Aurones: interesting natural and synthetic compounds with emerging biological potential.
ABSTRACT Aurones [2-benzylidenebenzofuran-3(2H)-ones] are either natural or synthetic compounds, belonging to the flavonoid family. They are isomeric to flavones and provide a bright yellow color to the plants in which they occur. Today, a literature survey indicates that the related flavonoids have been studied not only for their physiological properties and effects on Nature, but also for their therapeutic potential. Aurones are recently attracting the interest of an increasing number of research groups, and, since the last review, some interesting advances have been made in understanding the aurones. In this review, we report the recent advances made on the synthetic routes towards aurones. We also highlight their activity in different biological areas, as well as applied genetic plant modifications to produce these colored compounds. Their synthesis, structure-activity relationships and the importance of the substitution pattern will also be mentioned. Finally, some aspects regarding the possible development of aurones will be discussed briefly.
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ABSTRACT: The health-promoting property of diets rich in fruits and vegetables is based, in part, on the additive and synergistic effects of multiple antioxidants. In an attempt to further enhance food quality, we introduced into crops the capability to synthesize a yellow antioxidant, aureusidin, that is normally produced only by some ornamental plants. For this purpose, the snapdragon (Antirrhinum majus) chalcone 4'-O-glucosyltransferase (Am4'CGT) and aureusidin synthase (AmAs1) genes, which catalyse the synthesis of aureusidin from chalcone, were expressed in tobacco (Nicotiana tabacum) and lettuce (Lactuca sativa) plants that displayed a functionally active chalcone/flavanone biosynthetic pathway. Leaves of the resulting transgenic plants developed a yellow hue and displayed higher superoxide dismutase (SOD) inhibiting and oxygen radical absorbance capacity (ORAC) activities than control leaves. Our results suggest that the nutritional qualities of leafy vegetables can be enhanced through the introduction of aurone biosynthetic pathways.Plant Biotechnology Journal 08/2012; · 6.28 Impact Factor
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ABSTRACT: Tyrosinase is a copper-containing enzyme found in plants and bacteria, as well as in humans, where it is involved in the biosynthesis of melanin-type pigments. Tyrosinase inhibitors have attracted remarkable research interest as whitening agents in cosmetology, antibrowning agents in food chemistry, and as therapeutics. In this context, commercially available tyrosinase from mushroom (TyM) is frequently used for the identification of inhibitors. This and bacterial tyrosinase (TyB) have been the subjects of intense biochemical and structural studies, including X-ray diffraction analysis, and this has led to the identification of structural homology and divergence among enzymes from different sources. To better understand the behavior of potential inhibitors of TyM and TyB, we selected the aurone family—previously identified as potential inhibitors of melanin biosynthesis in human melanocytes. In this study, a series of 24 aurones with different hydroxylation patterns at the A- and B-rings were evaluated on TyM and TyB. The results show that, depending on the hydroxylation pattern of A- and B-rings, aurones can behave as inhibitors, substrates, and activators of both enzymes. Computational analysis was performed to identify residues surrounding the aurones in the active sites of both enzymes and to rationalize the interactions. Our results highlight similarities and divergence in the behavior of TyM and TyB toward the same set of molecules.ChemBioChem 05/2014; · 3.06 Impact Factor
Aurones: Interesting Natural and Synthetic Compounds with
Emerging Biological Potential
Clemens Zwergela, François Gaaschta,b, Sergio Valentea, Marc Diederichb, Denyse Bagrela and
aLaboratoire d’Ingenierie Moléculaire et Biochimie Pharmacologique, Institut Jean Barriol,
Université Paul Verlaine-Metz, 1 Boulevard Arago, 57070 Metz, France
bLaboratoire de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg, 9 rue Edward Steichen,
L-2540 Luxembourg, Luxembourg
Received: August 18th, 2011; Accepted: December 16th, 2011
Aurones [2-benzylidenebenzofuran-3(2H)-ones] are either natural or synthetic compounds, belonging to the flavonoid family. They are isomeric to flavones
and provide a bright yellow color to the plants in which they occur. Today, a literature survey indicates that the related flavonoids have been studied not only
for their physiological properties and effects on Nature, but also for their therapeutic potential. Aurones are recently attracting the interest of an increasing
number of research groups, and, since the last review, some interesting advances have been made in understanding the aurones.
