Pentacylic triterpenes from Lavandula coronopifolia: structure related inhibitory activity on α-glucosidase

Article abstract of DOI:10.1080/14786419.2019.1655017

Ten pentacyclic triterpenes (1-10) were isolated from Lavandula coronopifolia. We evaluated their α-glucosidase inhibitory activity, and found that the aglycones, 1, 2, 3, 4, 7 and 10 showed superior IC₅₀ values to the positive control. In order to explain the structural requirements for α-glucosidase inhibitory activity, eleven derivatives were prepared, including one new compound, 2-formyl-(A)1–19α-hydroxy-1-norursane-2, 12-dien-28-oic acid 10c. The results demonstrated that a free hydroxyl at ring-A and a free carboxylic group at position 28 are key structural features for the α-glucosidase inhibitory activity, also that an ursane skeleton is optimum for the activity. Additionally, enzyme kinetic analysis of pomolic acid 2, the most potent compound, revealed that it inhibited α-glucosidase in a mixed-type manner. The molecular docking simulation validated this type of inhibition and highlighted the role of the C-3 hydroxyl and C-28 carboxylic groups in interaction with the enzyme in silico.

Full text of DOI:10.1080/14786419.2019.1655017

Natural Product Research
Formerly Natural Product Letters
ISSN: 1478-6419 (Print) 1478-6427 (Online) Journal homepage: https://www.tandfonline.com/loi/gnpl20
Pentacylic triterpenes from Lavandula
coronopifolia: structure related inhibitory activity
on α-glucosidase
Marwa Elsbaey, Rogers Mwakalukwa, Kuniyoshi Shimizu & Tomofumi
Miyamoto
To cite this article: Marwa Elsbaey, Rogers Mwakalukwa, Kuniyoshi Shimizu & Tomofumi
Miyamoto (2019): Pentacylic triterpenes from Lavandulaꢀcoronopifolia: structure related inhibitory
activity on α-glucosidase, Natural Product Research, DOI: 10.1080/14786419.2019.1655017
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NATURAL PRODUCT RESEARCH
https://doi.org/10.1080/14786419.2019.1655017
Pentacylic triterpenes from Lavandula coronopifolia:
structure related inhibitory activity on a-glucosidase
Marwa Elsbaeya,b, Rogers Mwakalukwac,d, Kuniyoshi Shimizuc and
Tomofumi Miyamotob
aDepartment of Pharmacognosy, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt;
bDepartment of Natural Products Chemistry, Graduate School of Pharmaceutical Sciences, Kyushu
c
University, Fukuoka, 812-8582, Japan; Department of Agro-environmental Sciences, Graduate School
of Bioresource and Bioenvironmental Science, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka,
d
819-0395, Japan; Department of Pharmacognosy, School of Pharmacy, Muhimbili University of
Health and Allied Sciences, Dar es Salaam, P.O. Box 65013, Tanzania
ABSTRACT
ARTICLE HISTORY
Received 22 February 2019
Accepted 31 July 2019
Ten pentacyclic triterpenes (1-10) were isolated from Lavandula
coronopifolia. We evaluated their a-glucosidase inhibitory activity,
and found that the aglycones, 1, 2, 3, 4, 7 and 10 showed super-
ior IC50 values to the positive control. In order to explain the
structural requirements for a-glucosidase inhibitory activity, eleven
derivatives were prepared, including one new compound, 2-for-
myl-(A)1–19a-hydroxy-1-norursane-2, 12-dien-28-oic acid 10c. The
results demonstrated that a free hydroxyl at ring-A and a free car-
boxylic group at position 28 are key structural features for the
a-glucosidase inhibitory activity, also that an ursane skeleton is
optimum for the activity. Additionally, enzyme kinetic analysis of
pomolic acid 2, the most potent compound, revealed that it
inhibited a-glucosidase in a mixed-type manner. The molecular
docking simulation validated this type of inhibition and high-
lighted the role of the C-3 hydroxyl and C-28 carboxylic groups in
interaction with the enzyme in silico.
KEYWORDS
Triterpene; a-glucosidase;
SAR; Lavandula; mixed
inhibitior; catalytic; allosteric
CONTACT Marwa Elsbaey
marwaelsebay1611@mans.edu.eg
Supplemental data for this article can be accessed at https://doi.org/10.1080/14786419.2019.1655017.
ß 2019 Informa UK Limited, trading as Taylor & Francis Group

