Recent Insights into the biosynthesis and biological activites of natural Xanthones

854 Current Medicinal Chemistry, 2010, 17, 854-901

0929-8673/10 $55.00+.00 © 2010 Bentham Science Publishers Ltd.

Recent Insights into the Biosynthesis and Biological Activities of Natural

Xanthones#

H.R. El-Seedi*,1,2,

M.A. El-Barbary2, D.M. H. El-Ghorab

2, L. Bohlin

1, Anna-Karin Borg-Karlson

3,

U. Göransson1 and R. Verpoorte

4

1Pharmacognosy Division, Department of Medicinal Chemistry, Uppsala University, Biomedical Centre, Box 574, SE-

75123, Uppsala, Sweden; 2Department of Chemistry, Faculty of Science, El-Menoufia University, 32512, Shebin El-

Kom, Egypt; 3

Ecological Chemistry Group, Department of Chemistry, KTH SE-100 44 Stockholm, Sweden; 4Section of

Metabolomics, Institute of Biology, Box 9502, 2300 RA, Leiden, The Netherlands

Abstract: This review focuses on recent advances in our understanding of the complex biosynthetic pathways and diverse biological activities of naturally occurring xanthones. The biosynthesis section covers studies published from 1989 to 2008 on xanthone production in plants and fungi, while the bioactivity review presents tabulated activities of more than 250 xanthones described in studies published from 2001 to 2008, together with structural information and indications of their wide-ranging potential uses as pharmacological tools. A large number of relevant papers have been published on these subjects (128 cited here), illustrating the diversity of the xanthones and their possible uses.

Keywords: Biological activity, Alzheimer’s disease, anti-cancer, anti-microbial, anti-inflammatory, neuropharmacology, car-dioprotective, biosynthesis.

#Dedicated with great respect and regards to Prof. L. Bohlin on the occasion of his 60

th birthday.

INTRODUCTION

Xanthones are natural polyphenolic compounds that are present in higher plants, fungi and lichens [1]. The biological activities of these compounds are associated with their tri-cyclic scaffold, but vary depending on the nature and/or po-sition of the substituents [2]. For this reason, Lesch and Bräse [3] have described the xanthone scaffold as a “privi-leged structure” since compounds of this structural class can interact with diverse drug targets. The basic xanthone skele-ton is symmetric, but it has a mixed biogenetic origin in higher plants and the carbons are often numbered according to a biosynthetic convention, in which carbons 1-4 are as-signed to the acetate-derived ring A and carbons 5–8 to the shikimate-derived ring B [4]. The numbering is not always uniform in the literature, but the IUPAC provisional recommendations of 2004 for the parent compound 9H-xanthen-9-one are used in this review (Fig. 1).

O

O

AB

1

2

3

45

6

7

8

4a10a

8a 9a

10

9

Fig. (1). Basic xanthone skeleton.

A number of reviews on naturally occurring xanthones have been published. The more recent reviews cover the lit-erature concerned with the identification of xanthones, with brief reference to the bioactivity of the isolated compounds [1], or the biological and pharmacological activities of xan-thones [2, 5].

In this review, we present an updated literature survey of naturally occurring xanthones published in the last eight

*Address correspondence to this author at the Pharmacognosy Division,

Department of Medicinal Chemistry, Uppsala University, Box 574, SE-

75123 Uppsala, Sweden; Tel: +46-18-4714496; Fax: +46-18-509101;

E-mail: [email protected]

years (from January 2001 to May 2008), providing a tabu-lated index of their bioactivities along with their pharmacol-ogical evaluations and structures. In addition, we discuss the xanthones biosynthetic pathways and attempt to correlate observed oxygenation patterns of natural xanthones with recognized oxygenation patterns.

BIOSYNTHESIS OF XANTHONES

The biosynthetic pathways of xanthones have been stud-ied for 40 years and have been discussed in several reviews [4, 6-8]. The central step in the xanthone biosynthetic path-way is the formation of the C13 skeleton [9], key precursors of which may be polyhydroxybenzophenones. Thus phenyla-lanine, which is formed from shikimate by losing two carbon atoms from the side chain, is oxidized to form m-hydroxybenzoic acid, which then combines with 3 units of acetate, yielding the intermediate shown in Scheme 1. Sub-sequent folding and ring closure gives a substituted benzo-phenone, which generates the central ring of the xanthone moiety via an oxidative phenol coupling reaction. This path-way has been confirmed in experiments in which Gentiana lutea plant was fed

14C-labeled phenylalanine or

14C-labeled

acetate, and the incorporation patterns were then analyzed [9].

The biosynthetic pathway of xanthones in the medicinal plant Centaurium erythraea starts with 3-hydroxybenzoate. The enzyme coenzyme-A ligase catalyzes the esterification of 3-hydroxybenzoic acid with coenzyme-A to form 3-hydroxybenzoyl-CoA, which is then condensed stepwise with three molecules of malonyl-CoA in reactions catalyzed by benzophenone synthase [10]. The resulting 2,3’,4,6-tetrahydroxybenzophenone is a central intermediate in xan-thone metabolism and is cyclized regioselectively to 1,3,5-trihydroxyxanthone in C. erythraea cell cultures, as illus-trated in Scheme 2 [11]. This oxidative phenol coupling is catalyzed by xanthone synthase, a cytochrome P450 enzyme. The activity of this membrane-bound enzyme requires

Recent Insights into the Biosynthesis Current Medicinal Chemistry, 2010 Vol. 17, No. 9 855

OHHO

O

NH2

OH

OO

O

O

O

HO

Shikmic acid derivative intermediate

3 acetate uints

OH

O OH

OHHO

12 3

45

61'

6'5'

4' 3'2'

O OH

OHHO

12

3

45

6

HO

1'2'

3'4'

5'6'

or

O OH

OHO

1,3,7-Trihydroxyxanthone

HO

OH

O OH

OHO


2,3',4,6-Tetrahydroxybenzophenone

Scheme 1. Proposed xanthone biosynthesis pathway in Gentiana lutea, according to analyses in which plants were fed 14

C-labeled phenyla-

lanine or 14

C-labeled acetate.

HO

OH

O

CoAS

OH

O

OH

O OH

OHHO

OH

O OH

OHO

Coenzyme A3 Malonyl-CoA

3-Hydroxybenzoic acid 3-Hydroxybenzoyl-CoA

12

3

45

61'

6'5'

4'3'

2'



OMe

O O

OMeO

OMe Prim

MeO

MeO

3,5,6,7,8-Pentamethoxy-1-O-primeverosylxanthone

xanthone synthase

benzophenone synthase3-hydroxybenzoate: coenzyme A ligase

Scheme 2. Proposed xanthone biosynthetic pathway in cell cultures of Centaurium erythraea.

oxygen and NADPH, and is strongly inhibited by established P450 inhibitors [12].

The reaction mechanism underlying the regioselective in-termolecular cyclization of the benzophenone is likely to be an oxidative phenol coupling involving two one-electron oxidation steps. The first one-electron transfer and a depro-tonation yields a phenoxy radical, which cyclizes benzophe-none via electrophilic attack. The intermediate resonance-stabilized hydroxyl-cyclohexadienyl radical loses an electron and a proton. This mechanism is strongly favored by the ortho-para-directing 3’-hydroxy group and supported by the

substrate specificities of the enzymes, which efficiently cata-lyze conversion of the 3-hydroxylated substrates.

In C. erythraea 2,3’,4,6-tetrahydroxybenzophenone is in-termolecularly regioselectively coupled to 1,3,5-trihydroxyxanthone, while in Hypericum androsaemum 2,3’,4,6-tetrahydroxybenzophenone is coupled to 1,3,7-trihydroxyxanthone. This phenol coupling occurs via active sites in ortho-position to the 3’-hydroxy group at C-2’ in C. erythraea and para-position to the 3’-hydroxy group at C-6’ in H. androsaemum, as shown in Scheme 3 [11].

856 Current Medicinal Chemistry, 2010 Vol. 17, No. 9 El-Seedi et al.

Alternative pathways of xanthone biosynthesis in cell cultures of H. androsaemum have also been reported [13]. Xanthone products in cell cultures of H. androsaemum arise biosynthetically from 1,3,7-trihydroxyxanthone, which is in turn formed by regioselective cyclization of 2,3’,4,6-tetrahydroxybenzophenone [11]. Benzophenone synthase from H. androsaemum acts most efficiently on benzoyl-CoA, though 3-hydroxybenzoyl-CoA is also converted to a lesser extent. In cell cultures of H. androsaemum, stepwise condensation of benzoyl-CoA with three molecules of malo-nyl-CoA yields 2,4,6-tetrahydroxybenzophenone. The re-ported presence of benzophenone 3’-hydroxylase in these cultures strongly suggests that alternative pathways lead to the formation of 2,3’,4,6-tetrahydroxybenzophenone from 2,4,6-Trihydroxybenzophenone. The 3’-hydroxy group is essential for the subsequent oxidative phenolic coupling re-action catalyzed by xanthone synthase [11]. It has been found that 2,3’,4,6 tetrahydroxybenzophenone is in-tramolecularly converted to 1,3,7-trihydroxyxanthone, as shown in Scheme 4 [13].

The findings regarding biosynthetic pathways in the pre-vious two cell cultures agree well with substitution patterns of the xanthones that accumulate in them. C. erythraea cul-tures contain 5-oxygenated xanthones, while H. androsae-mum cultures mainly accumulate 7-oxygenated xanthones. The 1,3,5- and 1,3,7-trihydroxyxanthones are precursors for most xanthones, thus regioselective intermolecular cycliza-tion of 2,3’,4,6-tetrahydroxybenzophenone represents an important branch point in plant xanthone biosynthesis [9].

Other demonstrated biosynthetic pathways of xanthone formation in plants involve intermediate glycosidation at an early stage of benzophenone biosynthesis before cyclization of the two rings. This pathway occurs in the herb Hypericum annulatum, in which 2,3’,4,6 tetrahydroxybenzophenone-2’-O-glucoside has been shown to be a precursor of 1,3,7-trihydroxyxanthone (gentisein). The transformation could occur via acidic or enzymatic hydrolysis of the glucoside and subsequent dehydration involving hydroxyls from phloro-glucinol rings A and B located ortho to the carbonyl group.

O OH

OHHO

12

3

45

6


O OH

OHO

12

3

45

61'6'

5'4'

3'2'

OH

O OH

OHO

12

3

45

6

1'6'

5'

4'3'

2'

-e-

-H+

Hypericum androsaemumCentaurium erythraea

OH

O OH

OHOH

O OH

OHOH

HO

O OH

OHOH

HO

OH

O OH

OHOH

-e--e-

-H+ -H+

OH

O OH

OHO


O OH

OHO


HO

HO

HO

1'2'

3'

4'5'

6'

Scheme 3. Reaction mechanism underlying the regioslective oxidative coupling of 2,3’,4,6-Tetrahydroxybenzophenone to form xanthones in

Centaurium erythraea and Hypericum androsaemum


This would confirm the hypothesis that some xanthones are formed in plants by dehydration of 2,2’-dihydroxy-benzophenones [14]. The intermediate precursors appear to be benzophenone O-glycosides ortho to the carbonyl func-tion, see Scheme 5 [14]. Recent phytochemical investiga-tions of benzophenone O-glycosides and xanthones of H. annulatum have found that the content of 2,3’,4,6-tetrahydroxybenzophenone-2’-O-glucoside depends on the phenophase of the plant, being smaller in sterile plants and increasing in plants with flowers, whereas the gentisein con-

tents decline. This trend correlates with the hypothesis that 2,3’,4,6-tetrahydroxybenzophenone-2’-O-glucoside could be a precursor of gentisein [15].

Xanthones produced by fungi, such as Aspergillus strains, have a complex biosynthetic pathways; from an-thraquinones to xanthone derivates and from xanthones to coumarins, starting with the polyketide synthase-catalyzed generation of norsolorinic acid. This intermediate is �immers� to averantin, which was further oxidized and converted into averufin. Averufin appears to be transformed

OHOH

OO

OH

SACo

O

OH

SACo

O

OHO

OHHO

HOOHO

OHHO

O

O

OH

OH

HO

O

O

OH

OH

HO

HO

O

O

OH

OH

HO

HO

3 Malonyl-CoA3 Malonyl-CoA

Coenzyme CoACoenzyme CoA

Bebzophenone3'-hydroxylase

Benzophenone synthase

3-hydroxybenzoate: coenzyme A ligase

Xanthone synthase

Xanthone-6-hydroxylase

3-Hydroxybenzoic acid Benzoic acid

3-Hydroxybenzoyl-CoABenzoyl-CoA

2,3',4,6-Tetrahydroxybenzophenone2,4,6-Trihydroxybenzophenone

1,3,7-Trihydroxyxanthone1,3,6,7-Tetrahydroxyxanthone

-Mangostin

1'2'

3'

4'5' 6'

Scheme 4. Proposed biosynthesis of xanthone in cell cultures of Hypericum androsaemum.


by cleavage and further oxidative rearrangement to hy-droxyversicolorone then to versicolorin-A. Versicolorin-A is then transformed to the xanthone demethylsterigmatocystin. This is expected to require the activity of several enzymes encoded by genes in a biosynthetic cluster [16].

Henry and Townsend [17] proposed that reaction steps in the conversion of versicolorin-A to demethylsterigmatocys-tin are most consistent with the following order: oxidation-reduction-oxidation. Such a reaction sequence is also consis-tent with the three types of enzymes now known to be in-volved in versicolorin-A to sterigmatocystin conversion. The first step in the proposed conversion process is epoxidation of the B ring of versicolorin-A, catalyzed by the cytochrome P450 mono-oxygenase VerA, giving structure [i] in Scheme 6. This intermediate is predicted to rearrange to a dienone in-termediate (structure ii), followed by Ver-1-catalyzed deoxy-genation. Cluster gene aflY encodes an enzyme that is pre-dicted to catalyze the Baeyer-Villiger oxidation of such a dienone [18], and the dienone in Ver-1 defective mutants may revert to versicolorin-A by acid-catalyzed dehydration, while in aflY mutants (which express functional Ver-1) the products formed by Ver-1-catalyzed reduction of the dienone (structure iii) may revert to versicolorin-A or 6-deoxyversicolorin-A, if R= OH or R= H, respectively. Step-wise successive O-methylations catalyzed by two substrate-specific SAM-dependent O-methyltransferases (aflO fol-lowed by aflP) then follow, resulting in the conversion of demethylsterigmatocystin to O-methylsterigmatocystin [19]. Recent genetic evidence suggests that a single cytochrome P450 converts this penultimate intermediate to aflatoxin B1, a process involving net oxidative cleavage of the xanthone A-ring, O-demethylation, dehydration, decarboxylation, and rearrangement [20], as illustrated in Scheme 6.