In this review, we report the recent advances made on the synthetic routes towards aurones. We also highlight their activity in different biological areas, as well
as applied genetic plant modifications to produce these colored compounds. Their synthesis, structure–activity relationships and the importance of the
substitution pattern will also be mentioned. Finally, some aspects regarding the possible development of aurones will be discussed briefly.
Keywords: Aurones, 2-Benzylidenebenzofuran-3(2H)-ones, Biological activity, Synthesis.
Flavonoids represent a large class of natural products in the plant
kingdom, exhibiting multiple biological activities . Aurones play
an important role in the pigmentation of some flowers and fruits and
contribute especially to the bright yellow color of flowers . They
also exhibit a strong and broad variety of biological activities. For
example they have been described as antifungal agents , as insect
antifeedant agents , as inhibitors of tyrosinase , and as
antioxidants . Not widely distributed in nature, aurones, (Z)-2-
benzylidene-benzofuran-3(2H)-ones, are one of the less common
and lesser-known representatives of a flavonoid subclass . This is
probably the reason why they have received little attention in
comparison to the structurally similar and widely investigated
flavones and isoflavones .
There are, however, a few notable exceptions. Aureusidin, a
common aurone (1), is an inhibitor of iodothyronine- deiodinase, an
enzyme involved in hormone synthesis and regulation . Synthetic
aurones bind to the nucleotide-binding domain of P-glycoprotein
, to inhibit cyclin-dependent kinases in connection with
antiproliferative properties , and to act as anticancer agents
Synthesis of aurone derivatives: A very popular way to prepare
aurones was developed by Varma et al. His method is based
on the aldol–like condensation of benzofuran-3(2H)-ones with
benzaldehydes . This, and some other more or less classical
methods for the synthesis, were reviewed by Boumendjel et al. in
2003 . Since then, several new or refined methods have been
Lawrence et al. studied the naturally occurring aurone 1, isolated
from Uvaria hamiltonii, and prepared a series of analogues
based structurally on known tubulin binding agents, which were
Figure 1: Aureusidin, an example of a common aurone.
subsequently evaluated for anticancer activity . The authors
employed well-known methods to afford their aurone derivatives.
The synthetic avenue described by Lawrence et al., for example,
consisted of the preparation of benzofuranone (4) (Scheme 1) via a
polyphosphoric acid (PPA) cyclisation of the phenoxyacetic acid 3,
which was in turn prepared by the condensation of phenol 2 with
The synthesis of aurone 1 required the use of the TBDMS-protected
benzaldehyde 5, prepared in
dihydroxybenzaldehyde using tert-butyldimethylsilyl chloride in the
presence of imidazole .
high yield from 3,4-
Scheme 1: Reagents and conditions (i) ClCH2CO2H, NaH, DMF, rt, overnight;
(ii) PPA, 80ºC, 8h .
To obtain the aurone, the protected benzaldehyde is condensed with
the appropriate benzofuranone 4 in the presence of neutral alumina.
This method was originally described by Varma et al. .
Subsequent treatment with tetra-butylammonium fluoride afforded
the deprotected aurone 1 (Scheme 2).
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389 - 394
390 Natural Product Communications Vol. 7 (3) 2012 Zwergel et al.
Scheme 2: (i) Al2O3, DCM, rt, overnight, (ii) to remove TBDMS TBAF, DCM,
rt, 30 min.
As for all the natural derivatives isolated by Atta ur Rahman and
Choudhary et al. , an example of which is aurone 1, the
synthetic approach yielded the geometric (Z)-isomer, this being
generally more stable thermodynamically than the (E)-isomer.
