You are on page 1of 11

Arch. Pharm. Chem. Life Sci.

2014, 347, 229–239 229

Review Article
A Review (Research and Patents) on Jasmonic Acid and
Its Derivatives

Abdollah Ghasemi Pirbalouti1,2, Seyed Ebrahim Sajjadi3, and Keykavous Parang4

1
Department of Medicinal Plants, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
2
Medicinal Plants Program, Stockbridge School of Agriculture, College of Natural Science, Massachusetts
University, Amherst, MA, USA
3
Department of Pharmacognosy, School of Pharmacy, Isfahan University of Medical Sciences, Isfahan, Iran
4
Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island,
Kingston, RI, USA

In medicinal chemistry there is a growing interest in using small molecules, including plant stress
hormones. Jasmonic acid (JA) and its volatile methyl ester (MJ), collectively termed jasmonates, are
lipid-derived cyclopentanone compounds that occur ubiquitously and exclusively in the plant
kingdom. This review covers the synthesis, usage, and biological activities of JA and its derivatives. A
brief overview of the available information on JA and its features is given, followed by a detailed review
of JA and its derivatives as drugs and prodrugs; the properties in plants and the synthesis in recent
patents are described. This review shows the direction of long-term drug/nutraceutical safety trials and
provides insights for future research in this area. Research on JA continues to be of major interest.
Recent innovations offer hope for the development of new therapeutics in related fields. It is
anticipated that several analogs can be advanced to preclinical and clinical studies.

Keywords: Anticancer / Cosmetics / Drugs / Jasmonic acid / Natural products

Received: August 4, 2013; Revised: September 12, 2013; Accepted: September 17, 2013

DOI 10.1002/ardp.201300287

Introduction and isoleucine (JA-isoleucine) (3), 12-oxophytodienoic acid (12-


OPDA), and glycosyl esters were found to be widespread in
()-Jasmonic acid ((3R,7R,9Z)-jasmonic acid; ()-(JA)) (1) and its angiosperms, gymnosperms, and algae [4, 6]. Jasmonates are
methyl ester (MJ) (2) were first identified in the essential oils of lipid-derived cyclopentanone compounds that occur ubiqui-
jasmine (Jasminum grandiflorum L.) and rosemary (Rosmarinus tously and exclusively in the plant kingdom. Here, JA and
officinalis L.), and their chemical structures were subsequently JA-Ile as well as its precursor cis-(þ)-OPDA exert their biological
determined [1, 2]. In addition, JA was first isolated from the activities in plant responses to biotic (insects and pathogens,
culture filtrate of the fungus Lasiodiplodia theobromae (syn. L. by inducing phytoalexin production) and abiotic stress as well
theobromae) in 1971 [3]. In the 1980s, a class of phytohormones as in development, whereas most of the JA derivatives have
derived from the metabolism of membrane fatty acids, only limited biological activity or are even inactive like the
collectively known as jasmonates, attracted considerable hydroxylated derivatives [4–10].
attention [4]. Among the classes of metabolites originating A study [11] has shown that MJ is involved in the primary
from JA and MJ are free and conjugated forms of polyamines, metabolism of a microalga (Schizochytrium mangrovei). For
quinones, terpenoids, alkaloids, phenylpropanoids, glucosi- example, MJ was found to regulate the key enzymes in the
nolates, and antioxidants [5]. In addition, leucine (JA-leucine) synthesis of squalene, an important intermediate in the
cholesterol biosynthetic pathway. Insects utilize many of
these substances as airborne signals for intraspecific commu-
Correspondence: Dr. Abdollah Ghasemi Pirbalouti, Department of nication. For instance, cis-jasmone, MJ, and two C8 alkanals are
Medicinal Plants, Shahrekord Branch, Islamic Azad University, P.O. emitted from male Amauris ochlea butterfly hair-pencils [12, 13]
Box 166, Shahrekord, Iran.
E-mail: ghasemi@iaushk.ac.ir, aghasemipir@psis.umass.edu and MJ is emitted from male oriental fruit moth hair-
Fax: þ98 381 336 1060 pencils (Grapholitha molesta (Busck.)), as pheromones that