It has been shown that, in micro-organisms, xanthones and the xanthone derivatives xanthoquinodins are mostly formed from eight acetate units. Xanthoquinodins are a re-cently discovered family of heterodimers comprised of an octaketide-derived anthraquinone and a xanthone linked in an “end-to-body” fashion. Examples include xanthoqui-nodins Al, A2, A3, B1 and B2; anticoccidial antibiotics that have been isolated from fungi species of the genus Humicola [21]. The origins of all the carbons of xanthoquinodin A1 have been unambiguously determined by experiments in which cultures have been fed

13C-labeled acetate unit precur-

sors, which have demonstrated that xanthoquinodin A1 is a heterodimer of octaketide-derived anthraquinone and xan-thone anthraquinone moieties linked in a unique fashion. The proposed biosynthetic sequence of xanthoquinodin-A1 [VI] is shown in Scheme 7. First, two anthraquinones (elminthosporin [II]) are produced from two octaketides via

decarboxylation of the tail. One molecule of [II] is subjected to oxidative cleavage at the B ring, yielding a hypothetical benzophenone intermediate. Similar decarboxylation and oxidative cleavage steps have been reported in a biosynthetic study on related compounds [22, 23]. The phloroglucinol moiety (C ring) of this intermediate rotates between [Iva] and [Ivb]. A tricyclic xanthone [V] is formed from this in-termediate [IV]. Next, the xanthone [V] and anthraquinone [III] are connected at the two sites to form the skeleton of [VI]. Finally, one methyl residue is introduced from me-thionine, yielding [IV]. These findings show that xanthoqui-nodin-A1 is a heterodimer of octaketide-derived xanthone and anthraquinone moieties coupled in a unique fashion. Xanthoquinodins-A2, B1 and B2, all of which have the same skeletal structure as xanthoquinodin Al, are produced in an analogous biosynthetic sequence. Many compounds have been reported to be �immers comprised of octaketide-derived anthraquinones and/or anthrones [24].

BIOLOGICAL ACTIVITIES AND PHARMACOLO-

GICAL EVALUATIONS

Naturally-occurring xanthones comprise an important class of compounds that possess a wide range of biological properties [25], and hence have well-known roles in medici-nal chemistry [2, 5]. In this section, biological activities re-ported in the period 2001-2008 are described, in the order illustrated in Fig. (2), with emphasis on their uses (and po-tential utility) as therapeutic agents and/or pharmacological tools.

1. Insecticidal and Anthelmintic Activities

Xanthonol (1) has been shown to have moderate insecti-cidal and anthelmintic activities against Aedes aegypti, Lucilia sericata, and Haemonchus contortus, with LD90 val-ues of 8, 33, and 50 μM, respectively [26]. Hence, it is con-sidered to be a promising lead for safe, efficacious systemic antiparasitic drugs with new modes of action, which are ur-gently needed to effectively treat human and animal infec-tions, since the efficacy of current insecticides and an-thelmintics, even with the latest approved treatments, is lim-ited by low therapeutic indices, environmental hazards, de-velopment of resistance, and/or lack of systemic effects [26].

ANTIMICROBIAL ACTIVITY

Bacterial and fungal resistance to antibiotics has become a serious problem in the treatment of infectious diseases. Searches for new antifungal agents are also of great impor-tance because of the increased incidence of infections by

O OH

OH

OH

HO

OGlc

AB16

23

45

1'

2'3'

4'

5'6'

O OH

OH

OH

HO

OH

AB

O OH

OH

HO

O

AB1

6

23

45

1'2'

3'4'

5'6'

D-GlcH2O

2,3',4,6 tetrahydroxybenzophenone-2'-O-glucosideis 1,3,7-trihydroxyxanthone

Scheme 5. Proposed benzophenone-O-glucoside precursor of xanthones in Hypericum annulatum.


O OH

OH

OH

HO

O

O O OHOH

HO

O

O

O

O OHOH

HO

O

O

OH

O

O OHOH

HO

O

O

O

HydroxyversicoloroneVersicolorin A

Norsolorinic acid

Averufin

O OHOH

O

O

O OHOH

HO

O

OH

O

O OH

COOH

OOH

OH

Ver A

ii

iv

Ver-1

AflY

+H2O

O O

O

O OHOH

O O

O

O OMeOH

-CO2

-H2O

AflO O O

O

O OMeOMe

O O

O

O

OMe

O

Demethylsterigmatocystin Sterigmatocystin O-methylsterigmatocystin

Alfatoxin B1

O OHO

R

O

OH

iii

i

AflP

6-Deoxyversicolorin-A

Ver-1

-CO2

O OH

OH

OH

HO

O

OH

Averantin

Scheme 6. Proposed biosynthesis of Alfatoxin B1 inculding biosynthesis of Sterigmatocystin.


OH

O O O O

O

O

O O O

OH O OH

O

OH O OH

O

OH O OH

OH O OH

O

HO

OOH

OH O OH

HO

OOH

O

OH O OH

OH

HO

O

O

OH O OH

OH

MeO

O

O

OH

OH

O

methyl of menthionine

Elminthosporin [II]

[IVa] [IVb]

Xanthoquinodin-A1 [VI]

'End to body' coupling

[I]

[III]

[IV]

[V]

A B C

X 22 [acetate unit x 8]

Scheme 7. Proposed biosynthesis pathway of xanthoquinodin-A1in Humicola species.

Fig. (2). Biological activities and pharmacological evaluations of naturally occurring xanthones.

Biological activities & pharmacological evaluations

of naturally occurring xanthones

F

Insecticidal and anthelmintic activities

Antiprotozoal activity

Antimicrobial Activity

Anti-HIV-1 activity

Antioxidant activity

Anti-atherosclerotic activity

Hypotension inhibitory effect

Cardioprotective effect & cardiovascular activity

Inhibitory activity against MAO & neuropharmacological activity

Inhibition of cholinesterase activity

Binding to transthyretin

-Glucosidase inhibitory activityα

Anti-inflammatory activity

Inhibition of COX activity

Immunosuppressive effect

Cytotoxicity & cancer chemoprevention activities

Gastro-protective effect

1

23

4

56

7


Table 1. Antimicrobial Activities of Naturally Occurring Xanthones

xanthonol (1)

O

O OHOHO

OOH OH

OHOH

OOMe

O

O

Compound Microorganism investigated

against

MIC

(μM)

References

Antimycobacterial active compounds

2

O

O OH

O

HO

O

MeO2C

Artoindonesianin-C

Mycobacterium tuberculosis 12.5 Namdaung et al., 2006 [29]

3

O

O OH

OMe

MeO

HO

-Mangostin

M. tuberculosis H37Ra strain 6.25 Suksamrarn et al., 2003 [30]

4

O

O OH

OH

MeO

HO

-Mangostin


5

O

O OH

OHHO

O

Garcinone-B


6

O

O OH

HO

Pre

O

Demethylcalabaxanthone


7

O

O OH

O

PreOH

Trapezifolixanthone



(Table 1). Contd…..


against

MIC

(μM)

References

8

O

O

OH

OH

HO

HO

-Mangostin

M. tuberculosis H37Ra strain 25 Suksamrarn et al., 2003 [30]

9

O

O OH

OH

MeO

HO

OH

Garcinone-D


10

O O

OH

MeO

HO

OHO

Mangostanin


11

O

O OH

OO

HO

pre

Mangostenone-A


12

O

O OH

O

pre

O

HO

Tovophyllin-B


Antifungal active compounds

13

O

O OH

O

Laurentixanthone-A

Candida gabrata 2.44 Nguemeving et al., 2006 [31]

C. gabrata 0.61 Nguemeving et al., 2006 [31] 14 Laurentixanthone-B

C. albicans 19.53 Nguemeving et al., 2006 [31]




against

MIC

(μM)

References

C. glabrata 3 Fukai et al., 2003 [32]

Cryptococcus neoformans 3 Fukai et al., 2003 [32]

Aspergillus fumigatus 3 Fukai et al., 2003 [32]

15

O

O OH

HO

OH

OH

Cudraxanthone-S

A. nidulans 3 Fukai et al., 2003 [32]

Candida albicans 25 Wang et al., 2005 [33]

C. glabrata 8 Fukai et al., 2003 [32]

Aspergillus fumigatus 8 Fukai et al., 2003 [32]

A. nidulans 8 Fukai et al., 2003 [32]

16

O

O OH

HO O

OH

Toxyloxanthone-C Cryptococcus neoformans 8 Fukai et al., 2003 [32]

Antibacterial active compounds

17

O

O OH

HO

O

Nigrolineaxanthone-F

MRSAa 2 Rukachaisirikul et al., 2003 [34]; 2005 [35]

18

O

O

HO O

O

OH

Brasilixanthone-A


19

O

O OH

OH

OH

OH

Nigrolineaxanthone-N


20

O

OHO

O

OH

O

Nigrolineaxanthone-G





against

MIC

(μM)

References

21

O

O

OH

O O

OH

OH

Nigrolineaxanthone-I

MRSAa 4 Rukachaisirikul et al., 2003 [34];

2005 [35]

MRSAa 4 Rukachaisirikul et al., 2003 [34];

2005 [35] 22

O

OHO

O

OH

6-Deoxyjacareubin

Bacillus subtilis 4.6 Boonnak et al., 2006 [36]

10 Mangostanin MRSAa 4 Panathong et al., 2006 [37]

Bacillus substilis <1.10 Boonnak et al., 2006 [36]

MRSAa 8 Deachathai et al., 2005 [38]

S. aureus ATCC 25923 b 8 Deachathai et al., 2005 [38]

Pseudomonas aeruginosa 18.7 Boonnak et al., 2006 [36]

Shigella sonei 18.7 Boonnak et al., 2006 [36]

2 -Mangostin

Streptococcus faecalis 1.1 Boonnak et al., 2006 [36]

MRSAa 16 Deachathai et al., 2005 [38] 23

O

O OH

OH

MeO

HO

Cowaxanthone

S. aureus ATCC 25923 b 16 Deachathai et al., 2005 [38]

24

O

O

O

OH

O

O

Me

COOH

R

(24) Moreollic acid

R=OMe

MRSAa 25 Sukpondma et al., 2005 [39]

25 (25) Morellic acid

R= H

MRSAa 25 Sukpondma et al., 2005 [39]

Enterococcus faecalis JCM 7783 c 1.56 Fukai et al., 2005 [40]

E. faecalis JU 1856 c 1.56 Fukai et al., 2005 [40]


E. faecium JCM 5804 c 1.56 Fukai et al., 2005 [40]

E. faecium JU 1858 c 1.56 Fukai et al., 2005 [40]


E. gallinarum JU 2786 c 1.56 Fukai et al., 2005 [40]

Bacillus substilis PCI-219 1.56 Fukai et al., 2004 [41]

MSSA JCM-2874 d 1.56 Fukai et al., 2004 [41]

MRSA a 1.56 Fukai et al., 2004 [41]

26

O

O

HO

OH

OH

Gerontoxanthone-H or cudraxanthone-H

Micrococcus luteus 1.56 Fukai et al., 2004 [41]




against

MIC

(μM)

References








Bacillus substilis 2.3 Boonsri et al., 2006 [42]

Streptococcus faecalis 4.6 Boonsri et al., 2006 [42]

Salmonella typhi 1.1 Boonsri et al., 2006 [42]



27

O

O OH

OH

HO OH

Gerontoxanthone-I


Enterococcus faecalis JU 1856 c 6.25 Fukai et al., 2005 [40]








28

O

O OH

HO

OH

R1

OH

R2

Alvaxanthone

R1 = H, R2 =











29

R1 = , R2 = H

Isoalvaxanthone












30

O

O OH

OH

HO

1,3,7-Trihydroxy-2-prenylxanthone





against

MIC

(μM)

References

Bacillus substilis <1.1 Boonsri et al., 2006 [42]; Boon-nak et al., 2006 [36]

Pseudomonas aeruginosa 9.3 Boonsri et al., 2006 [42]; Boon-nak et al., 2006 [36]

Salmonella typhi <1.1 Boonsri et al., 2006 [42]; Boon-nak et al., 2006 [36]

Staphylococcus aureus <1.1 Boonsri et al., 2006 [42]; Boon-nak et al., 2006 [36]

31

O

OHO

HO O

OH

Xanthone-V1 Streptococcus faecalis <1.1 Boonsri et al., 2006 [42]; Boon-nak et al., 2006 [36]

Bacillus substilis 18.7 Boonsri et al., 2006 [42] 32

O

O OH

OH

OH

Formoxanthone-A

Staphylococcus aureus 37.5 Boonsri et al., 2006 [42]




33

O

O OH

OH

HO O

Formoxanthone-C





34

O

OHO

OH

OHO

Macluraxanthone


35

O

O

MeO

HO

O

OMe

OH

Pruniflorone-A

Staphylococcus aureus 18.7 Boonnak et al., 2006 [36]

Bacillus substilis <1.1 Boonnak et al., 2006 [36] 36 OH

R1= , R2=

Pruniflorone-C

Staphylococcus aureus <1.1 Boonnak et al., 2006 [36]

Bacillus substilis <1.1 Boonnak et al., 2006 [36]



37

R1= , R2 =

OH

Pruniflorone-E

Streptococcus faecalis <1.1 Boonnak et al., 2006 [36]




against

MIC

(μM)

References


Staphylococcus aureus 9.3 Boonnak et al., 2006 [36]

38

O

O

O

HO OMe

O

Pruniflorone-F

Streptococcus faecalis 04.6 Boonnak et al., 2006 [36]

Bacillus substilis 18.7 Boonnak et al., 2006 [36] 3 -Mangostin


Bacillus substilis 9.3 Boonnak et al., 2006 [36] 39

O

OHO

OHO

MeO

OH

1,6-Dihydroxy-7-methoxy-6',6'-dimethyl-2H-

pyrano(2',3':3,2)-8-(3-hydroxy-3-methylbutyl)xanthone


Bacillus substilis <1.1 Boonsri et al., 2006 [42]


40

O

OHO

OHO

OH

3,4-Dihydrojacareubin


Bacillus substilis 8.24 Nkengfack et al., 2002 [43] 41

O

O OH

HO

O

OH

Globulixanthone-C

Staphylococcus aureus 14.05 Nkengfack et al., 2002 [43]

Bacillus substilis 12.5 Nkengfack et al., 2002 [43] 42

O

O

OH

OH

OMe

Globulixanthone-D

Staphylococcus aureus 8 Nkengfack et al., 2002 [43]

