Synthesis of lupeol derivatives and their antileishmanial and antitrypanosomal activities

Article abstract of DOI:10.1080/14786419.2017.1353982

The natural product lupeol 1 was isolated from aerial parts of Vernonia scorpioides with satisfactory yield, which made it viable to be used as starting material in semisynthetic approach. Ten lupeol derivatives 2–11 were prepared by classical procedures. Including, five new esters derivatives 7–11, which were obtained by structural modifications in the isopropylidene fragment. All semisynthetic compounds and lupeol 1–11 were confirmed by ¹H NMR, ¹³C NMR and HRMS. Their antiprotozoal activity was evaluated in vitro against L. amazonensis and T. cruzi. Derivative 6 showed the best antitrypanosomal activity (IC₅₀?=?12.48?μg/mL) and the lowest cytotoxic derivative (CC₅₀?=?161.50?μg/mL). The mechanism of action of the most active derivatives (4, 6 and 11) is not dependent from the enzyme trypanothione reductase.

Full text of DOI:10.1080/14786419.2017.1353982

Natural Product Research
Formerly Natural Product Letters
ISSN: 1478-6419 (Print) 1478-6427 (Online) Journal homepage: http://www.tandfonline.com/loi/gnpl20
Synthesis of lupeol derivatives and their
antileishmanial and antitrypanosomal activities
Vanessa R. Machado, Louis P. Sandjo, Giovanni L. Pinheiro, Milene H.
Moraes, Mario Steindel, Moacir G. Pizzolatti & Maique W. Biavatti
To cite this article: Vanessa R. Machado, Louis P. Sandjo, Giovanni L. Pinheiro, Milene H.
Moraes, Mario Steindel, Moacir G. Pizzolatti & Maique W. Biavatti (2017): Synthesis of lupeol
derivatives and their antileishmanial and antitrypanosomal activities, Natural Product Research,
DOI: 10.1080/14786419.2017.1353982
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Date: 18 July 2017, At: 01:35

Natural Product research, 2017
ꢁꢁpꢂ://ꢃꢄi.ꢄꢅg/10.1080/14786419.2017.1353982
ꢀ
Synthesis of lupeol derivatives and their antileishmanial and
antitrypanosomal activities
a
a
b
c
Vanessa R. Machado , Louis P. Sandjo , Giovanni L. Pinheiro , Milene H. Moraes ,
c
b
a
Mario Steindel , Moacir G. Pizzolatti and Maique W. Biavatti
ꢆ
dꢇpꢆꢅꢁmꢇnꢁ ꢄf Pꢀꢆꢅmꢆꢈꢇꢉꢁiꢈꢆꢊ sꢈiꢇnꢈꢇꢂ, Fꢇꢃꢇꢅꢆꢊ univꢇꢅꢂiꢁy ꢄf sꢆnꢁꢆ cꢆꢁꢆꢅinꢆ (uFsc), Fꢊꢄꢅiꢆnópꢄꢊiꢂ, sꢆnꢁꢆ
b
cꢆꢁꢆꢅinꢆ, Bꢅꢆziꢊ; dꢇpꢆꢅꢁmꢇnꢁ ꢄf cꢀꢇmiꢂꢁꢅy, Fꢇꢃꢇꢅꢆꢊ univꢇꢅꢂiꢁy ꢄf sꢆnꢁꢆ cꢆꢁꢆꢅinꢆ (uFsc), Fꢊꢄꢅiꢆnópꢄꢊiꢂ, sꢆnꢁꢆ
cꢆꢁꢆꢅinꢆ, Bꢅꢆziꢊ; dꢇpꢆꢅꢁmꢇnꢁ ꢄf Miꢈꢅꢄbiꢄꢊꢄgy, Immꢉnꢄꢊꢄgy ꢆnꢃ Pꢆꢅꢆꢂiꢁꢄꢊꢄgy, Fꢇꢃꢇꢅꢆꢊ univꢇꢅꢂiꢁy ꢄf sꢆnꢁꢆ
ꢈ
cꢆꢁꢆꢅinꢆ (uFsc), Fꢊꢄꢅiꢆnópꢄꢊiꢂ, sꢆnꢁꢆ cꢆꢁꢆꢅinꢆ, Bꢅꢆziꢊ
ABSTRACT
ARTICLE HISTORY
