Current Medicinal Chemistry, 2003, 10, 2621-2630 2621

Aurones: A Subclass of Flavones with Promising Biological Potential

Ahcène Boumendjel*

Département de Pharmacochimie Moléculaire, UMR-CNRS 5063, Faculté de Pharmacie de Grenoble 38706, La

Tronche - France
Abstract: Aurones [2-benzylidenebenzofuran-3(2H)-ones] are the secondary metabolites natural compounds
belong to the flavonoids family, and structurally are the isomers of flavones, widely present in fruits and
flowers where they play significant role in the pigmentation of the part of plant in which they occur. Literature
survey clearly indicates that flavones, chalcones, flavonols and isoflavones have been studied largely for their
therapeutical potential. Somehow, aurones still are less studied and it is only recently that these compounds
have begun to be investigated.
In this review, we report the recent advances made on the therapeutical potential of aurones in different
biological areas. Their synthesis, structure-activity relationships, the importance of the substitution pattern
will also be discussed. Finally, some aspects regarding the possible development of aurones will be
highlighted briefly.

Keywords: Aurones, 2-benzylidenebenzofuran-3(2H)-ones; Biological activities; Synthesis; SAR

I. INTRODUCTION II. AURONES

One of the representative classes of plant secondary Aurones, [2-benzylidenebenzofuran-3(2H)-ones], which

metabolites, the flavonoids, which consist of two main are structurally the isomeric of flavones, are met in
groups, flavones and isoflavones. Isoflavones are structurally vegetables, and especially in fruits and flowers where they
distinct from other flavonoid classes in that they contain a contribute to their coloration [1;20-23]. In a recent work,
C 15 skeleton arranged on 1,2-diphenylpropane. Flavones Atta-Ur-Rahman and co-workers have reported the occurrence
contain a C15 skeleton based on 1,3-diphenylpropane. They of aurones in marine organisms [24] as well.
are classified according to the C3 portion, and include the
yellow chalcones and aurones; the pale yellow, ivory 4' 4'
1 B 1 B
flavones, flavonols and their glycosides; the red, blue, and O 1'
O 1'
7
purple anthocyanins and anthocyanidins Fig. (1). A C 2 7
2
A C
The distribution of flavonoids in the plant kingdom has 3 3
4
already been reviewed by Harborne [1]. Up to now, over 5 5 4
O O
6500 flavonoids have been identified and new structures are
being reported. Unlike alkaloids or terpenoids, whose flavone flavanone
skeletons are rich and varied, flavonoids have only limited
4' 4
skeletal varieties Fig. (1) and the diversity is due to the 1 B A
1' 1
substitution pattern, such as hydroxylation, methoxylation, 7
O
4' 6'
prenylation or glycosylation. As integral constituents of the A C 2 β
B
diet, they exert a wide range of beneficial effects on human 1' α
OH
health, including protection against cardiovascular diseases 5 4 3 2'
and different forms of cancer [2-3]. They likely produce such O O
biological effects through their free radical-scavenging flavonol chalcone
antioxidant activities and metal ion-chelating abilities [4-6]. 1
They have been largely investigated for their anticancer O 4'
7 2
potential in several modes of action [7-11]: inhibition of B
A C 1
aromatase [12,13], topoisomerase [14], protein kinase C 1'
6 O
[15], several protein-tyrosine kinases [16] and cyclin- 4
3 2 1'
5 B A C
dependent kinase [17]. O 4' 3
In addition to their anticancer effect, antiviral activities of 4
O
flavones have also been reported [18,19] recently. isoflavone aurone

Fig. (1). Structures of flavonoids sub-classes.

*Address correspondence to this author at the Laboratoire de
Pharmacognosie, Département de Pharmacochimie Moléculaire, Faculté In addition to their pigmentation role, aurones have been
de Pharmacie de Grenoble, 38706 La Tronche, France; Tel: (33) 4 76 51 described as phytoalexins, used by the plant as defence
86 88; Fax: (33) 4 76 63 71 65; E-mail: Ahcene.Boumendjel@ujf- agents against various infections. For example, Mabry and
grenoble.fr

0929-8673/03 $41.00+.00 © 2003 Bentham Science Publishers Ltd.