Bacillus substilis 3.12 Nkengfack et al., 2002 [43]

Staphylococcus aureus 4.51 Nkengfack et al., 2002 [43]

43

O

O OH

MeO

OH

HO

O

O

O

Globulixanthone-E

Vibrio anguillarium 5.56 Nkengfack et al., 2002 [43]




against

MIC

(μM)

References

44

O

O OH

OHHO

MeO

Rubraxanthone

Staphylococcus aureus 12 Azebaze et al., 2004 [44]




45

O

O OH

HO O

OH

Gerontoxanthone-G





16 Toxyloxanthone-C





15 Cudraxanthone-S


Morganella morgani 9.76 Nguemeving et al., 2006 [31]

Shigella dysenteriae 4.88 Nguemeving et al., 2006 [31]

S. flexneri 4.88 Nguemeving et al., 2006 [31]

Streptococcus faecalis 1.22 Nguemeving et al., 2006 [31]

Bacillus megaterium 2.44 Nguemeving et al., 2006 [31]

B. stearothermophilus 4.88 Nguemeving et al., 2006 [31]

13 Laurentixanthone-A

B. subtilis 4.88 Nguemeving et al., 2006 [31]

Pseudomonas aeruginosa 4.88 Nguemeving et al., 2006 [31]

Shigella flexneri 19.35 Nguemeving et al., 2006 [31]

14 Laurentixanthone-B

Bacillus subtilis 2.44 Nguemeving et al., 2006 [31]

46

O

O

O

OH

O

COOH

MeO

O

OMe

Scortechinone-P

MSSA SK-1 a 16 Rukachaisirikul et al., 2005 [45]




against

MIC

(μM)

References

MSSA SK-1 a 2 Rukachaisirikul et al., 2005 [45] 47

O

O

O

OH

O

R2

R1

MeO

O

R1=COOH, R2= Me

Scortechinone-B

S. aureus ATCC 25923 b 8 Rukachaisirikul et al., 2005 [45]


O

O

O

OH

O

R2

R1

MeO

O

R1=Me, R2= COOH

Scortechinone-F


49

O

O

O

OH

O

R2

R1

MeO

O

R1=Me, R2= CHO

Scortechinone-H



O

O

O

OH

O

COOH

MeO

O

OMe

H

Scortechinone-I


51

O

O

O

OH

O

MeO

OH

Scortechinone-J





against

MIC

(μM)

References

Antibacterial active compounds (IC50, μM)

52

O

O OH

HO

HO O

Caloxanthone-A

S. aureus 9 Yimdjo et al., 2004 [46]

Antibacterial active compounds (LD50, μM)

S. aureus <1.1 Rezanka and Sigler, 2007 [47] 53

O

O OH

HO

OH

OH

OH

O

OOH OH

OHCOOMe

OHOH

OHO

HOO

Hirtusneanoside

Bacillus subtilis <1.1 Rezanka and Sigler, 2007 [47]

MIC Minimum Inhibitory Concentration; IC50 activity value, half-maximal inhibitory concentration; LD50 activity value, half-maximal lethal dose aStaphylococcus aureus methicillin-resistant strains, bS. aureus penicillin-sensitive strain, dS. aureus methicillin-sensitive strain, cEnterococcus spp. vancomycin-resistant strains.

opportunistic fungi, especially in patients whose immune system has been compromised by AIDS, cancer, diabetes, age or other causes. Many antifungal compounds have been identified, but safe and effective antifungal drugs have not yet been developed because of the high degree of similarity between fungi and mammalian cells [27].

However, several studies have shown that diverse xan-thone compounds exhibit significant moderate to high inhibi-tory activities against diverse human pathogenic microorgan-isms (Table 1); particularly multi drug-resistant organisms such as the methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). These compounds warrant further attention as possible anti-biotics with activities against various human pathogenic mi-croorganisms [28].

ANTIPROTOZOAL ACTIVITY

Protozoa such as trypanosomes, leishmania and the malaria parasites (Plasmodium spp.) are serious parasites of multicellular animals. Malaria poses major health problems in many regions of the world, and the recent emergence and rapid spread of chloroquine-resistant strains of Plasmodium falciparum threaten to increase the annual death toll [48]. Xanthones could play significant roles in attempts to counter malaria (and other diseases, such as leishmaniasis and trypanosomiasis) since a range of the compounds have proven to have activities against various protozoa, as listed in Table 2.

Notably, prenylated xanthones from Garcinia subellip-tica have shown trypanocidal activity against epimastigotes and trypomastigotes (1

st and 3

rd stages) of Trypanosoma

cruzi, the etiologic agent for Chagas’ disease [56]. Most en-couragingly, garciniaxanthone-B (81) exhibited high, signifi-cant activity with MC100 values of 66 and 8 M, respec-tively, while garciniaxanthone-A (82), subelliptenone-B (83), subelliptenone-A (84), 1,3,5,6-tetrahydroxy-4,7,8-tri(3-methyl-2-butenyl)xanthone (85) and 12b-hydroxy-des-D-garcigerrin-A (86) showed moderate activities against the two stages of the parasite, with MC100 values 66-190 M [56].

ANTI-HIV-1 ACTIVITY

Two xanthones, 1,3,8-trihydroxy-2,4-dimethoxyxanthone (87) and euxanthone (88), reportedly displayed anti-HIV-1 activities in the syncytium assay with EC50 values of 17.9 and 18.8 μM [57]. In addition, morellic acid (25), gambogic acid (89) and dihydroisomorellin (90) have shown moderate HIV-1 inhibitory activities in the reverse transcriptase assay with IC50 values of 11, 15 and 42.3 μM, respectively [58].

2. Antioxidant Activity

Recent studies have indicated, unsurprisingly, that radi-cal-based approaches can be helpful for treating free-radical-induced diseases [59]. Xanthones may also be valuable in this context, since they have remarkable antioxidant activi-ties, as shown by the scavenging activities measured in


Table 2. Antiprotozoal Activities of Naturally Occurring Xanthones

Compound Protozoa investigated against IC50 (μM) References

54 1,8-Dihydroxy-3,7-dimethoxyxanthone Plasmodium berghei NK-65 e 15 Dua et al., 2004 [49]

55 4,8-Dihydroxy-2,7-di-methoxyxanthone P. berghei NK-65 e 9 Dua et al., 2004 [49]

56 1,2-Dihydroxy-6,8-dimethoxyxanthone P. berghei NK-65 e 3 Dua et al., 2004 [49]

P. falciparum FcM29 f 6.4 Azebaze et al., 2006 [50] [50]; 2007 [48] 3 -Mangostin

P. falciparum F32 e 5.3 Azebaze et al., 2006 [50] [50]; 2007 [48]

P. falciparum FcM29 f 5 Azebaze et al., 2007 [48] 57

O

O

O

HO OH

OH

Tovophyllin-A

P. falciparum F32 e 5.6 Azebaze et al., 2007 [48]

P. falciparum FcM29 f 5.5 Azebaze et al., 2006 [50] [50]; 2007 [48] 58

O

O OH

HO

OH

O

Allanxanthone-C

P. falciparum F32 e 6.8 Azebaze et al., 2006 [50] [50]; 2007 [48]

P. falciparum FcM29 f 5.8 Azebaze et al., 2007 [48] 59

O

O OH

OMe

HO

1,7-Dihydroxy-3-methoxy-2-(3-methylbut-2-

enyl)xanthone

P. falciparum F32 e 8 Azebaze et al., 2007 [48]

60

O

O OH

MeO

HO

R

R=OMe

5-O-Methylcelebixanthone

P. falciparum 3.2 Laphookhieo et al., 2006 [51]

61

O

O OH

MeO

HO

R

R=OH

Celebixanthone


4 -Mangostin P. falciparum 7.2 Laphookhieo et al., 2006 [51]




62

O

O

O

OH

O

MeO

Cochinchinone-C


P. falciparum FcM29 f 8.9 Azebaze et al., 2006 [50] 63

O

O OH

OHHO

HO

Norcowanin

P. falciparum F32 e 2.8 Azebaze et al., 2006 [50]

64

O

O

O

OH

OH

MeO

MeO

Gaboxanthone

P. falciparum f 3.53 Ngouela et al., 2006 [52]

65

O

O

O

OH

OH

MeO

MeO

Symphonin


66

O

O

OH

OH

OH

MeO

MeO

Globuliferin


67

O

O OH

HO

OH

R

R=OH

Isocudraniaxanthone-A

P. falciparum f 2.3 Hay et al., 2004 [53]




68

O

O OH

HO

OH

R

R=OMe

Isocudraniaxanthone-B


69

O

O OH

HO

OH

O

2-Deprenylrheediaxanthone-B


34 Macluraxanthone P. falciparum f 1.9 Hay et al., 2004 [53]

70

O

O OH

O

HO

Dombakinaxanthone


6

Demethylcalabaxanthone

P. falciparum f 1 Hay et al., 2004 [53]

71

O

O OH

OH

O

Calothwaitesixanthone


72

O

O OH

OH

O

Calozeyloxanthone


73

O

O OH

OH

OH

6-Deoxy- -mangostin





74

O

O

OO

OH

OH

Caloxanthone


75 1,4,5-Trihydroxyxanthone P. falciparum f 3.5 Hay et al., 2004 [53]

Trypanosoma brucei 5 Mbwambo et al., 2006 [54] 76

O

O OH

OH

O

1,5-Dihydroxy-6'[(4"-methyl-3'-pentenyl)pyranoxanthone

T. cruzi 8 Mbwambo et al., 2006 [54]

T. brucei 2 Mbwambo et al., 2006 [54] 77

O

O OH

OH

OH

4[(E)-3,7-Dimethylocta-2, 6-dienyl]-1,3,5-

trihydroxyxanthone

T. cruzi 5.7 Mbwambo et al., 2006 [54]

T. brucei 0.87 Mbwambo et al., 2006 [54]


Plasmodium falciparum 10 Mbwambo et al., 2006 [54]

78

O

O OH

OH OH

1,4,5-Trihydroxy-3-(3-methylbut-2-enyl)xanthone

Leishmania infantum 27 Mbwambo et al., 2006 [54]

Trypanosoma brucei 0.4 Mbwambo et al., 2006 [54]


Plasmodium falciparum 6.7 Mbwambo et al., 2006 [54]

79

O

OH OH

O

O OH

OHR

OH

OH O

R = -H

Garcilivin-A

Leishmania infantum 32 Mbwambo et al., 2006 [54]




80

O

OH OH

O

O OH

OHR

OH

OH O

R = -H

Garcilivin-B

Trypanosoma brucei 7.7 Mbwambo et al., 2006 [54]

31 Xanthone-V1 Leishmania donovani 1.4 Lenta et al., 2007 [55]

eChloroquine-sensitive strains, fChloroquine-resistant strains.

experiments with the stable 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical listed in Table 3.

In addition, virgataxanthone-A (124) and griffipavixan-thone (125) reportedly have moderate antioxidant activity, based on their ability to scavenge the stable DPPH free radi-cal, with EC50 values of 24.00 and 11.50 g/100mL, respec-tively [66]. Furthermore, autooxidation of linoleic acid can be moderately inhibited (>83%) by 0.5 mg/ml of 1,5,8-trihydroxy-3-methoxyxanthone (99), while 6-hydroxy-3,5-dimethoxy-1-[(6-O- -D-xylopyranosyl- -D-glucopyranosyl) oxy]xanthone (100) showed week activity (>6% at a concentration of 0.5 mg/ml). Moreover, 2,8-dihydroxy-1,6-dimethoxyxanthone (97) and 1,8-dihydroxy-3,5-dimethoxyx-anthone (98) didn't show any inhibition of the autoxidation of linoleic acid at the same concentration. 1,8-Dihydroxy-3,5-dimethoxyxanthone (98) has week superoxide scaveng-ing activity (reducing superoxide levels by >8%) in assays described by Rana and Rawat [62], while 2,8-dihydroxy-1,6-dimethoxyxanthone (97), 1,5,8-trihydroxy-3-methoxy-xanthone (99) and 6-hydroxy-3,5-dimethoxy-1-[(6-O- -D-xylopyranosyl- -D-glucopyranosyl)oxy]xanthone (100) have no activity in the same assay [62]. Both 1,3,5-trihydroxy-2-(2',2'-dimethyl-4'-isopropenyl)cyclopentanylxanthone (126) and 5-O-demethylpaxanthonin (127) also have potent anti-oxidant activity. These compounds can reportedly strongly inhibit iodophenol-enhanced chemiluminescence by a horse-radish peroxidase/perborate/luminol system, with values of 1.94 and 1.78 M, respectively, and show strong ability (with values of 2.92 and 2.75 M, respectively) to scavenge the radical cation 2,2'-azinobis(3-ethylbenzothiozoline-6-sulfonate) [67]. -Mangostin (8) has also shown strong hy-droxyl radical-scavenging activity, with an IC50 value of 0.20

M [68].

ANTI-ATHEROSCLEROTIC ACTIVITY

Many catecholic xanthones are anti-atherosclerotic since they have anti-low density lipoprotein (LDL) oxidation and acyl CoA:cholesterol acyltransferase (ACAT) inhibition ac-tivities (Table 3), both of which are potentially useful for treating and/or preventing atherosclerosis and hypercholes-terolemia. Their antiatherogenic activities have been tested by assaying their ability to inhibit foam cell formation in animal models and, as shown in Table 4, cudraxanthone-D (103), isocudraniaxanthone-B (68), 1,3,6,7-tetrahydroxy-4-(1,1-dimethyl-2-propenyl)-8-prenylxanthone (105), cudrax-

anthone-L (106), cudraxanthone-M (107) and macluraxan-thone-B (108) all exhibited potent anti-LDL oxidation activi-ties. However, 1,3,7-trihydroxy-4-(1,1-dimethyl-2-pro-penyl)-5,6-(2,2-dimethylchromeno)-xanthone (128), cudraxanthone-C (129), 1,3,6,7-tetrahydroxy-4-(1,1-dimethyl-2-propenyl)-8-prenylxanthone (105) and cudraxan-thone-M (107) preferentially inhibited hACAT-2, rather than hACAT-1, whereas cudraxanthone-D (103), isocudraniaxanthone-B (68), cudraxanthone-L (106) and macluraxanthone-B (108) showed similar specificities against both hACAT-1 and -2 [69].

HYPOTENSION INHIBITORY EFFECT

Exogenous platelet activating factor (PAF) initiates ana-

phylactic hypotension, in a similar manner to histamine [71], and is a potent mediator of many pathological conditions,

such as allergies, inflammation, thrombosis and asthma [72].

