Synthesis of lantadene analogs with marked in vitro inhibition of lung adenocarcinoma and TNF-α induced nuclear factor-kappa B (NF-κB) activation

Article abstract of DOI:10.1016/j.bmcl.2014.06.068

The new series of pentacyclic triterpenoids reduced lantadene A (3), B (4), and 22β-hydroxy-3-oxo-olean-12-en-28-oic acid (5) analogs were synthesized and tested in vitro for their NF-κB and IKKβ inhibitory potencies and cytotoxicity against A549 lung cancer cells. The lead analog (11) showed sub-micromolar activity against TNF-α induced activation of NF-κB and exhibited inhibition of IKKβ in a single-digit micromolar dose. At the same time, 11 showed promising cytotoxicity against A549 lung cancer cells with IC₅₀ of 0.98 μM. The Western blot analysis further showed that the suppression of NF-κB activity by the lead analog 11 was due to the inhibition of IκBα degradation, a natural inhibitor of NF-κB. The physicochemical evaluation demonstrated that the lead analog 11 was stable in the simulated gastric fluid of pH 2, while hydrolyzed at a relatively higher rate in the human blood plasma to release the active parent moieties. Molecular docking analysis showed that 11 was hydrogen bonded with the Arg-31 and Gln-110 residues of the IKKβ.

Full text of DOI:10.1016/j.bmcl.2014.06.068

Bioorganic & Medicinal Chemistry Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis of lantadene analogs with marked in vitro inhibition
of lung adenocarcinoma and TNF-
(NF- B) activation
a induced nuclear factor-kappa B
j
Monika a, , Ankesh Sharma a, , Sharad Kumar Suthar a, , Vaibhav Aggarwal a, Hong Boon Lee b,
Manu Sharma a,
⇑
a Department of Pharmacy, Jaypee University of Information Technology, Waknaghat 173234, India
b Cancer Research Initiative Foundation, Drug Discovery Laboratory, 12A Jalan TP5, Taman Perindustrian UEP, 47600 Subang Jaya, Selangor Darul Ehsan, Malaysia
a r t i c l e i n f o
a b s t r a c t
Article history:
The new series of pentacyclic triterpenoids reduced lantadene A (3), B (4), and 22b-hydroxy-3-oxo-olean-
Received 21 May 2014
Revised 19 June 2014
Accepted 20 June 2014
Available online xxxx
12-en-28-oic acid (5) analogs were synthesized and tested in vitro for their NF-
potencies and cytotoxicity against A549 lung cancer cells. The lead analog (11) showed sub-micromolar
activity against TNF- induced activation of NF- B and exhibited inhibition of IKKb in a single-digit
micromolar dose. At the same time, 11 showed promising cytotoxicity against A549 lung cancer cells
with IC50 of 0.98 M. The Western blot analysis further showed that the suppression of NF- B activity
by the lead analog 11 was due to the inhibition of I degradation, a natural inhibitor of NF- B. The
physicochemical evaluation demonstrated that the lead analog 11 was stable in the simulated gastric
fluid of pH 2, while hydrolyzed at a relatively higher rate in the human blood plasma to release the active
parent moieties. Molecular docking analysis showed that 11 was hydrogen bonded with the Arg-31 and
Gln-110 residues of the IKKb.
jB and IKKb inhibitory
a
j
l
j
Keywords:
Tumor necrosis factor-alpha
Nuclear factor-kappa B
Inhibitor of nuclear factor-kappa B kinase b
A549 lung cancer cells, Lantadene analogs
j
Ba
j
Ó 2014 Elsevier Ltd. All rights reserved.
Lung cancer ranks as the first malignant tumor killer world-
wide.1,2 The treatment options include chemotherapy and radia-
tion therapy as well as the combination of both the therapies, as
an effort to reduce the tumor mass and halt the disease progres-
sion. However, the success rate of these therapies is low and the
prognosis of the patients is usually very poor.3 At the molecular
level, it has been established fact that nuclear factor-kappa B
importance not only in developing new therapeutics for lung can-
cer but also to improve therapeutics indices of known cytotoxic
drugs.
In the last few years, pentacyclic triterpenoids lantadene A (1)
and B (2) isolated from the leaves of weed Lantana camara L.
