies demonstrated that curcumin has potent cytotox-
icity towards many cell lines derived from leukemia,12 cervical can-
cer,13 colorectal carcinoma,14 prostate cancer15 and human breast
O
O
H3CO
HO
OCH3
OH
⇑
Corresponding authors. Tel.: +91 11 27667465; fax: +91 11 27667501.
E-mail addresses: wang@gsu.edu (B. Wang), dsrawat@chemistry.du.ac.in (D.S.
Figure 1. Structure of curcumin.
Rawat).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.11.004

S. Manohar et al. / Bioorg. Med. Chem. Lett. 23 (2013) 112–116
113
the major skeleton of the structure. In addition, analogues were
prepared by adding extra groups at two ends to examine the solu-
bility issue (Fig. 2).
β-Diketone moiety
O
O
For the mono ketone part, either a five-membered ring or a six-
membered ring was incorporated. The impact of rigidity was stud-
ied. For the linker on both ends, different lengths of the alkyl chain
were applied to study the impact of size. For the substitution group
of NR1R2, the following groups were used: bromo, morpholino, pip-
eridino, dimethylamino, imidazole, 2-methyl imidazole and aze-
pano group. The impact of the polarity and size of the
substitution on two side chains was studied. Overall, a series of
43 analogues having the general structure shown in Figure 3 have
been designed and prepared using one synthetic route (Scheme 1).
For the synthesis of desired monocarbonyl analogues of curcu-
min, commercially available starting materials p-hydroxy benzal-
dehyde (1) or vanillin (2) were reacted with an excess amount of
H3CO
HO
OCH3
OH
Active methylene group
Can be modified to incorpate groups
which can act as binding sites
Curcumin: Poor bioavailability and
metabolically unstable
Structural
modification
Mono-carbonyl
moiety increases
metabolic stability
aliphatic linear dibromoalkanes in the presence of
a base
(Scheme 1). The resulting aldehydes (3–8) with free bromo group
at terminal position was subjected to nucleophilic substitution by
different aromatic or aliphatic secondary amino functionalities to
yield the corresponding amino substituted aldehydes (9–33) in
high yield. The resulting compounds (9–33) were coupled with
cyclopentanone or cyclohexanone in an alkaline medium in an aldol
type of condensation to yield the desired curcumin analogues in
good to excellent yield (70–90%) (35–76). Synthesis of analogue
34 was achieved by directly coupling cyclopentanone with 4-(2-
bromoethoxy)-3-methoxybenzaldehyde (3) via aldol condensation.
All the synthesized compounds (Table 1) were screened for their
cytotoxicity against the HeLa cancer cell line at three different con-
centrations. In the first screening, all compounds were tested at a
O
O
O
N
N
R R
R
R
Atoms capable of
hydrogen bonding
High potency and superior bioavailability and
improved metabolic stability
Figure 2. Modification of central b-diketone group and aryl substitution pattern.
concentration of 50
compounds had cytotoxicity at 50
for the 2nd round screening at 2.5, 2 or 1
l
M by the MTT assay. The result showed most
M, and hence they were tested
M. Data showed that 11
l
O
l
compounds displayed comparable or better cytotoxicity than the
control compound doxorubicin. All 11 active compounds were
tested in the MTT assay with three replicated of every concentra-
tion (concentration from10 to 0.25 lM) in HeLa, PC3, DU145, KB
or Molt4 cell lines. The MTT data were analyzed by curve-fitting
R
R
n1
1R2RN
NR1R2
O
O
n
n
34-76
Figure 3. General structure of molecules in the present investigation.
using Sigma plotting to obtain the IC50 values (Table 2).
CHO
CHO
CHO
a
b
R
O
R
R
OH
O
1, R= H
2, R= OMe
1R2RN
n
n
Br
n = 1-3 (3-8)
n = 1-3 (9-33)
c
O
1R2RN
NR1R2
n
n1
O
O
n
R
R
n = 1-3
1 = 1,2
n
34-76
Scheme 1. Reagents and conditions: (a) aliphatic dibromoalkane, K2CO3, DMF, 80 °C, 1 h, 50–60%; (b) different secondary amines (HNR1R2), K2CO3, DMF, 80 °C, 6 h, 80–90%;
(c) cyclic ketones, 20% (w/v) NaOH, MeOH, rt, overnight, 70–90%.