The inhibitory effects of xanthones isolated from various plants on PAF-induced hypotension have been evaluated,

using a blood pressure monitoring in vivo assay method.

Guanandin (130), caloxanthone (74), 1,3,5,6-tetrahydroxy-2-isoprenylxanthone (131), 6-deoxyjacareubin (22) and patu-

lone (132) all strongly inhibited such hypotension; by 66, 67,

62, 61 and 65 %, respectively [70]. These values are report-edly higher than that of ginkgolide-B, a recognized natural

PAF-antagonist from Ginkgo biloba.

CARDIOPROTECTIVE EFFECT AND CARDIOVA-

SCULAR ACTIVITY

Xanthones have been shown to have beneficial effects on

several cardiovascular diseases, including atherosclerosis,

hypertension, thrombosis and ischemic heart disease [73]. More specific reports include the following. Two xanthone

compounds, gentiacaulein (133) and gentiakochianin (134),

have been reported to induce vasodilation in rat aortic prepa-rations [74]. Wang et al. [25] have shown that 1-hydroxy-

2,3,5-trimethoxyxanthone (135), a simple tetraoxygenated

xanthone from Halenia elliptica (Gentianaceae), induces potent concentration-dependent relaxation in rat coronary

artery rings pre-contracted with 1 μM of 5-

hydroxytryptamine (EC50, 1.67 μM), while one of its major metabolites, 1,5-dihydroxy-2,3-dimethoxyxanthone (136),

induces a relaxation effect with an EC50 of 4.4 μM [75].


O

O OH

O

O

(81) Garciniaxanthone-B

O

O OH

OHO

HO

HO

(82) Garciniaxanthone-A

O

O OH

OH

OH

HO

(83) subelliptenone-B

O

O OH

OH

HO

OH

(84) subelliptenone-A

O

O OH

HO

OH

OH

(85) 1,3,5,6-tetrahydroxy-4,7,8-tri(3-methyl-2-

butenyl)xanthone

O

O OH

OHOH

(86) 12b-Hydroxy-des-D-garcigerrin-A

O

O

O

OH

O

O

COOH

(89) Gambogic acid

O

O

O

OH

O

O

OHC

(90) Dihydroisomorellin

Table 3. Antioxidant Activities of Naturally Occurring Xanthones

Compound Free Radical-Scavenging Activity of

DPPH (%)

References

91

O

O OH

OH

HO

Cochinchinone-A

20.7 Mahabusarakam et al., 2006 [59]




DPPH (%)

References

92

O

O OH

OH

HO

HO

Cochinchinone-B


62 Cochinchinone-C 1.7 Mahabusarakam et al., 2006 [59]

93

O

O

O

OH

O

MeO

OH

Cochinchinone-D


4 2 Deachathai et al., 2006 [60]

-Mangostin


94

O

O OH

OH

HO

l,3,7-Trihydroxy-2,4-bis(3-methyl-2-butenyl)xanthone



-Mangostin


34 Macluraxanthone 5.2 Mahabusarakam et al., 2006 [59]


Garcinone-B



Garcinone-D


61 Celebixanthone 79.3 Mahabusarakam et al., 2006 [59]

95

O

O OMe

HO

OH

OH

Afzeliixanthone-A

17.7 Waffo et al., 2006 [61]




DPPH (%)

References

96

O

O OMe

MeO

OH

OH

Afzeliixanthone-B

14 Waffo et al., 2006 [61]

64 Gaboxanthone 28 Ngouela et al., 2006 [52]

65 Symphonin 23 Ngouela et al., 2006 [52]

66 Globuliferin 54 Ngouela et al., 2006 [52]

97 2,8-Dihydroxy-1,6-dimethoxyxanthone 31.1 Rana and Rawat, 2005 [62]

98 1,8-Dihydroxy-3,5-dimethoxyxanthone 14.9 Rana and Rawat, 2005 [62]

99 1,5,8-Trihydroxy-3-methoxyxanthone 97.1 Rana and Rawat, 2005 [62]

100

O

O

OMe

O

OMe

HO

OHOH

HOO

OR

6-Hydroxy-3,5-dimethoxy-1-[(6-O- -D-xylopyranosyl- -D-glucopyranosyl)oxy]xanthone

40.3 Rana and Rawat, 2005 [62]

101 2-Hydroxy-1,7-dimethoxyxanthone 47.8 Lannang et al., 2005 [63]

102 1,5-Dihydroxyxanthone 39.5 Lannang et al., 2005 [63]

103 3,6,8-Trihydroxy-1-methylxanthone 12.9 Abdel-Lateff et al., 2003 [64]

104

O

O OH

HO

OMeHO

Cudraxanthone-D

17.4 Lee et al., 2005 [65]

68 Isocudraniaxanthone-B 31.8 Lee et al., 2005 [65]

105

O

O OH

HO

OHHO

1,3,6,7-tetrahydroxy-4-(1,1-dimethyl-2-propenyl)-8-

prenylxanthone

21.3 Lee et al., 2005 [65]




DPPH (%)

References

106

O

O OH

HO

HO OH

Cudraxanthone-L

13.7 Lee et al., 2005 [65]

107

O

O OH

HO O

HO

Cudraxanthone-M

10.4 Lee et al., 2005 [65]

108

O

O OH

HO

HO OH

Macluraxanthone-B

15.4 Lee et al., 2005 [65]

109

O

O OH

O

OH

Dulcisxanthone-A

2 Deachathai et al., 2005 [38]

110

O

O OH

OMeHO

HO

Dulcisxanthone-B


111

O

O

HO

O

O

OH

Isonormangostin





DPPH (%)

References

112

O

O OH

OMe

MeO

HO

l,6-Dihydroxy-3,7-dimethoxy-2-(3-methyl-2-butenyl)xanthone


113

O

O OH

HO

MeO

Cowanin


23 Cowaxanthone 16 Deachathai et al., 2005 [38]

114

O

O OH

HO

OMe

l,7-Dihydroxy-3-methoxy-2-(3-methyl-2-butenyl)xanthone


115

O

O OH

OMe

OH

OH

1,5,8-Trihydroxy-3-methoxy-2-(3-methyl-2-butenyl)xanthone


116

O

O OH

HO O

O

BR-xanthone-A


117

O

O OH

OH

MeO

HO

OH

Mangostenol


118

O

O OH

OH

MeO

HO

l,3,6-Trihydroxy-7-methoxy-2,5-bis(3-methyl-2-

butenyl)xanthone





DPPH (%)

References

119

O

O OH

R1

OH

R2

8-Desoxygartanin


120

O

O OH

OH

OH

OH

Gartanin


121 1-Hydroxy-3,4,5-trimethoxyxanthone 2 Deachathai et al., 2006 [60]

122

O

O OH

O O

OH

Rheediaxanthone-A


123

O

OHO

OHO

MeO

3-Isomangostin


O

O OH

OHHO

OH

(124) virgataxanthone-A

O

O

OH

OH

HO

OO

OHHO

OH

OH

(125) griffipavixanthone

O

O OH

OH

OH

(126) 1,3,5-trihydroxy-2-(2',2'-dimethyl-4'-

isopropenyl)cyclopentanylxanthone

O

O OH

HO OH

OH

(127) 5-O-demethylpaxanthonin


Table 4. Antioxidant Activities Against LDL, and Inhibitory Activities Against hACAT-1 & -2 of Tested Catecholic Xanthones

Compound LDL (IC50, M) hACAT-1 (IC50, M) hACAT-2 (IC50, M)b

128

O

O

HO

O OH

OH

1,3,7-Trihydroxy-4-(1,1-dimethyl-2-propenyl)-5,6-(2,2-dimethylchromeno)xanthone

12.6 40 28.8

129

O

OOH

OHHO

OMe

Cudraxanthone-C

20 19.2

103 Cudraxanthone-D 6.2 57.6 75.2

68 Isocudraniaxanthone-B 0.8 148 132.8

105 1,3,6,7-tetrahydroxy-4-(1,1-dimethyl-2-

propenyl)-8-prenylxanthone

2.6 89.6 41.6

106 Cudraxanthone-L 3.8 68.0 74.4

107 Cudraxanthone-M 2.2 56.8 23.2

108 Macluraxanthone-B 4.5 96.0 112.0

In addition, increases in oxidative stress and antioxidant deficits have been suggested to play major roles in isoproter-enol (ISO)-induced myocardial infarction, and -mangostin (3) has been found to act as a cardiotonic [76]. Accordingly, in rats, pre-treatment with -mangostin suppresses lipid per-oxidation, reduces activities of serum marker enzymes (LDH, CPK, GOT and GPT), inhibits reductions in the ac-tivities of endogenous antioxidants (SOD, CAT, GPx, GST and GSH) and hence reduces damage in the myocardium during ISO-induced myocardial infarction [77]. The findings indicate that -mangostin (3) has a strongly protective effect against lipid peroxidation and stimulates the antioxidant tis-sue defense system during ISO-induced myocardial infarc-tion in rats. -Mangostin (3) also exhibits a vasorelaxant effect, as determined using aortic rings from guinea pigs, induced by KCl or noradrenaline, with a maximum relaxa-tion of 17.8% at a concentration of 100 M [48].

3. Anti-Inflammatory Activity

ICAM-1, VCAM-1 and E-selectin play important roles in the recruitment of leukocytes to sites of inflammation, and blocking the expression of these molecules (or preventing their interaction with the receptors), which has been shown to be important in controlling various inflammatory diseases

[79]. Madan et al. [78] demonstrated that 1,4-dihydroxyxanthone (137) inhibits the expression of cell ad-hesion molecules; such as ICAM-1, vascular cell adhesion molecule-1 (VCAM-1) and E-selectin, on human endothelial cells in a concentration- and time-dependent reversible man-ner.

INHIBITION OF COX ACTIVITY

-Mangostin (8), a tetraoxygenated diprenylated xan-thone isolated from Garcinia mangostana (Guttifereae), has potent inhibitory activity against prostaglandin E2 release and inhibits the activities of both constitutive COX (COX-1) and inducible COX (COX-2) in a concentration-dependent manner, with IC50 values of about 0.8 and 2 M, respectively [80].

IMMUNOSUPPRESSIVE EFFECTS

In a screening program for immunomodulatory constitu-ents from fungi, two simple xanthones were found to have suppressive effects on the proliferation (blastogenesis) of mouse splenic lymphocytes stimulated with the mitogens concanavalin A (Con A) and lipopolysaccharide (LPS). Nidulalin-A (138) and pinselin (139) exhibited significant


immunosuppressive effects against the Con A-induced pro-liferation, with IC50 values of 0.15 and 5.1 μM, and against LPS-induced proliferation with IC50 values of 0.06 and 7.4 μM, respectively [81].

4. Inhibition of Cholinesterase Activity

Alzheimer’s disease is the most common age-related de-generative brain disorder, which causes gradual, irreversible losses of memory and other mental abilities [82]. The search for new cholinesterase inhibitors is an important strategy to identify new drug candidates to treat Alzheimer’s disease and related dementias. Most currently known natural inhibi-tors of acetylcholinesterase (AChE) are alkaloids, which have the disadvantages of short half-lives and/or undesirable side effects [83, 84]. However, in a search for non-alkaloid cholinesterase inhibitors, four xanthones – bellidifolin (140), bellidin (141), swertianolin (142) and norswertianolin (143) – exhibited potent inhibitory activities against AChE with MIC values of 0.01, 0.04, 0.08 and 0.5 μM, respectively [85]. In addition, allanxanthone-A (144) showed low activity against AChE (IC50 = 95 μM), but significant activity against butyrylcholinesterase (BChE) [55]. The exact physiological role of BChE is still elusive, but it is generally viewed as a backup for the homologous AChE [86].

Since multiple pathogenic factors, including aggregated amyloid- peptide and tau protein, excessive levels of transi-tion metals, oxidative stress and reduced acetylcholine lev-els, are implicated in Alzheimer’s disease, multipotent agents with diverse targets are expected to be more effective for treating Alzheimer’s disease than single-target counterparts [87, 88]. Desired multiple pharmacological effects can be

combined into one xanthone molecule, since the pharma-cophores to exert diverse effects are mainly associated with the tricyclic scaffold, but vary depending on the nature and/or position of the different substituents. In a theoretical evaluation of xanthones as multipotent agents, they were found to be efficient radical scavengers, MAO (isoenzyme A and B) inhibitors and potential AChE inhibitors [87].

INHIBITORY ACTIVITY AGAINST MAO AND

NEUROPHARMACOLOGICAL ACTIVITY

As listed in Table 5, a number of simple xanthones have been shown to have significant ability to inhibit monoamine oxidase-A (MAO-A) (Table 5), an FAD-containing enzyme of the outer mitochondrial membrane that exists as two isoenzymes (MAO-A and MAO-B), and plays an important role in the metabolism of several neurotransmitters, includ-ing dopamine and serotonin [89]. The dysfunction of MAO is thought to be responsible for a number of neurological disorders. For example, it has been associated with depression, drugs abuse, attention deficit disorder and irregular sexual maturation.

Further searches for compounds with neurotrophic activ-ity or nerve growth factor (NGF)-potentiating activity [91, 92, 93] led to the isolation of five prenylated xanthones from G. xanthochymus that elicited marked enhancement of (NGF)-mediated neurite outgrowth in PC12D cells: 1,3,5,6-tetrahydroxy-4,7,8-tri(3-methyl-2-butenyl)xanthone (85), garciniaxanthone-E (181) [94], 1,4,5,6-tetrahydroxy-7,8-di(3-methylbut-2-enyl)xanthone (182), 1,2,6-trihydroxy-5-methoxy-7-(3-methylbut-2-enyl)xanthone (183) and 12b-hydroxy-des-D-garcigerrin-A (86) [95].