2622 Current Medicinal Chemistry, 2003, Vol. 10, No. 23 Ahcène Boumendjel

HO OH

OH HO OH
HO O
OH
OH OH
HO O HO O
O OH
O
O
OH
O O
OH OH

aureusidin amaronol A
HO disulfuretin (biaurone)

Fig. (2). The structure of aureusidin, auronol (amaronol) and a biaurone (dislufuretin).

co-workers have reported that aurones can be biosynthesized methoxylated, glycosylated and to less extent as biaurones
in response to elicitor-treated cell suspension cultures of [30,31]. Hydrated aurones (auronols) were also reported in
Cephalocereus senilis. Elicitor-induced de novo synthesis of literature, Fig. (2) [30,31] and a method of the absolute
cephalocerone (6-hydroxy-4,5-methylenedioxyaurone) was configuration determination has been recently reported by
demonstrated by incubating elicited cactus cultures with Bekker and co-workers [32].
[ 3 H]phenylalanine, which resulted in the labelling of
cephalocerone together with other phenolic compounds [25-
II.1. Biosynthesis of Aurones
27].
Compared to the naturally abundance of flavones, Nishino and co-workers have made a significant
aurones have a limited occurrence and have been less contribution to elucidate the pathway for biosynthesis of
investigated. The best known aurone and the frequently cited aurones [33,34] and have studied the close relation between
is aureusidin, which has been isolated from several species chalcones and aurones biosynthesis. It was established that
of Cyperus [28] where it occurs as the 6-glucoside (aureusin) an enzyme named aureusidin synthase is responsible for the
or 4-glucoside (cernuoside) [29]. Like all subclasses of transformation of a variety of chalcones to aurones. After
flavonoids, aurones are mostly found as hydroxylated, screening of a panel of hydroxylated and glucosylated

3
OH
4
HO 4' 2' OH

6' hydroxylation*
OH O then oxydation at C-3 and C-4
O
OH O
3
OH
4 HO OH
HO 4' 2' OH

6'
OH O
OH O oxydation at C-3 and C-4

HO O HO OH

HO O HO O
cyclization rearrangement

O O
OH OH

aureusidin

Scheme 1. Aurone biosynthesis from chalcones, catalyzed by aureusidin synthase. *The oxidation at C-3 can be accomplished
through two mechanisms. Hydroxylation then oxidation or oxidation without implying the hydroxylation step.
Aurones: A Subclass of Flavones with Promising Biological Potential Current Medicinal Chemistry, 2003, Vol. 10, No. 23 2623

OH OH O
R ZnCl2 base
NC X R R
X
x= Cl, Br
O O

O R1
R 1-C6H4-CHO R
KOH/MeOH
O

Scheme 2.

chalcones, it is found that only chalcones, which are The Benzofuran-3(2H)-one Route
hydroxylated at the 2’ and 4-positions, are transformed to
In this method, the key intermediate, benzofuran-3(2H)-
aurones. Moreover, the enzyme is definitely specific to
one, is obtained through Friedel-Crafts acylation of phenol
chalcones, because flavanones (4’,5,7-trihydroxyflavones) are
derivatives with a halogenoacetonitrile followed by a
inert for the enzyme action. The mechanistic investigations

R1 1. oxidation of the O R1
OH α,β-double bond
R
R 2. cyclisation and
elimination
O
O

Scheme 3. Synthesis of aurones from chalcones.

