Ximenynic acid: A versatile lead molecule for drug development

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Int J Pharma Bio Sci 2019 Oct; 10(4): (P) 93-99 ISSN 0975-6299
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Review Article Natural chemistry
International Journal of Pharma and Bio Sciences
XIMENYNIC ACID: A VERSATILE LEAD MOLECULE FOR
DRUG DEVELOPMENT
RAKESH S. SHIVATARE
1*
, DR. DHEERAJ H. NAGORE
2
, DR. SOHAN CHITLANGE
3
AND
DR. GAYATRI GANU
4
1,2
Ph.D research scholar, JJT university, Jhunjhunu, Rajasthan, India.
3
Dr. D. Y. Patil institute of Pharmaceutical research and sciences, Pimpri, India.
4
Vice president clinical research, Mprex healthcare, Pune, India
ABSTRACT
With the growing concern over the unhealthy consequences of using chemical preservatives like sodium
benzoate, benzoic acid etc.in the food industry, investigation towards natural and herbal substances has
been increasing. Ximenynic acid (or Santalbic acid) is one of the few acetylenic fatty acids predominantly
exists in the seed oil of Santalaceae, Olacaceae, and Opiliaceae families. A number of in vitro and in vivo
studies have revealed therapeutic effects of ximenynic acid against various diseases. In general,
ximenynic acid exhibits many biological activities and pharmacological effects, including antibacterial,
antifungal, anti-inflammatory activities. However, a detailed analysis of the pharmacology, phytochemistry
and analytical methods for characterisation of ximenynic acid is scarce. The aim of present review is to
coherently discuss some of the most important applications of ximenynic acid and unites the results
obtained from several studies reporting the biological properties of this molecule. .The present review
paper reveals new perspective for investigations of biological properties of ximenynic acid and developing
novel formulations.
KEYWORDS:
Ximenynic acid, Santalaceae, Pharmacological activities, Phytochemistry, Bioavailability.
Received on: 19-08-2019
Revised and Accepted on: 03-10-2019
DOI: http://dx.doi.org/10.22376/ijpbs.2019.10.4.p93-99
Creative commons version 4.0
RAKESH S. SHIVATARE*
Ph.D research scholar, JJT university, Jhunjhunu, Rajasthan, India.

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INTRODUCTION
Fatty acids turn out to be building blocks of a huge
group of natural substances called lipids.
1,2
In foods,
they are generally present as triacylglycerols (fats and
oils) and glycerophospholipids. To an extent, fatty acids
are also established in the appearance of partial
acylglycerols (Mono and diacylglycerols). They also
occur as esters with other hydroxy compounds (e.g.
sterols), amides (sphingolipids), and free compounds.
3
Acetylenic acids, are a class of fatty acids having one or
more triple bonds . They are found in plants, fungi,
microbes, and marine organisms.
4,5
They have been
accounted to hold a miscellany of pharmacological
properties, including antibacterial, antifungal,
antiparasitic, and antitumor activities.
6,7
The set of the
acetylenic fatty acids with a chain length of seventeen
and twenty-one carbon atoms are very huge. Fourty of
the one hundred and thirty-six specified compounds
occur are natural, others are synthetic. Almost all of the
naturally occurring acetylenic fatty acids were identified
in higher plants but a few of the C
18
and C
20
acids were
found in mosses
8-12
and microorganisms. Chemically
they have maximum three double or four triple bonds
but overall not more than five unsaturated bonds are
present per molecule.
13
Santalbic acid (or ximenynic
acid), octadeca-11-trans-en-9-ynoic acid, is one of the
few acetylenic fatty acids occurring at higher levels in
plant seed oils.
14
Similar to the numerous unusual fatty
acids, ximenynic acid is a distinguishing component of
the seed oils of only a few closely connected plant
families. It crops up in the angiosperm order Santalales,
i.e. in the conventional ‘‘santalalean’’ plant families
Santalaceae, Olacaceae and Opiliaceae, and has not
been found outside the Santalales
15
. In the most recent
two decades, however, these original families have
been divided and numerous novel plant family names
and circumscriptions have been projected.
16-17
With few
exceptions, plants with ximenynic acid in their seeds
originate frequently on those continents that were
formed after the break-up of the old Gondwanaland
supercontinent.
18
In certain plants, ximenynic acid can
attain up to 95.0 % of the total seed oil fatty acids
19
and
pretty often levels above 70 % of total fatty acids have
been found. Since ximenynic acid holds a chemically
fascinating reactive conjugated enyne group, it could be
of significance as a raw material for the chemical
industry. In addition to this, seed oil fatty acids with
unusual functional groups are also of significant curiosity
in plant chemotaxonomy and plant evolution (Table 1).