(Verbenaceae) have attracted a lot of interest because of their
anticancer properties.6–10 These compounds along with reduced
lantadene A (3), reduced lantadene B (4), and 22b-hydroxy-
3-oxo-olean-12-en-28-oic acid (5) showed potent cytotoxic effects
in antitumor screening launched by the National Cancer Institute,
(NF-
including lung cancer. The tumor samples obtained from lung can-
cer patients showed high levels of NF- B activation in both small
jB) is constitutively activated in a variety of solid tumors,
j
cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC),
and is significantly associated with disease advancement in meta-
static stages and poor prognosis in lung cancer patients.4 Besides
USA11 and were found to be potent inhibitors of NF- B.6,7,12
j
Recently, we reported the synthesis of C-3, C-17, and C-22 analogs
of lantadenes with marked inhibition of lung adenocarcinoma and
this, the NF-
cers, and both chemotherapeutics and radiation therapy induce
NF- B activation in cancer cells, which contributes towards resis-
tance to these therapies.5 Thus, it is assumed that blockage of
NF- will increase the efficacy of anticancer therapeutics.
jB is constitutively activated in a variety of other can-
NF-j
B.13–15 The promising results obtained with a diverse but lim-
ited series of target compounds prompted us to further explore the
new analogs of lantadenes. The new C-3 and C-22 analog series
were synthesized and evaluated for their in vitro anticancer
activity and inhibition of tumor necrosis factor-alpha-induced
j
jB
Therefore, the development of NF-
jB inhibitors can be of prime
(TNF-a-induced) NF-jB activation in the lung adenocarcinoma cell
line A549. The most active analogs were evaluated in vitro for their
inhibitory potency against the recombinant inhibitor of nuclear
factor-kappa B kinase b (IKKb) in a non-radioisotope Kinase-Glo
Luminescent Kinase assays, while the lead analog was further
⇑
Corresponding author. Tel.: +91 1792 239407; fax: +91 1792 245362.
E-mail address: lantadene@hotmail.com (M. Sharma).
Authors have made an equal contribution.
http://dx.doi.org/10.1016/j.bmcl.2014.06.068
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Monika,; et al. Bioorg. Med. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.bmcl.2014.06.068

2
Monika et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
studied for its effect on I
j
B
a
protein by employing the Western
tetrahydrofuran (THF) mixture as the solvent. The compound 5
was synthesized in 76.47% yield by alkali hydrolysis of 1 and 2
using 10% ethanolic potassium hydroxide. For the synthesis of
compounds 6–13, the acidic group of aromatic acids was first con-
verted into the anhydride group by the reaction of an acid with
acetyl chloride in the presence of pyridine in dichloromethane
(DCM) (Supplementary data: Scheme S1). The aromatic acids were
refluxed with an equimolar amount of acetyl chloride to afford
solid to semisolid anhydride products of respective acids, which
were used in the next step without further purification. In the con-
cluding step of the synthesis of compounds 6–19, appropriate
anhydrides were refluxed with compounds 3, 4, and 5 in pyridine
in the presence of 4-dimethylamino pyridine (4-DMAP) to afford
the crude products, which were chromatographed over silica gel
(100–200 mesh) and eluted with varying ratios of hexane and ethyl
acetate to yield the final purified products (6–19).
blot technique. The most active ester analogs were also studied
for their stability in the acidic pH and hydrolysis in the human
blood plasma. The lead analog was further docked with the crystal
structure of IKKb to predict the possible binding mode of the
analog.
Continuing our research interests in lantadene analogs as anti-
cancer agents, we have synthesized a new series of C-3 and C-22
analogs. The sequence of steps involved in the synthesis of com-
pounds is summarized in Scheme 1. The lantadene A (1) and B
(2) are pentacyclic triterpenoids of oleanane series and were iso-
lated from the leaves of weed Lantana camara Linn. The isolated
compounds 1 and 2 differ only in the arrangement of atoms at
the C-22 ester side chain with E conformation is present in the 1,
while the side chain of compound 2 possesses Z conformation.
