Acyl derivatives of boswellic acids as inhibitors of NF-κB and STATs

Article abstract of DOI:10.1016/j.bmcl.2011.10.112

Boswellic acid acylates including their epimers were synthesized and screened against a panel of human cancer cell lines. They exhibited a range of cytotoxicity against various human cancer cell lines thereby leading to the development of a possible SAR. One of the identified lead compounds was found to be an inhibitor of the NF-κB and STAT proteins, warranting further investigations to be developed into a potential anticancer lead.

Full text of DOI:10.1016/j.bmcl.2011.10.112

Bioorganic & Medicinal Chemistry Letters 22 (2012) 431–435
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Acyl derivatives of boswellic acids as inhibitors of NF-jB and STATs
⇑
Ajay Kumar, Bhahwal A. Shah , Samar Singh, Abid Hamid, Shashank K. Singh, Vijay K. Sethi,
⇑
Ajit K. Saxena, Jaswant Singh, Subhash C. Taneja
Natural Product Microbes Division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu Tawi 180 001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Boswellic acid acylates including their epimers were synthesized and screened against a panel of human
cancer cell lines. They exhibited a range of cytotoxicity against various human cancer cell lines thereby
leading to the development of a possible SAR. One of the identified lead compounds was found to be an
Received 14 June 2011
Revised 14 October 2011
Accepted 31 October 2011
Available online 9 November 2011
inhibitor of the NF-
jB and STAT proteins, warranting further investigations to be developed into a poten-
tial anticancer lead.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Boswellic acids
Acyl derivatives
Anti-cancer
NF-j
B
STAT
The gum exudate of Boswellia serrata comprises of four major
triterpenic acids known as boswellic acids (BAs), that is, b-boswellic
malignancies, facilitating cell proliferation and inhibition of apopto-
sis.18 Stat3 and Stat6 have also been implicated in promoting immu-
nosuppressive myeloid derived suppressor cells (MDSCs).19,20
About 50% of acute myeloid leukemia (AML) cases also show consti-
tutively active Stat3. Inhibition of constitutively active Stat3 has
acid (BA), 3-O-
a-acetyl-b-boswellic acid (ABA), 11-keto-b-boswellic
acid (KBA) and 3-O-
a-acetyl-11-keto-b-boswellic acid (AKBA). The
gum resin of B. serrata is traditionally used in Ayurvedic system of
medicine for the treatment of various ailments.1 In the past many
reports have appeared related to their activities against inflamma-
tion,2,3 arthritis,4 ulcerative colitis,5 chronic colitis,6 asthma7 and
hepatitis.8 However, it is the anticancer activity that has attracted
the most attention in the recent past due to their ability to induce
apoptosis.9,10 They have been reported to inhibit the growth and in-
duce apoptosis in brain tumors,11 malignant glioma cells,12 colon
cancer cells13 and leukemic cells.14 They have also been found to
be more potent inhibitors of topoisomerase I and II in comparison
to camptothecin, amsacrine or etoposide, using pure topoisomerase
assay.15 Thus, prompted by the potential of BAs and our interest in
the identification and development of potent anticancer leads based
on the natural products16 including BAs,17 we herein report our
work on alkyl–acyl derivatives of BAs and their potential as inducers
of apoptosis. We further envisaged exploring the effect of the most
been shown to induce AML cell apoptosis.21 NF-
j
B is known to reg-
ulate the expression of several anti-apoptotic genes such as IAPs,
Bcl-2, Bcl-xL and survivin.22 In addition, NF-
B regulates the expres-
sion of several genes involved in cancer cell proliferation and
inflammation; these include COX-2, TNF- , IL-1b, IL-6, IL-23, etc.
Interestingly, some of these genes are also regulated by Stat3. Par-
ticularly, the association of NF- B and Stat3 plays an important role
in all aspects of cancer development. In fact Stat3 and NF- B are clo-
j
a
j
j
sely linked and both of these two transcription factors require each
other for their persistent activation in the cancer cells.18 Stat3 is
found to be crucial for growth of several cancer types but its expres-
sion is dispensable for normal cells in postembryonic stage.23 This
makes NF-jB and Stat3 an ideal target for the development of anti-
cancer therapeutics.