As part of an alternative synthetic approach, Kraus et al., employed
a Steglich esterification followed by a Suzuki coupling . They
started with the esterification of commercially available phenol 2
with 3,3-dibromoacrylic acid 6. A Fries rearrangement led from the
ester 7 to ketone 8. After cyclisation of 8, the authors initially
expected a bromoketone, originally assigned as 9. However, Suzuki
coupling with phenylboronic acid 11 provided a different
compound. After considering alternative structures through NMR
studies, they revised 9 to 10. This implies that the Suzuki coupling
led to aurone 12 (Scheme 3).
The Suzuki reaction is more commonly conducted with aryl
bromides or iodides than with chlorides . Interestingly, when
the authors exchanged 3,3-dibromoacrylic
dichloroacrylic acid the reaction led to flavones 9 and not to
aurones. The rationale for the remarkable divergence still remains
As a further alternative synthetic pathway, Harkat et al. described a
three-step procedure to form aurone derivatives using a gold(I)-
catalyzed cyclisation of 2-(1-hydroxyprop-2-ynyl)phenols. The
classical aldol-like coupling reaction sometimes results in low
yields and requires the synthesis of benzofuran-3(2H)-ones from
substituted 2-phenoxyacetic acids by an intramolecular Friedel –
Craft reaction. Such a reaction is usually carried out under harsh
conditions and yields are modest .
acid to 3,3-
Scheme 3: Synthetic route towards aurones via Steglich esterification followed
by Suzuki coupling .
Scheme 4: Three-step procedure to form aurone derivatives using a gold (I)-
catalyst R= H- , Br- , MeO-, NO2- and R’ Cl-, MeO- .
Table 1: Reaction conditions for catalytic condensation of aurones.
In contrast, the group prepared various 2-(1-hydroxy-3-arylprop-2-
ynyl) phenols (13) by addition of 2 equivalents of lithium
arylacetylides, with or without substituents, at low temperature in
THF to yield several substituted salicylaldehydes (Scheme 4). The
propynol obtained was then subjected to cyclisation (Table 1).
Only the combination of gold(I)chloride and potassium carbonate
enabled the cyclisation to the arylidene alcohol 14. Oxidation with
MnO2 afforded the corresponding aurones (15). Using this method,
the synthesis of different natural aurones was achieved, including
the 4’chloroaurone from Spatoglossum variabile, which has been
isolated previously by Atta ur Rahman and Choudhary .
Agrawal et al. described a similar cyclisation using pyridine-Hg
(OAc)2, as well as CuBr2, in dimethylsulfoxide (Scheme 5). As part
of this procedure, to a molar amount of Hg(OAc)2 in cold pyridine
the 2'-hydroxychalcone 16 was added and the solution refluxed for
10-15 min. Then the reaction was cooled, treated with diluted HCl,
and then diluted with ice-cold water. Recrystallization led to the
pure Z-isomer of 17. As part of a second method, the authors used a
few milligram of CuBr2 in DMSO and 2-hydroxychalcones. After
refluxing this mixture for about 60 to 90 min, the reaction was
cooled and quenched with water. Filtration and recrystallization in
EtOH yielded the desired aurones (17) .
Scheme 5: Cyclisation by mercury (II) acetate in pyridine and cupric bromide in
dimethylsulfoxide R= H-, Br-; R1= H-, CH3-; R2= H-, OCH3-, Cl- .