The natural product lupeol 1 was isolated from aerial parts of Vernonia
scorpioides with satisfactory yield, which made it viable to be used as
starting material in semisynthetic approach. Ten lupeol derivatives
rꢇꢈꢇivꢇꢃ 13 Fꢇbꢅꢉꢆꢅy 2017
aꢈꢈꢇpꢁꢇꢃ 5 Jꢉꢊy 2017
KEYWORDS
anꢁiꢊꢇiꢂꢀmꢆniꢆꢊ;
ꢆnꢁiꢁꢅypꢆnꢄꢂꢄmꢆꢊ; ꢊꢉpꢇꢄꢊ;
ꢊꢉpꢇꢄꢊ ꢇꢂꢁꢇꢅꢂ ꢃꢇꢅivꢆꢁivꢇꢂ;
ꢂꢇmiꢂynꢁꢀꢇꢂiꢂ
2
–11 were prepared by classical procedures. Including, five new esters
derivatives 7–11, which were obtained by structural modifications
in the isopropylidene fragment. All semisynthetic compounds and
1
13
lupeol 1–11 were confirmed by H NMR, C NMR and HRMS. Their
antiprotozoal activity was evaluated in vitro against L. amazonensis
and T. cruzi. Derivative 6 showed the best antitrypanosomal
activity (IC = 12.48 μg/mL) and the lowest cytotoxic derivative
5
0
(
CC50 = 161.50 μg/mL). The mechanism of action of the most
active derivatives (4, 6 and 11) is not dependent from the enzyme
trypanothione reductase.
1
. Introduction
The trypanosomatid protozoan parasites play a lead role in developing countries healthcare
problems associated with illness such as Chagas disease in Latin America (Trypanosoma
CONTACT Mꢆiqꢉꢇ W. Biꢆvꢆꢁꢁi
mꢆiqꢉꢇ.biꢆvꢆꢁꢁi@ꢉfꢂꢈ.bꢅ
sꢉppꢊꢇmꢇnꢁꢆꢊ ꢃꢆꢁꢆ fꢄꢅ ꢁꢀiꢂ ꢆꢅꢁiꢈꢊꢇ ꢈꢆn bꢇ ꢆꢈꢈꢇꢂꢂꢇꢃ ꢆꢁ ꢀꢁꢁpꢂ://ꢃꢄi.ꢄꢅg/10.1080/14786419.2017.1353982.
©
2017 Infꢄꢅmꢆ uK limiꢁꢇꢃ, ꢁꢅꢆꢃing ꢆꢂ tꢆyꢊꢄꢅ & Fꢅꢆnꢈiꢂ Gꢅꢄꢉp

2
V. R. MACHADO ET AL.
cruzi), human African trypanosomasiasis (HAT or sleeping sickness) (Trypanosoma brucei) in
sub-Saharan Africa and leishmaniasis (caused by over 20 different Leishmania species) in
tropical and sub-tropical countries (Barrett et al. 2003; Stuart et al. 2008). These infections
are also recognised as neglected tropical diseases (NTDs) and represent a very challenging
and fatal condition for one-sixth of the world’s population (World Health Organization 2013).
NTDs represent a serious public health problem in Brazil, especially because Chagas disease
and leishmaniasis are endemic and have caused about 61.394 deaths between years 2000
and 2011 (Martins-Melo et al. 2016).
To overcome the unsatisfactory treatment available and provide an affordable therapy,
there is a permanent need to screen of innovative scaffolds against parasites responsible
for these diseases. Nature is a continuous source of new leads compounds with a wide range
of bioactivity also after some chemical modification. Pentacyclic triterpenoids are metabo-
lites with rigidity, lipophilicity and high number of natural stereogenic centres (Xu et al.