The idea behind the preparation of the alkyl–acyl analogs was to
study the effect of alkyl–acyl groups of varying carbon length on 3-
hydroxyl functionality as well as on its stereochemistry for the bio-
activity of BAs, which consequently may help in the establishmentof
a possible SAR and suggest directions for future studies. Thus, vari-
ous acyl analogs of boswellic acids and their epimers were prepared
active molecule/s on NF-
members of STAT (signal transducer and activator of transcription
protein) family. Many previous studies have shown that NF-
jB (nuclear factor-kappa B) and some
jB
and some STATs (Stat3, Stat5 and Stat6) are persistently active in
many types of leukemia and other tumor types. Stat5 and Stat6
are found to be persistently activated in various haematopoietic
using acylating agents. In order to prepare the specific 3-O-a-for-
myl-b-boswellic acid (5), BA was added slowly to the formylating re-
agent (prepared by adding formic acid to acetic anhydride) with
constant stirring at room temperature. The other acyl analogs of
⇑
Corresponding authors.
E-mail addresses: bashah@iiim.ac.in (B.A. Shah), sctaneja@iiim.ac.in (S.C. Taneja).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.10.112

432
A. Kumar et al. / Bioorg. Med. Chem. Lett. 22 (2012) 431–435
BA were prepared by standard method of using anhydrides, that is,
The preliminary screening results of BAs analogs at 50 lM con-
acetic, propanoic and n-butyric anhydrides in presence of dimethyl
centration showed that the propionate 6, 11-ketobutyrate 11 and
3-epi propionate 22 derivatives potently inhibited the growth
(84–98%) of all the cell lines used [HT-29 (colon), SW-620 (colon),
Colo-205 (colon), Hep-2 (larynx), DU-145 (prostate), PC-3 (pros-
tate)], whereas the natural compound 1 effectively inhibited the
cell growth (92–100%) in prostate cancer cell lines DU-145 and
PC-3 (Table 1). The n-butyrate 7 also showed high cytotoxic activ-
ity (>88%) in all the cancer cell lines except in PC-3 where it
showed 77% growth inhibition (Table 1). The 11-keto propionate
10 as well was found to exhibit significantly enhanced cytotoxicity
when compared to 1, displaying >85% growth inhibition in HT-29,
SW-620 and Colo-205 cell lines. Its growth inhibitory activity was
improved against larynx Hep-2 cancer cell line; however, it was
less effective in DU-145 and PC-3 as compared to 1.
amino pyridine (DMAP) as a catalyst in dry DCM to produce 3-O-
acetyl-b-boswellic acid (3), 3-O- -propionyl-b-boswellic acid (6)
and 3-O- -n-butyryl-b-boswellic acid (7), respectively, in almost
quantitative yields. Likewise, 3-O- -formyl-11-keto-b-boswellic
acid (9), 3-O- -acetyl-11-keto-b-boswellic acid (4), 3-O- -propio-
nyl-11-keto-b-boswellic acid (10) and 3-O- -n-butyryl-11-keto-b-
a-
a
a
a
a
a
a
boswellic acid (11) were also prepared in high yields. Besides, it
was also envisaged to improve hydrophilicity by suitably changing
the functionality. Therefore, additional carboxylic acid functionality
at C-3 was introduced through the formation of hemisuccinates. The
reaction was accomplished by reacting succinic anhydride with 1/2
in presence of pyridine to afford 3-O-a-hemisuccinyl-b-boswellic
acid (8) and 3-O- -hemisuccinyl-11-keto-b-boswellic acid (12),
a
respectively, in 85% yield (Scheme 1).