19-
23
While the demand for ximenynic acid has a growing
trend, it is essential to review the most current
biosynthesis methods of this ximenynic acid. The aim of
this article is to provide an outline of the current
methods for the extraction, identification, and purification
of ximenynic acid, as well as the current findings
regarding its pharmacological activities and the different
approaches carried out to boost the use of ximenynic
acid in diverse formulations.
Table 1
Physico-chemical properties of ximenynic acid
24-26
1
Chemical Names
Santalbic acid; Trans
-
11
-
Octadecen
-
9
-
ynoic acid
2 Molecular Formula C
18
H
30
O
2
3 CAS Number 557-58-4
4 Molecular Weight 278.436 g/mol
5
Structure
6 Boiling Point 416.79 °C.
7 Density 0.9±0.1 g/cm
3
8 Vapour Pressure 0.0±2.1 mmHg at 25°C
9 Index of Refraction 1.484
10
Molar Refractivity 85.1±0.3 cm
3
11
LogP 6.76
12
Flash Point 200.0±18.7 °C
13
Polar Surface Area
37
Å
2
14
Polarizability 33.7±0.5 10
-
24
cm
3
15
Surface Tension 37.5±3.0 dyne/cm
16
logP (o/w) 6.254 (est)
17
Soluble in water, 0.04157 mg/L
PLANT SOURCES OF XIMENYNIC ACID
Nickrentet al.(2010)proposed a revised classification of plants belonging to Santalaceae and Olacaceaefamilies.
28
A
number of plants mentioned in Table2can currently be considered to be members of a new plant family.
17

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Table 2
Occurrence of santalbic acid in various seed oils
14
Plant
Famil
y
Content
Author
Year
Santalum album Santalaceae
84.00 GLC-area-% Morris LJ 1966
Santalumobtusifolium Santalaceae
71.50 GLC-area-% Vickery JR 1984
Exocarpossparteus Santalaceae
69.70 GLC-area-% SundarRao K 1992
Exocarposaphyllus Santalaceae
67.50 GLC-area-% SundarRao K 1992
Olaxbenthamiana Olacaceae 63.00 GLC-area-% Aitzamuller K 1996
Osyris alba Santalaceae
57.10 GLC-area-% Mikolajczak KL
1963
Cansjerarheedii Opiliaceae 55.40 GLC-area-% Aitzamuller K 1996
Exocarposcupressiformis Santalaceae
53.20 GLC-area-% Aitzamuller K 1996
Santalumacuminatum Santalaceae
52.50 GLC-area-% Aitzamuller K 1996
Santalummurrayanum Santalaceae
45.00 GLC-area-% Hatt HH 1956
Comandrapallida Santalaceae
43.00 GLC-area-% Mikolajczak KL
1963
Santalumspicatum Santalaceae
37.27 GLC-area-% Liu Y 1995
Ximeniaamericana Olacaceae 26.50 GLC-area-% Rovesti Paolo 1979
Ximeniacaffra Olacaceae 24.30 GLC-area-% Ligthelm SP 1954
Ximenia spp. Olacaceae 24.00 GLC-area-% Ligthelm SP 1952
Ximeniacaffra var. natalensis Olacaceae 22.00 GLC-area-% Ligthelm SP 1954
Ximeniaamericanavarmicrophylla.