The isolated compounds 1 and 2 were selectively reduced into
the corresponding compounds 3 and 4 in 87.60–89.88% yield, using
sodium borohydride as a reducing agent and methanol (MeOH):
The synthesized compounds were evaluated for their potential
to inhibit TNF-a-induced NF-jB activation in lung adenocarcinoma
Scheme 1. Synthesis of lantadene analogs 3–19. Reagents and conditions: (a) NaBH4, MeOH-THF, stir 7 h; (b) 10% ethanolic KOH, reflux 6 h; (c) R0-CO-O-CO-CH3 (6–13)/R0-
CO-O-CO-R0 (14–19), 4-DMAP, pyridine, reflux 92–95 °C, 10–14 h.
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Monika et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
3
Table 2
cell line A549. The human lung adenocarcinoma A549 cell line,
transiently co-transfected with NF- B-luc was used to monitor
the effects of lantadene analogs on TNF- -induced NF- B activa-
In vitro IKKb inhibition by parent compounds (3 and 4) and analogs (11 and 13)
j
a
j
Compd.
IC50 (lM)
tion. The compounds (1–19) were evaluated in a dose-dependent
manner to determine the concentration needed to inhibit 50% of
3
4
11
13
2.62 0.82
4.24 0.94
1.36 0.06
1.54 0.04
TNF-
1–4 showed inhibition of TNF-
range of 1.56–0.98 M. The reduction of a C-3 keto group of com-
a-induced NF-
jB activation (IC50). The parent compounds
a
-induced NF- B activation in the
j
l
Results are given as the mean of at least three independent experiments with
triplicates in each experiment.
pounds 1 and 2 into the C-3 hydroxyl group of compounds 3 and 4
led to an increase in the activity, whereas hydrolysis of a C-22 ester
side chain of compound 1 and 2 into the compound 5 led to a
decrease in the activity. It was observed that the C-22 ester side
cytokines, such as TNF-
a has been involved in stimulating cancer
cell proliferation, particularly during chronic inflammation of the
chain played a critical role in the inhibition of TNF-
a-induced
lungs.18 Since, the lantadene analogs showed marked inhibition
NF- B activation in lung adenocarcinoma cell line A549. The
j
of NF-jB, they were further evaluated for their in vitro cytotoxicity
hydrolysis of the C-22 ester functionality in lantadenes led to a sig-
nificant reduction in activity, supporting the notion that the mech-
anism of inhibition is likely through a covalent Michael addition of
nucleophiles (such as SH from cysteine) from protein candidate(s)
to lantadenes.13 The introduction of 3-methoxybenzoyloxy and 4-
chlorobenzoyloxy functionality at C-3 position of compound 4 led
to an increase in the activity, whereas the 2- and 3-flurobenzoyl-
oxy functionalities at C-3 position decreased the activity, signifi-
cantly. The alkyl and branched chain esters at C-3 position of 3
and 4 were found to be the least active. The results of inhibition
against lung cancer cells A549. The cytotoxicity profile of parent
compounds (1–5) and ester analogs (6–19) are reported in Table 3.
The parent pentacyclic triterpenoids 1, 2, 3, and 4 showed cytotox-
icity against A549 lung cancer cells with IC50 values of 2.84, 1.19,
0.79, and 0.43
IC50 >10 M. The introduction of 3-methoxybenzoyloxy (11) and 4-
chlorobenzoyloxy (13) groups in compound 4 showed marked
cytotoxicity with IC50s of 0.98 and 1.12 M, respectively (Table 3).
From the cytotoxicity profiles of compounds 1–19, it was evident
that the removal of the ester side chain at C-22 position led to a
decrease in the activity. The strongly electrophilic a,b-unsaturated
carbonyl group of the ester side chain seems to play an important
lM, respectively, whereas the compound 5 showed
l
l
of TNF-
cell line by compounds 1–19 are shown in Table 1.