ß 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim


230 A. Ghasemi Pirbalouti et al. Arch. Pharm. Chem. Life Sci. 2014, 347, 229–239

attract receptive females [12, 13]. The jasmonate biosynthesis obtained by biotransformation were specifically active on
in plants is analogous to the eicosanoid biosynthesis several types of cancer cells [27]. One of the a-haloenone
in animal cells. In animals, eicosanoids are synthesized analogs, methyl 5-chloro-4,5-didehydrojasmonate or J7, a
from arachidonic acid (C20:4) while in plants a-linolenic methyl jasmonate (MeJA) analog, induced significant apopto-
acid (C18:3), which undergoes several steps of oxidation, sis by activation of caspase-3 and the mitochondrial apoptosis
cyclization, and reduction, is the major source of jasmo- signaling pathway in Hep3B cells [28]. JA and MJ caused
nates [6, 8, 14]. apoptotic death, as shown by flow cytometric DNA profiles
and the elevation of caspase-3 activity.
Toxicity studies Generally, three potential mechanisms of action have been
proposed to explain the anticancer activity of jasmonates,
Various studies have shown that JA and MJ do not cause including (i) the bioenergetics mechanism involving severe
significant toxicity [15–18]. Umukoro and Abimola [19] depletion of ATP via mitochondrial perturbation, (ii) the
reported that, when MJ was administered intraperitoneally induction of re-differentiation via mitogen-activated protein
in doses ranging from 100 to 500 mg/kg, it was well tolerated kinase (MAPK) activity, and (iii) apoptosis induction via the
by mice and did not produce acute toxic symptoms or death in generation of ROS and elevation of the pro-apoptotic Bcl-2
the animals. Results of several studies on acute toxicity, skin proteins [8, 18].
irritation, mucous membrane (eye) irritation, skin sensitiza- Jasmonates have shown antiproliferative activity indepen-
tion, phototoxicity, and photoallergy of methyl dihydrojas- dent of cellular mRNA transcription, protein translation [29],
monate indicated that the LD50 for oral administration was and p53 expression [30]. Recent studies have been performed
>5 g/kg, and for skin use, the LD50 was >2 g/kg. No irritation to determine the mechanism by which jasmonates induce
was observed in the human repeated-insult patch test and in apoptosis [21]. It was found that MJ acted directly on
several animal studies. Furthermore, no irritation was mitochondria as it induced swelling, the release of cyto-
detected in the mucous membrane (eye) test. Sensitization chrome c, and the perturbation of mitochondria isolated from
reactions in animal and human studies and photoirritation several different cancer cell lines [15]. MJ was also reported to
and photoallergy studies in humans did not show any induce mitochondria-mediated apoptosis in lung carcinoma
significant toxicity [20]. cells through the induction of the pro-apoptotic Bax/Bcl-XS
proteins and the activation of caspase-9 and -3 via ROS
Biological activities of JA derivatives production [31]. Treatment of irradiated prostate adeno-
carcinoma cells with MJ resulted in suppression of the anti-
Anticancer activity apoptotic Bcl-2 protein and an elevation of caspase-3
JA and its derivatives, which are fatty acid-derived cyclo- activity [32]. These data indicate that MJ has direct toxic
pentanones, occur ubiquitously in the plant kingdom and effects on mitochondria, strongly suggesting that mitochon-
have shown diverse biological activities. The first report on dria are the target organelles of jasmonates [21]. Goldin
jasmonate-induced anticancer activities exhibited their et al. [33] reported that MJ was able to detach the enzyme
capacity to cause both cell death and suppression of cell hexokinase from the mitochondrial fractions (MF) isolated
proliferation [8, 15–18]. Jasmonates are small hydrophobic from four different cancer types (both cancer cell lines and
compounds that act as plant stress hormones and can tumors extracted from animals).
increase the survival of lymphoma-bearing animals and
humans, and induce death in human leukemia, lung, colon, Antidepressant and anti-aggressive activities
prostate, neuroblastoma, breast, and melanoma cell lines, as The possibility that sufficient amounts of MJ enter the brain
well as in leukemic cells from chronic lymphocytic leukemia through the blood–brain barrier to exert behavioral effects
(CLL) patients [8, 15, 17–24]. has been reported in previous studies [34]. MJ has been shown
MJ was studied in topical application for precancerous and to demonstrate antidepressant properties based on its ability
cancerous skin lesions [25]. The results of a study [26] to reduce the period of immobility in the forced swim and tail
indicated that a ()-JA derivative, 3-hydroxy-2(S)-(2Z-butenyl)- suspension tests in mice [34]. Umukoro et al. [35] also reported
cyclopentane-1(S)-acetic acid, obtained by biotransformation that the mechanism of effects of MJ as antidepressant could
with the fungus Gibberella fujikuroi, was able to inhibit the involve the facilitation of both serotonergic and noradrener-
growth of both androgen-sensitive (LNCaP) and androgen- gic neurotransmission. A study revealed that MJ exhibited
insensitive (DU-145) prostate cancer cells. The apoptosis specific anti-aggressive activity through affecting 5-HT1B
evocated by this new molecule appeared, at least in part, to receptors. Thus, MJ could be used in the treatment of reactive
be associated with an increase in reactive oxygen species (ROS) aggression in humans [35]. The effects of natural and novel
production [26]. A study indicated that three JA derivatives synthetic jasmonates in experimental metastatic melanoma

ß 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.archpharm.com


Arch. Pharm. Chem. Life Sci. 2014, 347, 229–239 Jasmonic Acid and Its Derivatives 231

studies indicated that MJ and its synthetic derivatives Antimicrobial and antioxidant activities
suppressed B16-F10 cell motility and inhibited the develop- Antibacterial activity assessment of JA produced by Botryo-
ment of experimental lung metastases of these cells [36]. sphaeria rhodina, a fungal plant pathogen that causes cankers
on some plant species, showed that the crude extract
Anti-inflammatory activities containing JA had high antimicrobial potential against
The results of studies on the potential anti-inflammatory Escherichia coli and Pseudomonas aeruginosa, but no effect on
effects of MJ derived from the red alga Gracilaria verrucosa Staphylococcus aureus [46]. The results of an invention
showed that MJ was comparable to or more effective than indicated that growth of Candida albicans and Aspergillus
prostaglandin-like compounds [37, 38]. In the evaluation niger was inhibited by 1 and 10 mg/mL MJ while this
of MJ analogs for their anti-inflammatory activities, the compound had no antimicrobial activity against Lactobacillus
a-haloenones exhibited potent activity higher than those acidophilus [47].
of natural anti-inflammatory prostaglandins [38]. Methyl Several studies [48–69] have indicated that exogenous
4,5-didehyrojasmonate also exhibited in vitro anti-inflam- application of jasmonates on plants increases the amounts of
matory potency comparable to that of the most potent natural antimicrobial and antioxidant agents in extracts
natural anti-inflammatory prostaglandin 15d-D [39]. Among and essential oils (Table 1). Wang et al. [68] reported that
these jasmonate analogs, the a-haloenones inhibited the MJ treatment also significantly enhanced the content of
production of pro-inflammatory mediators (nitric oxide flavonoids, the antioxidant capacities, and the inhibition
(NO), interleukin (IL)-1b, IL-6, and tumor necrosis factor A549 cell and HL-60 cell proliferation, and induced apoptosis
(TNF)-a) through the down-regulation of NF-kB activity in in HL-60 cells. The inhibitory effect on cancer cell proliferation
lipopolysaccharide (LPS)-activated murine macrophages and the induction of apoptosis could be the result of the
(RAW264.7) [40]. synergistic effects of polyphenols in the berries. Cao et al. [69]
concluded that a postharvest application of MJ positively
Anti-nociceptive activities affected the antioxidant levels, the antioxidant activity, and
The anti-nociceptive activities of MJ were evaluated in rodents, the overall quality of loquat (Eriobotrya japonica Lindl.)
using the acetic acid-induced writhing, tail immersion, fruit. They also indicated that MJ might exert its effect on
formalin-induced paw licking, and Randall–Selitto paw increasing the phenolics content in loquat fruit by inhibiting
pressure tests. MJ demonstrated significant inhibitory activity the polyphenol oxidase activity. The increased contents of
against acetic acid-induced nociception [19]. The effects of phenolics and flavonoids elicited by MJ treatment resulted in
jasmone and MJ on the sarcoplasmic reticulum (SR) enhanced antioxidant activity [69]. The modification of
Ca2þ-ATPase were demonstrated in a series of experiments antioxidant enzymes (SOD, APX, GPX, and CAT) can play an
conducted on the purified Ca2þ-ATPase from rabbit fast-twitch important protective role by avoiding the deleterious effects
skeletal muscles [41]. Joumaa et al. [42] reported that MJ was triggered by elevated levels of ROS observed in the initial
a potent, reversible, and specific stimulator of the SR Ca2þ moments after JA exposure [70, 71]. Different effects of MJ
pump in slow-twitch skeletal muscle and could be used as a on protective enzyme activities could be associated with the
valuable pharmacological tool for improving relaxation and H2O2 metabolism [70, 71]. Lee et al. [72] demonstrated that MJ
for studying calcium signaling issues. MJ appears to be a treatment significantly increased the amount of phenolic
convenient tool for the selective activation of SR Ca2þ-ATPase compounds and the antioxidant activity of buckwheat
in slow-twitch skeletal muscles. sprouts, resulting in the suppression of adipogenesis and
ROS production in 3T3-L1 cells.
Antiparasitic activities Some antimicrobial proteins have been shown to be
Gold et al. [43] reported that jasmonates had significant induced by JA. These proteins could play a crucial role in
antiparasitic effects on human parasites, Plasmodium falcipa- the protection of plants against microbial infection.
rum (an intraerythrocytic protozoan parasite, which is the Studies have shown a positive correlation between the
causative agent of the most severe form of malaria), and exogenous application of MJ and the synthesis of phenolic
Schistosoma mansoni (a parasitic worm residing in blood vessels, compounds as the main natural antimicrobial agents [73, 74].
causing a serious human infestation). Another study [44] A study [75] showed that MJ increased the biosynthesis of
indicated that MJ induced a time- and dose-dependent vitamin C (L-ascorbic acid) in plant cell suspensions.
decrease in the number of live Trichomonas vaginalis, an
important human parasite of the urogenital tract. Other JA and its derivatives in plants
researchers [45] also reported on the potential of employing
MJ as a treatment for trichomoniasis, including its use against The widespread occurrence of jasmonates in the plant
metronidazole-resistant strains. kingdom and in some lower eukaryotes as well as their