Olacaceae 21.90 GLC-area-% Ligthelm SP 1954
Jodinarhombifolia Santalaceae
20.30 GLC-area-% Spitzer V 1994
Leptomeriaaphylla Santalaceae
19.50 GLC-area-% Hatt HH 1960
Agonandrabrasiliensis Opiliaceae 18.80 GLC-area-% Aitzamuller K 2000
Exocarposcupressiformis Santalaceae
16.70 GLC-area-% Badami RC 1981
Pyrulariapubera Santalaceae
10.00 GLC-area-% Badami RC 1981
Agonandraexcelsa Opiliaceae 8.90 GLC-area-% Aitzamuller K 1997
Agonandrasilvatica Opiliaceae 7.60 GLC-area-% Aitzamuller K 2000
Opiliaamentacea Opiliaceae 7.60 GLC-area-% Aitzamuller K 1996
Heisteriaacuminata Olacaceae 7.50 GLC-area-% Aitzamuller K 1999
Agonandraexcelsa Opiliaceae 5.00 GLC-area-% Aitzamuller K 2000
Agonandrasilvatica Opiliaceae 4.80 GLC-area-% Aitzamuller K 2000
Heisteriasilvanii Olacaceae 3.49 GLC-area-% Spitzer V 1997
Pyrulariaedulis Santalaceae
1.40 GLC-area-% Zhang JY 1989
Ongokea gore Olacaceae 1.00 GLC-area-% Morris LJ 1963
Acanthosyrisspinescens Santalaceae
1.00 GLC-area-% Powell RG 1966
Malaniaoleifera Olacaceae 0.17 GLC-area-% Aitzamuller K 1992
ISOLATION OF XIMENYNIC ACID
FROM PLANT
CHEMICAL IDENTIFICATION AND
PURIFICATION OF XIMENYNIC ACID
IN EXTRACTS
Bulocket al(1963), in their study on “Acetylenic Fatty
Acids in Seeds and Seedlings of Sweet Quandong”
have obtained stones of the fruit of Santalum
acuminatum from the Human Nutrition Unit, University of
Sydney. These stones have a diameter of about 1 cm
and look like small peach stones. A stone was busted
and the kernel was ground which was further extracted
with chloroform and methanol to yield oil. The oil was
saponified with 80% methanolic potassium hydroxide
(0.5 mol/l) for 2 h at 70°C. After acidification with
aqueous sulphuric acid, the free fatty acids were
extracted with light petroleum and diethyl ether. A fatty
acids comprising of ximenynic acid, oleic acid and
some minor other fatty acids were obtained. As the
methyl esters of ximenynic acid and oleic acid could not
be separated by reverse phase, purification was
performed on a straight phase , with hexane/isopropanol
as the mobile phase. This resulted crude methyl ester
mixture. After saponification, ximenynic acid with a
purity of 95%, containing 5% eicosenoic acid was
obtained.
27
Yandi et al (1996), in their study on
“separation and identification of ximenynic acid isomers
in the seed oil of Santalum spicatumR Br. as their 4,4-
dimethyloxazoline derivatives” extracted seed oil from
the mature seeds of S. spicatum by grinding seed
samples and extracting with hexane in a Soxhlet
apparatus for 2 h. Anhydrous sodium sulfate was used
to dry the solution followed by removal of the solvent
using the Buchi rotatory evaporator under reduced
pressure at 60°C to yield a viscous, pale yellow oil.
Isolation of trans ximenynic acid was done by refluxed a
sample of the oil with potassium hydroxide in 95%
ethanol (200 mL) for 1 h. The mixture was cooled and
acidified with 6 M HCI to pH 1. Ximenynic acid was
obtained by crystallization from hexane.
Recrystallization from hexane gave trans-ximenynic acid
as white flakes. The seed oil of Santalum spicatumwas
found to contain a significant amount of ximenynic acid,
a long-chain acetylenic fatty acid, as a major component
(34%). The identity of trans-ximenynic acid was
confirmed after isolation by ultraviolet, infrared,
1
H and
13
C nuclear magnetic resonance (NMR) spectroscopy
and gas chromatography/ mass spectrometry (GC/MS).
The cis isomer of ximenynic acid was also found (<1%)
in some samples. The cis and trans isomers were

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characterized by GC/MS comparison of their methyl
esters and 4,4-dimethyloxazoline derivatives.
28,29
BIOLOGICAL AND
PHARMACOLOGICAL EFFECTS OF
XIMENYNIC ACID
30-47
Ximenynic acid has shown a wide range of
pharmacological applications due to its significant
antioxidant properties. The Patent filing of formulations
containing ximenynic acid has increased over the past
few years. Conventionally, ximenynic acid is used as
antimicrobial, antifungal, and antiallergic agents. Current
research has shown its pharmacological benefits for the
treatment of various chronic diseases such as cancer,
skin diseases, hair loss, and hypercholesterolemia. Add
Reference
ANTI-PROLIFERATION ACTIVITY
Anti-proliferation activities of Ximenynic acid were
evaluated by Fang et al. (2016) in HepG2 human
hepatoma cell line and the underlying mechanisms.
They demonstrated the anti-proliferation and pro-
apoptosis activities of ximenynic acid by cell viability
assay and flow cytometry analysis. The results revealed
that ximenynic acid blocked G1/S phase transition by
inhibiting the protein expression of the cell cycle
associated protein general control of amino acid
synthesis yeast homolog like 2 (GCN5L2), and the
mRNA expression of cyclin D3 and cyclin E1. They
found that ximenynic acid may inhibit the growth of
HepG2 cells by selective inhibition of COX-1 expression,
which leads to cell cycle arrest, and alters the apoptosis
pathway and expression of angiogenic factors.