Thanigaimalai and Yang described a synthetic route to aurones via
oxidation of 2-hydroxy-6-cyclohexylmethoxychalcones
thallium (III) nitrate (Scheme 6) . In continuation of their
previous work [21,22] they treated different chalcones (18) with
thallium (III) nitrate in methanol, first at room temperature for 24 h,
and then heated to 65°C, followed by addition of hydrochloric acid
in a one pot oxidative cyclisation to achieve the corresponding
isoflavones (not shown) and/or aurones (19) depending on the
electronic nature of substituents on ring B of the chalcones. The
strong electron donating groups in the para-position of ring B led to
isoflavones, the weak electron donating group to a mixture of both
aurones and isoflavones, and the electron withdrawing groups
ended with aurones (19). Again NMR studies of the aurone
Aurones with emerging biological potential Natural Product Communications Vol. 7 (3) 2012 391
Scheme 6: (i) Thallium (III) nitrate (TTN), methanol, overnight at rt; (ii)
hydrochloric acid, 50°C, 5 h. R= -H, -Cl, -CHO, -COOCH3, -NO2, -COOH .
derivatives revealed that their oxidative cyclisation method gave
only Z- isomers, as reported in the literature [23,24].
Aurones and their role in coloring flowers: There are many
beautiful flowers in nature and they show a variety of shapes and
colors. Such diversity is acquired through evolutionary processes to
ensure successful reproduction by attracting pollinators or by
promotion of wind pollination . The color is especially
important to attract pollinators, such as insects and birds. For plant
breeders, the color of flowers is one of their most important targets.
Such breeders have come up with many different-colored hybrids
and cultivars using natural mutants or genetically related species.
Recent advances in genetic modification techniques enable the
production of desirable and novel flower colors . Many
researchers exploit the knowledge of flavonoid biosynthesis
effectively to obtain unique flower colors. Transgenic blue-violet
flowers, for instance, are already on the market today and transgenic
blue roses have been reported .
For creating transgenic plants with yellow colors, aurones are often
used as pigments of choice. Ono and Fukuchi-Mizutani revealed
that regulation of aurone biosynthesis led to production of yellow
flowers in a Torenia hybrid .
Scheme 7: Biosynthetic route towards aurones.
Interestingly, the biosynthetic avenue leading to aurones differs
somewhat from the chemical synthetic pathways discussed earlier.
In transgenic flowers, the coexpression of Antirrhinum majus
chalcone 4’-O-glucosyltransferase (Am4’CGT) in the cytoplasm and
A. majus aureusidin synthase (AmAS1) in the vacuole combined
with down-regulation of anthocyanin biosynthesis by RNA
interference (RNAi) resulted in yellow flowers. These two enzymes
will produce aureusidin 6-O-glucoside (21) via a 2’,4’,6’,4-
tetrahydroxychalcone 4’-O-glucoside 20. The authors suggested
that the chalcones (19) are 4’-O-glucosylated in the cytoplasm, their
4’-O-glucosides transported to the vacuole, and therein
enzymatically converted to aurone 6-O-glucosides (Scheme 7).
Since chalcones are common throughout the plant kingdom, the
strategy to generate yellow flowers by production of aureusidin 6-
O-glucoside is widely applicable to most plant species producing
chalcones. Moreover, this genetic “trick” opens the door to
molecular breeding strategies which generate monotonous yellow
flowers that dominantly produce aurone 6-O-glucoside .
Aurones as fluorescent probes with potential applications:
Organic molecules that fluoresce in the visible region of the
electromagnetic spectrum might be useful as probes in biological
systems . Such probes should cause minimal perturbation of the
biological macromolecule, possess background fluorescence and be
easy to use. There are three general types of fluorophores of interest
here: xanthenes (fluorescein, rhodamine), boron dipyrromethenes
and cyanines. Some of them already absorb and fluoresce in the
visible region, but most of these molecules are relatively bulky with
small Stokes’ shifts [1, 2]. Shanker and Dilek recently published
aurone derivatives as potential fluorescent probes for biomolecules
that can be observed with visible light . Even the largest
molecule they prepared for this study is smaller than the xanthene
dyes. The UV–Vis absorption characteristics of naturally occurring
aurones have been well documented [14, 15]. An amine substituent
at the 4-position of aurone 22 leads to the largest red shift in the
absorption maximum compared with that of the parent molecule.