2
M. ELSBAEY ET AL.
1. Introduction
The enzyme a-glucosidase is a key enzyme in the digestive system that breaks down
dietary carbohydrates into absorbable glucose (Zhang et al. 2017). a-Glucosidase inhib-
itors can delay glucose absorption from the small intestine and hence lower postpran-
dial glucose and insulin levels, accordingly, they are widely used in treatment of type
2 diabetes (Van De Laar et al. 2005).
Lavandula coronopifolia Poire is a shrub-like perennial, growing in rocky habitat and
desert plains (Lis-Balchin 2003). Reviewing the literature, it was clear that the plant
chemistry and biological activity is under investigated. Few studies reported hepato-
protective (Farshori et al. 2015) and antimicrobial (Ait Said et al. 2015) activities of L.
coronopifolia. Also flavonoids (El-Garf et al. 1999) and triterpenes (Singab et al. 2000)
were previously isolated from the plant. The majority of Lavandula species are trad-
itionally used to treat diabetes, furthermore the plant is among the medicinal plants
that used for the management of diabetic mellitus in the Ethiopian and Eritrean flora
(Meresa et al. 2017). In this study we afford a rational for its use in management
of diabetes.
Our chemical investigation of L. coronopifolia resulted in isolation of ten pentacy-
clic triterpenes; five of them are reported for the first time from the plant. Eleven
derivatives were prepared by esterification, acetylation and oxidation. We investi-
gated the a-glucosidase inhibitory activity of the natural pentacyclic triterpenes as
well as the prepared derivatives. The IC50 values displayed by these related triter-
penes revealed an insight on some essential structural features of a-glucosidase
inhibitory activity. Additionally, we investigated the possible inhibition mechanism
of the most potent compound, pomolic acid 2 by enzyme kinetics and dock-
ing study.

NATURAL PRODUCT RESEARCH
3
Figure 1. Structures of triterpenes isolated from L. coronopifolia (1-10) and the prepared
derivatives, A: (CH3)3SiCHN2/20% MeOH in Benzene, B: (CH3CO)2O/Pyridine, C: PCC/DCM, D:
Jones/Acetone.
2. Results and discussion
2.1. a-Glucosidase assay
A series of natural pentacylic triterpenes (1-10) were isolated from L. coronopifolia
(Figure 1). These triterpenes have different hydroxylation pattern and belong to three
types of skeletons: ursane, oleane and ring-A contracted triterpene skeleton. Upon
investigating the a-glucosidase inhibitory activity of these related structures, we could
determine a preliminary insight toward their structure activity relationship. Following,
eleven derivatives were prepared by methylation (1a-4a, 7a, 8a, 10a) at free