The configuration of hydroxyl function in the naturally occurring
BAs at C-3 is a. Therefore, to study the effect of change of configura-
tion at C-3 on cytotoxicity, we envisaged the preparation of 3-epi
analogs. To achieve it, we first protected the carboxyl function in
1/2 by esterification via reaction with diazomethane (CH2N2) in
Deregulation of apoptosis is a hallmark of all cancer cells and the
compounds that are capable of inducing apoptosis in cancer cells are
considered to be important in anticancer therapeutics. On the basis
of preliminary screening of toxicity in different cancer cell lines, the
derivatives 6, 7, 10, 11 and 22 were selected to study their apoptotic
functioning. We used a p53 ‘null’ human myeloid leukemia HL-60
cell line for apoptotic screening because of the reason that p53 is
a tumor suppressor gene that provides a vital genetic defence
against development of cancer24 and is reported to be mutated in
about half of the cancers.25 Thus, a compound with an ability to in-
duce apoptosis in HL-60 cells may have wider applicability in other
cancers as well. Apoptosis is a complex phenomenon, which is reg-
ulated by genetic mechanisms and is principally characterized by
morphological and biochemical changes in the nucleus, including
internucleosomal DNA fragmentation. The most active compounds
were thus analyzed for their potential to induce DNA fragmentation
in HL-60 cells. All the selected compounds caused DNA fragmenta-
diethyl ether to afford methyl-3-a-hydroxyurs-12-en-24-oate (13)
and methyl-3- -hydroxy-11-oxours-12-en-24-oate (14), respec-
a
tively, in 95% yield. The formation of esters was followed by their
oxidation with pyridinium chlorochromate (PCC) in dichlorometh-
ane to convert them to corresponding 3-keto derivatives, that is,
methyl-3-oxours-12-en-24-oate (15) and methyl-3, 11-dioxours-
12-en-24-oate (16), respectively, in 85% yield. The 3-keto deriva-
tives were then quantitatively reduced by NaBH4 in methanol to
stereoselectively produce methyl-3-b-hydroxyurs-12-en-24-oate
(17) and methyl-3-b-hydroxy-11-oxours-12-en-24-oate (18),
respectively, having (S) or b-configuration at C-3, as the steric hin-
drance caused by the b-substituent groups mainly in the A/B ring
(e.g., 25-Me, 24-COOMe) facilitated the approach of hydride reagent
tion at 50 lM concentration in HL-60 cells, which was visible in the
form of a ladder of 180–200 bp fragments or multiples of it (Fig. 1A).
In order to identify the most active molecule we used MTT assay to
calculate the IC50 values and relative cytotoxicity of selected analogs
from
a side. The methyl esters thus obtained were hydrolyzed with
KOH/MeOH in a high pressure reaction vessel at 98–100 °C to afford
3-epi-b-boswellic acid (19) and 3-epi-11-keto-b-boswellic acid (20),
respectively in 90% yield (Scheme 2).
in HL-60 cells. The results showed IC50 value of 11 is lowest at 11 lM
(Fig. 1B) whereas, the IC50 values of other analogs were found to be
higher than 11 (Fig. 1B). Normal cell line hGF was also treated with
11 for comparative studies on toxicity. The IC50 of 11 in hGF cells
was calculated as 80 lM (Fig. 1C). Therefore, comparatively low tox-
icity in normal cell line (hGF) further strengthened the candidature
The 3-O-acyl analogs of 3-b-hydroxy-b-boswellic acid were sim-
ilarly prepared using alkyl anhydrides in dry DCM using DMAP as a
catalyst to obtain 3-O-b-acetyl-boswellic acid (21), 3-O-b-propio-
nyl-b-boswellic acid (22) and 3-O-b-n-butyryl-b-boswellic acid
(23), respectively. Similarly, 3-O-b-acetyl-11-keto-b-boswellic acid
(25), 3-O-b-propionyl-11-keto-b-boswellic acid (26) and 3-O-b-n-
butyryl-11-keto-b-boswellic acid (27) were also prepared. The
3-epi BAs were also subjected to hemi succinate formation using
succinic anhydride and pyridine to produce 3-O-b-hemisuccinyl-b-
boswellic acid (24) and 3-O-b-hemisuccinyl-11-keto-b-boswellic
acid (28) in almost quantitative yields (Scheme 2).
of 11 for detailed studies.