O

O OH

(130) Guanandin

O

O OH

OHHO

OH

(131) 1,3,5,6-tetrahydroxy-2-

isoprenylxanthone

O

O

OHHO

O

OH

(132) patulone

O

OOH

OHCOOMe

(138) Nidulalin-A

O

OOH

OH

CH2OOMe

(139) PinselinO

OHOH

OHO

HO O O OH

OMe

OH

(142) swertianolin

O

OHOH

OHO

HOO O OH

OH

HO

(143) norswertianolin

O

O OH

OH

OH

(144) Allanxanthone-A


Table 5. Inhibitory Activities of Naturally Occurring Xanthones Against MAO-A

Xanthone compound IC50 against MAO-A

( M)

References

145 Xanthone 0.84 Nunez et al., 2004 [89]

146 1-Hydroxyxanthone 0.31 Nunez et al., 2004 [89]




150 1-Hydroxy-3-methoxyxanthone 0.11 Nunez et al., 2004 [89]

151 3-Hydroxy-4-methoxyxanthone 65 Nunez et al., 2004 [89]




155 1-Hydroxy-3,5-dimethoxyxanthone 29 Nunez et al., 2004 [89]

156 1-Hydroxy-3,7,8-trimethoxyxanthone 19 Nunez et al., 2004 [89]

157 5-Hydroxy-1,7-dimethoxy-4-methylxanthone 24 Nunez et al., 2004 [89]

102 1,5-Dihydroxyxanthone 0.73 Nunez et al., 2004 [89]

158 3,5-Dihydroxyxanthone 4.5 Nunez et al., 2004 [89]

159 1,3-Dihydroxy-2-methylxanthone 3.7 Nunez et al., 2004 [89]

160 1,3-Dihydroxy-4-methoxyxanthone 4.3 Nunez et al., 2004 [89]

161 1,5-Dihydroxy-3-methoxyxanthone 0.04 Nunez et al., 2004 [89]

162 1,3-Dihydroxy-2,5-dimethoxyxanthone 51 Nunez et al., 2004 [89]

150 Gentiacaulein 0.49 Tomi et al., 2005 [90]

163 4-Cholro-1,3-dihydroxy-2-methylxanthone 27 Nunez et al., 2004 [89]

164 4-Bromo-1,3-dihydroxy-2-methylxanthone 14.9 Nunez et al., 2004 [89]

165 1,3,5-Trihydroxyxanthone 3.8 Nunez et al., 2004 [89]

166 1,3,7-Trihydroxyxanthone 8 Nunez et al., 2004 [89]

167 1,3,5-Trihydroxy-2-methoxyxanthone 2.7 Nunez et al., 2004 [89]

99 1,5,8-Trihydroxy-3-methoxyxanthone 0.66 Nunez et al., 2004 [89]

151 Gentiakochianin 8.5 Nunez et al., 2004 [89]

168 1,3,6-Trihydroxy-2,5-dimethoxyxanhone 32 Nunez et al., 2004 [89]

169 1,3,5,8-Tetrahydroxyxanthone 13 Nunez et al., 2004 [89]

170 Norathyriol 25 Nunez et al., 2004 [89]

171 1,3,7,8-Tetrahydroxyxanthone 24 Nunez et al., 2004 [89]

172 1-Methoxyxanthone 0.9 Nunez et al., 2004 [89]



175 4-Methoxyxanthone 30 Nunez et al., 2004 [89]

176 1,3-Dimethoxyxanthone 20.2 Nunez et al., 2004 [89]

177 3,4-Dimethoxyxanthone 31 Nunez et al., 2004 [89]

178 3,5-Dimethoxyxanthone 36 Nunez et al., 2004 [89]

179 1,3,5-Trimethoxyxanthone 58 Nunez et al., 2004 [89]

180 1,2,3,5-Tetramethoxyxanthone 37 Nunez et al., 2004 [89]


Compounds that have (NGF)-potentiating activity may be useful in the treatment of neurological disorders, such as Parkinson’s disease, Alzheimer’s disease, Huntington’s dis-ease, amyotrophic lateral sclerosis and human immunodefi-ciency virus associated dementia [96, 97, 98].

5. -Glucosidase Inhibitory Activity

-Glucosidase inhibitors are receiving increasing atten-tion in biomedical research for their potential utility in treat-ing numerous diseases, including diabetes mellitus type II [99], cancer [100] and HIV [101]. The diverse therapeutic roles of these inhibitors stem from the crucial biochemical and physiological roles of carbohydrates [102]. For instance, by retarding the cleavage of complex carbohydrates the di-rect absorption of glucose after meals can be attenuated in vivo, thus regulating blood sugar levels in diabetics [103]. In addition, the spread of cancer and structural changes of cell surface glycoconjugates within neoplasmic cells are pro-moted by glycosidases in the sera and interstitial fluid around the tumor, thus by inhibiting these glycosidases cancer

growth may be retarded [104]. As a third example, -glucosidase inhibitors have reduced the rate of viral prolif-eration in HIV infection [101].

Cudratricusxanthone-A (184), 1,3,7-trihydroxy-4-(1,1-dimethyl-2-propenyl)-5,6-(2-2-dimethylchromeno)-xanthone (128), macluraxanthone-B (108), cudraxanthone-M (107), cudratricusxanthone-F (185), 1,3,6,7-tetrahydroxy-2-(3-methylbut-2-enyl)-8-(2-methylbut-3-en-2-yl)xanthone (186) and cudraxanthone-L (106) have all been found to exhibit moderate inhibitory activities against -glucosidase with IC50 values of 16.2, 24.9, 31.7, 32.0, 35.8, 38.2 and 37.7 μM, re-spectively [105].

BINDING TO TRANSTHYRETIN (TTR)

TTR is one of the three major thyroid hormone-binding proteins in human plasma, and hence plays a major role in the metabolism of circulating thyroxine (T4), and in the pathogenic processes associated with various neurode-generative diseases, including amyloid disease; a disorder in

O

O

OHHO

OH

OH

(181) garciniaxanthone-E

O

O OH

HO

OH OH

(182) 1,4,5,6-tetrahydroxy-7,8-di(3-methylbut-

2-enyl)xanthone

O

O OH

HO

OMe

OH

(183) 1,2,6-trihydroxy-5-methoxy-7-(3-methylbut-

2-enyl)xanthone

O

O OH

OR

HO

HO

(184) Cudratricusxanthone-A

R = H

(185) Cudratricusxanthone-F

R = Me

O

O

HO

HO OH

OH

(186) 1,3,6,7-Tetrahydroxy-2-(3-methylbut-2-

enyl)-8-(2-methylbut-3-en-2-yl)xanthone

O

OOH

OH

OH

(191) 1,5-dihydroxy-6-(4-hydroxy-3-methylbutyl)-

xanthone

O

O OH

OHO

OH

(192) Jacareubin

O

O OH

OH

OH

OH

HO

(193) 1,3,5,6-tetrahydroxy-2-(3-hydroxy-3-

methylbutyl)-xanthone

O

O OH

OAc

OAc

AcO

(194) 1-hydroxy-3,5,6-tri-O-acetyl-2-(3,3-dimethylallyl)-

xanthone

O

O

O

OH

OH

HO

HO

OHOH

HOO

OH

(195) mangiferin


Table 6. Cytotoxic Activities of Naturally Occurring Xanthones

Compound Cell line investigated

against

Activity ( M) References

Cytotoxic active compounds (ED50, M)

P-388 e 3.25 Chen et al., 2004 [110] 196 1,6-Dihydroxy-5,7-dimethoxyxanthone

HT-29 i 5.48 Chen et al., 2004 [110]

P-388 e 4.71 Chen et al., 2004 [110] 102 1,5-Dihydroxyxanthone

HT-29 i 5.01 Chen et al., 2004 [110]

P-388 e 2.76 Chen et al., 2004 [110] 197 1,6-Dihydroxy-3-methoxyxanthone

HT-29 i 7.51 Chen et al., 2004 [110]

P-388 e 4.74 Chen et al., 2004 [110] 198 1,6-Dihydroxy-3,5-dimethoxyxanthone

HT-29 i 7.28 Chen et al., 2004 [110]

P-388 e 5.11 Chen et al., 2004 [110] 199 1,6-Dihydroxy-3,5,7-trimethoxyxanthone

HT-29 i 6.25 Chen et al., 2004 [110]


HT-29 i 0.84 Chen et al., 2004 [110]


HT-29 i 5.32 Chen et al., 2004 [110]

P-388 e 1.21 Chen et al., 2004 [110] 88 Euxanthone

HT-29 i 3.94 Chen et al., 2004 [110]

P-388 e 7.28 Chen et al., 2004 [110] 171 5-Hydroxy-1-methoxyxanthone

HT-29 i 4.74 Chen et al., 2004 [110]

P-388 e 2.13 Reutrakul et al., 2007 [58]

KB h 7.71 Reutrakul et al., 2007 [58]

Col-2 i 1.44 Reutrakul et al., 2007 [58]

BCA-1 c 2.59 Reutrakul et al., 2007 [58]

LU-1 f 2.61 Reutrakul et al., 2007 [58]

201

O

O

O

OH

O

O

MeO

7-Methoxydoxymorellin

ASK g 0.78 Reutrakul et al., 2007 [58]






202

O

O

O

OH

OH

O

2-Isoprenylforbesione

ASKg 0.71 Reutrakul et al., 2007 [58]






203

O

O

O

OH

O

HOOC

O

O

8,8a-Epoxymorellic acid





against







204

O

O

O

OH

O

O

R3

R2

R1

R1 = Me, R2 = Me, R3 = H

Desoxymorellin







205

O

O

O

OH

O

O

R3

R2

R1

R1 = CHO, R2 = Me, R3 = H

Isomorellin







206

O

O

O

OH

O

O

R3

R2

R1

R1 = CH2OH, R2 = Me, R3 = H

Isomorellinol







25 Morellic acid







89 Gambogic acid






207

O

O

O

OH

OH

O

Desoxygambogenin





against






208

O

O

O

OH

OH

O

R

Hanburin







209

R =

R = H

Forbesione





90 Dihydroisomorellin


210

O

O OH

OH

OR SO3K

R = Me

1,3-Dihydroxy-5-methoxyxanthone-4-

sulfonate

P-388 e 3.46 Hong et al., 2004 [111]

211

O

O OH

OH

OR SO3K

R = -D-glucopyranosyl

1,3-Dihydroxy-5-O- -D-

glucopyranosylxanthone-4-sulfonate

P-388 e 15.69 Hong et al., 2004 [111]

P-388 e 4.88 Chen et al., 2004 [110] 212

O

OOH

OMe

OH

HO O

Linixanthone-A

HT-29 i 5.34 Chen et al., 2004 [110]

P-388 e 1.43 Chen et al., 2004 [110] 213

O

O

OMe

OH

O

Linixanthone-B

HT-29 i 3.14 Chen et al., 2004 [110]




against


P-388 e 1.44 Chen et al., 2004 [110] 214

O

O

OMe

OMe

OH

Linixanthone-C

HT-29 i 1.54 Chen et al., 2004 [110]

P-388 e 3.49 Chen et al., 2004 [110] 215

O

O

OH

OH

MeO O

10-O-Methylmacluraxanthone

HT-29 i 5.25 Chen et al., 2004 [110]

P-388 e 1.67 Chen et al., 2004 [110] 216

O

O

OMe

OH

HO O

Rheediachromenoxanthone

HT-29 i 4.68 Chen et al., 2004 [110]

P-388 e 0.42 Chen et al., 2004 [110] 42 Globulixanthone-D

HT-29 i 0.98 Chen et al., 2004 [110]

217

O

O

HO OH

O

OH

Garcinianone-A

brine shrimp 7.7 Chiang et al., 2003 [112]

218

O

O

HO OH

O

OH

Garcinianone-B

brine shrimp 25.8 Chiang et al., 2003 [112]

Cytotoxic active compounds (IC50, M)

MCF-7 c 14.5 Tanaka et al., 2004 [113] 88 Euxanthone

A-549 f 19.5 Tanaka et al., 2004 [113]

MCF-7 c 8.5 Tanaka et al., 2004 [113] 219 1,7-Dihydroxy-

4-methoxyxanthone A-549 f 15.2 Tanaka et al., 2004 [113]

MCF-7 c 10 Tanaka et al., 2004 [113] 220 1,3,5,6-Tetrahydroxyxanthone

A-549 f 9.3 Tanaka et al., 2004 [113]




against


MDA-MB-231 c 9.67 Shadid et al., 2007 [114]

MCF-7 c 24.33 Shadid et al., 2007 [114]

CaOV-3 a 13.83 Shadid et al., 2007 [114]

221

O

O

O

OH

OH

O

MeO

Cantleyanone-A

HeLa b 20.67 Shadid et al., 2007 [114]


MCF-7 c 0.42 Shadid et al., 2007 [114]


222

O

O

O

OH

OH

O

HO

7-Hydroxyforbesione



MCF-7 c 17.67 Shadid et al., 2007 [114]


223

O

O

OH

OH

OH

OH

1,3,5,8-Tetrahydroxy-4-(1,1-Dimethylprop-2-enyl)xanthone



MCF-7 c 0.83 Shadid et al., 2007 [114]


224

O

O

O

OH

O

O

MeO

OH

Cantleyanone-B



MCF-7 c 1.48 Shadid et al., 2007 [114]


225

O

O

O

OH

O

OOH

MeO

Cantleyanone-C





against



MCF-7 c 4.4 Shadid et al., 2007 [114]


226

O

O

O

OH

OH

O OH

MeO

Cantleyanone-D



MCF-7 c 0.38 Shadid et al., 2007 [114]


227

O

O

O

OH

OH

O

Deoxygaudichaudione-A


228

O

OHO

OHO

OH

2'3'

4'

5'

6'

1,5,6-Trihydroxy-6',6'-dimethyl-2H-pyrano

(2',3':3,4)-2-(3-methylbut-2-enyl)xanthone

MDA-MB-435S c 5.88 Yang et al., 2007 [115]

229

O

OHO

HO O

HO

1,6,7-Trihydroxy-6',6'-dimethyl-2H-

pyrano(2',3':3,2)-4-(3-methylbut-2-

enyl)xanthone

MDA-MB-435S c 6.05 Yang et al., 2007 [115]

A-375 d 17.6 Azebaze et al., 2007 [48]

H-187 f 2.4 Laphookhieo et al., 2006 [51]

MCF-7 c 3.7 Boonnak et al., 2006 [36]

HeLa b 3.2 Boonnak et al., 2006 [36]

HT-29 i 4.5 Boonnak et al., 2006 [36]

KB h 3.2 Boonnak et al., 2006 [36]

DLD-1 i 7.5 Nakagawa et al., 2007 [116]

3 -Mangostin

LH-60 j 6.8 Matsumoto et al., 2003 [117]




HT-29 i 4.8 Boonnak et al., 2006 [36]


4 -Mangostin

LH-60 j 7.6 Matsumoto et al., 2003 [117]




against


8 -Mangostin LH-60 j 6.1 Matsumoto et al., 2003 [117]

230

O

OHO

OH

OH

Mangostinone

LH-60 j 19 Matsumoto et al., 2003 [117]

231

O

OHO

OHHO

HO

Garcinone-E


232

O

OHO

OMe

HO

2-Isoprenyl-1,4-dihydroxy-3-methoxyxanthone


56 Tovophyllin-A A-375 d 12.1 Azebaze et al., 2007 [48]

61 Celebixanthone


91 Cochinchinone-A H-187 f 0.65 Laphookhieo et al., 2006 [51]

62 Cochinchinone-C H-187 f 2.3 Laphookhieo et al., 2006 [51]


HT-29 i 6.0 Boonnak et al., 2006 [36]