2
2
004) that have been reported with antiparasitic activity (Warfield et al. 2014; Isah et al.
016). Lupeol 1 is a lupane-type pentacyclic triterpene widespread in the plant kingdom
and it has been investigated as chemopreventive and for the treatment of a large spectrum
of health conditions (Chaturvedi et al. 2008; Saleem 2009; Siddique & Saleem 2011). However,
the antileishmanial and antitrypanosomal activities are not well explored as ascertained in
the literature. Lupeol 1 showed in vitro antitrypanosomal activity (Trypanosoma brucei brucei)
with IC value of 19.3 μg/mL, whereas against Leishmania sp. it displayed a weak activity
5
0
(
IC 100 μg/mL) (Fournet et al. 1992; Hoet et al. 2007; Araújo et al. 2016).
50
On the basis of the aforementioned data, this study aims to report the synthesis of lupeol
esters derivatives focusing on the isopropylidene fragment modifications. The prepared
derivatives were assessed for antiparasitic effect against amastigote forms of Leishmania
amazonensis and Trypanosoma cruzi. Additionally, the possible involvement of the enzyme
trypanothione reductase (TcTR) has been investigated by enzymatic assay due to its unique
and essential role for the survival of these parasites.
2
. Results and discussion
2
.1. Chemistry
The synthetic route performed in this work was designed to obtain lupeol derivatives, by
creating a new functional group on the allylic Me group at C30. Thus, triterpene 1 isolated
from aerial parts of Vernonia scorpioides underwent an acetylation on the OH group at C3.
As depicted in Scheme 1, product 2 and lupeol 1 were separately treated with selenium
dioxide (SeO ) under reflux conditions in ethanol, to afford, respectively, the allylic aldehyde
2
3
and 4 in moderate yield (Sharpless & Lauer 1972; Gutiérrez-Nicolás et al. 2012). The α,β-un-
1
saturated carbonyl derivatives 3 and 4 were characterised by H NMR spectrum that showed
a singlet at δ 9.50 (CHO) and two broad singlet at δ 6.29 and δ 5.91 corresponding the olefinic
hydrogens. Alcohols 5 and 6, were obtained by reducing the aldehydes intermediates with
NaBH in ethanol (Johnson & Rickborn 1970; Khan et al. 2014). The new OH group inserted
4
at C30 of 5 was acylated with aliphatic and aromatic acyl chlorides under mild esterification
conditions using DCC and DMAP in dichloromethane, resulting in five new lupeol esters
derivatives 7–11 in moderate to excellent yields (Mallavadhani et al. 2004). The NO is a
2
withdrawing electron group and its position para of the carbonyl might consequently reduce

NATURAL PRODUCT RESEARCH
3
Scheme 1. synꢁꢀꢇꢁiꢈ pꢅꢄꢈꢇꢃꢉꢅꢇ fꢄꢅ ꢁꢀꢇ pꢅꢇpꢆꢅꢆꢁiꢄn ꢄf ꢊꢉpꢇꢄꢊ ꢇꢂꢁꢇꢅ ꢃꢇꢅivꢆꢁivꢇꢂ. rꢇꢆgꢇnꢁꢂ ꢆnꢃ ꢈꢄnꢃiꢁiꢄnꢂ: (ꢆ)
aꢈ o, dMaP, eꢁoaꢈ, ꢅꢁ.; (b) sꢇo , eꢁoh, ꢅꢇflꢉx; (ꢈ) NꢆBh , eꢁoh, 0 °c ꢁꢄ ꢅꢁ.; (ꢃ) ꢈꢄꢅꢅꢇꢂpꢄnꢃing ꢆꢈyꢊ ꢈꢀꢊꢄꢅiꢃꢇ,
2
2
4
dcc, dMaP, ch cꢊ , ꢅꢁ.