In order to analyze whether the toxicity caused by these deriv-
atives is purely due to apoptosis or other types of cell death also
plays some role (necrosis and autophagy), we employed flow
cytometer based analysis after staining the HL-60 cells with
annexin-v-FITC/propidium iodide (to analyze apoptosis and necro-
sis) and acridine orange (to analyze autophagy). It was observed
R1
R1
R2
R2
(i)
HO
RO
COOH
COOH
5. R = -COH, R1=R2= H
9.
4.
1
R = -COH, R +R2 = O
1 / 2
3. R = -COCH3, R1=R2= H
R = -COCH3, R +R2 = O
1
1
2
10. R = -COC2H5,R1+R2 = O
11. R = -COC3H7, R1+R2 = O
6
7
8.
. R = -COC2H5, R =R = H
1
2
. R = -COC3H7, R =R = H
R = -COCH2CH2COOH, R =R = H12. R = -COCH2CH2COOH, R +R2 = O
1
2
1
Scheme 1. Reagents: (i) R2O, DMAP, DCM (95%).

A. Kumar et al. / Bioorg. Med. Chem. Lett. 22 (2012) 431–435
433
R1
R2
R1
R2
R1
H
R2
(ii)
(i)
H
H
H
H
H
HO
HO
O
COOH
COOMe
COOMe
1. R1 = R2= H
13. R1 = R2 = H
15. R1 = R2 = H
. R1 + R2 = O
. R1 + R2 = O
. R1 + R2 = O
16
2
14
(iii)
R1
R2
R1
R2
R1
R2
H
H
(v)
(iv)
H
H
HO
HO
RO
COOH
COOMe
COOH
19. R1 = R2 = H
20. R1 + R2 = O
1
2
21
17. R1 = R2 = H
18. R1 + R2 = O
. R = -COCH3, R =R = H
1
2
22
. R = -COC2H5, R =R = H
23. R = -COC3H7, R1=R2= H
24. R = -COCH2CH2COOH, R1=R2= H
25. R = -COCH3, R1+R2 = O
. R = -COC2H5, R +R2 = O
1
26
27
. R = -COC3H7, R +R2 = O
1
28. R = -COCH2CH2COOH, R1+R2 = O
Scheme 2. Reagents and conditions: (i) CH2N2, ether (95%) (ii) PCC, DCM, rt (80%) (iii) NaBH4, MeOH, rt (90%) (iv) KOH, MeOH (88%) (v) R2O, DMAP, DCM (95%)
Table 1
In vitro cytotoxicity of natural BAs and their analogs against different human cancer cell lines. All the cell lines were treated with 50
(10 M), mitomycin c (10 M) and adriamycin (2 M) were used as positive control. Data are shown as mean values of three similar experiments SEM (standard error of the
mean).