Acetylation of the amine (aurone 23) shifts the absorption and
emission maxima to shorter wavelengths, while restricting the
rotation of the amine nitrogen in 24 shifts the absorption and
emission maxima to longer wavelengths.
Figure 2: Aurones which may serve as potential fluorescent probes .
On one hand, xanthenes have high quantum yields in polar
environments, while on the other hand the aminoaurones
investigated so far need to have a hydrophobic environment to be
useful fluorescent probes. The molecules investigated can also be
observed using common microscopy excitation sources. The authors
further speculated that Z- and E-isomers can be interconverted
photochemically and, therefore, may have applications as
photoactivated switches. As a proof of concept, they showed that
the absorption and emission maxima of aurones may be varied to
suit a particular application through functional group selection .
Biological roles, targets and activities: Aurones and others sub-
classes of flavonoids, such as flavones and chalcones, have been
studied for their numerous biological activities. Aurones, however,
are only studied sparingly compared with the others sub-classes
[29,30]. Nevertheless, recent studies have revealed promising
biological properties of this group of natural molecules. In this
review we will describe the most relevant biological properties of
aurones discovered so far.
Aurones as antiparasitic agents: Recently, Souard et al.
synthesized and analyzed 35 aurones for their potential as
antimalarial drugs. All of these compounds were found to be
non- cytotoxic in human cell lines and among them, seven had
an IC50 below 5 ?M in the antiplasmodial assay. The most active
392 Natural Product Communications Vol. 7 (3) 2012 Zwergel et al.
Table 2: Overview of some most bioactive aurones reported so far.
Structure Effect/Target Structure
Anti-inflammatory  
(breast cancer) 
(Influenza virus) 
(anti-motility and angiogenesis)
R= -OH, -OAc
(Hepatitis C virus) 
Skin disease 
compound was tested in vivo on mice and was not toxic to the
mouse itself, but the antiplasmodial effect appeared to be less
efficient compared with the in vitro studies due to its low solubility.
The structure–activity relationship
dimethoxylation at positions C4 and C6, a halogen atom at position
4’, and the substitution of the intracyclic oxygen atom with an N-H
group increased the activity of the compounds. However, a long
chain had an adverse effect. Concerning the azaaurones, an ethyl
moiety at C4’ rather than C2’, substitution of the ethyl group by an
acetylenyl group, methoxylation at the 4’-position, and a
dimethylamino moiety improve the efficiency of the molecules (25)
Aurones as antimicrobial agents: Aurones also exert antibacterial
and antifungal properties. A recent article published in 2010
reported that a series of synthetic aurone analogues are efficient
antibacterial and antifungal molecules. All of these compounds
exhibited moderate to good antibacterial activity against E.coli, B.
subtilis, S. aureus, K. pneumoniae and P. vulgaris. Concerning their
antifungal activity, all of these compounds were able to inhibit
different fungal strains, including A. fumigatus, A. niger, T. virdie,
C. albicans and P. chrysogenum at a concentration of 25 ?g/mL and
with different efficiency (26) .
Aurones as anti-viral agents: A series of different flavonoids has
been analyzed for neuraminidase inhibition potency, a glycoprotein
involved in the infection process of the influenza virus. Among this
list of 25 flavonoids, most of the aurones tested were described as
good neuraminidase inhibitors. The structure–activity relationship
revealed that a glycosyl group at any position, and a hetero-function
at C3 or C4 decrease this effect, and an OH group at C6 or C4’, a
double bond between C-2 and the phenylidene, and a hetero-
function at C3 are essential for the activity (27) .