ß 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.archpharm.com


232 A. Ghasemi Pirbalouti et al. Arch. Pharm. Chem. Life Sci. 2014, 347, 229–239

Table 1. Effects of exogenous jasmonate application on secondary metabolites in plants.

Species Composition Application Refs.


Coleus blumei Benth Rosmarinic acid In vitro [48]
Lavandula vera D.C. Rosmarinic acid In vitro [49]
Mentha  piperita L. Rosmarinic acid In vitro [50]
Basil (Ocimum basilicum L.) Total phenolics (rosmarinic acid and caffeic acid) In vitro [51]
Panax ginseng C.A. Meyer Ginsenosides In vitro [52]
Strawberry Anthocyanins In vitro [53]
Grapevine (leaves and berries) Anthocyanins, stilbenes, such as In vitro [53, 57]
resveratrol and viniferin
Taxus species Paclitaxel In vitro [54]
Nicotiana species Alkaloids, terpenoids, and phenolics In vitro [55]
Hyoscyamus muticus L. Alkaloids, terpenoids, and phenolics In vitro [56]
Kudzu [Pueraria lobata (Willd) Ohwi.] Isoflavonoids In vitro [58]
Hypericum perferatum L. Hypericine In vitro [59]
Tomato leaves Caffeoylputrescine In vitro [60]
Hypericum perferatum L. (leaves) Hypericine Foliar application [61]
Thyme (Thymus daenensis Celak.) Oxygenated monoterpenes Foliar application [62]
Marigold (Calendula officinalis L.) flowers Total phenolics and flavenoids Foliar application [63]
Sage (Salvia officinalis L.) leaves Thymol and a-pinene Foliar application [64]
Strawberries (fruit) Total phenolics and anthocyanins Postharvest [65]
Romaine lettuce (Lactuca sativa L.) and radish sprout Total phenolics and carotenoids Postharvest [66]
Chinese kale (Brassica alboglabra Bailey) Glucosinolates, neoglucobrassicin (total phenolics) Postharvest [67]
Blackberries (Rubus sp.) Flavonoids Postharvest [68]
Loquat (Eriobotrya japonica Lindl.) fruit Total phenolics Postharvest [69]

capacity to regulate processes in insects support the notion in both the wounded leaves and distal unwounded leaves in
that jasmonates have critical biological properties [8]. several plant families [84, 85]. Several plant-derived chemicals
that can regulate the expression of wound-inducible protein-
Enhanced levels of jasmonates and biological ase inhibitor genes have been identified. These chemicals
outcomes include oligouronides originating from the plant cell wall. JA
Levels of jasmonates found in intact plants usually range from and its MJ have been shown to activate the synthesis of
10 to 100 ng/g fresh weight, but can be much higher in some proteinase inhibitor proteins in response to wounding [85].
plants or plant organs under biotic (insect and pathogen
attacks) and abiotic stresses (drought, osmotic stress, UV light, Jasmonates and gene expression
chilling, ozone, and heat) or after mechanical wounding Jasmonates have been demonstrated to activate genes
(herbivores, pathogens, mechanical stress, and other environ- encoding antifungal proteins such as thionin [86], osmotin
mental insults) [76–78]. The increased levels of jasmonates [87], and a novel ribosome-inactivating protein, JIP60 [88],
lead to dramatic reprogramming of the expression of genes and several other genes involved in phytoalexin bio-
involved in root growth and flower development, senescence synthesis [89].
and tendril coiling, the formation of secondary metabolites or
production of specialized metabolites, and other metabolic Jasmonatas in resistance to insects
pathways [10, 79, 80]. The highest amounts of jasmonates Resistance to insect pests and oomycete pathogens in the
occur in fruit parts, especially the immature pericarp, in model plant Arabidopsis appears to depend on defense
flowers and in vegetative plant parts, e.g., leaves, stems, and signaling pathways that involve jasmonates and other
germs [4]. Jasmonates increase the levels of endogenous secondary messenger molecules [90]. The application of
secondary metabolites, reduce the development and oviposi- exogenous jasmonates can result in enhanced resistance to
tion of herbivores, increase the attraction of predators and insect pests and microbial pathogens [91, 92]. Postharvest
parasitoids, and enhance the parasitism rates of herbivores diseases are responsible for substantial losses of vegetables
for a wide variety of plant species [81–83]. Wounding by and fruits as they are natural hosts of fungal pathogens. JA or
chewing herbivores, mechanical damage, pathogen attacks, MJ have potential applications in postharvest treatment by
and abiotic stress result in the localized and systemic alleviating chilling injury and maintaining quality in many
accumulation of high levels of proteinase inhibitor proteins horticultural and floriculture crops.