l
M of test compounds for 48 h, 5-flurouracil
l
l
l
Compound
Conc (
l
M)
HT-29 colon
SW-620
Colo-205
Hep-2 larynx
DU-145 prostate
PC-3
% Growth inhibition SEM
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
10
10
02
66 0.88
39 0.38
93 0.88
88 0.76
76 0.83
93 1.17
64 0.83
85 1.01
52 0.66
91 1.15
85 1.20
90 1.17
84 1.17
88 1.01
88 1.34
73 0.88
87 1.34
94 0.83
43 0.69
35 0.50
85 0.76
92 0.88
95 1.2
100
100
28 0.83
93 1.26
88 1.01
87 1.38
94 1.57
93 1.83
67 1.26
69 0.38
85 1.34
97 0.69
3
0.19
44 0.69
76 1.02
95 1.33
93 1.02
77 1.26
90 0.84
95 1.35
64 0.88
96 0.69
38 0.51
54 0.88
87 0.69
44 0.84
59
1
85 0.83
90 1.26
91 1.45
89 0.83
93 1.01
83 1.2
25 0.33
93 0.66
51 0.69
85 1.01
72 0.88
86 1.07
94 1.57
55 0.88
54 0.66
69 0.88
98 0.50
95
1
72 0.38
63 0.57
89
96 0.66
0.50
1
5
4
0.38
2
0.19
43 0.88
70
6
0.38
35 0.57
67 0.96
33 0.38
17 0.57
46 0.96
67 0.83
34 0.83
11 0.19
26 0.66
50 0.69
1
65
1
34 0.66
30 0.69
22 0.69
21 0.33
81 1.07
49 0.76
32 0.57
86 0.83
67 1.07
19 0.38
54 0.69
7
0.33
50 0.88
23 0.33
10 0.50
0
0
3
7
5
0.33
0.19
0.19
5
8
0.38
0.19
9
0.19
3
4
0.19
0.19
10 0.38
63 0.69
45 1.26
35 0.76
89 1.45
79 1.34
70 0.76
44 0.57
31 0.76
92 0.66
57 0.88
13 0.57
44 0.38
64 0.96
62 0.69
17 0.38
41 1.55
60 0.92
88 1.01
69 0.88
51 0.69
42 0.50
87 0.33
63 0.69
11 0.33
47 0.83
63 0.69
66 0.66
19 0.50
29 0.22
58 0.69
64 1.02
89 1.01
84 0.83
87 0.69
88 0.66
89 1.26
48 0.69
83 0.83
89 1.33
92 0.88
83 1.07
72 0.88
70 0.67
56 0.51
95 1.17
83 0.84
35 0.88
62 0.51
96 1.17
94 0.69
62 0.84
16 0.33
5
0.57
44 1.07
72 0.96
79 1.17
83
1
91 0.88
28 0.33
29 0.37
43 0.83
81 1.45
4
0.19
5FU
Mitomycin C
Adriamycin
44 1.02
55 1.22
72 1.07
35 0.50
48 0.56
90 1.25
55 0.88
86 1.25

434
A. Kumar et al. / Bioorg. Med. Chem. Lett. 22 (2012) 431–435
Fig. 1. (A) DNA fragmentation induced by selected dervatives of boswellic acids. Apoptotic DNA ladder was observed when 2 Â 106 HL-60 cells were treated with various
derivatives of BAs at 50 lM concentration for 6 h. The cells treated for 6 h with 4 lM camptothecin were used as positive control. (B) Inhibition of cell proliferation by
selected dervatives of BAs in HL-60 cells and (C) in hGF cells. The cell proliferation analysis was performed in HL-60 and hGF cells by using MTT. The cells were incubated with
each analog for 48 h at indicated concentrations and thereafter mitochondrial competence of MTT reduction as an index of cell viability determined. OD of untreated control
was taken as 100% viability. IC50 values of all the compounds are depicted in the B and C.
that all the derivatives at concentration 50
l
M induced cell death
with 11 reduced the expression of NF-
spective of the concentration of 11 (20 and 50
expression of NF- B (p50) was more potently inhibited at 50
concentration of 11 (Fig. 3A).
The anti-apoptotic members of STAT family contribute to the
cancer cell growth by employing different mechanisms. Both the
unphosphorylated and phosphorylated forms of STAT proteins
work together for cancer cell survival. The analysis of anti-apopto-
tic members of Stat family (Stat3, Stat5 and Stat6) revealed differ-
ential expression of these proteins in HL-60 cells. The
j
B (p65) by about 90% irre-
predominantly by apoptosis, whereas the number of cells undergo-
ing necrosis was relatively insignificant after 6 h exposure. None of
the compounds produced autophagic death in HL-60 cells (data not
shown). However, as expected, 11 was found to be the most effec-
tive of all the analogs producing approximately 80% of apoptotic
cell population at the end of 6 h treatment, suggesting that it
may be probably a potential candidate for further development
to an anti-cancer therapeutic lead. The butyrate analog 11 exhib-
ited relatively lower IC50 values and showed greater potential for
inducing apoptosis, therefore, warranted more studies to under-
stand its molecular mechanism of action (Fig. 2).
lM), while the
j
lM
unphosphorylated Stat3a, Stat3b, Stat5 and Stat6 were highly ex-
pressed in control HL-60 cells (Figs. 3B and C). However, treatment
of HL-60 cells with 11 for 6 h strongly reduced the expression of all
the unphosphorylated Stat proteins. The expression analysis of
phosphorylated STAT proteins revealed that HL-60 cells show very
high level of pStat3 (Ser 727) (Fig. 3B), which signifies the impor-
tance of pStat3 in the proliferation of HL-60 cells. Other STAT pro-
teins showed varied expression in the control cells, where pStat3
(Ser 727) and pStat3 (Thr 705) had significantly high expression.
pStat5 (Tyr 694/699) and pStat6 (Tyr 641) showed significantly
low level of protein (Fig. 3C). However, the treatment with 11
strongly reduced the expression of phosphorylated forms of all
the members of STAT family studied. The data clearly suggests that
For the validation of the effectiveness of 11 against few among
many putative molecular targets in cancer cells, we analyzed the
expression of NF-
family in HL-60 cells. The transcription factors NF-
j
B and some anti-apoptotic members of STAT
B and Stat3
j
are persistently active in most of the cancers and are involved in
the regulation of genes required for cancer cell proliferation, sur-
vival, angiogenesis and invasion. Both these proteins work in con-
junction with each other for the growth of cancer cells and require
each other for their constitutive activity. In view of the importance
of NF-
ily, we analyzed the effect of 11 on the expression of these proteins
in HL-60 cells. The control cells showed a high level of NF- B (p65)
and NF- B (p50) in the whole cell fraction, whereas 6 h treatment
jB and Stat3 and other procancerous members of STAT fam-
j
cytotoxic effect of 11 is mediated by the inhibition of NF-
jB-Stat3
j
tango along with other anti-apoptotic members of STAT family.
Fig. 2. Effect of selected boswellic acid analogs on the relative efficiency of induction of apoptosis and necrosis in HL-60 cells. The cells were incubated with each analog at
50 M concentration for 6 h and stained with annexin v-FITC/PI. The dot plots are the representative of one of the three experiments. Values in the lower right quadrant
l
represent the apoptotic population, in the upper right as post apoptotic and in the upper left as necrotic. Other conditions are the same as described in the methods. The data
shown are representative of one of the three similar experiments.

A. Kumar et al. / Bioorg. Med. Chem. Lett. 22 (2012) 431–435
435
Fig. 3. Effect of 11 on the expression of NF-
jB and procancerous STAT proteins in HL-60 cells. (A) The cells were treated with or without 11 (20 and 50
lM) for 6 h. Total cell
lysates were prepared for immunoblot analysis of NF-jB (p50 and p65). Protein samples (70 lg) were loaded on 10 % SDS–PAGE gel for western blot analysis. b-Actin was
used as internal control to represent the same amount of protein applied for SDS–PAGE. Data are representative of one of three similar experiments. (B and C) Western blot
analysis for STAT proteins as indicated in the figure. 8% SDS–PAGE was used to resolve the STAT proteins; other conditions are same as in A.
6. Gupta, I.; Parihar, A.; Malhotra, P.; Gupta, S.; Ludtke, R.; Safayhi, H.; Ammon, H.
P. Planta Med. 2001, 67, 391.
7. Gupta, A.; Gupta, V.; Parihar, A.; Gupta, S.; Ludtke, R.; Safayhi, H.; Ammon, H. P.
Thus, based on this data, compound 11 can be further studied as an
effective anti-cancer lead.
