Bioorganic & Medicinal Chemistry Letters
Synthesis of new heterocyclic lupeol derivatives as nitric oxide
and pro-inflammatory cytokine inhibitors
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Pamita Bhandari, Neeraj Kumar Patel, Kamlesh Kumar Bhutani
Department of Natural Products, National Institute of Pharmaceutical and Education Research (NIPER), Sector 67, S.A.S. Nagar, Mohali 160 062, Punjab, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of heterocyclic derivatives including indoles, pyrazines along with oximes and esters were syn-
thesized from lupeol and evaluated for anti-inflammatory activity through inhibition of lipopolysaccha-
ride (LPS) induced nitric oxide (NO) production in RAW 264.7 and J774A.1 cells. All the synthesized
molecules of lupeol were found to be more active in inhibiting NO production with an IC50 of
Received 5 March 2014
Revised 9 May 2014
Accepted 12 May 2014
Available online xxxx
18.4–48.7
L-NAME (IC50 = 69.21 and 73.18
substitution at phenyl ring of indole moiety leads to potent inhibition of NO production with half
maximal concentration ranging from 18.4 to 41.7 M. Furthermore, alkyl (11, 12) and p-bromo/iodo
(15, 16) substituted compounds at a concentration of 20 g/mL exhibited mild inhibition (29–42%) of
LPS-induced tumor necrosis factor alpha (TNF- ) and weak inhibition (10–22%) towards interleukin
1-beta (IL-1b) production in both the cell lines. All the derivatives were found to be non-cytotoxic when
l
M in both the cell lines when compared to the specific nitric oxide synthase (NOS) inhibitor,
l
M on RAW 264.7 and J774A.1 cells, respectively). The halogen
Keywords:
Lupeol
Heterocyclic derivatives
Anti-inflammatory activity
Nitric oxide
l
l
a
Tumor necrosis factor-alpha
tested at their IC50
inhibitors of NO.
(l
M). These findings suggest that the derivatives of lupeol could be a lead to potent
Ó 2014 Published by Elsevier Ltd.
Injury leads to inflammation which involves the assemblage of
cells and exudates in irritated tissues.1 Chronic inflammatory
diseases such as psoriasis, ulcerative colitis and rheumatoid arthri-
tis usually occurred due to ungoverned production of pro-inflam-
matory cytokines.2 Among the cytokines, nitric oxide (NO) is a
potent pro-inflammatory mediator and at low concentration regu-
lates physiological homeostasis in the cardiovascular system.3
Overproduction of NO by inducible nitric oxide synthase (iNOS)
generally destroys functional normal tissues during acute and
and other plants, these compounds can be an integral part of the
human diet.6 Consequently, much research interest has been
focused on the pharmacological evaluation and efficient isolation
of triterpenoids from plants.7,8 Lupeol had been studied for more
than a century and is reported to exhibit a broad spectrum of phar-
macological activities against some prominent disease such as
inflammation, diabetes, arthritis, cardiovascular ailments, renal
disorders, hepatic toxicity, microbial infections and cancer.9–20 Ear-
lier studies on the synthetic modifications of lupeol resulted in the
preparation of antimalarial, antidiabetic and antihypoglycemaic
analogues.21,22 Accordingly, chemical modifications, of the struc-
ture of lupeol, were required to improve the biological activities
while showing less toxicity. Therefore, in order to find potent
anti-inflammatory derivatives, in present work, considerable struc-
tural modifications have been performed mainly on the A ring. The
Fischer indolization of lupeol, modifications of ring A at C-3 posi-
tion and the isoprenyl unit at C-30 resulted in the preparation of
different derivatives which were evaluated for anti-inflammatory
activity on RAW 264.7 and J774A.1 cells along with their
cytotoxicity.
chronic inflammation.4 Tumor necrosis factor-alpha (TNF-
a),
another pro-inflammatory cytokine plays an important role in
inflammation cascades, and induces itself as well as other
inflammatory cytokines.5
Natural products represent promising scaffolds with high
chemical and structural diversity and wide array of biological
activities. Out of the structurally diverse compounds from tropical
plants, the triterpenoids are often found in significant quantities,
and a wide array isolated and characterized. Lup-20(29)-en-3b-
ol, commonly known as lupeol, a pentacyclic triterpenoid with
30 carbon atoms, biosynthetically derived from the cyclization of
squalene has a vast occurrence in diverse plant families. Since
the triterpenes are widely distributed in food, medicinal herbs
Lupeol was isolated from the bark of Embelica officinalis in
good yield (1.4%). For the isolation of lupeol, the air dried bark
of E. officinalis was ground to fine powder and extracted with
n-hexane and the combined percolations were concentrated to
dryness under reduced pressure. The lupeol was isolated by
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0960-894X/Ó 2014 Published by Elsevier Ltd.