Several aurone derivatives synthesized by Haudecoeur and Ahmed-
Belkacem were analyzed to target the hepatitis C virus RNA-
dependent RNA polymerase. The authors identified the aurone
target site by site–directed mutagenesis as the thumb pocket I of the
polymerase. They identified seven aurone derivatives as potent
inhibitor molecules with an IC50 below 5 ?M. Interestingly, all of
these compounds are non-cytotoxic towards cultured human Huh7
and HEK293 cells. This data permitted the authors to identify
analysis revealed that
important substituents for biological acitivity: on the A ring, a
hydroxy group at position C4 or a dihydroxy substitution at
positions C4 and C6; on the B ring, hydroxy groups at positions
C2’, C4’ – or C3’, C4’ or a hydrophobic and a bulky substituent or
an alternative core (28) .
Aurones as anti-inflammatory agents: The aurone derivatives
synthesized by Bandgar and Patil, described as antibacterial and
antifungal molecules, also show anti-inflammatory properties. They
are able to inhibit the production of TNF-? (tumor necrosis factor-
alpha) and IL-6 (interleukin-6), two cytokines that are often
involved in diseases, such as autoimmune diseases, diabetes,
arthrosclerosis and cancer .
The anti-inflammatory potential of aurone derivatives was
confirmed by a second study. Several aurones were synthesized as
sulfuretin derivatives, a molecule already described as an anti-
inflammatory agent able to reduce the production of nitric oxide and
prostaglandin E2, two pro-inflammatory molecules. Results show
that these synthetic compounds are less cytotoxic and some of them
are more efficient than sulfuretin. Analysis of the structure–activity
relationships revealed that a hydroxyl-function at C6 is important to
decrease the synthesis of prostaglandin E2 and that methoxy groups
on the B ring are useful to reduce the production of nitric oxide (26,
Aurones as anti-cancer agents: A series of aurones have been
synthesized and analyzed for their ability to target ABCG2 (ATP –
binding cassette sub – family G member 2), an ABC protein
transporter responsible for the breast cancer multidrug resistance
mechanism. Results have shown that aurones are able to inhibit the
ABCG2 efflux transporter in a dose-dependent manner and have a
low cytotoxic effect against several cancer and healthy cell lines
In another study, Cheng and Zhang synthesized a series of
4’–substituted 5–hydroxyaurone derivatives. These compounds
have been tested for their cytotoxic effects on both cancer and non-
cancer cell lines. Results show that some aurones are cytotoxic
toward cancer cell lines, but exert weaker activities against non-
cancer cell lines. These compounds have also been tested in vitro
regarding their ability to inhibit cell motility and angiogenesis, two
Aurones with emerging biological potential Natural Product Communications Vol. 7 (3) 2012 393
processes implicated in cancer cell invasion and metastasis
development. The authors identified two synthetic compounds that
are able to beneficially modulate these two mechanisms involved in
cancer development (31) .
Aurones to treat skin diseases: Some aurones are able to inhibit
human tyrosinase, an enzyme which plays a role in the melanin
synthesis pathway. Melanin is the natural pigment of human skin
and has been implicated in several dermatological diseases.
Analysis of the structure–activity relationship indicates that
hydroxyl groups on the B ring are necessary for the activity and
hydroxyl groups at the 4,6 and 4’ positions strongly increase
efficiency (32) .
Alzheimer’s disease: A novel series of aurone derivatives has been
synthesized as radiolabelled probes to detect ?-amyloid plaques in
Alzheimer’s disease. In vitro results show that these compounds
have only one high affinity binding site for ?-amyloid peptides.
Biodistribution performed on mice revealed that these molecules
have a good brain uptake and a fast clearance from the brain, which
are two important properties for in vivo amyloid probes .
In conclusion, aurones seem to provide a promising scaffold for
medicinal chemistry. The possibility to access heterocyclic
analogues of benzofuranes, as well as an almost unlimited number
of arylaldehydes available, will provide ample opportunities to
produce libraries of aurones or related aza-, thio-, and seleno-
aurones for studies of their possible biological activities.
Acknowledgments - Our work has received funding from the
European Community's Seventh
(FP7/2007-2013) under grant agreement n° 215009 (RedCat).
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