4
M. ELSBAEY ET AL.
carboxylic group (C-28), acetylation (2 b, 10 b) and oxidation (2c, 10c) of free hydroxyl
group of ring-A at (C-3 or C-1 in case of ring-A contracted type). These transformations
were made in order to elucidate the role of these functional groups in the activity.
As shown in Table S1, compounds 2, 1, 10, 2a, 7, 2c, 10c, 2 b and 3 showed con-
siderable a-glucosidase inhibitory activity, with IC50 values of 5.3, 17.5, 19.2, 58.5, 69.5,
116.8, 160.4, 170.2 and 178.4 mM, respectively. Meanwhile compounds 8a and 4 were
less active with IC50 values of 225.7 and 231.0 mM, respectively. All were superior to
acarbose, the positive control, 371.9 mM. Compound 3a showed comparable IC50 value
to acarbose, 392.1 mM, while the IC50 values of the remaining compounds
were >400 mM.
Regarding the skeleton, the IC50 value of oleanolic acid 7 was almost four times of
that of ursolic acid 1, which suggested the effect of the ursane skeleton on the activ-
ity. Also the IC50 value of hyptadienic acid 10 was almost three times of that of
pomolic acid 2, suggesting that the contracted ring-A might weaken the activity.
These findings suggested that an ursane skeleton with six membered ring-A, is the
most optimum for the a-glucosidase inhibitory activity.
Regarding C-28 site, all the prepared methyl ester derivatives, 1a-4a, 7a-8a and
10a showed dramatically reduced activity as compared to their parent free acid; sug-
gesting that a free carboxylic group at position 28 is essential for activity. Even though
compound 2a displayed superior IC50 value to the positive control, still the activity is
reduced about 10 times upon on esterification.
Regarding hydroxyl substituents, we investigated the C-3 hydroxyl of pomolic acid
2 and C-1 hydroxyl of hyptadienic acid 10. The prepared acetyl derivatives 2 b and
10 b, also the oxo derivatives 2c and 10c, showed greatly raised IC50 values as com-
pared to their parent triterpene. These results suggested the importance of a free
hydroxyl group at ring-A. This is in accordance with previous literature, confirming
that C-3 hydroxyl group is essential for activity (Fatmawati et al. 2013) since it interacts
with the enzyme through hydrogen bonding (Wu et al. 2015). It is worth to note that
acetylation had a higher negative impact on activity than oxidation, since the oxo-
derivatives were slightly more active than the acetyl derivatives, which will be more
cleared later on.
At the same time, the 19a-hydroxy ursolic acid 2, showed three times reduced IC50
value as compared to ursolic acid 1, suggesting that the presence of a hydroxyl group at
position 19, is important for eliciting the activity. Meanwhile the presence of di or poly
hydroxyl substituents in ring-A at positions 1, 2 and 23 had a negative impact on the activ-
ity. This was demonstrated by the decreased activity of the ursanes; 2a-hydroxy pomolic 3
and 2 a, 23 dihydroxy pomolic 4 as compared to pomolic acid 2; also for the oleane; 2a-
hydroxy oleanolic 8 as compared to oleanolic acid 7, suggesting that hydroxylation at
ring-A specifically at positions 2 and 23 dramatically decreases the activity.
The poly hydroxylated 28-O-glucosyl derivatives 5, 6 and 9 displayed poor inhibi-
tory effects with IC50 value >400 mM, confirming our previous suggestion on the role
of free carboxylic group and that di or poly hydroxyl substituents at ring-A weakens
the activity.
It is worth to note that among the tested triterpenes, pomolic acid 2 was found to
be the most potent inhibitor on a-glucosidase, possessing all the favorable features

NATURAL PRODUCT RESEARCH
5
Figure 2. Lineweaver-Burk plot for the inhibition mode of compound 2 against a-glucosidase at
different concentrations of inhibitor (0, 5, 10 lM).
for the a-glucosidase inhibitory activity, an ursane skeleton, a free hydroxyl group at
C-3, free carboxylic group (C-28) and a hydroxyl group at C-19. Pomolic acid deriva-
tives also displayed strong activity despite being reduced about thirty times by acetyl-
ation in 2 b, about twenty times by oxidation in 2c and about ten times by
esterification in 2a.
2.2. Kinetic study of pomolic acid 2
Due to its interestingly high inhibitory activity against a-glucosidase, we investigated
the possible underlying mechanism of inhibition by pomolic acid 2. According to the
Lineweaver-Burk plot (Figure 2), we concluded that, pomolic acid 2 is a mixed inhibi-
tor (Whiteley 1999). This type of inhibition is similar to noncompetitive inhibition
except that binding of the substrate or the inhibitor affect the enzyme’s binding affin-
ity for the other (Ha and Bhagavan 2011).
2.3. Molecular docking analysis of pomolic acid 2
In order to validate the results of the enzyme kinetic study, a molecular docking simu-
lation of pomolic acid 2 with a-glucosidase was undertaken (Tables S3-S6, Figures S22-
S23). As shown in Figure S23, pomolic acid interacted with both catalytic and allosteric
sites on a-glucosidase. At the catalytic site, it displayed three H-bond interactions
through C-3 hydroxyl to the amino acid residues His112 and Asp215, and through C-
28 carboxylic to Gln353. It also displayed hydrophobic interactions with Tyr72, Tyr158,
Phe178, Val216, Phe303, and Arg315. The mentioned residues are also responsible for
binding of acarbose, a known comptetive inhibitor, with a-glucosidase (Ali et al. 2017).
Moreover, at allosteric site 4, pomolic acid 2 interacted with the amino acid residues

6
M. ELSBAEY ET AL.
Tyr292 and Ser295 through H-bonding to C-28 and with Trp 14, Lys262, Ile271, and
His258 through hydrophobic interactions. Oleanolic acid, a known allosteric inhibitor,
interacted with a-glucosidase at the same residues (Ding et al. 2018). These findings
are in good agreement with the suggested mixed inhibition mode for pomolic acid 2.
2.4. Chemistry
Based on analysis of their MS and spectral data as well comparison to literature, the
isolated compounds were identified as: ursolic acid (1) (Morocho et al. 2018),
pomolic acid (2) (Sidjui et al. 2014), tormentic acid (3) (Woo et al. 2014), myrianthic
acid (4) (Ojinnaka et al. 1984), nigaichigoside F1 (5) (Chen et al. 2013),
1b,2a,3b,19a,23-pentahydroxy-urs-12-en-28-oic acid 28-O-b–D-glucopyranosidate (6)
(Singab et al. 2000), oleanolic acid (7), maslinic acid (8) (Woo et al. 2014),
1b,2a,3b,19a,23-pentahydroxy-olean-12-en-28-oic acid 28-O-b–D-glucopyranosidate (9)
(Singab et al. 2000) and hyptadienic acid (10) (Wang et al. 2009).
Following to isolation, eleven derivatives, including one new compound (10c), were
prepared by esterification (1a-4a, 7a, 8a, 10a), acetylation (2 b, 10 b) and oxidation
(2c, 10c). Theses derivatives were characterized as: ursolic acid methyl ester (1a) (Seo
et al. 1975), pomolic acid methyl ester (2a) (Lontsi et al. 1998), 3-O-acetyl-pomolic acid
(2 b) (Neto et al. 2000), 3-oxo-pomolic acid (2c) (Cheng and Cao 1992), tormentic acid
methyl ester (3a) (Lontsi et al. 1998), myrianthic acid methyl ester (4a) (Ojinnaka et al.
1984), oleanolic acid methyl ester (7a), maslinic acid methyl ester (8a) (Seo et al.
1975), hyptadienic acid methyl ester (10a), 1-O-acetyl-hyptadienic acid (10 b) (Rao
et al. 1990).
Compound (10c) was identified as 2-formyl-(A)1–19a-hydroxy-1-norursane-2,12-
dien-28-oic acid. According to literature, this compound has never been previously
described; eventhough, its oleane isomer has been reported (Thao et al. 2014). The
1H-NMR spectrum of compound 10c was similar to that of hyptadienic acid 10 except
for replacement of the oxygenated methylene at d(H) 4.08 (H, dd, 14.7, 1.8) and 4.17
(H, dd, 14.7, 1.7) by an aldehydic proton signal at d(H) 9.62 (H, s). In the 13C-NMR spec-
trum, oxygenated methylene signal was replaced by a carbonyl signal at d(c) 191.5
(C-1) corresponding to aldehyde group. It also showed a noticeable downfield shift in
positions C-2 and C-3 at d(c) 157.1 and 164.2, respectively confirmed oxidation of the
secondary alcohol into aldehyde. The molecular formula C30H44O4 was confirmed by
the negative molecular ion peak at m/z 467.3177 [M-H]À in HRESIMS.
3. Experimental
For general experimental procedures, isolation procedures (Figure S20), a-glucosidase
assay see supplemental file.
3.1. Plant material
The plant material (2.5 kg) was collected in Feburary, 2017 from Wady Hagol, Suez
governorate, Egypt. Authentication was done by Prof. Ibrahim Mashaly, at Ecology and

NATURAL PRODUCT RESEARCH
7
Botany Department, Faculty of Science, Mansoura University. A voucher specimen has
been deposited at the herbarium of the Pharmacognosy Department, Faculty of
Pharmacy, Mansoura University (02-17-LC-Mansoura).
Compound (10c): 2-formyl-(A)1–19a-hydroxy-1-norursane-2,12-dien-28-oic acid, col-
1
orless gum, HRESIMS m/z 467.3177 [M-H]-, calcd for (C30H43O4, 467.3161). H-NMR: d(H)
9.65 (H, s, H-1), 6.56 (H, s, H-3), 5.46 (H, s, H-12), 1.12 (3 H, s, Me-23), 1.00 (3 H, s, Me-
24) , 1.17 (3 H, s, Me-25) , 0.92 (3 H, s, Me-26) , 1.24 (3 H, s, Me-27) , 1.15 (3 H, s, Me-29),
0.87 (3 H, s, Me-30) .13C-NMR: d(c) 191.5 (C-1), 157.1 (C-2), 164.2(C-3), 44.1 (C-4), 62.8 (C-
5), 17.3 (C-6), 33.9 (C-7), 41.4 (C-8), 43.5 (C-9), 50.9 (C-10), 26.3 (C-11), 128.0 (C-12),
139.1 (C-13), 41.5 (C-14), 28.9 (C-15), 25.6 (C-16), 48.6 (C-17), 54.4 (C-18), 72.8 (C-19),
41.6 (C-20), 25.9 (C-21), 38.1 (C-22), 22.2 (C-23), 28.9 (C-24), 18.4 (C-25), 19.5 (C-26),
24.2 (C-27), 184.7 (C-28), 27.4 (C-29), 15.2 (C-30).
3.2. Derivatization reactions
The methyl ester derivatives 1a-4a and 7a, 8a were prepared by dissolving the start
material in 20% MeOH in benzene; followed by addition of trimethylsilyldiazomethane
(Urosa et al. 2015). The O-acetyl derivatives 2 b and 10 b were prepared by dissolving
the start material 2 and 10 in pyridine, followed by addition of acetic anhydride
(Cheng et al. 2013). Compound 2c was prepared by treating 2 with PCC in DCM
ꢀ
(Sandjo et al. 2011). Compound 10c was prepared by Jones oxidation (Tag et al. 2012)
of 10. All the products were purified over silica gel using EtOAc in Hexane as a solvent
system.
4. Conclusion
We investigated the structure activity relationship of twenty one related pentacylic tri-
terpenes, as a-glucosidase inhibitors. The results demonstrated that a carboxylic group
at C-28 site and a free hydroxyl group at ring-A are crucial structural features for the
a-glucosidase inhibitory activity. In the meantime, additional di or poly hydroxyl sub-
stituents at ring-A weaken the activity. In contrast, C-19 hydroxyl substitution can elicit
the activity. It was concluded that an ursane skeleton is favorable for activity over ole-
ane or ring-A contracted skeletons. Furthermore, enzyme kinetic analysis and molecu-
lar docking simulation of pomolic acid 2, the most active compound, revealed it acted
as a mixed inhibitor.
Disclosure statement
No potential conflict of interest was reported by the authors.
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