The NF- B activation pathway in most of the cells involves
a-induced NF-jB activation in A549 lung adenocarcinoma
j
role in binding of compounds to the receptor site.
dimers composed of p50 and p65 or c-Rel and is often activated
The I
activation of NF-
radation of I
appreciable degree of inhibition of TNF-
tion in the lung adenocarcinoma cell line A549, was chosen for fur-
ther study. To explore whether the inhibition of TNF- -induced
NF- B activation was due to the inhibition of I degradation,
the cells were treated with various concentrations of compound
11 for 8 h and then exposed to 0.1 nmol TNF- for 30 min. The cell
extracts were then subjected to Western blot analysis for an esti-
mation of I level in the cytoplasm. The results showed that
TNF- induced the I degradation in the control cells, whereas
in the cells pretreated with compound 11, TNF- failed to induce
the degradation of I (Fig. 1A and B).
jB
a
is a natural inhibitor of oncogenic protein NF-
B requires phosphorylation and subsequent deg-
. The lead lantadene analog 11, which showed an
-induced NF- B activa-
jB. The
by microbial infections, pro-inflammatory growth factors and cyto-
kines, including TNF-a 16
.
The TNF-
receptor 1 (TNFR1) and recruitment of multiple
adaptor proteins and kinases, resulting in the activation of IKKb,
causing phosphorylation or degradation of inhibitor of NF- B pro-
teins (I B proteins), which releases NF- B from the cytoplasm to
a engagement induces trimer-
j
jBa
ization of TNF-
a
a
j
j
a
j
j
j
jBa
the nucleus, where it carry out transcription of proteins responsible
for proliferation and differentiation of cancer cells.17 As compounds
a
11 and 13 showed the potent NF-jB inhibition; therefore, we fur-
ther evaluated the effect of parent compounds 3 and 4 and their
analogs 11 and 13 against upstream kinase IKKb that has been
reported to activate the NF-jB pathway. The compounds were eval-
uated in vitro for their inhibitory potential against the recombinant
IKKb in a non-radioisotope Kinase-Glo Luminescent Kinase Assays
(Promega, USA). It was found that 11 and 13 remarkably inhibited
jBa
a
jBa
a
jBa
A successful ester analog should be stable in the acidic pH of the
stomach and should be hydrolyzed in the blood plasma to release
the active parent moieties. The compounds 11 and 13 that
emerged as the most potent ester analogs from the synthesized
IKKb with IC50s of 1.36 and 1.54
lM, respectively (Table 2).
The NF- B is a positive mediator of cell growth and prolifera-
j
tion. The mutual interplay between NF-jB and pro-inflammatory
Table 1
Table 3
TNF-
a
-induced NF-
j
B activation inhibitory activities of parent compounds (1–5) and
In vitro cytotoxicity profile of parent compounds (1–5) and analogs (6–19) against
analogs (6–19)
A549 cell line
Compd
IC50
(
lM)
Compd
IC50
(l
M)
Compd
IC50
(
lM)
Compd
IC50 (lM)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1.06 0.46
1.56 0.04
0.98 0.02
1.02 0.62
6.42 1.24
1.94 0.24
1.80 0.60
2.32 0.01
2.04 0.02
1.64 0.74
0.74 0.24
0.96 0.36
0.82 0.02
3.12 0.42
15
16
17
18
19
2.82 0.24
3.12 0.12
>10
>10
>10
1
2
3
4
5
6
7
8
9
10
11
12
13
14
2.84 0.72
1.19 0.28
0.79 0.01
0.43 0.03
>10
2.04 0.04
1.96 0.24
>10
6.86 1.32
1.84 0.42
0.98 0.08
1.32 0.32
1.12 0.02
>10
15
16
17
18
19
Cisplatin
>10
>10
2.56 0.36
>10
>10
21.3 3.62
Results are given as the mean of at least three independent experiments with
triplicates in each experiment.
Results are given as the mean of at least three independent experiments with
triplicates in each experiment.
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4
Monika et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
Figure 1. The effect of the lead compound 11 on TNF-a-induced IjBa degradation. The TNF-a-induced and IKK mediated IjBa degradation leads to an activation of NF-jB,
which then transmigrates into nucleus, where it binds with the DNA and carry out transcription of proteins responsible for oncogenesis. (A) Western blot analysis describing
the effect of compound 11 on TNF- -induced I degradation. The protein bands obtained in the Western blot indicate that compound 11 was able to suppress the
degradation of I , which subsequently decreased the activity of NF- B. (B) The densitometry analysis of the Western blots shows the relative intensity of IkB /b-actin. The
-treated versus 0; ⁄⁄⁄⁄P < 0.0001, 0.5 TNF-
-treated versus 0; #P < 0.0001, 1.0 TNF-
-treated versus 1.0;
a
jBa
j
B
a
j
a
results shown are the mean SD of three separate experiments. A P value <0.05 was considered significant. ⁄⁄⁄⁄P < 0.0001, 0 TNF-
a
a-
treated versus 0; nsP > 0.05 or not significant, 0.5 TNF-
$P < 0.01, 1.0 TNF-
-treated versus 0 TNF- -treated.