2
2
the C=O reactivity explaining the moderate yield (derivative 7). The data regarding molecular
modification using lupeol scaffolds as a starting material are focused mainly at C3, and the
antiparasitic activity of semisynthetic lupeol derivatives were evaluated so far (Gauthier et al.
2006; Papi Reddy et al. 2009; Gao et al. 2011; Li et al. 2013; Bhandari et al. 2014). Recently,
modifications in the isopropylidene fragment have been described on the literature, how-
ever, focusing on the conversion of exocyclic double bond into heterocycles and rigid struc
-
tures (Khan et al. 2014).
2
.2. Biological assays
Based on the fact that isopropylidene fragment can play an important role on biological
system such as an electrophilic site for Michael addition, 10 lupeol derivatives containing
different substituents at C30 was prepared and their antiprotozoal activity were evaluated
in vitro against amastigote forms of L. amazonensis and T. cruzi and expressed as percentage
of parasite growth inhibition (Table 1). Compounds showing more than 50% of inhibition
at 50 μM were evaluated regarding their cytotoxicity potential in human macrophage cells
THP-1, and their selective index (SI) was determined. Amphotericin B 2 μM and benznidazole
20 μM were used as positive controls. DMSO 1% was used as negative control and did not
show any growth inhibition. In addition, the mechanism of action was investigated for the
most active compounds regarding the inhibition potential of recombinant trypanothione
reductase (rTcTR) enzyme.
The strategy applied in our work provided lupeol derivatives with inhibitory effect against
L. amazonensis and T. cruzi, especially the ones bearing a α,β-unsaturated carbonyl that
seems to be important to antiprotozoal activity. According to the biological data described
in Table 1, the aldehyde intermediate 4 showed the best inhibition potential for both

4
V. R. MACHADO ET AL.
Table 1. Pꢇꢅꢈꢇnꢁꢆgꢇ ꢄf pꢆꢅꢆꢂiꢁꢇ gꢅꢄwꢁꢀ inꢀibiꢁiꢄn, Ic ± sd, cc ± sd ꢆnꢃ sI vꢆꢊꢉꢇꢂ ꢄf ꢈꢄmpꢄꢉnꢃꢂ 1–11
50
50
ꢆnꢃ ꢁꢀꢇ ꢅꢇfꢇꢅꢇnꢈꢇ ꢃꢅꢉgꢂ ꢆgꢆinꢂꢁ inꢁꢅꢆꢈꢇꢊꢊꢉꢊꢆꢅ ꢆmꢆꢂꢁigꢄꢁꢇꢂ ꢄf L. amazonensis, T. cruzi ꢆnꢃ thP-1 ꢈꢇꢊꢊ ꢊinꢇ.
%
inhibition at 50 μM
IC50 (μg/mL)
SIb
Compoundsa L. amazonensis
T. cruzi
L. amazonensis
T. cruzi
CC50
L. amazonensis T. cruzi
lꢉpꢇꢄꢊ 1
6.00 ± 0.06
11.71 ± 1.86
4.24 ± 0.30
82.78 ± 0.97
3.11 ± 0.66
5.15 ± 0.93
9.91 ± 0.81
8.47 ± 0.36
3.24 ± 0.40
68.04 ± 4.76
–
38.69 ± 0.59
20.36 ± 1.09
77.03 ± 6.10
97.62 ± 0.38
31.14 ± 0.81
91.65 ± 0.76
Ndꢈ
29.10 ± 11.34
11.17 ± 5.52
77.36 ± 6.55
97.89 ± 0.19
–
–
–
–
–
Nd
–
–
–
–
–
1.06
–
–
–
–
–
2.72
–
–
–
–
2
3
4
5
6
7
8
139.50 ± 3.90
40.74 ± 4.12 39.43 ± 6.23 43.38 ± 2.74
1.10
–
12.94
–
–
–
–
–
–
–
–
–
–
12.48 ± 0.89 161.50 ± 24.00
–
–
–
–
–
–
10
1
1
35.60 ± 3.71 23.07 ± 0.65 96.74 ± 7.93
4.19
>49.11
Bꢇnzniꢃꢆzꢄꢊꢇ
20 μM)
–
10.18 ± 0.3
>500
(
ampꢀꢄꢁꢇꢅiꢈin 93.33 ± 0.59
B (2 μM)
–
0.08 ± 0.02
–
10
>142
–
ꢆ
tꢀꢇ ꢈꢄmpꢄꢉnꢃ 9 wꢆꢂ nꢄꢁ ꢇvꢆꢊꢉꢆꢁꢇꢃ.