31 Xanthone-V1




HT-29 i 0.7 Boonnak et al., 2006 [36]


HCT-116 i 2.37 Wang et al., 2005 [33]

BGC-823 m 3.01 Wang et al., 2005 [33]

SGC-7901 m 2.6 Wang et al., 2005 [33]

27 Gerontoxanthone-I

SMMC-7721 l 2.52 Wang et al., 2005 [33]

MCF-7 4.9 Boonsri et al., 2006 [42]

HeLa b 3.7 Boonsri et al., 2006 [42]

HT-29 i 5.3 Boonsri et al., 2006 [42]

33 Formoxanthone-C

KB h 3.3 Boonsri et al., 2006 [42]

40 3,4-Dihydrojacareubin HeLa b 3.4 Boonnak et al., 2006 [36]




against


K-562/ADR j 0.61 Han et al., 2006 [118] 233

O

O

O

OH

OH

O

Me

COOH

Gaudichaudic acid

K-562/S j 0.41 Han et al., 2006 [118]

K-562/ADR j 2.86 Han et al., 2006 [118] 234

O

O

O

OH

OH

O

R2

R1

R1 = Me, R2 = COOH

Isogambogenic acid

K-562/S j 2.1 Han et al., 2006 [118]

K-562/ADR j 3.04 Han et al., 2006 [118] 235

O

O

O

OH

OH

O

R2

R1

R1 = COOH, R2 = Me

Deoxygaudichaudione-A

K-562/S j 1.74 Han et al., 2006 [118]

Jurkat 0.32 Han et al., 2005 [119]

HL-60 e 0.17 Han et al., 2005 [119]

MCF7 0.24 Han et al., 2005 [119]

89 Gambogic acid

MDA-MB-468 c 0.33 Han et al., 2005 [119]

Jurkat 0.71 Han et al., 2005 [119]

HL-60 e 0.83 Han et al., 2005 [119]

MCF7 c 0.47 Han et al., 2005 [119]

MDA-MB-468 c 0.54 Han et al., 2005 [119]

K-562/ADR j 1.65 Han et al., 2006 [118]

236

O

O

O

OH

O

O

HOOC

Gambogoic acid-A K-562/S j 1.38 Han et al., 2006 [118]

K-562/ADR j 3.01 Han et al., 2006 [118] 237

O

O

O

OH

O

O

HOOC

Gambogenic acid

K-562/S j 2.41 Han et al., 2006 [118]

K-562/ADR j 2.43 Han et al., 2006 [118] 207 Desoxygambogenin

K-562/S j 0.91 Han et al., 2006 [118]

K-562/ADR j 1.86 Han et al., 2006 [118] 238 Isomorellic acid

K-562/S j 0.91 Han et al., 2006 [118]




against


K-562/ADR j 2.29 Han et al., 2006 [118] 25 Morellic acid

K-562/S j 1.48 Han et al., 2006 [118]

K-562/ADR j 1.53 Han et al., 2006 [118] 206 Desoxymorellin

K-562/S j 0.64 Han et al., 2006 [118]

K-562/ADR j 0.62 Han et al., 2006 [118] 208 Isomorellinol

K-562/S j 0.57 Han et al., 2006 [118]

79 Garcilivin-A MRC-5 f 2 Mbwambo et al. 2006 [54]

52 Caloxanthone-A KB h 5.69 Yimdjo et al., 2004 [46]

239 Monodictysin-B

(1,4,8-Trihydroxy-3,4a-dimethyl-

1,2,3,4,4a,9a-hexahydro-9H-xanthen-9-one)

Cyp-1A k 23.3 Krick et al., 2007 [120]

240 Monodictysin-C

(1,4,8-Trihydroxy-6-methoxy-

3,4a-dimethyl-1,2,3,4,4a,9a-hexahydro-9H-

xanthen-9-one)

Cyp-1A k 3 Krick et al., 2007 [120]

241 Monodictyxanthone

(8-Hydroxy-3-methyl-9-oxo-9H-xanthene-1-

carboxylic acid)

Cyp-1A k 34.8 Krick et al., 2007 [120]

242

O

O

OH

OH

OH

O

Termicalcicolanone-A

A-2780 a 40.6 Cao et al., 2007 [121]

243

O

O

OHO

OH

OH

Termicalcicolanone-B

A-2780 a 8.1 Cao et al., 2007 [121]

244

O

O OH

OH

MeO

MeO

1,3-Dihydroxy-6,7-dimethoxy-2,8-

diprenylxanthone

NCI- H187 f 3.69 Pattanaprateeb et al., 2005 [122]

HCT-116 i 1.89 Wang et al., 2005 [33]

BGC-823 m 2.04 Wang et al., 2005 [33]

SGC-7901 m 1.54 Wang et al., 2005 [33]

245

O

OHO

MeO

OH

OMe

Cudrafrutixanthone-A

SMMC-7721 l 2.66 Wang et al., 2005 [33]




against


HCT-116 i 12.62 Wang et al., 2005 [33]

BGC-823 m 19.88 Wang et al., 2005 [33]

SGC-7901 m 8.58 Wang et al., 2005 [33]

246

O

O OH

HO

O

O

Gerontoxanthone-A

SMMC-7721 l 13.88 Wang et al., 2005 [33]

HCT-116 i 3.14 Wang et al., 2005 [33]

BGC-823 m 3.04 Wang et al., 2005 [33]

SGC-7901 m 3.81 Wang et al., 2005 [33]

247

O

O OH

O OH

OH

Gerontoxanthone-B

SMMC-7721 l 3.43 Wang et al., 2005 [33]

HCT-116 i 1.24 Wang et al., 2005 [33]

BGC-823 m 3.15 Wang et al., 2005 [33]

SGC-7901 m 2.21 Wang et al., 2005 [33]

248

O

O OH

HO O

R2 R1

R3

Gerontoxanthone-C

SMMC-7721 l 3.25 Wang et al., 2005 [33]

SGC-7901 m 31.66 Wang et al., 2005 [33] 249

R1 = , R2 = OH, R3 = H

R1 = H, R2 = OMe, R3 =

Gerontoxanthone-E

SMMC-7721 l 21.71 Wang et al., 2005 [33]

HCT-116 i 1.59 Wang et al., 2005 [33]

BGC-823 m 1.4 Wang et al., 2005 [33]

SGC-7901 m 1.41 Wang et al., 2005 [33]

45 Gerontoxanthone-G

SMMC-7721 l 4.52 Wang et al., 2005 [33]

HCT-116 i 10.68 Wang et al., 2005 [33]

BGC-823 m 16.49 Wang et al., 2005 [33]

SGC-7901 m 13.13 Wang et al., 2005 [33]

250

O

O OH

HO

OMe

OH

Cudraxanthone-E

SMMC-7721 l 15.71 Wang et al., 2005 [33]

BGC-823 m 9.21 Wang et al., 2005 [33]

SGC-7901 m 1.8 Wang et al., 2005 [33]

26 Gerontoxanthone-H or Cudraxanthone-H

SMMC-7721 l 11.74 Wang et al., 2005 [33]

HCT-116 i 1.82 Wang et al., 2005 [33]

BGC-823 m 1.34 Wang et al., 2005 [33]

SGC-7901 m 1.54 Wang et al., 2005 [33]

15 Cudraxanthone-S

SMMC-7721 l 3.01 Wang et al., 2005 [33]

HCT-116 i 2.15 Wang et al., 2005 [33]

BGC-823 m 3.24 Wang et al., 2005 [33]

SGC-7901 m 1.86 Wang et al., 2005 [33]

16 Toxyloxanthone-C

SMMC-7721 l 3.16 Wang et al., 2005 [33]




against


HCT-116 i 1.25 Wang et al., 2005 [33]

BGC-823 m 2.21 Wang et al., 2005 [33]

SGC-7901 m 1.63 Wang et al., 2005 [33]

251

O

O OH

HO OH

OH

Toxyloxanthone-D

SMMC-7721 l 1.37 Wang et al., 2005 [33]

HCT-116 i 1.76 Wang et al., 2005 [33]

BGC-823 m 2.58 Wang et al., 2005 [33]

SGC-7901 m 1.89 Wang et al., 2005 [33]

28 Alvaxanthone

SMMC-7721 l 3.69 Wang et al., 2005 [33]

HCT-116 i 1.14 Wang et al., 2005 [33]

BGC-823 m 1.46 Wang et al., 2005 [33]

SGC-7901 m 1.21 Wang et al., 2005 [33]

29 Isoalvaxanthone

SMMC-7721 l 1.25 Wang et al., 2005 [33]

HCT-116 i 4.43 Wang et al., 2005 [33]

BGC-823 m 4.77 Wang et al., 2005 [33]

SGC-7901 m 3.59 Wang et al., 2005 [33]

67 Isocudraniaxanthone-A

SMMC-7721 l 3.62 Wang et al., 2005 [33]

MCF-7 c 9.3 Tanaka et al., 2004 [113] 252

O

O OH

HO OH

HO

HO

Hyperxanthone-C

A-549 f 11.2 Tanaka et al., 2004 [113]

MCF-7 c 18.5 Tanaka et al., 2004 [113] 253

O

O OH

HO OH

O

Hyperxanthone-E

A-549 f 19.3 Tanaka et al., 2004 [113]

MCF-7 c 18.5 Tanaka et al., 2004 [113] 117 1,3,6,7-Tetrahydroxy-4-(1,1-dimethyl-2-

propenyl)-8-prenylxanthone A-549 f 18.4 Tanaka et al., 2004 [113]

Cytotoxic active compounds (IG50, M)

NCI-H460 f 49.7 Wilairat et al., 2005 [123] 254

O

O

O

OH

O

OH

OMe

HO

trans-Kielcorin

SF-268 40.5 Wilairat et al., 2005 [123]

Cytotoxic active compounds (EC50, M)

102 1,5-Dihydroxyxanthone KB h 3.3 Nkengfack et al., 2002 [124] 161 Allanxanthone-A KB h 1.5 Nkengfack et al., 2002 [124] 255 1,5,6-Trihydroxy-3,7-dimethoxyxanthone KB h 2.5 Nkengfack et al., 2002 [124]

IG50, half-maximal growth inhibitory concentration; EC50, half-maximal effective concentration; ED50, half-maximal effective dose. aHuman ovarian cancer, bhuman cervical cancer, chuman breast cancer, dhuman melanoma, emammalian leukemia, fhuman lung cancer, grat glioma, hhuman oral cancer, ihuman colon cancer, jhuman leukemia, kphase-I enzyme of carcinogenesis initiation, lhuman hepatocellular carcinoma, mhuman gastric cancer.


which mutant or native TTR aggregates and subsequently forms amyloid fibrils that are deposited in tissues [106]. 2-hydroxy-1-methoxyxanthone (187), 1,6-dihydroxy-5-methoxyxanthone (188), 1,3-dimethoxy-5-hydroxyxanthone (189), 3,8-dihydroxy-1,2-dimethoxyxanthone (190) and 1,5-dihydroxy-6-(4-hydroxy-3-methylbutyl)-xanthone (191) have all exhibited significant binding activities to TTR, competitively displacing the natural protein ligand T4 in the T4-TTR binding sites [107].

6. Gastro-Protective Effect

Four prenylated xanthones isolated from Calophyllum brasilienses have been investigated for their gastro-protective activity. Deoxyjacareubin (23), jacareubin (192), 1,3,5,6-tetrahydroxy-2-(3-hydroxy-3-methylbutyl)-xanthone (193) and 1-hydroxy-3,5,6-tri-O-acetyl-2(3,3-dimethylallyl)-xanthone (194) all inhibited the gastric H

+,K

+-ATPase, with

IC50 values ranging from 47 μM to 1.6 mM [108]. These results suggest that these types of xanthones could have po-tentially important pharmacological and toxicological effects on gastric acid secretion, the final step of which is driven by the H

+, K

+-ATPase, and hence is considered to be one of the

best pharmacological targets for developing drugs to treat gastric disturbances. The glycosylated xanthone mangiferin (195) also reportedly has a gastro-protective function, sig-nificantly preventing gastric damage induced by both ethanol and indomethacin at fairly low oral doses (3, 10 and 30 mg/kg) [109].

7- Cytotoxicity and Cancer Chemoprevention Activities

Over 100 xanthone compounds, mainly prenylated and simple xanthones, have been investigated for their cytotoxic-ity against various mammalian cell lines, and shown moder-ate to potent activities (Table 6).

Further investigation of the antiproliferative effects of the three prenylated xanthones - (3), - (4) and -mangostin (8) in human colon cancer DLD-1 cells showed that all three strongly inhibited cell growth (and thus have antitumor po-tency). Furthermore, the antiproliferative effects of - (3) and -mangostin (8) were associated with apoptosis. Hence xanthones have promising potential as agents for cancer pre-vention and use in combined therapies with anti-cancer drugs [117, 125].

In addition to - (3) and -mangostin (4) six other preny-lated xanthones – cowaxanthone (23), cowanin (113), ru-braxanthone (44), cowanol (256), norcowanin (63) and 7-O-methylgarcinone (257) – have exhibited potent tumor-promoting inhibitory effects on Epstein-Barr virus early an-tigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells, with IC50 values of 220, 270, 398, 320, 340, 310, 315 and 210 (mol ratio/32 pmol TPA), respectively [126].

CONCLUSION

Xanthones have been of interest to natural product chem-

ists for decades, but until recently the main objectives of

these workers were to isolate xanthones from natural sources

and elucidate their structures. However, the focus has shifted

recently towards evaluation of their biological activities and

potential uses. For instance, - (3), - (4), and -mangostin

(8) were isolated in the 1970s but are still being investigated

today, inter alia as strong candidates as lead compounds for

multipotent agents to combat Alzheimer’s disease. An im-

portant aspect of these compounds that has been discovered

is that single xanthones may have multiple desirable phar-

macological effects, since pharmacophores with diverse ef-

fects share the same tricyclic scaffold, but have variations in

the nature and/or positions of substituents. It should be noted

that the inventory of natural products, especially xanthones,

remains far from complete, and the functional-group diver-

sity and architectural platforms of natural products generated

in their biosynthesis continue to provide lessons for synthetic

and medicinal chemists in strategies for making biologically active mimics.

Finally, two points should be noted that were not covered

in the above text (and hence are not strictly conclusions, but

warrant a mention). Firstly, the biological effects of many of

the examined xanthones have strong ethnopharmacological

implications, since they confirm traditional uses of the higher

plant species from which the active xanthones were isolated.