showed that aureusidin synthase acts also as an oxygenase. hydrolysis of the imine to the corresponding ketone and
For example, aurones formation from chalcones bearing a 4- finally cyclization of the 2-hydroxyacetophenonee. Acid-or
monohydroxy is automatically accompanied by the base-catalyzed condensation with benzaldehydes affords the
oxygenation at the 3-position (Scheme 1), but not in the aurones (Scheme 2) [36-38]. The condensation step can be
case of 3,4-dihydroxychalcones. carried out in eco-friendly conditions, such as dry conditions
Identification of aureusidin synthase and cloning of the or under focused microwave irradiation [39,40].
gene (AmAS1) encoding for aureusidin synthase are being Oxidative Cyclization of 2’-Hydroxychalcones
considered for use as valuable tools to generate yellow
2'-Hydroxychalcones have been converted to aurones
flower colours through genetic modification of aurone
under various conditions: Hg(OAc)2 in refluxed DMSO, by
biosynthesis [35]. amines catalysis, etc (Scheme 3) [41,42].
Recently, a more convenient synthesis method of aurones
II.2. Synthesis of Aurones from 2’-hydroxychalcones has been reported (Scheme 4). The
synthesis began with a bromination of 2’-acetoxychalcones
Aurones are synthesized by two main methods: from with n-tetrabutylammonium tribromide (TBATB), which
benzofuran-3(2H)-one, and by oxidative cyclization of 2’- provides the addition reaction product. The latter was
hydroxychalcones.

R1
OAc R1
TBATB OAc
R CH2 Cl2-MeOH R OMe
CaCO3
Br
O
O

O R1
KOH
R
EtOH-H2O

O
Scheme 4.
2624 Current Medicinal Chemistry, 2003, Vol. 10, No. 23 Ahcène Boumendjel

converted into aurones by treatment with a KOH/EtOH ability to bind to P-glycoprotein (Pgp), one of the
solution [43]. transmembrane transporters, which mediates the anticancer
drugs efflux out of the tumour cells [46-50]. We reported
Cushman and co-workers have reported the use of
that flavones bearing a hydroxyl at position 5, a methoxy
thallium (III) nitrate for oxidative cyclization of 2’-hydroxy-
4'-methoxychalcones [44,45]. group at position 7 and the α,β-double bond possess high
binding-affinity toward the C-terminal nucleotide-binding
The need for a methoxy group at 4'-position for the domain (NBD2) of Pgp [51]. As shown in Fig. (3), when
successful reaction, and the incorporation during the reaction these structural criteria were applied to aurones, we came up
of a methanol group into the B-ring make this method with the most active compounds among all subclasses of
restricted to the synthesis of ring-A dimethoxyaurone. flavonoids.
Finally, it should be mentioned that in the most reported Based on one of our previous results, which show that 4-
methods, aurones were obtained where the configuration of bromo and 4-iodochalcones bind tightly toward NBD2 of
the extra-cyclic double bond is exclusively Z as can be Pgp, we synthesized aurones bearing a halogen at 4’ position
assigned on the basis of the 1H NMR spectra. The chemical [52]. As shown in Table 1, the substitution gradually
shift of the olefinic proton in the Z isomer appears at about enhanced the binding affinity, with strong dependence on the
6.70 ppm (δ > 7 ppm for the E isomer) [44]. nature of the halogen, correlating to its hydrophobic
character and/or to the size [53]. The most active aurone was
II.3. The Biological Activity of Aurones the 4’-bromo derivative, which possesses higher binding
affinity than the most active halogenated chalcones and
In terms of biological activity, we can conclude that flavonols, Fig. (4).
flavones, isoflavones and chalcones have been and are being l l
extensively studied for their therapeutical potential; however,
the medicinal literature on aurones is very much in its HO OH HO O
infancy with trends and design just now emerging. In this
review, we attempt to cover some recent investigations on
OH
the biological activities of aurones and conclude by
discussing the structural features, required for the activity of OH O OH O
these molecules.
iodochalcone iodoflavonol
II.3.1. Aurones with Potential Use in Cancer KD = 0.25 µM KD = 1.6 µM
Chemotherapy
The biological activity of aurones in the cancer area has been Fig. (4). The most active halogenated chalcones and flavonols
reported by several research groups and their different modes as evaluated by their high binding affinity toward NBD2 of P-
of action have also been discussed. gp mouse.