a
-treated versus 0 TNF-
a
-treated; ⁄⁄⁄P < 0.001, 1.0 TNF-
a
a
a
a
Table 5
series were further explored for their stabilities in the chemical/
acidic and enzymatic media. For chemical stability studies, the
ester analogs 11 and 13 were exposed to the simulated gastric fluid
of pH 2 for 0, 2, 5, 8, and 12 h. Results of HPLC analysis of ester
analogs exposed to the simulated gastric fluid of pH 2 showed that
only 0.0%, 6.96%, 11.80%, 16.68%, and 22.75% of 11 and 0.0%, 7.84%,
13.48%, 19.72%, and 27.18% of 13 were hydrolyzed after the expo-
sure time of 0, 2, 5, 8, and 12 h, respectively (Table 4). It can be
inferred from the results of chemical hydrolysis studies that the
ester analog 11 showed slightly higher resistance towards hydroly-
sis in comparison with the 13 and both of them survived the
gastric pH conditions. To study plasma hydrolysis or susceptibility
of ester analogs 11 and 13 towards human plasma esterases, they
were exposed to 80% human plasma for 0, 15, 30, 60, and 120 min
and extent of hydrolysis was monitored by HPLC. On exposure to
human plasma, the ester analogs 11 and 13 were hydrolyzed at a
noticeably higher rate than the rate of their hydrolysis observed
in the simulated gastric fluid. A level of ester analogs hydrolyzed
was found to be 0.0%, 29.62%, 46.76%, 53.30%, and 64.68% of 11
and 0.0%, 29.76%, 47.82%, 55.70%, and 67.73% of 13 after the expo-
sure time of 0, 15, 30, 60, and 120 min, respectively (Table 5). The
ester analog 11 showed a slightly lesser degree of hydrolysis than
its counterpart 13. HPLC results indicated that the ester analogs 11
and 13 underwent rapid hydrolysis in human blood plasma to lib-
erate the parent drug molecules, to reach the site of action, while in
the simulated gastric fluid of pH 2, they survived the stomach pH
conditions. The analog 11 was hydrolyzed to a comparatively les-
ser extent than 13 due to the bearing of an electron releasing
methoxy group that decreased the electrophilicity of the C-3 ester
carbonyl carbon, whereas the analog 13 possessed the electron
Metabolic stability of the most potent ester analogs (11 and 13) in 80% human plasma
Time (min)
% Ester analog remaining unhydrolyzed in 80% human plasma
Compd 11
Compd 13
0
15
30
60
120
100
100
70.38
53.24
46.70
35.32
70.24
52.18
44.30
32.27
withdrawing chloro group. Additionally, the chloro substitution
in 13 was present at the para-position, while methoxy substitution
in 11 was present at the meta-position that further shielded the C-
3 ester carbonyl carbon from the nucleophilic attack with a greater
capacity than that of the para-substitution of 13.
The IKKb protein is made up of 8 chains and 676 amino acid res-
idues. The kinase domain of human IKKb is consisting of 15–312
residues. In order to rationalize the biological activity of the lead
analog 11 and to further predict the possible interactions that
might take place between the analog 11 and IKKb, it was docked
into the active site of IKKb. Results of molecular docking studies
indicated that the analog 11 showed estimated free energy of bind-
ing of ꢀ5.15 kcal/mol towards IKKb, while final intermolecular
energy of 11 was found to be ꢀ7.24 kcal/mol. The detailed stereo-
view of the complex formed by docking of the analog 11 into the
active site of target protein IKKb is presented in Figure 2A and B.