Secondly, many secondary metabolites found in the lichen-

forming fungi play major roles in the systematics of these

organisms because of their extensive parallels with the li-

chens’ morphology and clear ecological significance. How-

ever, despite their common occurrence in a number of im-

O

O OH

MeO

OHHO

OH

(256) cowanol

O

O OH

MeO

OHHO

(257) 7-O-methylgarcinone


portant genera, lichen xanthones have not yet been promi-nently used by lichen taxonomists.

REFRENCES

[1] Vieira, L.M.M.; Kijjoa, A. Naturally occurring xanthones: recent

developments. Curr. Med. Chem., 2005, 12, 2413-46.

[2] Pinto, M.M.M.; Sousa, M.E.; Nascimento, M.S. Xanthone deriva-

tives: new insights in biological activities. Curr. Med. Chem., 2005,

12, 2517-38.

[3] Lesch. B.; Bräse, S. A short, atom-economical entry to tetrahy-

droxanthenones. Chem. Int. Ed., 2004, 43, 115-118.

[4] Bennett, G.J.; Lee, H-H. Xanthones from Guttiferae. Phytochemis-

try, 1989, 28, 967-98.

[5] Fotie, J.; Bohle, D.S. Pharmacological and biological activities of

xanthones. Anti-Infect. Agent. Med. Chem., 2006, 5, 15-31.

[6] Carpenter, I.; Locksley, H.D.; Scheinmann F. Xanthones in higher

plants: biogenetic proposals and chemotaxonomic survey. Phyto-

chemistry, 1969, 8, 2013-25.

[7] Sultanbawa, M.U.S. Xanthonoids of tropical plants. Tetrahedron,

1980, 36, 1465-506.

[8] Peres, V.; Nagem, T.J. Trioxgyenated naturally occurring xan-

thones. Phytochemistry, 1997, 44, 191-214.

[9] Beerhues, L.; Barillas, W.; Peters, S.; Schmidt, W. (1999) Biosyn-

thesis of plant xanthones. In: Bioorganic chemistry. Highlights and

New Aspects, U Diederichsen, TK Lindhorst, B Westermann, L

Wessjohann, eds. (Weinheim, Germany: Wiley-VCH), pp. 322-

328.

[10] Beerhues, L. Benzophenone synthase from cultured cells of Cen-

taurium erythraea. FEBS Lett., 1996, 383, 264-66.

[11] Peters, S.; Schmidt, W.; Beerhues, L. Regioselective oxidative

phenol couplings of 2,3',4,6-tetrahydroxybenzophenone in cell cul-

tures of Centaurium erythraea Rafn. and Hypericum androsaemum

L. Planta, 1998, 204, 64-69.

[12] Barillas, W.; Beerhues, L. 3-Hydroxybenzoate: coenzyme A ligase

from cell cultures of Centaurium erythraea: isolation and charac-

terization. Biol. Chem., 2000, 381, 155-60.

[13] Schmidt, W.; Beerhues, L. Alternative pathways of xanthone bio-

synthesis in cell cultures of Hypericum androsaemum L. FEBS

Lett., 1997, 420, 143-46.

[14] Kitanov, G.M.; Nedialkov, P.T. Benzophenone O-glucoside, a

biogenic precursor of 1,3,7-trioxygenated xanthones in Hypericum

annulatum. Phytochemistry, 2001, 57, 1237-43.

[15] Zheleva-Dimitrova, D.; Gevrenova, R.; Nedialkov, P.; Kitanov, G.

Simultaneous determination of benzophenones and gentisein in

Hypericum annulatum Moris by high performance liquid chroma-

tography. Phytochem. Anal., 2007, 18, 1-6.

[16] Rawlings, B.J. Biosynthesis of polyketides. Nat. Prod. Rep., 1997,

14, 523-56.

[17] Henry, K.M.; Townsend, C.A. Ordering the reductive and cyto-

chrome P450 oxidative steps in demethylsterigmatocystin formation

yields general insights into the biosynthesis of aflatoxin and related

fungal metabolites. J. Am. Chem. Soc., 2005, 127, 3724-33.

[18] Ehrlich, K.C.; Montalbano, B.; Boue, S.M.; Bhatnagar, D. An

aflatoxin biosynthesis cluster gene encodes a novel oxidase re-

quired for conversion of versicolorin A to sterigmatocystin. Appl.

Environ. Microbiol., 2005, 71, 8963-65.

[19] Henry, KM.; Townsend, C.A. Synthesis and fate of O-

carboxybenzophenones in the biosynthesis of aflatoxin. J. Am.

Chem. Soc., 2005, 127, 3300-09.

[20] Prieto, R.; Woloshuk, C.P. Ordl, an oxidoreductase gene responsi-

ble for conversion of O-methylsterigmatocystin to aflatoxin in As-

pergillus flavus. Appl. Environ. Microbiol., 1997, 63, 1661-66.

[21] Tabata, N.; Suzumura, Y.; Tomoda, H.; Masuma, R.; Haneda, K.;

Kishi, M.; Iwai, Y.; Omura, S. Xanthoquinodins, new anticoccidial

agents produced by Humicola sp. production, isolation and phys-

ico-chemical and biological properties. J. Antibiot., 1993, 46, 749-

55.

[22] Nishida, H.; Tomoda, H.; Okuda, S.; Omura, S. Biosynthesis of

purpactin A. J. Org. Chem., 1992, 57, 1271-74.

[23] Assante, G.; Camarda, L.; Nasini, G. Secondary mould metabolites.

IX. Structure of a new bianthrone and of three new secoanthraqui-

nones from Aspergillus wentii Wehmer. Garz. Chim. Ital., 1980,

110, 629-31.

[24] Tabata, N.; Tomoda, H.; Matsuzaki, K.; Omura, S. Structure and

Biosynthesis of xanthoquinodins, anticoccidial antibiotics. J. Am.

Chem. Soc., 1993, 115, 8558-64.

[25] Wang, Y.; Shi, J-G.; Wang, M-Z.; Che, C-T.; Yeung, J.H.K.

Mechanisms of the vasorelaxant effect of 1-hydroxy-2,3,5-

trimethoxy-xanthone, isolated from a Tibetan herb, Halenia ellip-

tica, on rat coronary artery. Life Sci., 2007, 81, 1016-23.

[26] Ondeyka, J.G.; Dombrowski, A.W.; Polishook, J.P.; Felcetto, T.;

Shoop, W.L.; Guan, Z.; Singh, S.B. Isolation and insecti-

cidal/anthelmintic activity of xanthonol, a novel bis-xanthone, from

a non-sporulating fungal species. J. Antibiot., 2006, 59, 288-92.

[27] Brooks, G.F.; Butel, J.S.; Morse, S.A.; Nairm, R.; Mitchell, T.G.;

Heyneman, D. In: Jawetz, Melnick & Adelberg’s Medical Micro-

biology, 21edn. Appleton & Lange, Stamford, 1988; pp. 1-37 and

583-616.

[28] Fukai, T. Studies of constituents of licorice: chemistry and bioac-

tive compounds. Med. Plants Res., 2001, 24, 38-54.

[29] Namdaung, U.; Aroonrerk, N.; Suksamrarn, S.; Danwisetkanjana,

K.; Saenboonrueng, J.; Arjchomphu, W.; Suksamrarn, A. Bioactive

constituents of the root bark of Artocarpus rigidus subsp. rigidus.

Chem. Pharm. Bull., 2006, 54, 1433-36.

[30] Suksamrarn, S.; Suwannapoch, N.; Phakhodee, W.; Thanuhiranlert,

J.; Ratananukul, P.; Chimnoi, N.; Suksamrarn, A. Antimycobacte-

rial activity of prenylated xanthones from the fruits of Garcinia

mangostana. Chem. Pharm. Bull., 2003, 51, 857-59.

[31] Nguemeving, J.R.; Azebaze, A.G.B.; Kuete, V.; Carly, N.N.E.;

Beng, V.P.; Meyer, M.; Blond, A.; Bodo, B.; Nkengfack, A.E.

Laurentixanthones A and B, antimicrobial xanthones from Vismia

laurentii. Phytochemistry, 2006, 67, 1341-46.

[32] Fukai, T.; Yonekawa, M.; Hou, A-J.; Nomura, T.; Sun, H-D.; Uno,

J. Antifungal agents from the roots of Cudrania cochinchinensis

against Candida, Cryptococcus, and Aspergillus species. J. Nat.

Prod., 2003, 66, 1118-20.

[33] Wang, Y-H.; Hou, A-J.; Zhu, G-F.; Chen, D-F.; Sun, H-D. Cyto-

toxic and antifungal isoprenylated xanthones and flavonoids from

Cudrania fruticosa. Planta Med., 2005, 71, 273-74.

[34] Rukachaisirikul, V.; Kamkaew, M.; Sukavisit, D.; Phongpaichit, S.;

Sawangchote, P.; Taylor, W.C. Antibacterial Xanthones from the

leaves of Garcinia nigrolineata. J. Nat. Prod., 2003, 66, 1531-35.

[35] Rukachaisirikul, V.; Tadpetch, K.; Watthanaphanit, A.; Saeng-

sanae, N.; Phongpaichit, S. Benzopyran, biphenyl, and tetraoxy-

genated xanthone derivatives from the twigs of Garcinia ni-

grolineata. J. Nat. Prod., 2005b, 68, 1218-21.

[36] Boonnak, N.; Karalai, C.; Chantrapromma, S.; Ponglimanont, C.;

Fun, H-K.; Kanjana-Opas, A.; Laphookhieo, S. Bioactive preny-

lated xanthones and anthraquinones from Cratoxylum formosum

ssp. pruniflorum. Tetrahedron, 2006, 62, 8850-59.

[37] Panathong, K.; Pongcharoen, W.; Phongpaichit, S.; Taylor, W.C.

Tetraoxygenated xanthones from the fruits of Garcinia cowa. Phy-

tochemistry, 2006, 67, 999-1004.

[38] Deachathai, S.; Mahabusarakam, W.; Phongpaichit, S.; Taylor,

W.C. Phenolic compounds from the fruit of Garcinia dulcis. Phy-

tochemistry, 2005, 66, 2368-75.

[39] Sukpondma, Y.; Rukachaisirikul, V.; Phongpaichit, S. Antibacterial

caged- tetraprenylated xanthones from the fruits of Garcinia han-

buryi. Chem. Pharm. Bull., 2005, 53, 850-52.

[40] Fukai, T.; Oku, Y.; Hou, A-J.; Yonekawa, M.; Terada, S. Antimi-

crobial activity of isoprenoid-substituted xanthones from Cudrania

cochinchinensis against vancomycin-resistant enterococci. Phy-

tomedicine, 2005, 12, 510-13.

[41] Fukai, T.; Oku, Y.; Hou, A-J.; Yonekawa, M.; Terada, S. Antimi-

crobial activity of hydrophobic xanthones from Cudrania cochin-

chinensis against Bacillus subtilis methicillin-resistant Staphylo-

coccus aureus. Chem. Biodiv., 2004, 1, 1385-90.

[42] Boonsri, S.; Karalai, C.; Ponglimanont, C.; Kanjana-opas, A.;

Chantrapromm, K. Antibacterial and cytotoxic xanthones from the

roots of Cratoxylum formosum. Phytochemistry, 2006, 67, 723-27.

[43] Nkengfack, A.; Mkounga, P.; Meyer, M.; Fomum, Z.; Bodo, B.

Globulixanthones C, D and E: three prenylated xanthones with an-

timicrobial properties from the root bark of Symphonia globulifera,

Phytochemistry, 2002, 61, 181-87.


[44] Azebaze, A.G.B.; Meyer, M.; Bodo, B.; Nkengfack, A.E. Allanx-

anthone B, a polyisoprenylated xanthone from the stem bark of Al-

lanblackia monticola Staner L.C. Phytochemistry, 2004, 65, 2561-

64.

[45] Rukachaisirikul, V.; Phainuphong, P.; Sukpondma, Y.; Phong-

paichit, S.; Taylor, W.C. Antibacterial caged-tetraprenylated xan-

thones from the stem bark of Garcinia scortechinii. Planta Med.,

2005, 71, 165-70.

[46] Yimdjo, M.C.; Azebaze, A.G.; Nkengfack, A.E.; Meyer, A.M.;

Bodo, B.; Fomum, Z.T. Antimicrobial and cytotoxic agents from

Calophyllum inophyllum. Phytochemistry, 2004, 65, 2789-95.

[47] Rezanka, T.; Sigler, K. Hirtusneanoside, an unsymmetrical dimeric

tetrahydroxanthone from the lichen Usnea hirta. J. Nat. Prod.,

2007, 70, 1487-91.

[48] Azebaze, A.G.B.; Dongmo, A.B.; Meyer, M.; Ouhahouo, B.M.W.;

Valentin, A.; Nguemfo, E.L.; Nkengfack, A.E.; Vierling, W. Anti-

malarial and vasorelaxant constituents of the leaves of Allanblackia

monticola (Guttiferae). Annal. Tropic. Med. Parasitol., 2007, 101,

23-30.

[49] Dua, V.K.; Ojha, V.P.; Roy, R.; Joshi, B.C.; Valecha, N.; Usha

Devi, C.; Bhatnagar, M.C.; Sharma, V.P.; Subbarao, S.K. Anti-

malarial activity of some xanthones isolated from the roots of An-

drographis paniculata. J. Ethnopharm., 2004, 95, 247-51.

[50] Azebaze, A.G.B.; Meyer, M.; Valentin, A.; Nguemfo, E.L.;

Fomum, Z.T.; Nkengfack, A.E. Prenylated xanthone derivatives

with antiplasmodial activity from Allanblackia monticola Staner

L.C. Chem. Pharm. Bull., 2006, 54, 111-13.

[51] Laphookhieo, S.; Syers, J.K.; Kiattansakul, R.; Chantrapromma, K.

Cytotoxic and antimalarial prenylated xanthones from Cratoxylum

cochinchinense. Chem. Pharm. Bull., 2006, 54, 745-47.

[52] Ngouela, S.; Lenta, B.N.; Noungoue, D.T.; Ngoupayo, J.; Boyom,

F.F.; Tsamo, E.; Gut, J.; Rosenthal, P.J.; Connolly, J.D. Anti-

plasmodial and antioxidant activities of constituents of the seed

shells of Symphonia globulifera Linnf. Phytochemistry, 2006, 67,

302-06.

[53] Hay, A-E.; Helesbeux, J-J.; Duval, O.; Labaied, M.; Grellier, P.;

Richomme, P. Antimalarial xanthones from Calophyllum caledoni-

cum and Garcinia vieillardii. Life Sci., 2004, 75, 3077.