ß 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.archpharm.com


Arch. Pharm. Chem. Life Sci. 2014, 347, 229–239 Jasmonic Acid and Its Derivatives 233

Induction of volatiles by jasmonates Membrane lipids


Emission of volatiles is one of the diverse mechanisms used by
plants to withstand various environmental stresses. This Phospholipase
mechanism generates attractive compounds for pollinators
COOH
and seed-dispersing animals or repellents for a wide range of
α-Linolenic acid
herbivores. Aromatic volatile compounds are one of the
factors that determine fruit herbs and the quality of aromatic
plants. Manipulation of the volatile emission of a plant using 13-Lipoxygenase (13-LOX)
a chemical inducer allows for the investigation of the possible
effects of plant volatiles on community ecology. An elicitor
COOH
has the advantage of being able to induce (part of) the volatile 13(S)-Hydroperoxy linolenic acid

blend without the removal of plant tissue and offers the OOH
possibility to apply a controlled dose, whereas it is difficult
to control the amount of damage inflicted by herbivore Allene oxide synthase (AOS)
feeding [93].
Treatment of plants with JA or MJ has been reported to O

induce volatile emission similar to herbivore induction and 12,13(S)-Epoxy linolenic acid
extrafloral nectar production. The production of aromatic COOH

and volatile compounds increases with jasmonate treatment,


but the chemical classes of the volatile compounds can
Allene oxide cyclase (AOC)
vary [94]. For instance, MJ promotes anthocyanin synthesis in
O
apple skin [95].
cis-(+)-12-Oxophytodienoic acid
Senescence by jasmonates COOH

Senescence is a highly regulated, ordered series of events


involving the loss of photosynthesis, breakdown of the CO2-
fixing enzymes such as ribulose bisphosphate carboxylase/ 12-OPDA reductase
O
oxygenase (Rubisco) and other proteins, loss of chlorophyll,
removal of amino acids and, in some cases, accumulation of
new proteins. JA and MJ are biologically similar to abscisic COOH
acid (ABA) and have been shown to exhibit a senescence-
promoting activity in the leaves of many plant families [95].
3 × β-Oxidation
Induced senescence by MJ is characterized by a drastic loss of
chlorophyll, the degradation of Rubisco and the inhibition of O
its biosynthesis, and increases in the respiratory rate and in
protease and peroxidase activities [96, 97]. In addition, MJ Jasmonic acid
COOH
counteracts the anti-senescence action of kinetin similar to
ABA, acting as an antagonist [95]. Figure 1. Biosynthesis of JA (modified from [6, 100]).

Synthesis of JA and its derivatives


synthase (AOS). This epoxy compound is unstable and thus is
Jasmonates are oxygenated cyclic fatty acids derived from converted to cis-(þ)-12-oxophytodienoic acid (12-OPDA) by
linolenic acid via the octadecanoid pathway [14]. Jasmonates allene oxide cyclase (AOC). 12-OPDA biosynthesis occurs in
can be classified chemically as a subgroup of oxylipins, which the chloroplast. However, the final steps of JA production
are oxygenated fatty acids containing one or more oxygen are performed in peroxisomes. JA is synthesized from
atoms other than those in the carboxyl group [98]. Figure 1 12-OPDA through one step of reduction and three cycles of
demonstrates the biosynthetic pathway of jasmonates. The b-oxidation [6, 68]. JA can be converted to other related
biosynthesis starts with a-linolenic acid (18:3) present in components. MeJA and jasmone are the main odor compo-
the chloroplast membranes. Linolenic acid is oxygenated by nents of jasmine (J. grandiflorum L.) derived from JA [99]. MeJA is
13-lipoxygenase (13-LOX) to form 13-hydroperoxy-9,11,15- derived from JA via enzymatic methylation by JA carboxyl
octadecatrienoic acid (13-HPOT). In the next step, 13-HPOT methyltransferase (JMT) [100]. Conjugation of jasmonates
is oxidized to 13,13(S)-epoxy linolenic acid by allene oxide with amino acids (such as leucine and isoleucine) and sugars

ß 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.archpharm.com


234 A. Ghasemi Pirbalouti et al. Arch. Pharm. Chem. Life Sci. 2014, 347, 229–239

has been reported for plants and cell suspensions, Use in medicine and pharmacology
respectively [101]. Cancer
Figure 2 shows the structures of JA and some jasmonate The inventions by Flescher et al. [103, 104] provided methods
derivatives. There are two chiral centers in the jasmonate for novel jasmonate derivative preparations and pharmaceu-
molecule at the C3 and C7 positions and, thus, JA has four tical compositions. They reported that these compounds
stereoisomers [102]. Because of epimerization during extrac- could be useful for the prevention and treatment of breast,
tion and isolation, jasmonates are usually available as a prostate, skin, and blood cancers. Their invention provided a
mixture of two epimers. Figure 3 demonstrates the different method for the treatment of cancer by administering a
stereoisomers of JA [7]. therapeutically effective amount of the jasmonate derivatives
to the patient [103]. Another invention of Flescher and
Patents on JA Fingrut [105] is related to a pharmaceutical composition for
use in the treatment of a wide variety of malignancies in
There are several patents existing in the literature regarding mammals. They reported that the active ingredient, a
JA and its derivatives. Herein, we provide our evaluation of the therapeutically effective amount of a jasmonate compound,
recent patents related to JA. was nontoxic and targeted cancer cells, as opposed to healthy

O O

COOH COOCH 3

Jasmonic Acid Methyl Jasmonate

O
O

NH
HO
Jasmone
O

Jasmonyl-Isoleucine

O
O Glu

COOH

Tuberonic Acid-O-Glucopyranoside
Figure 2. Structures of JA and some jasmonate derivatives.

ß 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.archpharm.com


Arch. Pharm. Chem. Life Sci. 2014, 347, 229–239 Jasmonic Acid and Its Derivatives 235

Figure 3. Stereoisomers of JA (reprinted from [7]).

peripheral cells. The jasmonate derivatives were thiazole cancer and cardiovascular disease in humans. Resveratrol and
derivatives represented by the structure of formula I, plant extracts containing resveratrol are also effective in the
compounds represented by the structure of formula HA, prevention and treatment of atherosclerosis, as anti-inflam-
amino acid–jasmonate conjugates, or peptide–jasmonate matory and antihyperoxidative agents. The invention by
conjugates represented by the structure of formula II, and Flescher et al. [108] referred to assays for determining the
oligomers represented by the structures of formulas IV, V, or antitumor effects of jasmonate derivatives. They reported that
VI. The invention by Herzberg et al. [106] had an inhibitory a series of six synthesized jasmonate derivatives with
effect on cancerous cells such as breast cancer cells. An molecular weights below 2000 Da could be used as antitumor
invention by Bru Martinez et al. [107] relates to the combined drugs.
use of MJ and cyclodextrins to promote resveratrol production
by cells capable of synthesizing this compound, and its Muscle disorders
extracellular accumulation. Resveratrol is present in wine Broady [109] introduced a formulation of jasmonate for
and could be involved in the health effects of moderate wine improving skeletal muscle function in mammals, particularly
consumption. An increase in the consumption of resveratrol in humans. This invention claims to reduce muscle fatigue
has been proposed as a way of reducing the incidence of and/or increase skeletal muscle performance. Another

ß 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.archpharm.com


236 A. Ghasemi Pirbalouti et al. Arch. Pharm. Chem. Life Sci. 2014, 347, 229–239

formulation was provided by Bababunmi [110] for the and their applications. The process of their invention yields at
treatment of the adverse affects of skeletal muscle degenera- least 5% of the “cis” isomer defined according to the structures
tive diseases prevalent in humans in developing countries. in Fig. 2. The process of this invention comprises the
The formulation typically included a first component cultivation under aerobic conditions of one or more specific
including at least one of the compounds jasmone, JA, or strains of Diplodia gossypina in a nutrient medium, followed
oxo-phytodienoic acid and a second component including at either by the isolation of JA or the esterification of JA to form
least one antioxidant and carnitine. The formulation was MJ and subsequent isolation of MJ. In another invention by
designed to replenish the energy levels in disease-affected Mookherjee et al. [118], two methods were described for
muscle cells, reinstate calcium homeostasis within the muscle augmenting or enhancing the aroma or taste of foodstuffs
cells, and reduce the activity of oxidizing free-radical reactions with additives. These methods disclosed (i) a mixture of
typically caused by muscle degenerative diseases. In another dihydro-nor-MeJA and nor-MeJA in order to augment or
invention by Broady [111], a formulation was disclosed that enhance the aroma or taste of tropical flavored foodstuffs
contained jasmonate for improving cardiac muscle function. including guava nectar and (ii) a mixture of dihydro-nor-MeJA
and MeJA in order to augment or enhance the aroma or taste
Skin disorders of pear- or peach-flavored foodstuffs. An invention by Johnson
The invention of Herzberg and Revah [112] disclosed methods et al. [119] disclosed ethyl DL-jasmonate and related com-
of treating benign hyperproliferative diseases of the epidermis pounds as useful materials in perfumery. The compounds
by administering a composition comprising at least one were synthesized by the alkylation of a 2-carbo (lower alkoxy)-
jasmonate ester derivative, preferably MJ. This invention 3-oxocyclopentaneacetic acid lower alkyl ester.
introduced jasmonate ester derivatives as potent compounds The invention by Hurst et al. [120] disclosed methods for
useful for the treatment of disorders such as hyperprolif- isolating and enhancing the levels of jasmonates from cacao
erative diseases and actinic keratoses, with reduced side plant sources. JA and 12-hydroxy jasmonate sulfate were
effects. Dalko [113] disclosed a skin care composition of detected in various cocoa products. They reported that
(dihydro-)jasmonic acid derivatives suitable for topical the levels of these compounds can be manipulated to increase
application to dry skin and/or a dry scalp of non-inflammatory the beneficial health effects of a food product made with the
origin, e.g., in menopausal women. The invention by cocoa products. The invention also describes methods to
Malik [114] disclosed compositions (such as JA compounds, prepare edible products containing cocoa jasmonates.
a gibberellic acid compound, or a zeatin compound) and
methods employing compounds that can stimulate the Agricultural applications
proliferation of fibroblasts or keratinocytes and/or the When a plant encounters abiotic stress (intense light,
production of collagen by fibroblasts. These compositions herbicides, ozone, heat, chilling, freezing, drought, salinity,
and methods were claimed to be useful for treating gum- flooding, and heavy-metal toxicity), the plant increases the
and skin-related conditions. The invention by Boulle and production of ROS, creating oxidative stress. ROS cause
Dalko [115] claimed the cosmetic use of at least one JA chemical damage to the cellular constituents of the plant. JA
derivative in a formula for human hair care, treating alopecia and similar compounds such as MJ and dihydro-MeJA are
of natural origin and in particular androgenic alopecia known to stimulate a process called induced systemic
and stimulating or inducing the growth of keratin fibers, resistance (ISR), which assists in producing stress and disease
especially human keratin fibers, and halting their loss or tolerance. However, JA and its derivatives are generally oils,
increasing their density. They reported that this composition which are immiscible in water, leading to formulation and
can also maintain the hair in good condition and/or can application problems. An invention by Marks [121] disclosed
combat natural hair loss, especially in the case of men. the formula of a water-soluble salt. The invention contributed
to the use of jasmonate or related compounds in combination
Bladder dysfunction with crop input products (e.g., herbicides, pesticides, bioac-
An invention by Broady [116] disclosed a formulation or tive or biological seed treatment components, semiochem-
composition comprising jasmonate for modulating bladder icals, etc.) to induce biodefense activity in plants [122]. The
contractility and/or treating bladder dysfunction, particularly application of methyl jasmonate to grapes may decrease the
an overactive bladder in mammals (particularly in humans). fruit detachment force and promote the development of dry
stem scars on the berries, both of which could improve the
Use in the cosmetic and food industries quality of machine-harvested raisin grapes [123]. This allows
The invention of Blocker and coworkers [117] disclosed a the grapes to be harvested without damage to the fruit or
bioprocess for the high-yield production of food flavor- plant associated with traditional mechanical harvesting, and
acceptable JA and MJ, a novel JA isomer produced thereby, thereby eliminates the need for expensive hand picking [123].

ß 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.archpharm.com


Arch. Pharm. Chem. Life Sci. 2014, 347, 229–239 Jasmonic Acid and Its Derivatives 237