The closer inspection of the docked complex indicated that three
oxygen atoms of the 3-methoxybenzoyloxy, 22b-ester side chain,
and 28-carboxylic acid group of 11 participated in hydrogen bond
formations with the IKKb. The methoxy oxygen was hydrogen
bonded with the amino group hydrogen of Gln-110
(H3CAO. . .HAN, 2.5 Å). The oxygen atoms of the 22b-ester side
chain and the 28-carboxylic acid group were hydrogen bonded
with the amino group hydrogens of Arg-31. The 22b-ester oxygen
was 2.2 Å away from Arg-31 (O@CAO. . .HAN, 2.2 Å), while the 28-
carboxylic oxygen was placed at 2.3 Å distance from the Arg-31
(O@CAO. . .HAN, 2.3 Å), which resulted in the generation of third
hydrogen bond between 11 and IKKb. As we know that hydrogen
bond is formed between two electronegative atoms, where one
atom has a lone pair of electrons and another has acidic proton.
Molecular docking analysis showed that the 22b-ester side chain
Table 4
Chemical stability of the most potent ester analogs (11 and 13) in simulated gastric
fluid of pH 2
Time (h) % Ester analog remaining unhydrolyzed in simulated gastric fluid
Compd 11
Compd 13
0
2
5
8
12
100
100
93.04
88.20
83.32
77.25
92.16
86.52
80.28
72.82
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Monika et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
5
Figure 2. Molecular docking of the lead analog 11 in the active site of IKKb. (A) Amino acid residues Arg-31 and Gln-110 of IKKb involved in hydrogen bond interactions with
11 are highlighted. (B) Amino acid residues of IKKb present in the surroundings of 11 and also involved in hydrogen, hydrophobic, and van der Waals interactions with 11 are
highlighted.
along with 28-carboxylic group were crucial for the activity of 11,
wherein electronegative oxygen atoms were involved in hydrogen
bond formations with the protons of an electronegative nitrogen of
Arg-31. The substitution on benzoyloxy ring with the 3-methoxy
group also played a vital part in the potency of analog 11, as the
electron releasing methyl group further increased the electron
density on the methoxy oxygen (oxygen of OACH3 group) that
prompted the oxygen to undergo a hydrogen bond formation with
the proton attached to the another electronegative atom, the nitro-
gen of Gln-110. Taken together, the 3-methoxy group on 3-ben-
zoyloxy ring, 22b-ester side chain, and 28-carboxylic acid group
were critical for the IKKb inhibitory activity of the lead lantadene
to release the two active moieties. The most potent lantadene ana-
logs 11 and 13 are promising anticancer candidates against lung
cancer with promising inhibition of IKKb activity and warranting
further investigations.
Acknowledgments
Authors are thankful to Sophisticated Analytical Instrumenta-
tion Facility (SAIF), Panjab University, Chandigarh, India for spec-
tral analyses. We specially thank to Sh. Manish Kumar and Sh.
Anup Patyal of SAIF for timely carrying out NMR and Mass
experiments.
analog
3b-(3-methoxybenzoyloxy)-22b-senecioyloxy-olean-12-
en-28-oic acid (11). Apart from hydrogen bondings, the analog
11 was also interacted with the IKKb through hydrophobic and
van der Waals contacts. The hydrophobic interactions are one of
the major contributors to the stability of ligand at the binding site
of the receptor. An analysis of the docked complex showed that the
22b-ester side chain was positioned deep within the hydrophobic
pocket created by Met-17, Leu-21, Leu-30, Ile-33, and Val-41, while
the 3-methoxybenzoyloxy scaffold was positioned in the proximity
of non-polar residues Leu-108 and Phe-111. The ring A and B of
pentacyclic triterpenoid scaffold of the 11 further demonstrated
the strong hydrophobic interactions with the Pro-155 residue of
the IKKb. Although, van der Waals interaction is considered as a
weak interaction, still sum of a large number of van der Waals
interactions may add appreciably to the orientation, stability, and
binding of the ligand at the receptor site. Many residues, which
took part in such interactions, are also highlighted in Figure 2B.
In conclusion, the C-3 analogs of pentacyclic triterpenoids 3 and
Supplementary data
Supplementary data (experimental section, FT-IR, NMR, and
Mass spectra of all the compounds (1ꢀ19)) associated with this
article can be found, in the online version, at http://dx.doi.org/
10.1016/j.bmcl.2014.06.068.
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a
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Please cite this article in press as: Monika,; et al. Bioorg. Med. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.bmcl.2014.06.068