b
sI (sꢇꢊꢇꢈꢁivꢇ Inꢃꢇx) = cc /Ic .
5
0
50
ꢈ
Nd-nꢄꢁ ꢃꢇꢁꢇꢈꢁꢇꢃ ꢆꢁ ꢈꢄnꢈꢇnꢁꢅꢆꢁiꢄn ꢄf 50 µM.
parasites, L. amazonensis and T. cruzi, with 82.78 ± 0.97% and 97.62 ± 0.38%, respectively.
The antileishmanial activity was drastically reduced whenever the acetyl group was a
substituent on the hydroxyl at C3 (compound 3) (4.24 ± 0.30%), while for T. cruzi it showed
a mild decrease in activity (77.03 ± 6.10%). However, the alkylation at position C30 with a
long aliphatic side chain of derivative 3 increased 16-fold the inhibition potential against
L. amazonensis (compound 11: 68.04 ± 4.76%).
Among the 10 compounds evaluated, lup-20(29)-ene-diol 6 showed the best antitrypa-
nosomal activity with IC = 12.48 μg/mL and the lowest cytotoxic derivative (CC = 161.50
50
50
μg/mL). The dual inhibitory activity for both parasites L. amazonensis and T. cruzi was
observed in lupeol derivatives 4 and 11, however, the disubstituted analogue 11 showed
the highest selectivity index (4-fold higher in T. cruzi and 2-fold in L. amazonensis). The size
of the aliphatic chain seems to be important for the antiprotozoal activity, since the derivative
1
0 that presents three carbons less than the most active derivative 11 showed the lowest
inhibition of the series.
These active compounds (4, 6 and 11) against L. amazonensis and T.cruzi intracellular
amastigotes were tested against recombinant trypanothione reductase of T. cruzi (TcTR) in
order to investigate the mechanism of action of the semisynthetic lupeol derivatives. TR is
an important drug target in Trypanosomatidae family because it is unique and essential for
the parasite survival, since it is involved in the thiol-based metabolism protecting them from
oxidative damage. Lupeol derivatives 4, 6 and 11 inhibited 1.97, 2.15 and 16.24% of rTcTR
activity at 100 μM, respectively. These results suggest that the observed antitrypanosomal
and antileishmanial activity of lupeol derivatives is not due to TcTR inhibition.
3
. Experimental
.1. Instruments
The reactions were monitored by thin-layer chromatography (TLC) performed on silica gel
0 F254 (Machery-Nagel®) and spots were visualised with UV light and stained by a solution
3
6

NATURAL PRODUCT RESEARCH
5
of p-anisaldehyde. Melting points (in °C) were determined using a MQAPF-301 melting point
apparatus and are uncorrected. Chromatography was performed on silica gel 60 (0.063–
0.200 mm). NMR spectrum was recorded on a Bruker Fourier 300 MHz spectrometer. Chemical
shifts are reported in parts per million (ppm) relative to tetramethylsilane (TMS) as internal
standard. The coupling constants are reported in hertz (Hz) and signal multiplicities are
reported as singlet (s), broad singlet (brs), doublet (d), doublet of doublet (dd), triplet (t),
mulitplet (m). The mass spectra (HRMS) data were recorded on a XEVO G2-S QTof (Waters®)
instrument equipped with an electrospray ionization probe.