II.3.1.1. Aurones as Modulators of Pgp-Mediated Multidrug Table 1. Role of Aurone Substituents on the Affinity for
Resistance (MDR) NBD2 of Pgp

In an going program aimed at the discovery of flavonoids 4'

as MDR modulators, we screened a panel of aurones for their
M eO 6 O

MeO OH MeO 4
O O
OH

Substituent at 4’ position µ M)
KD (µ
OH O
OH O
chalcone aurone H 1.32 ± 0.33
KD = 4.6 µM KD = 1.3 µM
F 2.7 ± 0.8

Cl 0.46 ± 0.08
MeO O
Br 0.15 ± 0.07

I 0.26 ± 0.03

OH O Tested on human tumour cells over-expressing P-gp, we

flavone found out that 5,7-dimethoxyaurone potentiates
KD = 6.3 µM daunorubicin cytotoxicity on resistant K562 cells as much as
Fig. (3). Binding affinities of chalcones, aurones and flavones cyclosporin A, one of the reference drugs used in clinics to
toward the ATP-binding site of Pgp. KD is the dissociation overcome MDR [unpublished results]. Since daunorubicin
constant, which was measured by the quenching of protein experiments could not by themselves ascertain the effect of
intrinsic fluorescence due to a single tryptophan residue [49]. the tested compound on the Pgp transport activity, we
Aurones: A Subclass of Flavones with Promising Biological Potential Current Medicinal Chemistry, 2003, Vol. 10, No. 23 2625

performed an assay of Pgp transport function using mediators of several physiological actions in the periphery as
rhodamine-123, a fluorescent molecule acting as a probe of well as in the nervous system [63,64]. By using a
P-glycoprotein-mediated MDR [54]. The aurone was able to competitive radioligand binding assay, they screened
increase the intracellular accumulation of rhodamine-123, flavones, isoflavones and aurones for their interactions with
suggesting that the compound might act at least in part, by three subtypes of adenosine receptors, A1 , A2A and A3 .
inhibiting P-glycoprotein activity [55]. Among the aurones studied, the naturally occurring hispidol
Fig. (6 ) showed a K I = 0.35 µ M, with substantial
II.3.1.2. Inhibition of Cyclin-Dependent Kinases
selectivity for A1 receptor.
Cyclin-dependent kinases have a major role in the OH
regulation of the cell cycle division and compounds, which
are able to inhibit these enzymes, are of potential value as
antiproliferative agents [56,57]. In this domain, flavopiridol,
HO O
Fig. (5) is a well-established inhibitor of cyclin-dependent
kinases and is now undergoing clinical trials [58,59].
Working on cyclin-dependent kinases (CDKs) inhibitors as
anticancer agents, researchers at Novartis have designed hispidol
O
aurones as flavopiridol mimics. The design was based on the
fact that the X-ray crystal structure of CDK2 in complex Fig. (6).
with des-chloroflavopiridol showed the benzopyranone II.3.1.4 Anticancer Effects of Aurones Through DNA-
(chromenone) moiety of flavopiridol acting as a mimetic of Scission and Telomerase Inhibition
the adenine of ATP, which is the co-factor of the enzyme
In search for natural products with potential use in cancer
[60,61]. Therefore, it was reasoned that a 4-hydroxy
chemotherapy, Kinghorn and collaborators have reported
benzofuranone can be able to mimic the 5-
identifying an aurone, hamiltrone, Fig. (7) from Uvaria
hydroxychromenone of flavopiridol. Several aurones
hamiltonii extracts together with a variety of unknown and
possessing a N-methylpiperidinyl at the 7 position have
known flavonoids [65,66]. Tested on DNA strand-scission,
been synthesized and evaluated [62]. Tested on CDK1,
hamiltrone was found to be the most active compound.
CDK2 and CDK4, aurones were found to be as much active
Interestingly, the chalcone (hamilcone) and flavanone
as flavopiridol on CDK1 but at lower extent on CDK2 and
(hamiltone B), which are isomers of hamiltrone, were
CDK4. Owing to the importance of the hydroxyl group in
isolated too and were found to be 10 times less actives than
the piperidinol of flavopiridol, it is clear that more active
hamiltrone.
aurones can be obtained by introducing this structural
feature. HO OH OH
Me OH
Me
N N
MeO O MeO OH