A process using jasmonate was described for controlling pharmacological agents possessing new mechanisms of
sprouting in tubers and improving their processing qualities. action could soon become available. All these effects of JA
Tuber sprouting and/or melanization, which occurs during are indirect, due to the well-studied induction of the
processing such as cooking or frying, may be controlled by biosynthesis of secondary compounds like anthocyanins,
exposure of the tubers to an effective amount of a jasmonate. glucosinolates, terpenoids, or phenolics via transcription
The invention by Vargas Aispuro [124] claimed a method for factors such as the Myb, Myc, and ORCA families. JA and its
making it possible to control the color (color being a quality derivatives have emerged with medicinal, cosmetic, and
factor for the marketing) of table grapes using ethrel, MeJA, flavoring uses and diverse applications in agriculture systems.
and oligogalacturonides (OGAs). The synthesis and precise During the last 20 years, the vast majority of studies and
application of these components form a method permitting inventions have evidenced that JA, (þ)-7-iso-JA and MJ have
appropriate control of the coloration of this type of fruit, anticancer activity against various cancers (e.g., prostate,
together with the quantification of total anthocyanins. lymphoid, breast, blood, skin cancers, etc.). New formulations
Several inventions by diverse inventors provided seed and applications of existing JA derivatives have produced
treatment compositions as well as their use, methods for some recent inventions. In addition, JA and its derivatives can
treating seeds, and methods for protecting plants against be administered simultaneously with other chemotherapeu-
pests. They reported that seed treatment by JA or related tic agents or they can be administered sequentially. JA and its
members of the jasmonate family induced a resistance derivatives have also been evaluated as antiparasitic,
mechanism against one or more pests in a plant grown from antidepressant, anti-aggressive, and anti-inflammatory
the treated seed. The invention by Mark [125] provided agents. The corresponding patents focus on improving the
methods for reduced nicotine and nitrosamines in tobacco convenience and safety of administration and on expanding
used to manufacture consumer tobacco products, by applying the applications for the treatment of various conditions.
auxin, auxin analogs, and jasmonate antagonists during Formulations appropriate for pharmaceutical compositions
cultivation of the tobacco crop. An invention disclosed a containing jasmonate can be produced for oral, parenteral,
method of altering the alkaloid composition of a poppy plant, topical, inhalational, and suppository administration. The
including the step of applying an effective amount of jasmonate derivatives are used as skin care and hair care
MeJA [126]. The invention by Mcelroy [127] described a products (e.g., for treating hair, the scalp, dry and greasy skin).
method for improving the turf grass quality, e.g., for lawns, The compounds jasmone, MeJA, cis-jasmone and g-jasmolac-
golf courses, sports areas, and areas adjacent to roads, by tone, termed jasmonates, are considered the main odorous
applying JA. An invention by Feyereisen et al. [128] describes principles in the essential oil of jasmin flowers (jasmin oil)
methods for producing hybrid seeds using male-sterile used in perfumes. In addition, JA and its derivatives are also
plants, wherein fertility is restored in the plants by used to flavor fruit beverages, confectionery like sweets and
treatment with JA. candy, food products like cocoa, tooth cleansing products like
toothpaste, tobacco products, and pharmaceutical products.
Conclusion It is envisioned that JA and its derivatives continue to be
used in the biomedicine, cosmetic, food industries, and in
The recent years have been highly dynamic and productive for agriculture, with new biomedical applications emerging with
the field of JA research, with important discoveries emerging a better understanding of their mechanisms of action and
constantly. A number of novel JA derivatives have been their molecular interactions with biological targets.
synthesized, isolated, and characterized. A clearer picture of
jasmonate biosynthesis and functions has emerged that in The authors have declared no conflict of interest.
many respects resembles the synthesis and functions of
prostaglandins and leukotrienes in mammalians. Jasmonates
are produced from a-linolenic acid from lipids of damaged References
plant membranes. The biosynthesis of these signaling
[1] E. Demole, E. Lederer, D. Mercier, Helv. Chim. Acta 1962, 45,
compounds can be triggered through the activation of cell
675–685.
membrane receptors by pathogens, peptide signals, or
[2] L. Crabalona, CR Acad. Sci. (Paris) Ser. C. 1967, 264, 2074–2076.
wounding. These jasmonates are widely distributed in plants
[3] D. C. Aldridge, S. Galt, D. Giles, W. B. Turner, J. Chem. Soc. C.
and affect a variety of processes, including fruit ripening, 1971, 1623–1627.
production of viable pollen, root growth, and plant responses [4] A. Meyer, O. Miersch, C. Büttner, W. Dathe, G. Sembdner,
to wounding, abiotic stress, infections, and insects. Many of J. Plant Growth Regul. 1984, 3, 1–8.
these new compounds have already been shown to have [5] J. Memelink, R. Verpoorte, J. W. Kijne, Trends Plant Sci. 2001,
potent biological activity, promising that novel types of 6, 212–219.

ß 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.archpharm.com


238 A. Ghasemi Pirbalouti et al. Arch. Pharm. Chem. Life Sci. 2014, 347, 229–239

[6] N. C. Avanci, D. D. Luche, G. H. Goldman, M. H. S. Goldman, [39] S. M. Verbitski, J. E. Mullally, F. Fitzpatrick, C. M. Ireland,
Genet. Mol. Res. 2010, 9, 484–505. J. Med. Chem. 2004, 47, 2062–2070.
[7] M. J. Mueller, Physiol. Plant. 1997, 100, 653–663. [40] H. J. Lee, K. Maeng, H. T. Dang, C. Ryou, J. H. Jung, H. K. Kang,
[8] E. Flescher, Cancer Lett. 2007, 245, 1–10. J. Mol. Med. 2011, 88, 83–90.
[9] G. A. Howe, G. Jander, Annu. Rev. Plant Biol. 2008, 59, 41–66. [41] A. P. Starling, G. Hughes, J. M. East, A. G. Lee, Biochemistry
1994, 33, 3023–3031.
[10] A. J. K. Koo, G. A. Howe, Phytochemistry 2009, 70, 1571–1580.
[42] W. H. Joumaa, A. Bouhlel, W. Meme, C. Léoty, J. Pharm. Exp.
[11] C. J. Yue, Y. Jiang, Process Biochem. 2009, 44, 923–927.
Ther. 2002, 300, 638–646.
[12] T. C. Baker, R. Nishida, W. L. Roelofs, Science 1991, 214, 1359–
[43] D. Gold, I. Pankova-Kholmyansky, O. Fingrut, E. Flescher,
1361.
J. Parasitol. 2003, 89, 1242–1244.
[13] R. L. Petty, M. Boppré, D. Schneider, J. Meinwald, Experientia
[44] R. Vilela, R. F. S. Menna-Barreto, M. Benchimol, Parasitol. Int.
1977, 33, 1324–1326.
2010, 59, 387–393.
[14] B. A. Vick, D. C. Zimmerman, Plant Physiol. 1984, 75, 458–461.
[45] K. Ofer, D. Gold, E. Flescher, Int. J. Parasitol. 2008, 38, 959–
[15] R. Rotem, A. Heyfets, O. Fingrut, D. Blickstein, M. Shaklai, 968.
E. Flescher, Cancer Res. 2005, 65, 1984–1993.
[46] C. Hernandes, J. S. Coppede, S. I. V. Pereira, S. C. França,
[16] O. Fingrut, E. Flescher, Leukemia 2002, 16, 608–616. A. L. Fachin, M. V. Lourenço, Medicina (Ribeirão Preto) 2009, 42,
[17] S. Cohen, E. Flescher, Phytochemistry 2009, 70, 1600–1609. 217–270.
[18] E. Flescher, Anticancer Drugs 2005, 16, 911–916. [47] S. L. Greene, Y. Huang, L. Huang, I. F. Weart, S. P. Yang,
[19] S. Umukoro, S. O. Abimbola, J. Nat. Med. 2011, 6, 466–470. S. Malik, et al., Patent: Antimicrobial compositions comprising
[20] J. Scognamiglio, L. Jones, C. S. Letizia, A. M. Api, Food Chem. a jasmonic acid compound as active agent. EP1845964,
Toxicol. 2012, 50, 562–571. 2011.
[21] A. Heyfets, E. Flescher, Cancer Lett. 2007, 250, 300–310. [48] E. Szabo, A. Thelen, M. Petersen, Plant Cell Rep. 1999, 18, 485–
489.
[22] G. Jiang, J. Zhao, X. Xiao, D. Tao, C. Gu, Q. Tong, Cancer Lett.
2011, 302, 37–46. [49] M. Ilieva, A. Pavlov, Appl. Microbiol. Biotechnol. 1997, 47, 683–
688.
[23] E. Milrot, A. Jackman, E. Flescher, P. Gonen, I. Kelson, Y.
Keisari, L. Sherman, Invest. New Drugs 2013, 33, 333–344. [50] J. Krzyzanowska, A. Czubacka, L. Pecio, M. Przybys,
T. Doroszewska, A. Stochmal, W. Oleszek, Plant Cell Tissue
[24] C. Park, C. Y. Jin, H. J. Hwang, F. Flescher, Toxicol. In Vitro
Organ Culture 2012, 108, 73–81.
2012, 26, 86–93.
[51] H. J. Kim, F. Chen, X. Wang, N. C. Rajapakse, J. Agric. Food
[25] B. Palmieri, T. Iannitti, S. Capone, E. Flescher, Eur. Rev. Med.
Chem. 2006, 54, 2327–2332.
Pharmacol. Sci. 2011, 15, 333–336.
[52] K. W. Yu, W. Gao, E. J. Han, K. Y. Paek, Biochem. Eng. 2002, 11,
[26] A. Russo, C. L. Espinoza, S. Caggia, J. A. Garbarino, H. Peña-
211–215.
Cortés, T. M. Carvajal, et al., Cancer Lett. 2012, 326, 199–205.
[53] K. Miyanaga, M. Seki, S. Furusaki, Biotechnol. Bioeng. 2000, 67,
[27] M. Carvajal, L. Espinoza, S. Caggia, V. Cardile, J. A. Garbarino,
493–497.
H. Peña-Cortés, et al., Electron. J. Biotechnol. 2011, 14, 15.
[54] J. C. Linden, M. Phisalaphong, Plant Sci. 2000, 158, 41–51.
[28] C. Park, C. Y. Jin, C. Y. Kim, J. Cheong, J. H. Jung, Y. H. Yoo,
et al., Toxicol. In Vitro 2010, 24, 1920–1926. [55] M. Keinänen, N. J. Oldham, I. T. Baldwin, J. Agric. Food Chem.
2001, 49, 3553–3558.
[29] R. Rotem, O. Fingrut, J. Moskovitz, D. Blickstein, M. Shaklai,
E. Flescher, Leukemia 2003, 17, 2230–2234. [56] G. Singh, J. Gavrieli, J. S. Oakey, W. R. Curtis, Plant Cell Rep.
1998, 17, 391–395.
[30] O. Fingrut, D. Reischer, R. Rotem, E. Flescher, Br. J. Pharmacol.
2009, 146, 800–808. [57] R. Pezet, C. Perret, J. B. Jean-Denis, R. Tabacchi, K. Gindro,
O. Viret, J. Agric. Food Chem. 2003, 51, 5488–5492.
[31] J. H. Kim, S. Y. Lee, S. Y. Oh, S. I. Han, H. G. Park, M. A. Yoo,
et al., Oncol. Rep. 2004, 12, 1233–1238. [58] B. Thiem, A. Krawczyk, Herba Pol. 2010, 56, 48–56.
[32] D. Ezekwudo, R. Shashidharamurthy, D. Devineni, E. Bozeman, [59] T. S. Walker, H. P. Bais, J. M. Vivanco, Phytochemistry 2002, 60,
R. Palaniappan, P. Selvaraj, Cancer Lett. 2008, 270, 277–285. 289–293.
[33] N. Goldin, L. Arzoine, A. Heyfets, A. Israelson, Z. Zaslavsky, [60] H. Chen, A. D. Jones, G. A. Howe, FEBS Lett. 2006, 580, 2540–
T. Bravman, Oncogene 2008, 27, 4636–4643. 2546.
[34] S. Umukoro, A. O. Akinyinka, A. C. Aladeokin, Pharmacol. [61] B. Hamedi, A. Ghasemi Pirbalouti, P. Moradi, Planta Med.
Biochem. Behav. 2011, 98, 8–11. 2012, 78, PF17.
[35] S. Umukoro, A. T. Eduviere, A. C. Aladeokin, Pharmacol. [62] M. Ashrafi, A. Ghasemi Pirbalouti, M. Rahimmalek, B. Hamedi,
Biochem. Behav. 2012, 101, 271–277. J. Herbal Drugs 2012, 2, 75–80.
[36] D. Reischer, A. Heyfets, S. Shimony, J. Nordenberg, [63] A. Ghasemi Pirbalouti, A. Mosavi Haris, F. Tirgir, B. Hamedi,
Y. Kashman, E. Flescher, Br. J. Pharmacol. 2007, 150, 738–749. J. Herbal Drugs 2012, 3, 175–186.
[37] H. T. Dang, H. J. Lee, E. S. Yoo, B. Bao, J. S. Choi, J. H. Jung, [64] M. Rahimmalek, S. Azad, M. Yadegari, A. Ghasemi Pirba-
Bioorg. Med. Chem. 2008, 16, 10228–10235. louti, J. Herbal Drugs 2012, 2, 89–94.
[38] H. T. Dang, Y. M. Lee, G. J. Kang, J. Hong, S. M. Lee, S. K. Lee, [65] J. F. Ayala-Zavala, S. Y. Wang, C. Y. Wang, G. A. González-
et al., Bioorg. Med. Chem. 2012, 20, 4109–4116. Aguilar, Eur. Food Res. Technol. 2005, 6, 731–738.