In conclusion, the alkyl–acyl derivatives of BAs were synthe-
sized and screened for cytotoxicity against a panel of human can-
cer cell lines. The semi-synthetic compounds exhibited a range of
activities, thereby establishing a partial SAR which is summarized
as follows. (i) The alkyl–acyl analogs in general displayed improved
activity than the parent BAs, that is, higher acyl homologues (3–7
and 9–11) displayed better cytotoxicity indicating free hydroxyl
is not essential for activity, (ii) the attempts to increase hydrophi-
licity by way of C-3 hemi-succinate formation (8, 12, 24 and 28)
did not improve cytotoxicity, (iii) the esterification of acid group
(13–18) led to the reduction/ loss of activity, implying that C-24
acid moiety is important for activity and (iv) the 3-epi BAs
(19–28) did not display any significant improvement in activity,
Eur. J. Med. Res. 1998, 3, 511.
8. Safayhi, H.; Mack, T.; Ammon, H. P. Biochem. Pharmacol. 1991, 41, 1536.
9. Han, R. Stem Cells 1994, 12, 53.
10. Bhushan, S.; Kumar, A.; Malik, F.; Andotra, S. S.; Sethi, V. K.; Kour, I. P.; Taneja, S.
C.; Qazi, G. N.; Singh, J. Apoptosis 2007, 12, 1911.
11. (a) Jannsen, G.; Bode, U.; Breu, H.; Dohm, B.; Engelbrecht, V.; Gobel, U. Klin.
Padiatr. 2000, 212, 189; (b) Winkling, M.; Sarikaya, S.; Rahmanian, A.; Jodicke,
A.; Boker, D. K. J. Neurooncol. 2000, 46, 97.
12. Glaser, T.; Winter, S.; Groscurth, P.; Safayhi, H.; Sailer, E. R.; Ammon, H. P. Br. J.
Cancer 1999, 80, 756.
13. Liu, J. J.; Nilsson, A.; Oredsson, S.; Badmaev, V.; Zhao, W. Z.; Duan, R. D.
Carcinogenesis 2002, 23, 2087.
14. (a) Hoernlein, R. F.; Orlikowsky, T.; Zehrer, C.; Niethammer, D.; Sailer, E. R.;
Simmet, T.; Dannecker, G. E.; Ammon, H. P. J. Pharmacol. Exp. Ther. 1999, 288,
613; (b) Jing, Y.; Nakajo, S.; Xia, L.; Nakaya, K.; Fang, Q.; Waxman, S.; Han, R.
Leukocyte Res. 1999, 23, 43.
15. Syrovets, T.; Buchele, B.; Gedig, E.; Slupsky, J. R.; Simmet, T. Mol. Pharmacol.
2000, 58, 71.
indicating that a-configuration at C-3 is more important for cyto-
16. (a) Chib, R.; Shah, B. A.; Anand, N.; Pandey, A.; Kapoor, K.; Bani, S.; Gupta, V. K.;
Rajnikant, ; Sethi, V. K.; Taneja, S. C. Bioorg. Med. Chem. Lett. 2011, 21, 4847; (b)
Shah, B. A.; Kaur, R.; Gupta, P.; Kumar, A.; Sethi, V. K.; Andotra, S. S.; Singh, J.;
Saxena, A. K.; Taneja, S. C. Bioorg. Med. Chem. Lett. 2009, 19, 4394; (c) Shah, B.
A.; Chib, R.; Gupta, P.; Sethi, V. K.; Koul, S.; Andotra, S. S.; Nargotra, A.; Sharma,
S.; Pandey, A.; Bani, S.; Purnima, B.; Taneja, S. C. Org. Biomol. Chem. 2009, 7,
3230; (d) Shah, B. A.; Taneja, S. C.; Sethi, V. K.; Gupta, P.; Andotra, S. S.; Chimni,
S. S.; Qazi, G. N. Tetrahedron Lett. 2007, 48, 955.
toxicity. Thus, screening of BA derivatives lead to the identification
of compound 11 (3-O-n-butyryl-11-keto-b-boswellic acid) as a
promising lead that exhibited anti-cancer activity by inhibiting
the NF-jB and STAT proteins which may be further developed into
a potential anti-cancer therapeutic.