OH OH MeO MeO
HO O HO O O
OMe OMe O

hamilt rone hamilcone

Cl (chalcone)
(aurone)
OH
OH O OH O
OH
flavopiridol deschloroflavopiridol
Me MeO O
N
R2
MeO
hami ltone B
OMe O
(flavanone)
HO O
Fig. (7). Hamiltrone and its isomers; hamiltrone and hamilcone.
R1
In an independent study, the anti-tumour activity of 6,7-
O dihydroxyaurones was reported and the mode of action was
OH related to inhibition of telomerase, which participate in the
aurone mimic control of cell cycle [67]. The most active compound was
found to be 3’,4’-dichloro-6,7-dihydroxyaurone, which
Fig. (5). inhibit telomerase with and IC50 = 0.3 µM.
II.3.1.3 Interactions of Aurones with Adenosine Receptors II.3.1.5. Aurones as Cancer Chemopreventive Agents
In investigating the mechanisms of anticancer, anti- Oxygen free radicals are natural physiological products,
inflammation and inhibition of platelet aggregation and are highly reactive. They have an essential part in
properties of dietary flavonoids, Jacobsen and co-workers at biological process but a surproduction of free radicals may
NIH have explored the adenosine receptors route, which are
2626 Current Medicinal Chemistry, 2003, Vol. 10, No. 23 Ahcène Boumendjel

be disastrous, such as cancer implication by damaging DNA. macrophages. The mechanism of action of this class of
When natural defences (superoxide dismutases, catalase, compounds as antiprotozoal was investigated and revealed
gluthation peroxidases,..) are overloaded, free radical that their activity is induced through interference with the
scavengers (anti-oxidants) are of great value to prevent or respiratory mitochondrial enzymes, such as fumarate
minimize damages. Working actively in this area and by reductase [71].
using an anti-oxidant activity guided fractionation of plant Moreover, Kayser and co-workers have investigated for
extracts, Kinghorn and co-workers have reported potent anti- the first time the efficacy of a series of aurones and auronols
oxidative constituents of Cotinus coggygria and have shown to inhibit the intracellular growth of the parasitic protist
that compounds responsible for the activity are mainly
Cryptospordium parvum, which is a parasitic protozoan of
aurones, aurone glycosides, and biaurones [30,68].
human intestinal epithelial cells, for which no treatment is
II.3.2. Aurones for Treating Parasitic Infections currently known [72]. Using an in vitro ELISA assay, most
Kayser et al. have investigated the activity of synthetic of the aurones tested were active at 25 to 100 µM and
and naturally occurring aurones for their ability to inhibit inhibit the intracellular growth by more than 90%. The most
erythrocytic stages of plasmodium falciparum, one of the active compound was 3',4',6-trihydroxyaurone.
four Plasmodium species, causing severe malaria [69]. Using II.3.3. Aurones for Treating Microbial Infections
a resistant and sensitive strains of p. falciparum, aurones
In a patented work, scientists at Phytera, Inc. have
have exhibited an IC50 in the nanomolar range. Surprisingly,
studied aurones for their ability to inhibit microbial
the chloroquine resistant strain was more sensitive to
infections, such as fungal and bacterial infections [73,74].
aurones than the chloroquine sensitive strain. Structure-
The aurones studied were either synthetic (structures A and
activity relationship study showed that highly oxygenated
B) in Fig. (10) or naturally occurring dimeric aurones
and hydrophobic aurones are the most active ones. For,
obtained from plant cell cultures (structure C) in Fig (7).
example 4,6,4’-triacetyl-3’,5’-dimethoxyaurone Fig. (8)
The ability to inhibit infections has been evaluated in several
exhibited an IC50 of 7 nM.
fungal (mycoses) and bacterial agents by measuring growth
MeO OAc of the fungal, bacterial organism, or by using an enzyme-or
cell-based inhibition.
OMe OR 3
AcO O
OR4
R2O O
O
OAc