30
ANTI- INFLAMMATORY ACTIVITY
Dhanushka et al. (2012) isolated ximenynic acid from S.
acuminatum. Their studies revealed that ximenynic acid
exhibited anti- inflammatory properties on several rat
peritoneal leukocytes. Further studies on ximenynic acid
revealed that it alters the cytochrome P-450 enzyme in
rats, indicating a pharmacological change in the hepatic
metabolism.
31
ANTIMICROBIAL ACTIVITY
In 2017, Gautam and his co-workers assessed the
antimicrobial screening of petroleum ether and ethanol
extracts of Santalum album seeds by disc diffusion
method on two gram-positive bacteria, Bacillus subtilis,
Staphylococcus aureus, gram negative Pseudomonas
aeruginosa, Escherichia coli and the fungus Candida
albicans. The results of the investigations indicated
possible high potency of petroleum ether extract due to
ximenynic acid which could serve as chemotherapeutic
agent.
32
Jones et al. (1995) determined the degree of
antimicrobial activity of ximenynic acid, which is a major
constituent of the oil. They also found that ximenynic
acid was an inhibitor of Gram-positive bacteria and a
number of pathogenic fungi in standardized
bioassays.
33
Misra and Dey (2012) evaluated the
antibacterial properties of the five extracts and
compared with sandalwood oil by screening against nine
Gram-negative and five Gram-positive bacterial strains
by disc diffusion, agar spot, and TLC bioautography
methods. Bioautography results indicated the presence
of potential antimicrobial constituents in somatic embryo
extracts and sandalwood oil.
34
LARVICIDAL ACTIVITY
According to Mavundza et al. (2016), ximenynic acid
exhibited larvicidal activity against laboratory-reared
larvae of An. arabiensis mosquitoes, a potent malaria
vector in South Africa. A dose response bioassay was
performed for pure compounds to determine the EC50
values.
35
ANTI-CANCER ACTIVITY
Croft et al. (1987) tested the effects of ximenynic acid on
leukotriene B4 and thromboxane B2 production in rat
peritoneal leukocytes and compared them with non-
acetylenic compounds, linoleic and ricinoleic acids.
Ximenynic acid exhibited significant dose dependent
inhibition of leukotriene B4, thromboxane B2 and 6-
ketoprostaglandin F1 alpha production. These results
indicate that ximenynic acid differentially inhibits the
cyclooxygenase and lipoxygenase products of
stimulated leukocytes and that at high doses of these
fatty acids the effect on these products may be partially
due to inhibition of phospholipase A2.
36
HEPATIC MICROSOMAL
CYTOCHROME P-450 ACTIVITY
In another study undertaken by Jones et al. in 1994 on
ximenynic acid in hepatic cytochrome P-450, it was
found that the Hepatic microsomal cytochrome P-450
activity in animals fed for 20 days was significantly
higher (P < 0.05) than in controls. Histopathological
examination did not reveal any lesions in the tissues of
any animal fed quandong oil. The fact that ximenynic
acid was readily absorbed and widely distributed in
tissues was associated with an elevated level of hepatic
cytochrome P-450.
37
FATTY ACIDS INHIBITORY
ACTIVITIES
Nugteren and Christ in 1987 pinpointed a number of
fatty acids having moderate inhibitory potency, viz.
ximenynic acid, crepenynic acid, columbinic acid and
timnodonic acid (the precursor of prostaglandin E3).
24
Yandi and Robert designed the study to obtain basic
information on changes in tissue fatty acid composition
and on the metabolic fate of ximenynic acid in mice fed
with sandalwood seed oil (SWSO)-enriched diet. They
reported that the fatty acid composition of liver and
adipose tissue were markedly altered by dietary fats,
and mice fed on an SWSO-enriched diet were found to
contain ximenynic acid but only in low concentration
(0.3–3%) in these tissues. Ximenynic acid was not
detected in brain.
38
ANTIOXIDANT ACTIVITY
Dhanushka et al. (2012) further investigated that a
highly purified ximenynic acid increases cellular
detoxification, anti-oxidation capacity. It leads to a
strengthening of the extracellular matrix (ECM),
increases dermal strength and improves skin elasticity.
31

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VASCULAR BIO-ACTIVE AGENT
Nugteren and Christ (1987), studied the effect of
Ximenynic acid on prostaglandin biosynthesis. It was
found that acetylenic acids with unsaturated eighth and
tenth positions demonstrate a sixteen fold higher
potency in inhibiting prostaglandins than acetylenic fatty
acids with ninth and eleventh position unsaturation.