17. (a) Kaur, R.; Khan, S.; Chib, R.; Kaur, T.; Sharma, P. R.; Singh, J.; Shah, B. A.;
Taneja, S. C. Eur. J. Med. Chem. 2011, 46, 1356; (b) Khan, S.; Chib, R.; Shah, B. A.;
Wani, Z. A.; Dhar, N.; Mondhe, D. M.; Lattoo, S.; Jain, S. K.; Taneja, S. C.; Singh, J.
Eur. J. Pharm. 2011, 660, 241; (c) Raja, A. F.; Ali, F.; Khan, I. A.; Shawl, A. S.;
Arora, D. S.; Shah, B. A.; Taneja, S. C. BMC Microbiol. 2011, 11, 54; (d) Chashoo,
G.; Singh, S. K.; Sharma, P. R.; Mondhe, D. M.; Hamid, A.; Saxena, A.; Andotra, S.
S.; Shah, B. A.; Qazi, N. A.; Taneja, S. C.; Saxena, A. K. Chem. Biol. Interact. 2011,
189, 60; (e) Shah, B. A.; Kumar, A.; Gupta, P.; Sharma, M.; Sethi, V. K.; Saxena, A.
K.; Singh, J.; Qazi, G. N.; Taneja, S. C. Bioorg. Med. Chem. Lett. 2007, 17, 6411.
18. Yu, H.; Pardoll, D.; Jove, R. Nat. Rev. Can. 2009, 9, 798.
Supplementary data
Supplementary data (experimental procedures and character-
isation data) associated with this article can be found, in the online
version, at doi:10.1016/j.bmcl.2011.10.112.
References and notes
19. Ostrand-Rosenberg, S.; Sinha, P. J. Immunol. 2009, 182, 4499.
20. Cheng, P.; Corzo, C. A.; Luetteke, N.; Yu, B.; Nagaraj, S.; Bui, M. M.; Ortiz, M.;
Nacken, W.; Sorg, C.; Vogl, T.; Roth, J.; Gabrilovich, D. I. J. Exp. Med. 2008, 205,
2235.
21. Zhao, W.; Jaganathan, S.; Turkson, J. J. Biol. Chem. 2010, 285, 35855.
22. Ahn, K. S.; Aggarwal, B. B. Ann. N. Y. Acad. Sci. 2005, 1056, 218.
23. Schlessinger, K.; Levy, D. E. Cancer Res. 2005, 65, 5828.
1. Shah, B. A.; Qazi, G. N.; Taneja, S. C. Nat. Prod. Rep. 2009, 26, 72.
2. (a) Singh, S.; Khajuria, A.; Taneja, S. C.; Khajuria, R. K.; Singh, J.; Qazi, G. N.
Bioorg. Med. Chem. Lett. 2007, 17, 3706; (b) Singh, S.; Khajuria, A.; Taneja, S. C.;
Johri, R. K.; Singh, J.; Qazi, G. N. Phytomedicine 2008, 15, 400.
3. Ammon, H. P. Planta Med. 2006, 72, 1100.
4. Khanna, D.; Sethi, G.; Ahn, K. S.; Pandey, M. K.; Kunnumakkara, A. B.; Sung, B.;
Aggarwal, A.; Aggarwal, B. B. Curr. Opin. Pharmacol. 2007, 7, 344.
5. (a) Gupta, I.; Parihar, A.; Malhotra, P.; Singh, G. B.; Ludtke, R.; Safayhi, H.;
Ammon, H. P. Eur. J. Med. Res. 1997, 2, 37; (b) Singh, S.; Khajuria, A.; Taneja, S.
C.; Khajuria, R. K.; Singh, J.; Johri, R. K.; Qazi, G. N. Phytomedicine 2008, 15, 408.
24. Aylon, Y.; Oren, M. Cell 2007, 130, 597.
25. Liu, D. P.; Song, H.; Xu, Y. Oncogene 2010, 29, 949.