Fig. (8).
O
OR 1
In a related study, authors have reported for the first time
A: R1, R2 , R3, R4 = H, Ac
the drug-potential of aurones to treat leishmania infections
[70]. A panel of aurones substituted on positions 4,6,3’,4’ R4 R5
and 5’ have been evaluated in vitro by measuring the
inhibitory effects against extra-cellular promastigote stage of Y R3
different parasites, such as Leishmania donovani, R2 O O
L.infantum, L. enriettii, and L. major. Several derivatives
showed interesting leishmanicidal properties with moderate
toxicity for host cells. The active compounds are the less X
oxygenated, whereas the most active was 6-hydroxyaurone OR1 O
Fig. (9 ), which may indicate the importance of the B: R1, R 2 = H, Me, Ac, alkyl
hydrophobic factor. Tested against intracellular L. donovani R 3, R4, R 5 = H, halogen, alkyl, alkoxy,..
X, Y = H, benzyl, prenyl, alkyl, alkoxy
amastigotes residing within murine macrophages, aurones
were also active without significant toxicity for HO OH

R6 R5

HO O OH
R4 HO O
R2 O HO O OH
OH O
R3 O
O
O OH
R1 C
B Fig. (10). Aurones studied as antibacterial agents.
A
Some in vivo tests, which measure the impact of the
Fig. (9). A. Structures of aurones evaluated for their in vitro
leishamanicidal activity. R1 = H, Bz or Glc; R2 = OCH3, Bz or
aurone on prolonging the life of the infected mice, have been
OH; R3,R4, R5 = H or OH. B. The most active aurone.
reported. Mice sensitive and resistant to fluconazole
Aurones: A Subclass of Flavones with Promising Biological Potential Current Medicinal Chemistry, 2003, Vol. 10, No. 23 2627

(antifungal agent), infected with a pathogenic strain of have been described for their ability to fight diabetes
Candida albicans, were used in this study. The study complications, by inhibiting the Maillard reactions, which
showed that all untreated control animals died after 16 days, are non-enzymatic reactions of glucose with protein amino
and in the group treated with fluconazole, the survival was groups to form reversible Schiff base adducts [80,81]. The
about 30%. The survival in the group treated with an aurone latter react with proteins free amino groups, leading to cross-
(40 mg/kg body weight by oral administration) was about linking of proteins, responsible for diabetes complications
60% and the survival was about 70% when 20 mg/kg body [82]. Knowing that hyperglycemia in diabetes mellitus
weight were administered by intraperitoneal injection). In the contributes considerably to elevation of the Maillard reaction
fluconazole-resistant mice treated with an aurone (40 mg/kg rate, it is conceivable that suppressing this reaction can be of
body weight by oral administration) survival was 80% after high interest for preventing diabetes complications. Several
20 days, whereas in the group treated with fluconazole and synthetic or natural aurones and flavones have been evaluated
untreated animals, 0%. to the finding that the naturally occurring 3’,4’,6-
II.3.4. Antihormonal Activity of Aurones trihydroxyaurone (sulfuretin, Fig. (12) is one of the most
potent compound.
Based on the fact that some plants are used in traditional OH
medicine for their antihormonal properties [75], Auf’molk
and co-workers have conducted an activity-guided
purification of four plants namely Lycopus virginicus, OH
HO O
Melissa officinale, and Lithspermum extracts. In this study,
they targeted rat liver iodothyronine deiodinase [76], which
acts on the thyroid hormones by metabolizing (deiodination)
the extrathyroidal thyroxine [77,78]. Both in vitro and in O
vivo testing have concluded that the active components
involved in deiodinase inhibition are rosmarinic acid, ellagic sulfuretin
acid, luteolin-7β -glucoside and aurones, which were the
most active isolated compounds. Structure-activity Fig. (12). Structure of sulfuretin, studied to treat diabetes
relationship indicates that the presence of hydroxyl groups at complications.
4 and 4' positions, and the extra-cyclic double bond make
important structural elements. Compared with the known II.4. Structural Features That May Govern the Aurones
drugs, the study concluded that aurones are the most potent Biological Activity
non-iodinated inhibitors of rat liver iodothyronine
deiodinase. As expected, iodination considerably enhances In a general sense, flavones are inhibitors of a variety of
the activity, and iodination at 3’-position is the optimal Fig. ATP-dependent key-enzymes and proteins [83-94]. The
(11). Based on these structural criteria, 3’-iodo-4,6,4’- inhibitory activity is believed to be due to their ability to act
trihydroxyaurone was proposed as the most potent aurone for as ATP-competitive inhibitors and it has been postulated
the inhibition of rat liver iodothyronine deiodinase. To that flavones activity is due at least in part to the ability of
further investigate the structure-activity relationship, the benzopyran moiety (chromenone) to mimic the adenine
molecular modelling was used to study the conformational of ATP, which is required for the function of enzymes and
similarities between the thyroid hormone and the computer receptors, Fig. (13). The recent high-resolution structure of
generated aurone model [79]. It was found that aurones cyclin-dependent protein kinase2 (CDK2) co-crystallized
adopted antiskewed conformation close to the thyroxine with an eight-substituted derivative of chrysin (5,7-
conformation, attesting that they can be favourably fit in the dihydroxyflavone), L868276 has come to reinforce the ATP-
active site. mimicry hypothesis [95]. In the crystal structure, the 5-
l OH hydroxyl of L868276 is shown to interact with as many as
five residues normally interacting with the 6-amino group of
the adenine moiety of ATP, whereas the vicinal 4-carbonyl
HO of L868276 appears equivalent to the 1-nitrogen atom of
O
adenine.
The role played by the A/C rings of quercitin (5,7,3',4'-
O tetrahydroxyflavonol) in mimicking the adenine moiety of
OH
nucleotide ATP has been confirmed by co-crystallization of
l
quercetin with tyrosine kinase Hck [96].
l O
NH2 By analogy, we can imagine that aurones bearing a
hydroxyl group on 4 position induce their activity through
HO l CO2 - adenine mimicry. The size of the aurones and especially the
l C-ring, close to the 5-member ring of adenine, makes them
higher mimics than flavones, Fig. (13). Moreover, the fact
Fig. (11). Structures of thyroxine and the most active aurone. that in several cases aurones were reported to be more active
II.3.5. Aurones as Antidiabetes than their equally substituted chalcones and flavones isomers
indicates that the aurone conformation may play an
In recent patents, the utility of aurones as potential important role.
agents in one major therapeutic area has been reported. They
2628 Current Medicinal Chemistry, 2003, Vol. 10, No. 23 Ahcène Boumendjel