3
.2. Isolation of triterpene lupeol (1)
Lupeol was obtained from dried aerial parts (leaves and flowers) of Vernonia scorpioides
Lam.) Pers (Asteraceae). The remaining nonpolar fractions from previous phytochemical
(
fractionation of this plant and additional Soxhlet hexanes extract of the leaves were pooled
together and subjected to column chromatography on silica gel eluting with hexane–ethyl
acetate (90:10; v/v) as eluent system afforded 2 g of lupeol. The chemical characterisation
1
13
was based on H and C NMR analysis compared with literature data (Betancor et al. 1980).
3
.4. General synthesis
Solvents were used without further purification. Reagents were commercially available. The
experimental details relating to the synthetic procedures showed in Scheme 1 are available
on line in the supplementary material.
4
. Conclusion
Five new ester derivatives 7–11 were prepared in moderate to excellent yields from the
natural product lupeol 1 isolated from aerial parts of Vernonia scorpioides. The strategy for
structural modifications was applied in the isopropylidene fragment creating a new point
for functionalisation of the structure. All semisynthetic compounds and lupeol 1–11 were
evaluated in vitro regarding their inhibition potential over the growth of intracellular amas-
tigotes, the clinically relevant parasite form of L. amazonensis and T. cruzi. According to herein
results, the derivatives containing an α,β-unsaturated carbonyl moiety (3 and 4) were the
most active against both parasites, whereas against T. cruzi a free hydroxyl group (3 and 6)
seems to be important for the antitrypanosomal activity. Among the ester derivatives of
lupeol, a hydrophobic and spacial effect was observed for derivative 11 which showed both
antileishmanial and antitrypanosomal activity. None of the active compounds inhibited
trypanothione reductase activity.
Supplementary material
1H and 13C NMR data of the new compounds 7–11 (Figures S1–S10) are available on line in the sup-
plementary material as well as the experimental section.
Acknowledgements
The authors are grateful to Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq,
Brazil) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, Brazil) for financial

6
V. R. MACHADO ET AL.
support. L.P.S; M.S and M.W.B are members of the Research Network Natural Products against Neglected
Diseases (ResNetNPND).
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
This work was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq,
Brazil); Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, Brazil).
References
Araújo CRR, Silva RR, SilvaTM, Takahashi JA, Sales-Junior PA, Dessimoni-Pinto NAV, Souza-Fagundes EM,
Romanha AJ, Murta SMF, Alcântara AFC. 2016. Constituents from stem barks of Luehea ochrophylla
Mart and evaluation of their antiparasitic, antimicrobial, and antioxidant activities. Nat Prod Res.
10:1–6.
Barrett MP, Burchmore RJS, Stich A, Lazzari JO, Frasch AC, Cazzulo JJ, Krishna S. 2003.The trypanosomiases.
Lancet. 362:1469–1480.
Betancor C, Freire R, Gonzalez AG, Salazar JA, Pascard C, Prange T. 1980. Three triterpenes and other
terpenoids from Catha cassinoides. Phytochemistry. 19:1989–1993.
Bhandari P, Patel NK, Bhutani KK. 2014. Synthesis of new heterocyclic lupeol derivatives as nitric oxide
and pro-inflammatory cytokine inhibitors. Bioorg Med Chem Lett. 24:3596–3599.
Chaturvedi PK, Bhui K, ShuklaY. 2008. Lupeol: connotations for chemoprevention. Cancer Lett. 263:1–13.
Fournet A, Angelo A, Muñoz V, Roblot F, Hocquemiller R, Cavé A. 1992. Biological and chemical studies
of Pera benensis, a Bolivian plant used in folk medicine as a treatment of cutaneous leishmaniasis.
J Ethnopharmacol. 37:159–164.
Gao J, Li X, Gu G, Sun B, Cui M, Ji M, Lou HX. 2011. Efficient synthesis of trisaccharide saponins and their
tumor cell killing effects through oncotic necrosis. Bioorg Med Chem Lett. 21:622–627.
Gauthier C, Legault J, Lebrun M, Dufour P, Pichette A. 2006. Glycosidation of lupane-type triterpenoids
as potent in vitro cytotoxic agents. Bioorg Med Chem. 14:6713–6725.
Gutiérrez-Nicolás F, Gordillo-Román B, Oberti JC, Estévez-Braun A, Ravelo ÁG, Joseph-Nathan P. 2012.
Synthesis and anti-hiv activity of lupane and olean-18-ene derivatives. absolute configuration of
19,20-epoxylupanes by VCD. J Nat Prod. 75:669–676.
Hoet S, Pieters L, Muccioli GG, Habib-Jiwan JL, Opperdoes FR, Quetin-Leclercq J. 2007. Antitrypanosomal
activity of triterpenoids and sterols from the leaves of Strychnos spinosa and related compounds.
J Nat Prod. 70:1360–1363.
Isah MB, Ibrahim MA, Mohammed A, Aliyu AB, Masola B, Coetzer THT. 2016. A systematic review of
pentacyclic triterpenes and their derivatives as chemotherapeutic agents against tropical parasitic
diseases. Parasitology. 143:1219–1231.
Johnson MR, Rickborn B. 1970. Sodium borohydride reduction of conjugated aldehydes and ketones.
J Org Chem. 35:1041–1045.
Khan MF, Maurya CK, Dev K, Arha D, Rai AK, Tamrakar AK, Maurya R. 2014. Design and synthesis of
lupeol analogues and their glucose uptake stimulatory effect in L6 skeletal muscle cells. Bioorg
Med Chem Lett. 24:2674–2679.
Li W, Hao J, XiaoY. 2013. Synthesis and in vitro antitumor activities of lupeol dicarboxylic acid monoester
derivatives. Arch Pharmacal Res. 36:1447–1453.
Mallavadhani UV, Mahapatra A, Jamil K, Reddy PS. 2004. Antimicrobial activity of some pentacyclic
triterpenes and their synthesized 3-O-lipophilic chains. Biol Pharm Bull. 27:1576–1579.
Martins-Melo FR, Ramos AN, Alencar CH, Heukelbach J. 2016. Mortality from neglected tropical diseases
in Brazil 2000–2011. Bull World Health Organ. 94:103–110.

NATURAL PRODUCT RESEARCH
7
Papi Reddy K, Singh AB, Puri A, Srivastava AK, Narender T. 2009. Synthesis of novel triterpenoid (lupeol)
derivatives and their in vivo antihyperglycemic and antidyslipidemic activity. Bioorg Med Chem
Lett. 19:4463–4466.
Saleem M. 2009. Lupeol, a novel anti-inflammatory and anti-cancer dietary triterpene. Cancer Lett.
285:109–115.
Sharpless KB, Lauer RF. 1972. Selenium dioxide oxidation of olefins. Evidence for the intermediacy of
allylseleninic acids. J Am Chem Soc. 94:7154–7155.
Siddique HR, Saleem M. 2011. Beneficial health effects of lupeol triterpene: a review of preclinical
studies. Life Sci. 88:285–293.
Stuart K, Brun R, Croft S, Fairlamb A, Gürtler RE, McKerrow J, Reed S, Tarleton R. 2008. Kinetoplastids:
related protozoan pathogens, different diseases. J Clin Invest. 118:1301–1310.
Warfield J, SetzerWN, Ogungbe IV. 2014. Interactions of antiparasitic sterols with sterol 14α-demethylase
(CYP51) of human pathogens. SpringerPlus. 3:679–690.
World Health Organization. 2013. Sustaining the drive to overcome the global impact of neglected
tropical diseases:second WHO report on neglected tropical diseases. Geneva: World Health
Organization. (WHO/HTM/NTD/2013.1).
Xu R, Fazio GC, Matsuda SPT. 2004. On the origins of triterpenoid skeletal diversity. Phytochemistry.
65:261–291.