Thus ximenynic acid is considered a moderate
prostaglandin.
23
In addition, Sun et al. proposed that
plant derived acetylenic fatty acids block lipoxygenase
more than cyclooxygenase, and the capacity of
inhibition depends upon the chain length and the
positioning of unsaturation.
39
Sok et al. (1982) also
reported that acetylenic fatty acids inhibit leukotriene
activity more efficiently than prostaglandins.
40
These
findings substantiate that disruption of the eicosanoid
pathway by acetylenic fatty acids including ximenynic
acid acts differently to non-steroidal anti-inflammatory
drugs (NSAIDs). Croft et al (1987) have reported that
ximenynic acid inhibits leukotriene B4, thromboxane B2,
and 6-ketoprostaglandin F1α - prostaglandins of the
sheep vascular tissue. Based on these studies, the
authors proved that ximenynic acid produced a
vasodilative effect and increased blood circulation.
36
MICROVASCULAR KINETIC ACTIVITY
Bombardelli et al. (1994) first reported the microvascular
kinetic activity of ximenynic acid. This activity was first
evaluated on patients suffering from cellulitis or venous
insufficiency.
41
Subsequently, the microvascular kinetic
activity of ximenynic ethyl ester (a semi-synthetic
derivative of natural ximenynic acid) was patented in
1992 as a treatment for cellulitis, hair loss and erectile
dysfunction.
42-44
Bombardelli et al. (1994) demonstrated
that the application of ximenynic acid ester increased
microvascular blood flow and capillary density. Patients
experienced significant reduction symptoms without any
marked adverse reactions recorded; more over the
dermal appeal at the site of application has increased
significantly.
41
Commercial patents have claimed that
formulations containing ximenynic acid improved lipid
metabolism and also skin appeal when incorporated to
cosmetics.
43,45
XIMENYNIC ACID FOR HAIR LOSS
Messenger and Rundegren (2004), reported that neither
ximenynic acid nor other acetylenic fatty acids have
been reported to show any anti-androgenic
activity.
46
Inhibition of leukotrienes and thromboxane
would also result in a reduction of intracellular calcium
ions by inhibiting the activation of the IP3 receptor, but
the result would produce a similar vasodilatory effect.
Ximenynic acid ethyl ester (and its vasoactive
properties) was patented as a treatment and prevention
of hair loss by Bombardelli et al. (1997).
42
According to
Glynn et al,a topical formula with ximenynic acid
together with several other natural ingredients is used
for modulation and re-growth of hair.
47
CONCLUSIONS AND FUTURE
PROSPECTUS
The present review provides information about isolation,
biological and pharmacological activities of ximenynic
acid which can be used as an excipient or an active in
novel formulations. Ximenynic acid is acetylenic fatty
acids, that are consumed in fruits, vegetables, and plant
derived beverages. Additionally, there are fewer
formulations in the market containing ximenynic acid in
different dosage forms either alone or in combination
with other active ingredients. Both conventional and
innovative methods have been reported for the
extraction of ximenynic acid from natural sources.
Accurate comparison between procedures is not
straightforward because of the variance in the plant
materials. However, current trends in the extraction
process have been focused on the discovery and design
of green and sustainable extraction techniques to
optimize the extraction of ximenynic acid. Numerous
studies have reported diverse pharmacological activities
of ximenynic acid, including antioxidant, anti-
inflammatory, anticancer, and antimicrobial and skin
disorder.However, the observed pharmacological effects
do not always translate into the clinic because of the
poor bioavailability, less information of ximenynic acid.
To overcome this barrier, researchers have proposed
different strategies thatwill enhance bioavailability and
ultimately give health benefits. The present review
provides information about ximenynic acid. One major
challenge that the food and pharmaceutical industry
faces is toprovide basic-applied research and
technology innovations (e.g. ximenynic acid delivery
systems, synthesis of ximenynic acid derivatives) into
safe products providing health benefits for the
consumer.
AUTHORS CONTRIBUTION
STATEMENT
Mr.Shivatare R conceptualized and gathered the data
with regard to this Review. Dr.Nagore D, Dr.Ganu G,
and Dr.Chitlange S ranalyzed these data and necessary
inputs were given towards the designing of the
manuscript. All authors discussed the introduction,
isolation and pharmacological action to the final
manuscript.
CONFLICT OF INTEREST
Conflict of interest declared none.
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