1 3 6 1
H9 O
O N 4 N
7 2 A C
A C 8
1N 3
N 4
5
5 4 6 7 OH O
OH O NH2

5-hydroxybenzopyranone adenine 4-hydroxybenzofurranone

(A/C rings of flavones) (4/C rings of aurones)

Fig. (13). Structural analogy between 5-hydroxychromanone, adenine and 4-hydroxybenzofuranone.

Due to the high structural analogy between chalcones and of the biological activity of aurones is still to come. As
aurones, it is conceivable that aurones might be of great evidenced from the biological activities of aurones presented
interest in all biological areas where chalcones have been in this review, further investigations should be conducted,

OH O
O
cyclization

O O O

aurone active chalcone inactive flavanone

Fig. (14).

investigated. Chalcones would be less advantageous than especially the structure-activity relationship. The latter is
aurones because of the possible cyclization in situ to give easily affordable because of the relatively easy access to
the inactive flavanones Fig. (14). aurones. Hopefully, that these flower colouring molecules

H N H
N N
H O O
N Br

OH
O HN
Br
azaaurone 1 2
Fig. (15). Structural analogy between known inhibitors of CDKs (structures 1 and 2) and azaaurones.

Azaaurones Fig. (15) should be investigated too. The will provide not only useful therapeutics but also
latter are structurally similar to the naturally occurring pharmacological tools to understand and study enzymes and
aurones and, in addition, they also have an available proteins.
nitrogen for further extension and for branching different
substituents that may give rise to beneficial interactions with
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stimulate studying the biological activities of azaaurones [2] Formica, J.V.; Regelson, W. Food Chem. Toxicol., 1995, 33, 1061.
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