[54] Mbwambo, Z.H.; Kapingu, M.C.; Moshi, M.J.; Machumi, F.;

Apers, S.; Cos, P.; Ferreira, D.; Marais, J.P.J.; Berghe; D.V.; Maes,

J.; Vlietinck, A.; Pieters, L. Antiparasitic activity of some xan-

thones and biflavonoids from the root bark of Garcinia living-

stonei. J. Nat. Prod., 2006, 69, 369-72.

[55] Lenta, B.N.; Vonthron-Sénécheau, C.; Weniger, B.; Devkota, K.P.;

Ngoupayo, J.; Kaiser, M.; Naz. Q.; Choudhary, M.I.; Tsamo, E.;

Sewald, N. Leishmanicidal and cholinesterase inhibiting activities

of phenolic compounds from Allanblackia monticola and Sym-

phonia globulifera. Molecules, 2007, 12, 1548-57.

[56] Abe, F.; Nagafuji, S.; Okabe, H.; Higo, H.; Akahane, H. Trypano-

cidal constituents in plants 2.Xanthones from the stem bark of Gar-

cinia subelliptica. Biol. Pharm. Bull., 2003, 26, 1730-33.

[57] Reutrakul, V.; Chanakul, W.; Pohmakotr, M.; Jaipetch T.; Yooso-

ok, C.; Kasisit, J.; Napaswat, C.; Santisuk, T.; Prabpai, S.; Kongsa-

eree, P.; Tuchinda, P. Anti-HIV-1 constituents from leaves and

twigs of Cratoxylum arborescens. Planta Med., 2006, 72, 1433-35.

[58] Reutrakul, V.; Anantachoke, N.; Pohmakotr, M.; Jaipetch, T.; Sop-

hasan, S.; Yoosook, C.; Kasisit, J.; Napaswat, C.; Santisuk, T.; Tu-

chinda, P. Cytotoxic and anti-HIV-1 caged xanthones from the

resin and furits of Garcinia hanburyi. Planta Med., 2007, 73, 33-

40.

[59] Mahabusarakam, W.; Nuangnaowarat, W.; Taylor, W.C. Xanthone

derivatives from Cratoxylum cochinchinense roots. Phytochemi-

stry, 2006, 67, 470-74.

[60] Deachathai, S.; Mahabusarakam, W.; Phongpaichit, S.; Taylor,

W.C.; Zhang, Y-J.; Yang, C-R. Phenolic compounds from the

flowers of Garcinia dulcis. Phytochemistry, 2006, 67, 464-69.

[61] Waffo, A.F.K.; Mulholland, D.; Wansi, J.D.; Mbaze, L.M.; Powo,

R.; Mpondo, T.N.; Fomum, Z.T.; Konig, W.; Nkengfack, A.E. Af-

zeliixanthones A and B, two new prenylated xanthones from Gar-

cinia afzelii Engl. (Guttiferae). Chem. Pharm. Bull., 2006, 54, 448-

51.

[62] Rana, V.S; Rawat, M.S.M. A new xanthone glycoside and antioxi-

dant constituents from the rhizomes of Swertia speciosa. Chem.

Biodiv., 2005, 2, 1310-15.

[63] Lannang, A.M.; Komguem, J.; Ngninzeko, F.N.; Tangmouo, J.G.;

Lontsi, D.; Ajaz, A.; Choudhary, M.L.; Ranjit, R.; Devkota, K.P.;

Sondengam, B.L. Bangangxanthone A and B, two xanthones from

the stem bark of Garcinia polyantha Oliv. Phytochemistry, 2005,

66, 2351-55.

[64] Abdel-Lateff, A.; Klemke, C.; König G.M.; Wright, A.D. Two new

xanthone derivatives from the algicolous marine fungus Wardomy-

ces anomalus. J. Nat. Prod., 2003, 66, 706-8.

[65] Lee, B.W.; Lee, J.H.; Lee, S-T.; Lee, H.S.; Lee, W. S.; Jeongc, T-

S.; Park, K.H. Antioxidant and cytotoxic activities of xanthones

from Cudrania tricuspidata. Bioorg. Med. Chem. Lett., 2005, 15,

5548-52.

[66] Merza, J.; Aumond, M-C.; Rondeau, D.; Dumontet, V.; Ray, A-

M.L.; Seraphin, D.; Richomme, P.; Prenylated xanthones and to-

cotrienols from Garcinia virgata. Phytochemistry, 2004, 65, 2915-

20.

[67] Gamiotea-Turro, D.; Cuesta-Rubio, O.; Prieto-González, S.; Si-

mone, F.; Passi, S.; Rastrelli, L. Antioxidative constituents from the

leaves of Hypericum styphelioides. J. Nat. Prod., 2004, 67, 869-71.

[68] Chin, Y-W.; Jung, H-A.; Chai, H.; Keller, W.J.; Kinghorn, A.D.

Xanthones with quinone reductase-inducing activity from the fruits

of Garcinia mangostana (Mangosteen). Phytochem, 2008, 69, 754-

58.

[69] Park, K.H.; Park, Y-D.; Han, J-M.; Im, K-R.; Lee, B.W.; Jeong,

I.Y.; Jeong, T-S, Lee, W.S. Anti-atherosclerotic and anti-

inflammatory activities of catecholic xanthones and flavonoids iso-

lated from Cudrania tricuspidata. Bioorg. Med. Chem. Lett., 2006,

16, 5580-83.

[70] Oku, H.; Ueda, Y.; Linuma, M.; Ishiguro, K. Inhibitory effects of

xanthones from Guttiferae plants on PAF-induced hypotension in

mice. Planta Med., 2005, 71, 90-92.

[71] Ishiguro, K.; fukumoto, H.; Osada, S.; Isoi, K.; Semma, M. A prac-

tical reproducible measure of murine anaphylaxis: Blood pressure

monitoring of anaphylaxis and effect of Impatient blasamina L.

Phytother. Res., 1998, 8, 301-04.

[72] Prescott, S.M.; Zimmerman, G.A.; Stafforini, D.M.; Mclntyre,

T.M. Platelet-activating factor and related lipid mediators. Annu.

Rev. Biochem., 2000, 69, 419-45.

[73] Jiang, D.J.; Dai, Z.; Li, Y.J. Pharmacological effects of xanthones

as cardiovascular protective agents. Cardiovas. Drug. Rev., 2004,

22, 91-102.

[74] Chericoni, S.; Testai, L.; Calderone, V.; Flamini, G.; Nieri, P.;

Morelli, I.; Martinotti, E. The xanthones gentiacaulein and genti-

akochianin are responsible for the vasodilator action of the roots of

Gentiana kochiana. Planta Med., 2003, 69, 770-72.

[75] Wang, Y.; Shi, J-G.; Wang, M-Z.; Che, C-T.; Yeung, J.H.K.

Mechanisms of the vasorelaxant effect of 1,5-dihydroxy-2,3-

dimethoxy-xanthone, an active metabolite of 1-hydroxy-2,3,5-

trimethoxy-xanthone isolated from a Tibetan herb, Halenia ellip-

tica, on rat coronary artery. Life Sci., 2008, 82, 91-98.

[76] Asolkar, L.V.; Kakkar, K.K.; Chakra, O.J. (1992) Second supple-

ment to glossary of Indian medicinal plants with active principles.

Part I (A–K). New Delhi, India: Publication and Information Divi-

sion, CSIR.

[77] Sampath, P.D.; Vijayaraghavan, K. Cardioprotective effect of -

mangostin, a xanthone derivative from mangosteen on tissue de-

fense system against isoproterenol-induced myocardial infarction in

rats. J. Biochem. Mol. Toxicol., 2007, 21, 336-39.

[78] Madan, B.; Singh, I.; Kumar, A.; Prasad, A.K.; Raj, H.G.; Parmar,

V.S.; Ghosha, B. Xanthones as inhibitors of microsomal lipid per-

oxidation and TNF- induced ICAM-1 expression on human um-

bilical vein endothelial cells (HUVECs). Bioorg. Med. Chem.,

2002, 10, 3431-36.

[79] Yusuf-Makagiansar, H.; Anderson, M.E.; Yakovleva, T.V.; Mur-

ray, J.S.; Siahaan, T.J. Inhibition of LFA-1/ICAM-1 and VLA-

4/VCAM-1 as a therapeutic approach to inflammation and autoim-

mune diseases. Med. Res. Rev., 2002, 22, 146-67.

[80] Nakatani, K.; Nakahata, N.; Arakawa, T.; Yasuda, H.; Ohizumi, Y.

Inhibition of cyclooxygenase and prostaglandin E2 synthesis by -

mangostin, a xanthone derivative in mangosteen, in C6 rat glioma

cells. Biochem. Pharmacol., 2002, 63, 73-79.

[81] Fujimoto, H.; Asai, T.; Kim, Y-P.; Ishibashi, M. Nine constituents

including six xanthone-related compounds isolated from two asco-

mycetes, Gelasinospora santiflorii and Emericella quadrilineata,


found in a screening study focused on immunomodulatory activity.

Chem. Pharm. Bull., 2006, 54, 550-53.

[82] Scarpini, E.; Scheltens, P.; Feldman, H. Treatement of Alzheimer’s

disease: current status and new prespetives. Lancet Neurol., 2003,

2, 539-47.

[83] Erkinjuntti, T.; Gauthier, S.; Bullock, R.; Lilienfeld, S.; Damaraju,

C.V. Efficacy of galanthamine in probable vascular dementia and

Alzheimer’s disease combined with cerebrovascular disease: a ran-

domized trial. Lancet, 2002, 359, 1283-90.

[84] Lopez, S.; Bastida, J.; Viladomat, F.; Codina, C. Acetylcho-

linesterase inhibitory activity of some Amaryllidaceae alkaloids

and Narcissus extracts. Life Sci., 2002, 71, 2521-29.

[85] Urbain, A.; Marston, A.; Queiroz, E.F.; Ndjoko, K.; Hostettmann,

K. Xanthones from Gentiana campestris as new acetylcho-

linesterase inhibitors. Planta Med., 2004, 70, 1011-14.

[86] Schwarz, M.; Glick, D.; Loewensten, Y.; Soreq, H. Engineering of

human cholinesterases explains and predicts diverse consequences

of administration of various drugs and poisons. Pharmacol. Ther.,

1995, 67, 283-322.

[87] Mattson, M. P. Pathways towards and away from Alzheimer's

disease. Nature, 2004, 430, 631-39.

[88] Zhang, L.; Liao, C-C.; Huang, H-C.; Shen, Y-C.; Yang, L-M.; Kuo,

Y-H. Antioxidant phenylpropanoid glycosides from Smilax brac-

teata. Phytochemistry, 2008, 69, 1398-404.

[89] Nunez, M.B.; Maguna, F.P.; Okulika, N.B.; Castrob, E.A. QSAR

modeling of the MAO inhibitory activity of xanthones derivatives.

Bioorg. Med. Chem. Lett., 2004, 14, 5611-17.

[90] Tomi , M.; Tovilovi , G.; Butorovi , B.; Krsti , D.; Jankovi , T.;

Aljan i , I.; Menkovi , N. Neuropharmacological evaluation of di-

ethylether extract and xanthones of Gentiana kochiana. Pharmacol.

Biochem. Behav., 2005, 81, 535-42.

[91] Li, Y.; Matsunaga, K.; Ishibashi, M.; Ohizumi, Y. Littoralisone, a

novel neuritogenic iridolactone having an unprecedented hepta-

cyclic skeleton including four- and nine-membered rings consisting

of glucose from Verbena littoralis. J. Org. Chem., 2001, 66, 2165-

67.

[92] Li, Y.; Matsunaga, K.; Kato, R.; Ohizumi, Y. Verbenachalcone, a

novel dimeric dihydrochalcone with potentiating activity on nerve

growth factor-action from Verbena littoralis. J. Nat. Prod., 2001,

64, 806-08.

[93] Li, Y.; Matsunaga, K.; Kato, R.; Ohizumi, Y. Potentiation of nerve

growth factor-induced elongation of neurites by gelsemiol and 9-

hydroxysemperoside aglucone in PC12D cells. J. Pharm. Pharma-

col., 2001, 53, 915-19.

[94] Chanmahasathien, W.; Li, Y.; Satake, M.; Oshima, Y.; Ishibashi,

M.; Ruangrungsi, N.; Ohizumi, Y. Prenylated xanthones from Gar-

cinia xanthochymus. Chem. Pharm. Bull., 2003, 51, 1332-34.

[95] Chanmahasathien, W.; Li, Y.; Satake, M.; Oshima, Y.; Ishibashi,

M.; Ruangrungsi, N.; Ohizumi, Y. Prenylated xanthones with

NGF-potentiating activity from Garcinia xanthochymus. Phyto-

chemistry, 2003, 64, 981-86.

[96] Connor, B.; Dragunow, M. Xanthones and benzophenones from the

stems of Garcinia multiflora. Brain. Res. Rev., 1998, 27, 1-39.

[97] Helfti, F. Neurotrophic factor therapy for nervous system degenera-

tive diseases. J. Neurobiol., 1994, 25, 1418-35.

[98] Siegel, G.J.; Chauhan, N.B. Neurotrophic factors in Alzheimer’s

and Parkinson’s disease brain. Brain Res. Rev., 2000, 33, 199-227.

[99] Floris, A.L.; Peter, L.L.; Reinier, P.A.; Eloy, H.L.; Guy, E.R.;

Chris, W. -Glucosidase inhibitors for patients with type 2 diabe-

tes. Diabetes Care, 2005, 28, 154-63.

[100] Fernandes, B.; Sagman, U.; Auger, M.; Demetrio, M.; Dennism,

J.W. 1–6 Branched oligosaccharides as a marker of tumor pro-

gression in human breast and colon neoplasia. Cancer Res., 1991,

51, 718-23.

[101] Gruters, R.A.; Neefjes, J.J.; Tersmette, M.; de Goede, R-EY.; Tulp,

A.; Huisman, H.G.; Miedema, F.; Ploegh, H.L. Interference with

HIV-induced syncytium formulation and viral infectivity by inhibi-

tors of trimming glucosidase. Nature, 1987, 330, 74-77.

[102] Dwek, R.A.; Butters, T.D.; Platt, F.M.; Zitzmann, N. Targeting

glycosylation as a therapeutic approach. Nat. Rev. Drug. Disc.,

2002, 1, 65-75.

[103] Maki, K.C.; Carson, M.L.; Miller, M.P.; Turowski, M.; Bell, M.;

Wilder, D.M.; Reeves, M.S. High-viscosity hydroxypropylmethyl-

cellulose blunts postprandial glucose and insulin responses. