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REVIEW
NPR
Gerard P. McGlacken and Ian J. S. Fairlamb*

Department of Chemistry, University of York, Heslington, York, UK YO10 5DD.
E-mail: ijsf1@york.ac.uk; Fax: 44 1904 432516; Tel: 44 1904 434091
www.rsc.org/npr
2-Pyrone natural products and mimetics: isolation, characterisation

and biological activity
Published on 05 May 2005. Downloaded by University of Birmingham on 06/10/2014 06:52:17.
Received (in Cambridge, UK) 16th February 2005

First published as an Advance Article on the web 5th May 2005
Covering: December 1992 to December 2004

The review summarises natural products containing the 2-pyrone moiety. An emphasis has been placed upon the
biological activity associated with 2-pyrones, particularly with respect to potential therapeutic or anti-microbial
agents. Where appropriate, non-natural 2-pyrone analogues are discussed, particularly those derived from natural
product lead compounds.
1
2
2.1
2.2
2.3
2.4
2.5
2.6
2.7
2.8
2.9
3
4
4.1
4.2
4.3
4.4
4.5
5
6
Introduction
Naturally occurring 2-pyrones
Bufadienolides
Fusapyrones and 4-hydroxy-2-pyrones
Gibepyrones
Herbarins A and B
6-Alkyl-2-pyrones
Peripyrones
Coumarins
Styrylpyrones
Others
Isolation and structure elucidation
Biological activity
HIV inhibitors
Treatment of Alzheimers disease
Treatment of high cholesterol
Treatment of cancer
Other uses
Future lead compounds and directions
References
1 Introduction
2-Pyrone 1a is a six-membered cyclic unsaturated ester that
shares chemical and physical properties reminiscent of alkene
and aromatic compounds. It is highly abundant in bacteria,
microbial, plant, insect and animal systems and takes part in
many different types of biological processes such as defence
against other organisms, as key biosynthetic intermediates, and
as metabolites. Historically, simple 2-pyrones such as triacetic
acid lactone 1b and tetraacetic acid lactone 1c, are used as
precursors for the synthesis of biologically important compounds such as pheromones,1 solanopyrones,2 a-chymotrypsin,3
elastase,4 coumarins5 and analogues.6
Gerard McGlacken received his B.Sc. (Hons.) and Ph.D. from the National University of Ireland, Galway,
where he studied the asymmetric deprotonation of hydrazones under the supervision of Dr S. W. Breeden. He
is currently carrying out postdoctoral research with Dr I. J. S. Fairlamb at the University of York in England,
studying asymmetric Ru-catalysed cycloisomerisation reactions of 1,6-enynes and 1,6-dienes. Further interests
include the synthesis of substituted 2-pyrones using Pd-catalysed coupling reactions, and the investigation of
unusual observations associated with this class of substrates.
DOI: 10.1039/b416651p
Gerard P. McGlacken
Ian Fairlamb (born 1975, UK) was appointed to a lectureship in Organic Chemistry at York in late 2001,
following a successful Ph.D. under the guidance of Dr J. Dickinson investigating the rational design and
synthesis of squalene synthase inhibitors (1999), and a productive post-doctoral research stay with Professor
G. C. Lloyd-Jones, studying the mechanisms of various Pd-catalysed processes (200001). At the age of 28,
he was awarded the prestigious 2003 Meldola Medal and Prize by the Royal Society of Chemistry (awarded
in 2004) to recognise outstanding independent contributions in the application of transition metal catalysed
reactions, particularly involving palladium, to the synthesis of medicinally relevant molecules and natural
products. He is a recipient of a Royal Society University Research Fellowship (started October 2004) for
Understanding, controlling and exploiting unusual observations in Pd-catalysed reactions. Research is
broadly at the interface between Organic, Inorganic and Medicinal/Biological Chemistry. Key areas involve
transition metal chemistry, catalyst design (chiral and achiral), mechanistic understanding, with strong links
to medicinal chemistry and drug discovery; utilisation of palladium chemistry in pharmaceutical design,
particularly in the preparation of novel heterocyclic compounds such as 2-pyrones and related thio-derivatives,
and pyridines. The complexation of 2-pyrones and 2-pyridinones to a variety of transition metal moieties are
studied. Novel compounds are screened for interesting biological effects. The exploitation of medicinal lead
compounds possessing anti-cancer and carbon monoxide releasing properties is of interest to the research
group.
Ian J. S. Fairlamb
This journal is
The Royal Society of Chemistry 2005
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Some ten years ago, Dickinson reviewed the literature

on microbial 2-pyrones, dihydro-2-pyrones and secondary
metabolites belonging to fungi of several genera including
Alternaria, Aspergillus, Fusarium, Penicillium and Trichoderma.7
These exhibit a wide range of anti-fungal, cytotoxic, neurotoxic and phytotoxic properties. Investigations into their
plant growth-regulating,8,9 antitumour10,11 and HIV proteaseinhibiting qualities1214 have demonstrated the medicinal importance of 2-pyrones. Given the recent urry of reports in this
area, a review of the literature since 1992 is required. Here we
attempt to bring the reader up to date on this class of natural
products, focusing on investigations regarding the isolation of
naturally occurring 2-pyrones, their mimetics and application
as therapeutic and anti-microbial agents (dihydro-2-pyrones are
not covered here).
The phenomenal abundance of the 2-pyrone motif in naturally occurring molecules could justify several reviews. We do
not claim to cite every natural 2-pyrone isolated in the last
thirteen years, nor all synthetic 2-pyrone analogues exhibiting
biological effects. It is intended to give an insight and broad
overview of 2-pyrones from an eclectic array of natural sources.
Bioactivity will be discussed, along with the importance of 2pyrones in the treatment of HIV, Alzheimers disease, cancer and
other human diseases. Natural products based on 2-pyrones, and
related derivatives, form the basis of the material in this review.
The mortality of an assay of brine shrimp (Artemia salina L.)

larvae in a bioassay has proved a reliable and fast method to
test anti-tumour and cytotoxic activity.24 This method has been
used to test the zootoxicities of 6 and 7.23 Recently, structure
activity relationships of derivatives of 6 have been studied by
Altomare and co-workers.25 The parent compounds, 6 and
7, show considerable anti-fungal activity against moulds, low
zootoxicity and selective action, thus further investigations into
structural variants are warranted. Penta-acetylation of 6 to give
8 and 9 resulted in an increase in toxicity. The structural changes
to 6 causing an increase in toxicity in an A. salina bioassay
were attributable to lower hydrophobicity. YM-202204 10a and
S39163/F-1 10b were isolated from the culture broth of marine
fungus Phoma sp. Q60596.26 Compound 10a exhibited broad
spectrum anti-fungal activity in vitro and showed retardation
in fungal GPI-anchoring activity. GPI-anchoring represents a
mechanism involving the attachment of proteins to membranes
that are essential in yeast and fungi cells.27,28 Two new metabolites
11a and 11b were isolated from the phytopathogenic fungus
Neocosmospora vasinfecta NHL 2298, along with known 2pyrones.29 Their structures were elucidated by spectroscopic
methods; the absolute stereochemistry by X-ray analysis and
chemical synthesis.
2 Naturally occurring 2-pyrones

2.1 Bufadienolides
The bufadienolides are an important group of steroids containing the 2-pyrone moiety.15 They are characterised by a 2-pyrone
connected at the ve position by a steroid nucleus, e.g. bufalin 2.
A thorough review by Steyn and van Heerden provides an
insight into the chemical ndings of bufadienolides from 1977
to 1997.15 This class of 2-pyrones can be found in several
families of plants and animals and the biological activity of the
bufadienolides is diverse. The plant sources include the families Crassulacceae, Hyacinthaceae, Iridaceae, Melianthaceae,
Ranunculaceae and Santalaceae. Those from the family Crassulacceae can cause the symptoms of cardiac poisoning in
animals. Cytotoxic kalanchoside 3 was isolated from Kalanchoe
tomentosa, an ornamental plant from Madagascar.16 The animal
sources of bufadienolides include the Photinus (reies), Rhabdophis (snake) and Bufo or toad. Over eighty bufadienolides
have been isolated from the latter. The abundance of these
compounds in some species is extraordinary. For example, nine
new polyhydroxylated bufadienolides were isolated from the
nuchal glands of Rhabdophis tigrinus17,18 six of which are shown
(4af). Resibufogenin 5 was isolated from the Chinese toad
skin extract drug Chan Su, and found to signicantly inhibit a
leukaemia cell line.19
2.2 Fusapyrones and 4-hydroxy-2-pyrones
While 4-hydroxy-2-pyrone derivatives are relatively abundant,
little is known of their biosynthetic origin. One example of
a biosynthetic enzyme is 6-styryl-4-hydroxy-2-pyrone synthase
(SPS), identied in gametophytes of Equisetum arvense.20 The
synthesis of the 4-hydroxy-2-pyrone skeleton may well involve
enzymes belonging to the family of CHS-related proteins
(CHS = chalcone synthases).21 Fusapyrone 6 and deoxyfusapyrone 7 were originally isolated from the rice cultures of Fusarium
semitectum and structurally resolved by Evidente and coworkers.22 They were later tested for anti-microbial activity
in lamentous fungi and yeasts, including their zootoxic and
phytotic activities.23 Both compounds exhibited considerable
anti-fungal inhibitory activity and inhibitory activity toward
agents of human mycoses. Deoxyfusapyrone 7 stimulated the
root elongation of tomato seedlings at doses of 10 and 100 lM.
370
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The 2-pyrone 12 was isolated by the Mitsubishi Pharma group

from the culture broth of Epicoccum purpurascens. It shows
inhibitory properties toward telomerase.30 Initial studies towards
its total synthesis include the construction and characterisation
of the C-glycosidic moiety.31 The absolute stereochemistry
of 12 is not known. 4-Hydroxy-2-pyrone derivatives can be
formed after early termination, via two condensation reactions,
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with FP (100 ppm) resulted in an infection rate of 9% compared

with 54% in the untreated leaves.
of the valerophenone synthase (VPS) catalysed synthesis of

the bitter acids in hops (Humulus lupulus).21 The pyrone
synthase, 2PS, from Gerbera hybrida, synthesises 4-hydroxy-6methyl-2-pyrone.32 Other more elaborate 4-hydroxy-2-pyrones
are synthesised from 4-coumaroyl-CoA by CHS and related
enzymes, including bisnoryangonin 13 and 4-coumaroyltriacetic
acid lactone 14 (CTAL).33 The leaf resin of Mimulus aurantiacus
gave 3-geranyl-4-hydroxy-6-(2-hydroxypropyl)-2-pyrone 15.34
2.3
Gibepyrones
Gibepyrones are 6-substitued-3-methyl-2-pyrones. The rst

metabolite isolated from Gibberella fujikuroi bearing a 2-pyrone
function, produced six novel compounds gibepyrones AF (19a
d, 20 and 21).37 These were isolated from ICI 10% culture
medium, in which glucose had been replaced by calcium
lactate as the carbon source. Gibepyrone A 19a and B 19b
exhibited growth inhibitory activity against Bacillus subtilis,
Staphylococcus aureus, Saccharomyces cerevisiae and Candida
albicans.
2.4
Herbarins A and B
Two strains of the fungus Cladosporium herbarum were isolated

from the sponges Aplysina aerophoba and Callyspongia aerizusa,
affording two 2-pyrones named herbarin A 22 and B 23,38 along
with the known citreoviridin A 24. Compounds 22 and 23
exhibit inhibitory activity against Artemia salina. Compound
24 exhibited growth inhibitory activity in an insecticidal assay
against Spodoptera littoralis.
The structure of the previously misidentied compound (with
the 2-hydroxypropyl and geranyl group alternatively positioned
at the 3- and 2-positions, respectively) was unambiguously
assigned using spectroscopic methods. 6-Acetonyl-4-hydroxy2-pyrone 16, synthesised from acetyl-CoA, was isolated from
stilbene synthase (from the rhizomes of Tatar rhubarb, Rheum
tataricum L.). Ascosalipyrone 17 was isolated from the fermentation broth of A. salicorniae.35
As part of their study of non-pathogenic endophytes in
plant protection, Furumai and co-workers isolated a 2-pyrone
designated stupyrone 18 from Streptomyces sp. TP-A0569.36
Fistupyrone inhibited the in vivo infection of seedlings of
Chinese cabbage by Alternaria brassiciola TP-F0423, the cause
of Alternaria leaf spot, without any in vitro fungicidal activity.
Both macroscopic and microscopic means were utilised in
the evaluation of 18 on the infection of Chinese cabbage by
A. brassiciola TP-F0423. The disease effect was 12% of the
untreated plant at 100 ppm. On the untreated plants, spores
settled on the leaf and grew infectious hypha that penetrated
through the cuticle into the host plant. In the treated plant, the
spores did germinate but severely reduced numbers of spores
formed the infectious hypha. In fact, treatment of the leaves
2.5
6-Alkyl-2-pyrones
The genus Trichoderma is an excellent source of biologically

active natural products. One of these is a metabolite, 6-pentyl2-pyrone (6PP). By optimising the time of harvest, temperature,
light and spore inoculation, yields of 2 g of 6PP per kg of ground
corn have been achieved.39 The in vitro biological activity (antifungal and phytotoxic) was evaluated against various assays
including agar diffusion, agar dilution, air diffusion, wheat
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coleoptile and lettuce seed germination.40 At a concentration

of 0.1% (v/v) the 2-pyrone completely inhibited the outgrowth
of B. cinerea. The same compound could prove effective in
the control of B. cinerea rots in kiwi fruit. Fruit treated with
this food additive were less prone to accelerated ripening.41
The effect and metabolism of 6-pentyl-2-pyrone on Botrytis
cinerea has been reported.42 This compound is toxic to many
fungal plant pathogens including B. cinerea.43 Claydon reports
that unless fungal growth is totally suppressed, the fungi will
outgrow the 2-pyrone zones, suggesting that the 2-pyrone is
metabolised and that the metabolites are not toxic to the fungus.
These results were conrmed by experiments on B. cinerea.
Visible hyphal growth occurred after 7 days when the fungus
was treated with 120 lg mL1 , whereas no growth was observed
after 30 days when 220 lg mL1 was administered. HPLC
showed the metabolism of 6PP and the appearance of three
new components corresponding to 26, 27 and 28 (the structure
of 28 was tentatively assigned as either 28 or 29 based on MS
data). The presence of these compounds in the culture did not
suppress fungal growth, suggesting that these metabolites are
less toxic, due to their decreased lipophilicity. The 2-pyrone is
stable in 2M HCl and 2M CH3 COONa and only degraded to
2-heptanone on treatment with 1M NaOH. The transformation
of 25 to 26, 27 and 28 could not be denitely attributed to acid
or base hydrolysis. Cooney and co-workers isolated these three
2-pyrones, along with a new metabolite 29 from B. cinerea.44
The same group later identied four new metabolites of 25 from
three Pencillium isolates, a Sclerotinia isolate and a Fusarium
isolate. Further oxidation to carboxylic acids was observed.45
Pinus radiata also metabolised 6-pentyl-2-pyrone in 7985%
conversion to several isomers of 25, the most abundant being 5(2-pyron-6-yl)pentan-5-ol.46 6-Pentyl-2-pyrone is also produced
by Trichoderma harzianum, grown in liquid cultures containing
14
C labelled glucose. The study showed that ca. 1.2% of the
glucose was converted to 6PP.47
structure elucidation,50 and nally the rst total synthesis of

a potent member of the family, (+)-30a.51 The structurally
similar arisugacin,52 and territrems53 serve as selective inhibitors
of AChE and have potential for the treatment of Alzheimers
disease. The structurally related GERI-BP001 31 was isolated
from a culture of Aspergillus fumigatus F37.54 It inhibits acylCoA:cholesterol acyltransferase (ACAT), the enzyme responsible for the intercellular esterication of cholesterol. The total
synthesis was achieved in 1995.55 Phenylpyropene A 32a and
B 32b were isolated from the fermentation broth of Pencillium griseofulvum F195956 along with the previously reported
phenylpyropene C 32c.57 These compounds are structurally
similar to 30a58 and pyripyropene E,59 sharing the 2-pyrone and
sesquiterpene moieties, however these possess a phenyl ring in
place of pyridine. The level of inhibition is dependent on the
number of acetoxy groups and on the existence of an 11-hydroxyl
group32a is the most potent analogue.
2.7
2.6 Peripyrones
Aspergillus fumigatus FO-1289 was isolated from a soil sample from Tokyo (Japan). Four biologically active compounds,
pyripyropenes AD (30ad), sharing structural similarities
namely pyridine, 2-pyrone and sesquiterpene moieties, forming
a steroid-like structure, were isolated from the culture broth
of the producing strain.48,49 These demonstrated potent acylCoA:cholesterol acyltransferase (ACAT) inhibitory activity.
Pyripyropene C 30c was the most potent in screens with an
enzyme assay system using rat liver microsomes (IC50 = 53 nM).
The initial reports describing the isolation and biological
evaluation of 30ad were followed by relative and absolute
372
Nat. Prod. Rep., 2005, 22, 369385
Coumarins
Of the seventeen compounds isolated from the n-butanol

fraction of the leaves of Peucedanum japonicum, six contained
the coumarin moiety, e.g. 3335.60 All compounds were tested
for their radical scavenging capabilities. The coumarins were
less effective than other isolated compounds. Two new 6acylcoumarins, racemosol 36 and mammea A/AC cyclo F 37,
were isolated from the leaf extract of Mesua racemosa. Their
structures were solved by extensive spectroscopic analysis.61
Seven new coumarins, the achrocarpins AG, 3840, were
isolated62 from Ochrocarpos punctatus, along with ve known
coumarins.6366 These compounds exhibit broad spectrum cytotoxicity against the A2780 human ovarian cancer cell line.
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bearing the 2-pyrone moiety, are often detected in marine

microorganisms such as fungi, bacteria and algae.7072 The
decaturins A and B (45 and 46, respectively) were isolated from
Pencillium decaturense and Penicillium thiersii. Both compounds
feature a new polycyclic ring system and 46 exhibits potent
antiinsectan activity against the fall armyworm (Spodoptera
frugiperda).73
A recent analogue of luteoreticulin,74,75 griseulin 47 was

reported to show inhibitory activity against nematodes (P. redivivus, C. elegans, and H. glycines) and mosquito (A. eagypti).76
Lyga in his studies developed a convenient convergent synthesis
to both natural products, allowing variation of both phenyl and
2-pyrone rings.77
2.8 Styrylpyrones
Davidson and co-workers isolated four 2-pyrones from a

Streptomycete, named BD-26T(20), cultured from shallow water
marine sediment; Wailupemycins AC, 4850, and 3-epi-5deoxyenterocin and derivatives, 51.78 Compounds were tested for
anti-microbial activity against Bacillus subtilis, Staphylococcus
aureus and Escherichia coli in vitro. Compound 48 showed
inhibitory properties against E. coli, whereas compound 51a
exhibited activity against S. aureus.
Naturally occurring styrylpyrones, without a 4-hydroxy moiety,

include the previously known compounds, 41a and 41b, isolated
from the trunk wood and bark of an Aniba species and exotic 2pyrone dimers (possibly photochemical artifacts resulting from
dimerisation).67 The plant Miliusa balansae provides a new
styrylpyrone 42.68 Dihydro-5,6-dehydrokawain 43a was isolated
from Alpina speciosa leaves. It caused a 35% reduction in the
hypocotyl length of lettuce seedlings, compared to a control.69
Several derivatives were synthesised, with 43b the most potent,
showing a 66% reduction in hypocotyl length.
2.9 Others
The carboxylic acid 44 was isolated from the aspen blue stain
fungus Ophiostoma crassivaginata, along with fteen other compounds. A series of biologically active secondary metabolites,
Five novel cytotoxic compounds, NF00659 A1 52a, A2 52b, A3

52c, B1 52d and B2 52e, were isolated from a culture mycelium of
Aspergillus sp. (Table 1).10 These compounds possess potent antitumour properties against A2780 human ovarian carcinoma
and SW480 human colorectal adenocarcinoma cells. An elegant
structure elucidation (without stereochemistry) of the novel
tricyclic core is a feature of the study.79
Lin-Chi is an oriental crude drug used in the treatment of
mild ailments and to promote good health.80 It consists of the
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Table 1 Novel 2-pyrones based on generic structure 52
NF00659
R1
R2
A1 , 52a
A2 , 52b
A3 , 52c
B1 , 52d
B2 , 52e
I
II
Ac
I
II
OH
OH
OH
H
H
fruit bodies of the fungus Ganoderma lucidum. G. lucidum can

become infected with the mycoparacitic fungus, Cladobotryum
varium.
As part of a search for anti-fungal agents by Kikuchi and
co-workers, this fungus was isolated from its culture broth
and found to inhibit the mycelial growth of G. lucidum.81 Six
novel 2-pyrones, namely 53, 54ab, 54c, 54ef, were isolated
along with known 6. Cladobotrins II 54a and III 54b, and
rosellisin aldehyde 54d, exhibited inhibitory activity against G.
lucidum, indicating that a 5-formyl group might be necessary for
inhibitory activity.
2-Pyrone-4,6-dicarboxylic acid was isolated from Potentilla

anserine.82 While this compound has been isolated from bacteria,
e.g. Pseudomonas,83 this is the rst time that it has been shown
to be produced in plants. This was conrmed by the growth
of seedlings under sterile conditions, eliminating the possibility
that the 2-pyrone originated from bacteria or parasitic fungi.
Daldiniapyrone 55 was isolated from the ethyl acetate extract
of Daldinia concentrica along with known 2-pyrone, (+)orthosporin.84 Novel fermentation products 11G219a, b, c and
d of the 2-pyrone class were isolated from the fungal culture
LL-11G219.85 Isolation experiments were carried out by RPHPLC. The structure of 56 was assigned by 13 C, 1 H, DEPT
and COSY NMR along with analysis of the UV spectra and
HETCOR or HMQR measurements. The structures of 57, 58
and 59 were assigned by comparison of their NMR shifts. The
screening program was initiated in an effort to discover nonsteroidal androgen receptor agonists or antagonists.
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Nat. Prod. Rep., 2005, 22, 369385
As can be seen from the overlay of 56 with testosterone

(highlighted in bold), both compounds are well aligned and
possess more conformational freedom, and potentially could act
as testosterone mimetics. The butyl group of 56 is exible and
thus could t into a variety of enzyme pockets. Compounds 56
58 were shown to be attached in a membrane bound androgen
receptor assay. Epoxide 59 exhibited anti-fungal activity. Some
of the more structurally interesting biologically active 2-pyrones
are the macrocyclic 2-pyrone derivatives 61 and 62. These
compounds were isolated as secondary metabolites from the
red alga Phacelocarpus labillardieri.8689 The crude extracts from
these algae were shown to exhibit neuromuscular blocking
activity, which may be due to structures of this type. The use
of ring closing alkyne methathesis,90,91 potentially allows these
compounds to be prepared if the alkenyl regio- and stereoselectivity can be controlled and preserved.92 Fujimoto and
co-workers have isolated multiforisins AF.93,94 More recently
isolated compounds by the same group include multiforins G
I.95 These compounds are discussed in detail in the treatment
of Alzheimers in section 4.2. Two compounds, 63a and 63b,
were isolated from the bark of Peruvian medicinal plant palo
de Sangue or Brosimum rubescens.96
Isoprenoid-substituted 3-arylcoumarins, glyasperin L 64 from

Gylcyrrhiza aspera,97 and kanzonol W 65, from G. glabra98 were
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isolated. 4,4 -Di-O-methylscandenin 66 has been isolated from

Derris scandens.99 The biosynthetic origin of some coumarins
have been studied. Examples include the linear psoralen 68,
thought to be biosynthesised from umbelliferone 67.100 Related
analogues have been studied, employing labelled deuterated
marmesina known intermediate. The biosynthesis of 7acetoxy-4-methylcoumarin 69 has been studied using Trigonella
foenumgraecum.101 Examples of naturally occurring coumestans
include 4-hydroxycoumestrol 70102 and sigmoid K 71, isolated
from the Cameroonian medicinal plant Erythrina sigmoides.103
Both demonstrated anti-bacterial activity. Psoralidin 72 was
isolated from Psoralea corylifolia and exhibits cytotoxicity
against stomach cancer cell lines.104 Recently, a new 6-substituted
2-pyrone 73, along with 6-pentyl-2-pyrone, was isolated from the
cultural ltrate of Trichoderma viride. Viridepyronone showed
antagonistic activity in vitro toward Sclerotium rolfsii, which is
the cause of stem rot of artichoke.105 Pedras and co-workers
analysed a number of blackleg causing fungi.106 A new group
of metabolites has been identied able to attack the brown
mustard plant (Brassica juncea L.), a plant previously thought
to be resistant to blackleg disease. The known metabolites
phomapyrone A 74,107 phomenin B 79108 and infectopyrone
80109 were isolated, along with new 2-pyrones phomapyrones
DG (7578). The group has previously isolated a number
of similar compounds from Leptosphaeria maculans.110 The
methanol extract of whole plants of Hypericum japonicum gave
a new 2-pyrone saropyrone 81.111 15-Deoxyoxalicine 82 was
isolated from Penicillium decaturense and is a member of a rare
structural class.73
The territrems A, B and C were isolated from rice cultures of

Aspergillus terreus (Hyphomycetes) by Yang and co-workers and
will be discussed later in more detail (section 4.2).53,112,113 Crews
and co-workers isolated nectriapyrone A 83 and nectriapyrone
B 84 from an unidentied fungus obtained from a Stylotella
sp. sponge near Taveuni, Fiji.114 Aspergione B 85 was isolated
from an Aspergillus versicolor.115 Pyrenocines D 86 and E 87
were isolated from fermentation of Sargassum ringgoldianum,
the latter showing moderate toxicity against P388 leukaemia
cells.116 Leptosphaerolide 88 was isolated from L. oraemaris.117
3 Isolation and structure elucidation
The exhaustive procedures involved in the successful isolation
of naturally occurring 2-pyrones are exemplied in the isolation
of compound 89 and its derivatives.118 Chaetomium quadrangulatum was cultivated on sterilized rice at 25 C for 33 days.
The moldy rice was extracted with 30 L of EtOAc twice. This
extract was partitioned between n-hexane and water. Each layer
was concentrated affording an n-hexane, EtOAc and aqueous
fraction of 15.89, 16.07, and 7.60 g respectively. The layer
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39, 100 and 59% at 50 lg ml1 in the case of the n-hexane, ethyl
acetate (defatted organic layer) and aqueous layer, respectively.
Repeated chromatographic fractionation of the most active ethyl
acetate layer afforded compounds 92, 93 and 94 in 0.23, 0.19 and
0.057% yields, respectively. The 1 H and 13 C data of compound 92
were similar to those of 93.95 New NMR signals corresponding
to the acetoxy group at d 2.08 (s, 3H), d 20.9 (q, 1C) and d 170.8
(s, 1C), along with downeld shifts of C-11 and H-11, due to
added deshielding from the ester group, allowed the structure of
92 to be assigned (atom numbering as in original paper). The
structure was conrmed by acetylation of 2-pyrones 92 and 93.
Both gave an identical doubly acetylated derivative 96. NOE
contacts were observed between H-7 and H-11 (9%) and H-7
and H3 -9 (5%).
showing greatest inhibition of monoamine oxidase (MAO) was

the EtOAc at 29.6% (1.0 104 g mL1 ). The EtOAc fraction
was chromatographed on silica gel to give ve fractions (I
V). Fraction IV showed greatest inhibition and was further
chromatographed to give six fractions (af). Fractions IVb and
IVc were repeatedly chromatographed affording ve chromones
(983 mg) already described.119 Fraction IVd was further
chromatographed with n-hexaneacetone to give ve fractions
IVd1-5; fraction IVd3 was treated with CHCl3 precipitating 89
(32 mg) as a white solid. Similar repetitions, crystallisation and
HPLC separation afforded another ve 2-pyrones to conclude
the six new constituents from an Ascomycete. The structure
elucidation of the 2-pyrone chaetoquadrin F, isolated from the
EtOAc extract of an Ascomycete Chaetomium quadrangulatum,
has been reported.118 The optically active white powder showed
infrared data (m KBr cm1 : 3109 (OH), 1678 (C=O), 1655, 1591
(C=C), 1429, 1383, 1257, 1124, 1076 (CO)) suggesting an a,bunsaturated carbonyl system. The 1 H and 13 C data showed
the presence of two methyl groups, two methines and four
quaternary carbons. Further study by COSY and HSQC (1 Hdetected single-bond heteronuclear correlation through multiple
quantum coherence) suggested either 89 (a 2-pyrone) or 90 (a
4-pyrone). Methylation with CH2 N2 gave a new derivative 91.
NOE studies indicate that 90 is the precursor to 91. However,
closer inspection of the UV and 13 C NMR data show that the
precursor is 89. The characteristic differences seen in the UV
(absorptions at 290 (4.02) and 263 (4.01), in nm (log e), for 89
and 91, respectively) suggest that the precursor is a 2-pyrone and
that the methylated product is a 4-pyrone. Furthermore, the 13 C
NMR signal at C-4 shifted to d 183.6 (+15.9 ppm) indicating
that C-4, which has an aromatic carbon bearing a phenolic
group, was now after treatment with CH2 N2 a carbonyl carbon.
On treatment with (R)- and (S)-MTPA acids, both hydroxyl
substituents were esteried. The modied Moshers method120
was applied and the absolute conguration assigned as (S).
Another example is G. heterospora 74-T-542-1 which was cultivated on sterilized rice. The ethyl acetate layer was partitioned
between n-hexane and water. Evaporation of each solvent layer
and testing of the crude products showed suppression of the
Con A-induced proliferation of mouse splenic lymphocytes by
376
Nat. Prod. Rep., 2005, 22, 369385
In studies by Hua, tricyclic pyranopyrones were identied as

a biologically important class of compounds.121,122 The synthesis
of 97 was achieved via the condensation of 4-amino-6-methyl2-pyrone with 1-cyclohexenecarboxaldehyde, affording both 97
and 98 in a 1 : 1.5 ratio.123 It was not possible to determine the
structures of these compounds by 1 H or 13 C NMR spectroscopy.
For example, H-10 of 97 resonates at d 8.15, the equivalent
proton in 98 is at d 8.5 (H-6); neither possesses a beacon signal
identifying the isomeric structure (atom numbering as in original
paper). Recrystallisation of 97 from ethanol and diethyl ether
gave suitable crystals for X-ray diffraction studies (crystals of 98
were not suitable).
4
4.1
Biological activity
HIV inhibitors
Human immunodeciency virus (HIV) protease124 is one of

three essential viral enzymes in the replication of HIV. Inhibition of HIV protease (HIV PR) results in virus particles
View Article Online
that are non-infectious towards other cells.125 The enormous

resources dedicated to HIV research have identied inhibition
of HIV-1 protease as the successful target for the treatment of
AIDS.126,127 Despite these studies, many of the recent protease
inhibitors suffer from serious restrictions. These include low
bioavailability,128 short half-lives,128 signicant side-effects129,130
and the emergence of HIV strains resistant to these drugs.131
Whilst inhibitors have been developed that inhibit HIV PR,132
it is important that the investigation of easily prepared, diverse,
low molecular weight inhibitors continues, this considering the
occurrence of mutations and resulting inhibitor resistance. A
group at Parke-Davis has focused its attention on synthetic,
low molecular weight non-peptide molecules suitable for further
optimisation.133 A recent review by Hagen, Vara Prasad and Tait
identies the need for such advances.133 In their investigations,
approximately 150 000 chemical compounds were screened via a
high throughput scintillation proximity assay. The compounds
were initially screened as mixtures of ten at 100 lM each. Of
these, two lead compounds were chosen based on a number of
criteria such as purity, selectivity, toxicity etc. The coumarin PD
099560 99 and 2-pyrone PD 107067 100 exhibited IC50 values of
2.3 and 3.1 lM, respectively. The coumarin is similar in structure
to warfarin 101, which is a weak inhibitor of HIV protease6,134
and also interrupts HIV replication.135,136
Tummino in his studies found that 102 was the most potent
warfarin analogue. Coumarin 99 was the initial lead compound.
X-Ray crystallographic studies illustrated that this compound
was bound to HIV PR through two possible binding modes.
In each mode, the 4-hydroxycoumarin ring of the inhibitor
displaced two water molecules. The fused phenyl ring was
orientated in the S1 site. In one mode, the exible side chain
orientated itself towards Arg 108 in the S3 region, while in
the other it folded back towards the S2 region. Structural
modication led to a marked improvement in inhibitory activity.
For example, the IC50 value of 103 is 0.52 lM.137,138
4-Hydroxy-2-pyrones have become one of the most important
classes of anti-HIV agents.135 In the late 1990s, a move to
discover cyclic non-peptide HIV protease inhibitors capable of
displacing the active site structural water molecule took place.139
The reorganization following water removal can lead to smaller
and potentially more potent inhibitors.
High resolution X-ray diffraction studies on linear inhibitors
with HIV PR-1 have shown the presence of a tetra-coordinated
structural water molecule linking the inhibitor to the aps
of the HIV PR dimer.140,141 The detailed relevance of this water
molecule is beyond the scope of this review.142,143 4-Hydroxy-2pyrones can replace the water molecule found in the active site
of the enzyme and the hydroxyl group forms hydrogen bonds
with aspartates Asp 25 and Asp 125. Water is replaced, allowing
the lactone moiety to hydrogen bond with the aps Ile 50 and
Ile 150.144
Several modications to PD 107067 were carried out. Extension of the SPh region to SCH2 Ph and SCH2 CH2 Ph
leads to improved activity.145 X-Ray diffraction studies showed
improved interaction between the SCH2 Ph group and the
S1 pocket. Systematic substitution of the phenyl group in
SCH2 Ph led to improved activity, with an isopropyl ester
adjacent to the sulfur linkage being the most successful.146
Studies on the mode of action revealed a change in the
overall binding mode. The ester function resides in the S1 in
contrast to that without the isopropyl ester group, where it
occupies the S2 pocket. Substitution of the phenyl ring with a
hydroxyl at the para-position, 3,4-benzodioxyl and 3,5-dimethyl
groups, gave improved inhibition. Further studies suggested that
branching at the 3-position might well achieve simultaneous
pocket occupation at both the S1 and S2 pockets. Vara Prasad
et al. arrived at a new series of (4-hydroxy-6-phenyl-2-oxo-2Hpyran-3-yl)thiomethanes (Table 2).
The S-aliphatic series demonstrates, in general, increased
potency over the aryl series. X-Ray crystallographic studies of
104n and HIV-1 PR showed a unique mode of binding. In this
case the lactone function only forms a hydrogen bond with the
NH of Ile 50 (compared with previous examples where hydrogen
bonding was observed with Ile 50 and Ile 150). The interaction
with Asp 125 and Asp 25 is also different. In this case, the
enol function hydrogen bonds with Asp 125 and indirectly with
Asp 25 via a bridging water molecule. The branching needed to
occupy the S1 and S2 pockets results in a chiral centre. The need
for this chiral centre could be removed with substitution of the
SPh group, in which case the substituent and the phenyl group
itself could occupy both of these positions. A small library of
such compounds resulted in a highly inhibitory 2-pyrone 105c
(IC50 = 0.037 lM).147 X-Ray diffraction studies on 105a show
that the isopropyl group occupies the S1 pocket, whereas the
3-S-phenyl group partially occupies the S2 pocket.
Nat. Prod. Rep., 2005, 22, 369385
377
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Table 2 C-3-S-aryl substituted 4-hydroxypyran-2-ones
proliferation and germ tube production in a dose-dependent

manner. This inhibitory effect correlated with a reduction in
cellular RNA and protein; therefore a decline in protein synthesis
is most likely the mode of action. While this toxic effect may
occur in other biological systems, it should be mentioned that
inhibition of human cell lines is less pronounced on HIV-1 and
C. albicans.
Compound
R1
R2
IC50 /lM
104a
104b
104c
104d
104e
104f
104g
104h
104i
104j
104k
104l
104m
104n
104o
Ph
Ph
Ph
Ph
Ph
Benzyl
Benzyl
Benzyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclopentyl
Cyclopentyl
Cyclopentyl
H
Ph
Cyclohexyl
Isobutyl
Isopentyl
Ph
Isobutyl
CH2 cyclopropyl
Ph
Isobutyl
CH2 cyclopropyl
Neopentyl
Cyclopentyl
Isobutyl
CH2 cyclopropyl
84.3
0.78
2.44
0.41
0.39
0.48
0.26
0.084
0.48
0.32
0.15
0.30
0.22
0.058
0.069
A broad screening program identied phenprocoumon 107 as

a small molecule template for the inhibition of HIV protease.6
A favourable effect on activity was observed on replacement of
the 4-hydroxycoumarin ring system with a 4-hydroxy-2-pyrone
and with the introduction of carboxamide and sulfonamide
groups.6,154,155 Thus, modication of this compound based on
structureactivity relationships, identied 108, 109 and 110
and ultimately a dihydropyrone, as next generation leads.
The nal compound was dihydropyrone PNU-140690, which
subsequently underwent clinical trials (not shown).156 In a
parallel investigation, structureactivity relationship studies on
initial leads, replacing the carboxamide with a sulfonamide,
led to the identication of another series with excellent in
vitro antiviral activity.157 The most active 2-pyrone 111 has
an IC50 value of 0.6 lM and represented a new direction
for the discovery of non-peptidic HIV protease inhibitors. In
1996, Milne and co-workers identied fteen non-peptide HIV-1
protease inhibitors by pharmacophore searching of the NCI DIS
3D database.158 The most promising inhibitor identied against
HIV-1 protease was NSC 32180 112, a dimer of 4-hydroxy
coumarin (ID50 = 0.32 lM). The tetra-coumarin derivative,
bridged by a 1,4-benzene, NSC 158393 113, demonstrated
notable activity (ID50 = 1.7 lM) and antiviral activity in HIV1-infected CEM-SS cells (EC50 = 11.5 lM).
It was envisaged that the success to date with only three

pockets occupied, could be further improved by habitation of
the S3 pocket. Because this pocket is a spatial extension of
S1 , substitution of the 6-phenyl ring could ll S3 , furthermore
if these tethers extended beyond the active site opening they
could be used to alter the physical properties of the inhibitor.148
Compound 105c was the most potent with a IC50 value of
0.019 lM. Some tricyclic 2-pyrones were also prepared, but only
showed moderate binding afnities.133 More recently the focus
has shifted to 5,6-dihydro analogues.149
Compound 106 is the predominant constitutent of the

alcoholic extract of Aspergillus terreus.150 This extract has
shown exceptional inhibitory activity towards HIV-1 at low
concentration.151,152 In was thus logical to examine the effects
of 106 on eukaryotic cells and viruses.153 Infected H9 cells, an
in vitro model of chronic HIV infection, were treated with 106.
The effective dose to reduce 50% viral replication (ED50 ) was
12.5 lM, while the toxic dose for 50% of cells was 32.5 lM. This
gives a TD50 ED50 ratio of 2.6. The activity of 106 on these cells
indicates that this molecule inhibits viral replication at postintegrational stages. The mycotoxin was also tested on Candida
albicans which can complicate HIV infection. 106 decreased cell
378
Nat. Prod. Rep., 2005, 22, 369385
4.2
Treatment of Alzheimers disease
Alzheimers disease is an age related neuro-degenerative disorder characterised by progressive memory loss and global
loss of cognitive functions. The production and deposition of
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Table 3 Inhibitory activities of tacrine, arisugacins and territrems

against acetylcholinesterase and butyrylcholinesterase
amyloid-b (Ab) peptides is thought to play a role in the

pathogenic events leading to Alzheimers disease.159,160 Ab peptides are derived from an amyloid precursor protein (APP). The
impressive bioactivities of pyripyropene A 30a49 and arisugacin52
in this area stemmed the synthesis and biological investigation
of various analogues.121,161 Compound 30a has been shown to be
an acyl-coenzyme A:cholesterol O-acyltransferase (ACAT) inhibitor, whereas arisugacin inhibits acetylcholinesterase. Hua in
his studies identied active molecules by mimicking the action of
pyripyropene and synthesising tricyclic 2-pyrones with varying
functionalities.162 The common intermediate 114 is used for all of
the 2-pyrones prepared. The successful candidates 115 and 116
protected from death MC65 cells that conditionally expressed
with a partial APP fusion protein. Surprisingly, two regioisomers
were inactive, attributable to increased hydrophobicity.
Since approval by the United States Food and Drug

Administration (FDA) of E2020 (1-benzyl-4-[(5,6-dimethoxy1-oxaindan-2-yl) methyl] piperidine) for the treatment of
Compound
AChE (IC50 /nM)
BuChE (IC50 /nM)
Tacrine, 117
Arisugacin A, 118a
Arisugacin B, 118b
Territrem B, 118c
Territrem C, 118d
200
1
25.8
7.6
6.8
12
>21 000
>516 000
>20 000
>26 000
Alzheimers disease,163 further attention has focused on the inhibition of acetylcholinesterase (AChE). The recently isolated natural product arisugacin164 contains the 6-aryl-4-hydroxypyrone
moiety and this function is necessary for biological activity.165
Arisugacin A 118a has shown huge potential in the treatment of
Alzheimers and other dementia diseases.166,167 In vitro potency
greater than existing anti-dementia therapeutics such as tacrine
117,168 aricept169 and huperzine A, was reported.170,171 It is
suggested172 that effective inhibitors should contain a nitrogen
atom to mimic the binding action of the quaternary nitrogen
of acetylcholine, a neurotransmitter responsible for memory
and other cognitive functions. A positively charged nitrogen is
believed to associate with Trp 84 situated near the anionic
gorge of the active site.167
Interestingly, 118a bears no nitrogen atom, so it obviously
functions by an alternative mechanism. Based on a modelling
study by Omura
and the known signicance of the DEring,164 Hsung made the sensible assumption that binding with
AChE may take the form of an electron-donatingelectronwithdrawing interaction.172 Electron density from the dimethoxy
group is coupled with the electron-withdrawing 2-pyrone ring.172
This prompted the group to synthesise a small library of 6-aryl-4hydroxy-pyrones that are analogues of 118a. The original source
of 118a produces only a small amount of the drug; an efcient
total synthesis has been reported.173
Omura
and co-workers isolated potent and selective inhibitors of AChE from a culture broth of Penicillium sp. FO425952,164,174,175 along with 118a. Arisugacin B 118b, territrem
A 118c and territrem B 118d, selectively inhibit AChE (Table 3).174 Tacrine, an AChE inhibitor drug approved by the FDA
demonstrates improvement of cognitive function in patients with
AD. This drug suffers from dose-limiting side effects thought to
be related to inhibition of butyrylcholonesterase (BuChE).176
A comparison of four of the isolated 2-pyrones with tacrine is
shown in Table 3. The compounds show much greater selectivity
than tacrine, opening up the possibility for the treatment of
AD with fewer side effects. Compound 118a and 118b show IC50
values of 1 and 26 nM, respectively, and also protect mice against
amnesia induced by scopolamine.
The effect of functional group changes to the inhibitory
potencies on electric eel AChE has been reported.165 Saturation
of the C-2 double bond, or reduction of C-1, caused a loss of
over 90% in activity. Epoxidation of the C-2 double bond had
little effect on activity. The 2-pyrone moiety proved crucial to
activity, as its disassembly was detrimental to activity.
Nat. Prod. Rep., 2005, 22, 369385
379
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4.3 Treatment of high cholesterol
Hypercholesterolemia is a serious problem for our society.

One approach to this is to inhibit cholesterol biosynthesis.
Plant sterols such as compesterol and sitosterol are known to
reduce plasma cholesterol by inhibiting absorption.177 The mode
of action seems to be a simple competition with cholesterol
for incorporation into micelles. Another method for reducing
cholesterol absorption is the formation of complexes with
cholesterol that are excreted.178 New inhibitors of acyl-CoAcholesterol acyltransferase have been found in the fermentation
broth of Penicillium griseofulvum F1959.56 The ACAT inhibitory
activity of phenylpyropene A (32a), B (32b) and the previously
isolated C (32c) is thought to depend on the number of acetoxy
groups and the existence of the hydroxyl group (as 32a is the
most potent). A similar compound S1495 has been isolated
from a Penicillium sp.179
Other 2-pyrone acyl-CoA-cholesterol inhibitors are the terreulactones AD (D is shown, 119, along with terreulactone A
120, isolated from Aspergillus terreus).180
The absorption of dietary lipids into the body, following

digestion, involves gastric lipase and three pancreatic enzymes:
triglyceride lipase, phospholipase A2 , and cholesterol esterase
(CEase). CEase is thought to play a dual role. Firstly, it
participates in the hydrolysis of triglycerides and secondly it
catalyses the hydrolysis of cholesterol esters.181 The mode of
action of CEase is debatable. Rat studies suggest that rat CEase
binds to heparin on the cell membrane. This binding is thought
to be associated with its 11 amino acid repeating unit near the
C-terminal.182 Other studies (gene knockout), however do not
support these ideas in human CEase.183 Inhibitors of pancreatic
CEase have been shown to lower absorption of dietary cholesterol in animal studies.184186 3-Aryl-6-chloro-2-pyrones were rst
developed as irreversible inactivators of serine proteases thought
to function as suicide inactivators.187,188 The success of recently
synthesised 3-alkyl analogues may lie in their selectivity. While
the 3-alkyl versions inhibit chymotrypsin less successfully, they
do so reversibly and thus are promising as selective inhibitors.3
Moreover, inhibitor 121d inhibits CEase in the presence and
absence of bile salts. In the absence of bile salts, CEase adopts a
conformation in which the C-terminal hexapeptide is lodged in
the active site rendering a less competent active site.189,190 A series
of 3-alkyl-6-chloro-2-pyrones with cyclohexane rings tethered
to the 3-position has been synthesised. The length of the alkyl
group affects the inhibition of cholesterol esterase. For example,
in the case of 121d, the K i is as low as 0.025 lM.181
To extend the previous study by Deck and co-workers,181 on
the selective inhibition of porcine CEase by 6-chloro-2-pyrones
with aliphatic groups at the 3-position, this group investigated 2pyrones with a series of substituents at the 3- and 5-positions.191
Yeast CEase from Candida cylindracea (C. rugosa CRL 3) and
CRL 1 were compared to porcine pancreatic cholesterol esterase
for inhibition by these series and related CRL 1 were compared
to CEase for inhibition. The activity of CRL 1 and CRL 3 was
monitored in 25 mM Tris, pH 7, containing 6 mM taurocholate.
Hydrolysis of p-nitrophenylbutyrate (1 mM) was followed at
405 nm (25 C). Porcine CEase was monitored similarly. K i
values were obtained by measuring rates with and without the
380
Nat. Prod. Rep., 2005, 22, 369385
Table 4
Porcine
CEase
K i /lM
CRL 3
K i /lM
CRL 1
K i /lM
121a
0.04
58
960
121b
2.3
84
110
121c
2.2
12
120
121d
0.025
0.73
110
121e
0.13
96
120
121f
0.51
45
240
121g
0.80
16
>900
121h
0.50
53
225
Cpd.
Structure
addition of inhibitor. Small changes in the nature of the alkyl

group had profound effects on binding. Furthermore, no denite
pattern emerged as regarding the preferential position of an alkyl
group at the 3- or 5-position (Table 4). Porcine CEase has already
been demonstrated to function as a simple reversible competitive
inhibitor.181 Investigations into whether CRL 1 and CRL 3 act
in a similar fashion were pursued by extraction of the assay and
comparative TLC. Unfortunately, no presumption can be made
as to the similarities between CRL 2 and mammalian CEase.
For example, porcine CEase is 1450 times more sensitive than
CRL 3 to inhibition by 2-pyrone 121a. Further conict between
porcine CEase and CRL 1 and CRL 3 is observed in their mode
of action; CEase functions as a reversible inhibitor. While CRL 1
signicantly inhibited activity, removal of the inhibitor resulted
in complete recovery of activity, suggesting that the 2-pyrones
are not suicide inhibitors or irreversible inactivators of CRL 1.
Treatment of CRL 1 with an inhibitor, followed by analysis of
the resulting products showed products consistent with hydrolysis of the pyrone ring. In the case of CRL 3, recovery of activity
took several hours after removal of the inhibitor suggesting it
functions as a pseudosubstrate. Possible mechanisms include
(see scheme below): (1) suicide inhibition in which formation of
B is followed by attack of an active site nucleophile, followed by
deacylation to C; (2) simple substrate inhibition in which the acyl
chloride B hydrolizes to acylenzyme D followed by deacylation
to regenerate active enzyme E with liberation of the substituted
glutaconic acid product; (3) simple reversible inhibition where
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an active site nucleophile attacks the 6-position on the 2-pyrone

with release of chloride. Studies show that the 2-pyrone behaves
as a pseudosubstrate inhibitor in which acylation is much faster
than deacylation such that the acylenzyme accumulates and
rearranges to the acid chloride, which hydrolyses while tethered
to serine followed by slow hydrolysis and release of product.
4.4 Treatment of cancer

In a study aimed at investigating the anti-cancer properties
of tricyclic 2-pyrones with similar structures to pyripyropene
(30ad) and arisugacins (118ab), novel TCPs were synthesised
and tested for their ability to prevent leukaemic cells from
synthesising DNA and growing in vitro.192 The four pentahydro3-aryl-1-oxopyrano-[4,3-b][1]benzopyrans 122, 123ab and 124
all inhibit DNA synthesis by 7991% and tumour cell growth by
93100%. Tricyclic compounds that lack the aryl group either
show negligible or diminished anti-tumour activity, suggesting
that a greater conjugation is required for activity. Pyrone 122
compared well with the known anti-cancer drug CPT; while
it proved less potent, it does not show any acute toxicity
in vivo. A subsequent report introduced the novel 2-pyrone
125.193 Compounds 122 and 125 were tested for their ability
to disrupt microtubule (MT) dynamics; or to alter the mitotic
index and prevent murine EMT-6 mammary sarcoma cells from
synthesising DNA and proliferating in vitro. Compound 124
inhibits DNA synthesis, tubulin polymerisation and tumour cell
growth, but to a lesser extent than 125. The former compound
mimics the effect of vincristine (VCR) but not that of paclitaxel
on tubulin polymerisation. Further tests of these and related
2-pyrones revealed that 122 and 125 are more potent inhibitors
of DNA, RNA and protein synthesis than 124 at 1025 lM.122
However, 124 is more effective at inhibiting the growth of L1210
cells over a 4-day period at 525 lM. This inconsistency may be
due to a difference in the molecular target in the inhibition of
macromolecule synthesis and leukaemic cell growth.
Encouragingly, 124 is comparable with a number of anticancer drugs as an inhibitor of L1210 cell growth.
An array of N-substituted 4-aminocoumarin bicyclc and
tricyclic pyrones (R1 and R2 = several moieties) was synthesised and tested for anti-proliferative properties.194 The anti-
proliferative and cytotoxic properties were evaluated by testing

the compounds for their inhibitory properties on DNA synthesis
in Ehrlich cells (an experimental tumour of the mouse) and for
cytotoxicity by the MTT assay (HeLa cells, a tumour cell line of
human origin). The activity of the compounds depended on the
type of amino substituent.
In general, compounds showed increased anti-proliferative
activity over cytotoxic activity. The most active compound was
128 (NR1 R2 = NHPh) with an IC50 value of 1.75 lM in the
inhibition of DNA synthesis. Compound 126 (NR1 R2 = NHPh,
Y = OCH2 O, IC50 = 2.64 lM) shows good potential as an
anti-proliferative agent due to its negligible cytotoxic activity.
As seen in many examples of naturally occurring 2-pyrones,
variation of substituent at the 4-position is important. Novel
methods for the preparation of 4-substituted-6-methyl pyrones
(130132) that allow the introduction of a plethora of alkyl,
aryl, alkenyl and alkynyl substituents have been developed.195
These involve cross-coupling of an electrophilic pyrone ring
with trialkylboranes, arylboronic acids, alkenylboronic acids
and alkynes. The synthesis of simpler yet variable 2-pyrones
was then carried out and they were screened for inhibitory
Nat. Prod. Rep., 2005, 22, 369385
381
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activity against ovarian carcinoma (A2780) and human chronic

myelogenous leukaemia (K562) cell lines. The pyrones exhibited
good cytotoxic activities. The 4-alkynyl-6-methyl-2-pyrones,
130a and 130b, were most promising with IC50 values as low
as 4.0 and 1.8 lM for K562 and A2720 cell lines, respectively.196
4.5 Other uses

Over one third of all 2-pyrones screened by Fairlamb and coworkers showed prominent anti-proliferative activity.196 The 2pyrones showed widespread antimicrobial activity against Bacillus subtilis, Escherichia coli, Staphylococcus aureus, Schizosaccharomyces pombe and Botrytis cinerea.
Selective cyclooxygenase-2 (COX-2) inhibitors have many
useful applications. These include the treatment of neurodegenerative disorders such as Alzheimers disease197 as previously described, and inammatory diseases such as rheumatoid
arthritis.198 COX-2 inhibitors can also induce apoptosis in colon,
stomach, prostate and breast cancer lines.198201 Diaryl heterocycles constitutes a major class of COX-2 inhibitors. Optimum
potency and selectivity have been shown (via structural activity
relationship studies) to occur when a sulfonylmethyl group is
present at the para-position of one of the aryl rings and a uorine
substituent at the para-position of the other.202
Etoricoxib 133202,203 bears a 6-membered pyridine ring, SC
57666 134,204 both an SO2 Me and F group and Rolecoxib 135,205
a ve membered lactone similar to a 2-pyrone function.
Knaus and co-workers designed, synthesised and tested
various 2-pyrones with similar structural features to the above.206
136a, 136c and 138b showed an IC50 value of <1 lM with the
latter at 0.0032 lM. This value reects greater inhibition than
135 when compared using two determinations and an ovine
COX-2 assay kit. Using a docking experiment, the orientation
of the most potent inhibitor, 138b, within the COX-2 active site
was studied. Several hydrogen bonds seem to disrupt the salt
bridge between His 90, Arg 120, Tyr 355 and Glu 524 at the
mouth of the active site. The importance of the SO2 Me group
seems to involve its position in a hydrophobic cavity (lined by
Tyr 385, Trp 387, Tyr 348 and Ser 530) and its ability to hydrogen
).
bond with the OH of Ser 530 (4.41 A
382
Nat. Prod. Rep., 2005, 22, 369385
Further reports involved the synthesis of a large library of 6alkyl (alkoxy or alkylthio)-4-aryl-3-(4-methanesulfonylphenyl)2-pyrones with either a H or F substituent at the para-position of
the C-4 phenyl again designed as selective COX-2 inhibitors with
in vivo anti-inammatory and analgesic activities (139141).207
Compound 140 exhibited excellent in vitro COX-2 inhibitory
values (IC50 = 0.0032 lM) and selectivity (SI >120 000). Insights
into selectivity were gained using theoretical studies, which
reveal that the SO2 Me substituent of 139 orients itself in the
vicinity of the secondary pocket of COX-2. COX-1 possesses no
such accessible pocket, due to the presence of the bulky Ile 523
residue.
Investigations by the same group showed that 141 was a
potent and selective COX-2 inhibitor (IC50 = 0.02 lM).208 A
group of regioisomeric 3,4,6-triphenyl-2-pyrones with a MeSO2
pharmacophore at the para-position of either a C-3 phenyl
or a C-4 phenyl substituent on the central 2-pyrone ring was
prepared and evaluated. COX-2 inhibitory potency is sensitive
to the substituent electronic properties at the para-position of
the C-6 phenyl ring. An electron-withdrawing substituent (CF3 )
showed reduced selectivity and potency (IC50 >100 lM) towards
COX-2.
Future lead compounds and directions
The review highlights the abundance of 2-pyrone natural

products possessing broad spectrum bioactivities, reported in
the last thirteen years. Since 2-pyrones represent a rich source
for isolation studies and lead discovery, here lies a wonderful
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opportunity to design, synthesise and identify novel synthetic

2-pyrones and natural product 2-pyrone mimetics. The future
is bright for these compounds. The development of more
efcient syntheses to substituted 2-pyrones represents a synthetic
challenge. Here, cross-coupling (Sonogashira, Stille, Suzuki
etc.)209 and cyclisation strategies210 continue to be developed.
It is quite apparent that simple natural and non-natural 2pyrones possess important bioactivity, and although advanced
transformations are required for more elaborate structures, the
readers, particularly medicinal chemists, are encouraged to focus
on simple analogues or relatives, e.g. 2-pyridinones.
6 References
1 M. Chmielewski and J. Jurczak, J. Org. Chem., 1981, 46, 2230.
2 A. Ichihara, H. Tazaki and S. Sakamura, Tetrahedron Lett., 1983,
48, 5373.
3 W. A. Boulanger and J. A. Katzenellenbogen, J. Med. Chem., 1986,
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View Article Online / Journal Homepage / Table of Contents for this issue

Gerard P. McGlacken and Ian J. S. Fairlamb*

2-Pyrone natural products and mimetics: isolation, characterisation

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Received (in Cambridge, UK) 16th February 2005

Covering: December 1992 to December 2004

The Royal Society of Chemistry 2005

Nat. Prod. Rep., 2005, 22, 369385

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Some ten years ago, Dickinson reviewed the literature

The mortality of an assay of brine shrimp (Artemia salina L.)

2 Naturally occurring 2-pyrones

Nat. Prod. Rep., 2005, 22, 369385

The 2-pyrone 12 was isolated by the Mitsubishi Pharma group

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with FP (100 ppm) resulted in an infection rate of 9% compared

of the valerophenone synthase (VPS) catalysed synthesis of

Gibepyrones are 6-substitued-3-methyl-2-pyrones. The rst

Two strains of the fungus Cladosporium herbarum were isolated

The genus Trichoderma is an excellent source of biologically

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coleoptile and lettuce seed germination.40 At a concentration

structure elucidation,50 and nally the rst total synthesis of

Nat. Prod. Rep., 2005, 22, 369385

Of the seventeen compounds isolated from the n-butanol

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bearing the 2-pyrone moiety, are often detected in marine

A recent analogue of luteoreticulin,74,75 griseulin 47 was

Davidson and co-workers isolated four 2-pyrones from a

Naturally occurring styrylpyrones, without a 4-hydroxy moiety,

Five novel cytotoxic compounds, NF00659 A1 52a, A2 52b, A3

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Table 1 Novel 2-pyrones based on generic structure 52

fruit bodies of the fungus Ganoderma lucidum. G. lucidum can

2-Pyrone-4,6-dicarboxylic acid was isolated from Potentilla

Nat. Prod. Rep., 2005, 22, 369385

As can be seen from the overlay of 56 with testosterone

Isoprenoid-substituted 3-arylcoumarins, glyasperin L 64 from

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isolated. 4,4 -Di-O-methylscandenin 66 has been isolated from

The territrems A, B and C were isolated from rice cultures of

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showing greatest inhibition of monoamine oxidase (MAO) was

Nat. Prod. Rep., 2005, 22, 369385

In studies by Hua, tricyclic pyranopyrones were identied as

Human immunodeciency virus (HIV) protease124 is one of

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that are non-infectious towards other cells.125 The enormous

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Table 2 C-3-S-aryl substituted 4-hydroxypyran-2-ones

proliferation and germ tube production in a dose-dependent

A broad screening program identied phenprocoumon 107 as

It was envisaged that the success to date with only three

Compound 106 is the predominant constitutent of the