ß 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.archpharm.com


Arch. Pharm. Chem. Life Sci. 2014, 347, 229–239 Jasmonic Acid and Its Derivatives 239

[66] H. J. Kim, J. Fonseca, J. H. Choi, C. Kubota, J. Agric. Food Chem. [93] A. Kessler, I. T. Baldwin, Annu. Rev. Plant Biol. 2002, 53, 299–
2007, 55, 10366–10372. 328.
[67] B. Sun, H. Yan, F. Zhang, Q. Wang, Food Res. Int. 2012, 48, [94] X. Fan, J. P. Mattheis, J. K. Fellman, M. E. Patterson, J. Agric.
359–366. Food Chem. 1997, 45, 208–211.
[68] S. Y. Wang, L. Bowman, M. Ding, Food Chem. 2008, 107, 1261– [95] J. Ueda, J. Kato, Plant Physiol. 1980, 66, 246–249.
1269. [96] Y. Koda, Int. Rev. Cytol. 1992, 135, 155–199.
[69] S. F. Cao, Y. H. Zheng, K. T. Wang, H. Rui, Food Chem. 2009, [97] B. Parthier, J. Plant Growth Regul. 1990, 9, 57–63.
115, 1458–1463.
[98] L. Kienow, K. Schneider, M. Bartsch, H. P. Stuible, H. Weng,
[70] M. C. Parra-Lobato, N. Fernández-Garcia, E. Olmos, M. C. O. Miersch, et al., J. Exp. Bot. 2008, 59, 403–419.
Alvarez-Tinaut, M. C. Gómez-Jiménez, Environ. Exp. Bot. 2009,
[99] E. Steinegger, R. Hansel, Pharmakognosie und Phytopharmazie,
66, 9–17.
Vol. 341, Springer-Verlag, Berlin 1988.
[71] M. B. Ali, K. W. Yu, E. J. Hahn, K. Y. Paek, Plant Cell Rep. 2006,
[100] J. J. Cheong, Y. D. Choi, Trend Genet. 2003, 19, 409–413.
25, 613–620.
[101] G. Sembdner, B. Parthier, Annu. Rev. Plant Physiol. Plant Mol.
[72] Y. J. Lee, K. J. Kim, K. J. Park, B. R. Yoon, J. H. Lim, O. H. Lee,
Biol. 1993, 44, 569–589.
Int. J. Mol. Sci. 2013, 14, 1428–1442.
[102] R. A. Creelman, J. E. Mullet, Annu. Rev. Plant. Physiol. Plant Mol.
[73] R. Campos-Vargas, M. E. Saltveit, Physiol. Plant. 2002, 114,
Biol. 1997, 48, 355–381.
73–84.
[103] F. Flescher, Y. Kashman, D. Reischer, S. Shimony, US7683211
[74] B. Heredia, L. Cisneros-Zevallos, Food Chem. 2009, 115, 1500–
B2, 2010.
1508.
[104] F. Flescher, M. Herzberg, Y. Kashman, EP2402321, 2012.
[75] B. A. Wolucka, A. Goossens, D. Inze, J. Exp. Bot. 2005, 56,
2527–2538. [105] E. Flescher, O. Fingrut, EP1379229, 2007.
[76] M. J. Mueller, Physiol. Plant. 1997, 100, 653–653. [106] M. Herzberg, A. Harel, C. Mang, US8247439, 2006.
[77] J. Leon, J. J. Sanchez-Serrano, Plant Physiol. Biochem. 1999, 37, [107] R. Bru Martinez, G. M. A. Pedreño, S. Belchi Navarro,
373–380. L. Almagro Romero, EP2256209, 2010.
[78] C. Wasternack, Ann. Bot. (London) 2007, 100, 669–681. [108] E. Flescher, N. Goldin, M. Herzberg, EP2121967 A2, 2009.
[79] L. Pauwels, D. Inzé, A. Goossens, Trends Plant Sci. 2009, 14, [109] B. Broady, US0288485, 2012.
87–91. [110] E. A. Bababunmi, US6887499, 2005.
[80] Y. Sasaki-Sekimoto, N. Taki, T. Obayashi, M. Aono, [111] B. Broady, US 2012/0172450, 2012.
F. Matsumoto, N. Sakurai, et al., Plant J. 2005, 44, 653–668. [112] M. Herzberg, F. Revah, US0083529, 2012.
[81] M. Dicke, Entomol. Exp. Appl. 1999, 91, 131–142. [113] M. Dalko, EP1442737, 2006.
[82] A. Kessler, I. T. Baldwin, Science 2001, 291, 2141–2144. [114] S. Malik, US7098189, 2006.
[83] R. Mumm, K. Schrank, R. Wegener, S. Schulz, M. J. Hilker, [115] C. Boulle, M. Dalko, EP2448549, 2012.
Chem. Ecol. 2003, 29, 1235–1252. [116] B. Broady, US0149655, 2012.
[84] T. R. Green, C. A. Ryan, Science 1972, 175, 776–777. [117] M. I. Farbood, R. W. Blocker, L. B. McLean, M. P. Mclean,
[85] E. E. Farmer, C. A. Ryan, Plant Cell 1992, 4, 129–134. A. Y. Kim, M. A. Sprecker, et al., US6458569, 2002.
[86] L. Andresen, W. Becker, K. Schluter, J. Burges, B. Parthier, [118] B. D. Mookherjee, R. A. Wilson, F. L. Schmitt, M. H. Vock,
K. Apel, Plant Mol. Biol. 1992, 19, 193–204. US4294863, 1981.
[87] Y. Xu, P. F. L. Chang, D. Liu, M. L. Narasimhan, K. G. [119] F. Johnson, K. G. Paul, D. Favara, US 4014919, 1977.
Raghothama, P. M. Hasegawa, et al., Plant Cell 1994, 6, 1077– [120] W. J. Hurst, D. A. Stuart, A. I. C. Justavino, R. B. Van Breemen,
1085. US2011/0257263, 2011.
[88] B. Chaudhry, F. Muller-Uri, V. Cameron-Mills, S. Gough, [121] D. Marks, EP1740045, 2012.
D. Simpson, K. Skriver, J. Mundy, Plant J. 1994, 6, 815–824.
[122] R. P. Cargeeg, K. Seevers, US0077674, 2012.
[89] R. A. Creelman, M. L. Tierney, J. E. Mullet, Proc. Natl. Acad. Sci.
[123] M. W. Fidelibus, J. K. Burns, US 0018021, 2009.
USA 1992, 89, 4938–4941.
[124] I. D. C. Vargas Aispuro, EP2351478, 2011.
[90] M. McConn, R. A. Creelman, E. Bell, J. E. Mullet, Proc. Natl.
Acad. Sci. USA 1997, 94, 5473–5477. [125] D. Marks, EP1934157, 2011.
[91] I. T. Baldwin, Proc. Natl. Acad. Sci. USA 1998, 95, 8113–8118. [126] P. Cotterill, US0075822, 2009.
[92] N. I. Bower, R. E. Casu, D. J. Maclean, A. Reverter, S. C. [127] S. Mcelroy, EP2352372, 2011.
Chapman, J. M. Manners, Plant Sci. 2005, 168, 761–772. [128] R. Feyereisen, J. H. Park, US0101457, 2007.

ß 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.archpharm.com