114
S. Manohar et al. / Bioorg. Med. Chem. Lett. 23 (2013) 112–116
Table 1
36, 42, 47 and 68 showed very good activity with the IC50 in the
low micro molar range in HeLa cells though they have different
ring sizes at the ketone position. Some other compounds (40, 54,
Synthesized monocarbonyl analogues of curcumin
Compd.
R
n
NR1R2
n1
61 and 62) didn’t show cytotoxicity even at 50 lM although they
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
1
1
1
1
1
1
2
2
2
2
2
2
3
3
3
3
3
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
Br
1
1
1
1
1
1
1
1
2
1
1
1
1
1
1
1
1
1
2
1
1
1
1
1
1
1
2
1
2
1
1
1
2
1
2
1
2
1
2
1
1
1
1
have the same five- or six-member ring structures. Among all the
tested compounds, morpholino substitution on both sides of the
compounds showed relatively low cytotoxicity except for com-
pound 46. The length of the side chain does not seem to have a ma-
jor effect on the activities. For the most active compounds, a
methoxy group on the phenyl ring seems favor the inhibitory ef-
fect. For compounds having R = H (51–76), only compound 68
and 73 showed good activities with a long side chain n = 3.
Some symmetrical monocarbonyl analogues of curcumin were
tested for their antimalarial activity against CQ-sensitive (D6
clone) and CQ-resistant (W2 clone) strains of P. falciparum (Table 3)
Out of 20 compounds tested, potent activity were observed with
compounds 36, 37, 46, 49, 56 and 57 (in which the amine probe
is attached via ethylene/butylene linker with cyclopentanone ring)
against CQ-resistant strain of P. falciparum (IC50 ranging from 0.37
to 0.63 lM) when compared with standard drug chloroquine (CQ).
These compounds (36, 37, 46, 49, 56 and 57) also displayed mod-
erate to good activity against CQ-sensitive strains of P. falciparum
with IC50 ranging from 0.35 to 0.69 lM. All the compounds were
found to be non-toxic to Vero cells indicating their safety towards
mammalian cells (Table 3).
By observing the dataset of cytotoxicity and antimalarial activ-
ity, it was found that the cytotoxicity dataset was not large enough
for doing 3D-QSAR. The remaining dataset tested for antimalarial
activity against D6 clone was processed for developing a 3D-QSAR
model. All the work was done by using PHASE (Schrodinger, Inc.,
LLC, New York, USA), in Dell precision T3500 work station.
The common pharmacophore is generated and the best pharma-
cophore AAARR with 3 acceptor features and 2 ring aromatic fea-
tures is taken based upon the hypothesis scores. 3D-QSAR model
generated using training set (12 compounds) was validated using
test set (8 compounds). Model generated using partial least sqaure
(PLS) analysis showed correlation coefficient R2 of 0.96, test set
Morpholino
Piperidino
Dimethylamino
Imidazolo
2-Methyl imidazolo
Morpholino
Piperidino
Piperidino
Dimethylamino
Imidazolo
2-Methyl imidazolo
Morpholino
Piperidino
Azepano
Imidazolo
2-Methyl imidazolo
Piperidino
Piperidino
2-Methyl piperidino
Morpholino
Dimethylamino
Imidazolo
2-Methyl imidazolo
Azepano
Piperidino
Piperidino
Morpholino
Morpholino
Dimethylamino
Imidazolo
2-Methyl imidazolo
2-Methyl imidazolo
Piperidino
Piperidino
2-Methyl piperidino
2-Methyl piperidino
Morpholino
Morpholino
Dimethylamino
Azepano
Imidazolo
2-Methyl imidazolo
H
Table 3
In-vitro antimalarial activity of selected symmetrical monocarbonyl analogue of
curcumin
Veroa
Table 2
IC50 values of screened compounds against HeLa, Molt4, PC3, DU145 and KB cell lines
Compd.
P. falciparum (D6 clone)
P. falciparum (W2 clone)
IC50
(l
M)
S.I.
IC50
(l
M)
S.I.
Compd.
IC50
(
l
M)
34
35
36
37
38
39
43
44
45
46
47
48
49
50
56
57
71
72
75
76
CQ
ART
NA
—
NA
—
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
NC
HeLa
Molt4
KB
PC3
DU145
3.11
0.50
0.44
2.21
1.28
1.14
NA
2.01
0.69
1.74
1.36
0.53
4.00
0.45
0.35
NA
>2.6
>16.4
>21.6
>4.0
>6.5
>7.9
—
>4.0
>10.8
>4.3
>5.3
>14.9
>1.9
>21.6
>26.4
—
2.41
0.53
0.62
1.81
1.38
1.53
NA
3.01
0.63
2.85
1.82
0.56
4.48
0.37
0.43
NA
>3.4
>15.4
>15.4
>4.9
>6.0
>6.0
—
>2.6
>11.9
>2.6
>4.0
>14.0
>1.7
>26.4
>21.6
—
36
37
39
42
43
45
46
47
48
68
73
DOX.
0.4
0.5
0.9
0.02
0.03
0.1
4.4
>5
3.4
1.65
0.2
1.99
0.62
0.55
2.25
2.54
1.65
0.33
>5
>5
>5
>5
>5
>5
1.95
0.64
3.15
0.72
0.49
1.39
3.63
6.8
0.55
0.43
0.66
0.36
0.32
0.41
0.73
0.33
0.02
6.91
1.5
0.2
0.28
0.5
0.3
1.53
2.9
0.2
2.05
0.43
3.9
0.67
0.46
1.01
2.11
4.4
2.2
0.2
DOX: doxorubicin; HeLa: human cervical cancer cell; Molt4: human acute lym-
phoblastic leukemia cell; KB: human nasopharyngeal epidermal carcinoma; PC3:
human prostatic adenocarcinoma; DU145: human prostate cancer cell.
NA
2.04
1.09
0.053
0.019
—
NA
—
>4.3
>7.7
>160
>470
3.54
1.41
0.43
>2.5
>6.0
>20
We were delighted to find some compounds such as 36, 37, 39,
43, 46 and 47 showing higher potency than doxorubicin (Table 2).
From the cytotoxicity data, it is clear that the rigidity didn’t play
important role to impact the activity. For example, compounds
0.011
>800
a
Doxorubicin was taken as positive control; CQ: chloroquine; ART: artemisinin;
S.I.: selectivity index (IC50 for cytotoxicity to vero cells/IC50 for antimalarial activ-
ity); NA: not active; NC: not cytotoxic upto 9 M.
l

S. Manohar et al. / Bioorg. Med. Chem. Lett. 23 (2013) 112–116
115
Table 4
Summary of PHASE 3D-QSAR Statistical data
ID
PLS Factors
SD
R2
F
P
RMSE
Q2
Pearson-R
AAARR
1
2
3
0.0324
0.0375
0.0401
0.944
0.957
0.959
118.2
126.9
184.9
1.22 eÀ05
1.31 eÀ08
1.82 eÀ10
0.243
0.237
0.224
0.61
0.62
0.66
0.742
0.768
0.772
PLS-partial least squares, SD-standard deviation, R2-correlation coefficient, F-ratio of the model variance to the observed variance, P-the significance level of F when treated as
a ratio of chi-squared distributions, RMSE-root mean square error, Q2-test set prediction, Pearson-R-value of correlation between the predicted and observed activity for the
test set.
pIC50 of the compounds against experimental values. Figure 5
showed the visual representation of the QSAR model with point
of possible modification for activity improvement. It can be con-
cluded that if these compounds were modified at both ends by add-
ing hydrophobic groups, the activity of these compounds can be
enhanced still to a greater extent.
In conclusion, a series of monocarbonyl analogs of curcumin
have been synthesized. Among all the active compounds, 6 showed
nanomolar activities against the HeLa cell line, which are signifi-
cantly lower than that of doxorubicin. Some of the analogues also
showed comparable activities with doxorubicin in other cell lines.
Out of several compounds tested for antimalarial activity, 6 ana-
logues (36, 37, 46, 49, 56 and 57) were found to show excellent
activities against both CQ-resistant and CQ-sensitive strains of P.
falciparum. The results obtained so far should be very useful for
the further optimization of the new analogues for further clinical
development.
Acknowledgments
D.S.R. thanks Council of Scientific and Industrial Research (CSIR)
[No. 02(0049)/12/EMR-II] New Delhi, India for financial support.
S.M. is thankful to CSIR for the award of junior and senior research
fellowship. S.I.K. is thankful to United States Department of Agricul-
ture (USDA), Agricultural Research Service Specific Cooperative
Figure 4. Graph showing correlation between experimental and predicted
activities.
Agreement No. 58-6408-2-0009 for partial support of this work.
prediction Q2 of 0.66 and Pearson-R of 0.65 (Table 4). The high value
of variance ratio (F) observed for this model indicates its statistical
robustness which is further supported by significant level of
The authors declare no competing financial interest. BW thanks
Molecular Basis of Disease program at GSU for XCY and Georgia Can-
cer Coalition, and Georgia Research Alliance for financial support.
variance ratio (P). The value of P < 0.05 indicates greater degree of
Supplementary data
confidence which means F is significant at the 95% level. The low
standard deviation (SD) of 0.04 and RMSE value of 0.22 clearly
shows the model nicely predicted the experimental activities.
Figure 4 shows the graphical representation of phase predictive
Supplementary data (experimental details, characterization of
compounds, cell culture and MTT assay for anticancer activity,
Figure 5. Visual representation of QSAR model and best pharmacophore hypothesis with compound 57. Blue cube indicates positive coefficient (increase in activity) while
red cube indicates negative coefficient (decrease in activity); (A) Hydrogen bond donor regions; (B) Hydrophobic regions; (C) Positive ionic regions; (D) Electron withdrawing
regions.

116
S. Manohar et al. / Bioorg. Med. Chem. Lett. 23 (2013) 112–116
12. Hussain, A. R.; Al-Rasheed, M.; Manogaran, P. S.; Al-Hussein, K. A.; Platanias, L.
C.; Al Kuraya, K.; Uddin, S. Apoptosis 2006, 11, 245.
13. Beevers, C. S.; Li, F.; Liu, L.; Huang, S. Int. J. Cancer 2006, 119, 757.
14. Johnson, S. M.; Gulhati, P.; Arrieta, I.; Wang, X.; Uchida, T.; Gao, T.; Evers, B. M.
Anticancer Res. 2009, 29, 3185.
15. Shankar, S.; Chen, Q.; Sarva, K.; Siddiqui, I.; Srivastava, R. K. J. Mol. Signal. 2007,
2, 10.
16. Prasad, C. P.; Rath, G.; Mathur, S.; Bhatnagar, D.; Ralhan, R. Chem. Biol. Interact.
2009, 181, 263.
assay for in vitro antimalarial activity, PHASE methodology for
molecular modeling and dose–response curves) associated with
this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.bmcl.2012.11.004.
References and notes
1. Newman, D. J. J. Med. Chem. 2008, 51, 2589.
17. (a) Sarkar, F. H.; Li, Y. Cancer Treat. Rev. 2009, 35, 597; (b) Anand, P.;
Kunnumakkara, A. B.; Newman, R. A.; Aggarwal, B. B. Mol. Pharm. 2007, 4, 807;
(c) Burgos-Moron, E.; Calderon-Montano, J. M.; Salvador, J.; Robles, A.; Lopez-
Lazaro, M. Int. J. Cancer 2010, 126, 1771.
2. Anand, P.; Thomas, S. G.; Kunnumakkara, A. B.; Sundaram, C.; Harikumar, K. B.;
Sung, B.; Tharakan, S. T.; Misra, K.; Priyadarsini, I. K.; Rajasekharan, K. N.;
Aggarwal, B. B. Biochem. Pharmacol. 2008, 76, 1590.
3. (a) Ammon, H. P.; Wahl, M. A. Planta Med. 1991, 57, 1; (b) Hatcher, H.; Planalp,
R.; Cho, J.; Torti, F. M.; Torti, S. V. Cell. Mol. Life Sci. 2008, 65, 1631.
4. (a) Aggarwal, B. B.; Kumar, A.; Bharti, A. C. Anticancer Res. 2003, 23, 363; (b)
Surh, Y. J. Nat. Rev. Cancer 2003, 3, 768; (c) Sharma, O. P. Biochem. Pharmacol.
1811, 1976, 25; (d) Ruby, A. J.; Kuttan, G.; Babu, K. D.; Rajasekharan, K. N.;
Kuttan, R. Cancer Lett. 1995, 94, 79; (e) Sugiyama, Y.; Kawakishi, S.; Osawa, T.
Biochem. Pharmacol. 1996, 52, 519; (f) Srimal, R. C.; Dhawan, B. N. J. Pharm.
Pharmacol. 1973, 25, 447.
5. Cui, L.; Miao, J.; Cui, L. Antimicrob. Agents Chemother. 2007, 51, 488.
6. (a) Kiso, Y.; Suzuki, Y.; Watanabe, N.; Oshima, Y.; Hikino, H. Planta Med. 1983,
49, 185; (b) Venkatesan, N.; Punithavathi, D.; Arumugam, V. Br. J. Pharmacol.
2000, 129, 231.
18. Rosemond, M. J.; St John-Williams, L.; Yamaguchi, T.; Fujishita, T.; Walsh, J. S.
Chem. Biol. Interact. 2004, 147, 129.
19. (a) Yadav, B.; Taurin, S.; Rosengren, R. J.; Schumacher, M.; Diederich, M.;
Somers-Edgar, T. J.; Larsen, L. Bioorg. Med. Chem. 2010, 18, 6701; (b) Das, U.;
Sharma, R. K.; Dimmock, J. R. Curr. Med. Chem. 2001, 2009, 16; (c) Adams, B. K.;
Ferstl, E. M.; Davis, M. C.; Herold, M.; Kurtkaya, S.; Camalier, R. F.;
Hollingshead, M. G.; Kaur, G.; Sausville, E. A.; Rickles, F. R.; Snyder, J. P.;
Liotta, D. C.; Shoji, M. Bioorg. Med. Chem. 2004, 12, 3871; (d) Lagisetty, P.;
Powell, D. R.; Awasthi, V. J. Mol. Struct. 2009, 936, 23; (e) Katsori, A. M.;
Chatzopoulou, M.; Dimas, K.; Kontogiorgis, C.; Patsilinakos, A.; Trangas, T.;
Hadjipavlou-Litina, D. Eur. J. Med. Chem. 2011, 46, 2722; (f) Lagisetty, P.;
Vilekar, P.; Sahoo, K.; Anant, S.; Awasthi, V. Bioorg. Med. Chem. 2010, 18, 6109;
(g) Makarov, M. V.; Leonova, E. S.; Rybalkina, E. Y.; Tongwa, P.; Khrustalev, V.
N.; Timofeeva, T. V.; Odinets, I. L. Eur. J. Med. Chem. 2010, 45, 992.
20. (a) Liang, G.; Shao, L.; Wang, Y.; Zhao, C.; Chu, Y.; Xiao, J.; Zhao, Y.; Li, X.; Yang,
S. Bioorg. Med. Chem. 2009, 17, 2623; (b) Amolins, M. W.; Peterson, L. B.; Blagg,
B. S. Bioorg. Med. Chem. 2009, 17, 360.
21. (a) Aggarwal, N.; Kumar, R.; Dureja, P.; Rawat, D. S. J. Agric. Food Chem. 2009, 57,
8520; (b) Manohar, S.; Khan, S. I.; Rawat, D. S. Bioorg. Med. Chem. Lett. 2010, 20,
322; (c) Sharma, M.; Joshi, M. C.; Kumar, V.; Malhotra, S. V.; Rawat, D. S. Arch.
Pharm. 2011, 344, 567; (d) Manohar, S.; Khan, S. I.; Rawat, D. S. Chem. Biol. Drug
Des. 2011, 78, 124; (e) Sharma, M.; Joshi, P.; Kumar, N.; Joshi, S.; Rohilla, R. K.;
Roy, N.; Rawat, D. S. Eur. J. Med. Chem. 2011, 46, 480; (f) Kumar, N.; Khan, S. I.;
Atheaya, H.; Mamgain, R.; Rawat, D. S. Eur. J. Med. Chem. 2011, 46, 2816; (g)
Manohar, S.; Rajesh, U. C.; Khan, S. I.; Tekwani, B. L.; Rawat, D. S. ACS Med.
Chem. Lett. 2012, 3, 555; (h) Joshi, M. C.; Bisht, G. S.; Rawat, D. S. Bioorg. Med.
Chem. Lett. 2007, 17, 3226; (i) Bisht, G. S.; Rawat, D. S.; Kumar, A.; Kumar, R.;
Pasha, S. Bioorg. Med. Chem. Lett. 2007, 17, 4343; (j) Beena Kumar, N.; Rohilla, R.
K.; Roy, N.; Rawat, D. S. Bioorg. Med. Chem. Lett. 2009, 19, 1396; (k) Atheaya, H.;
Khan, S. I.; Mamgain, R.; Rawat, D. S. Bioorg. Med. Chem. Lett. 2008, 18, 1446.
7. Srivastava, R.; Dikshit, M.; Srimal, R. C.; Dhawan, B. N. Thromb. Res. 1985, 40,
413.
8. (a) Dikshit, M.; Rastogi, L.; Shukla, R.; Srimal, R. C. Indian J. Med. Res. 1995, 101,
31; (b) Nirmala, C.; Puvanakrishnan, R. Mol. Cell. Biochem. 1996, 159, 85; (c)
Nirmala, C.; Puvanakrishnan, R. Biochem. Pharmacol. 1996, 51, 47.
9. (a) Srinivasan, M. Indian. J. Med. Sci. 1972, 26, 269; (b) Babu, P. S.; Srinivasan, K.
Mol. Cell. Biochem. 1995, 152, 13; (c) Babu, P. S.; Srinivasan, K. Mol. Cell. Biochem.
1997, 166, 169; (d) Arun, N.; Nalini, N. Plant Foods Hum. Nutr. 2002, 57, 41.
10. Deodhar, S. D.; Sethi, R.; Srimal, R. C. Indian J. Med. Res. 1980, 71, 632.
11. (a) Cheng, A. L.; Hsu, C. H.; Lin, J. K.; Hsu, M. M.; Ho, Y. F.; Shen, T. S.; Ko, J. Y.;
Lin, J. T.; Lin, B. R.; Ming-Shiang, W.; Yu, H. S.; Jee, S. H.; Chen, G. S.; Chen, T. M.;
Chen, C. A.; Lai, M. K.; Pu, Y. S.; Pan, M. H.; Wang, Y. J.; Tsai, C. C.; Hsieh, C. Y.
Anticancer Res. 2001, 21, 2895; (b) Inano, H.; Onoda, M.; Inafuku, N.; Kubota,
M.; Kamada, Y.; Osawa, T.; Kobayashi, H.; Wakabayashi, K. Carcinogenesis 1999,
1011, 20; (c) Ereira, M. A.; Grubbs, C. J.; Barnes, L. H.; Li, H.; Olson, G. R.; Eto, I.;
Juliana, M.; Whitaker, L. M.; Kelloff, G. J.; Steele, V. E.; Lubet, R. A. Carcinogenesis
1996, 17, 1305; (d) Schaaf, C.; Shan, B.; Buchfelder, M.; Losa, M.; Kreutzer, J.;
Rachinger, W.; Stalla, G. K.; Schilling, T.; Arzt, E.; Perone, M. J.; Renner, U.
Endocr. Relat. Cancer 2009, 16, 1339; (e) Somers-Edgar, T. J.; Scandlyn, M. J.;
Stuart, E. C.; Le Nedelec, M. J.; Valentine, S. P.; Rosengren, R. J. Int. J. Cancer
1966, 2008, 122.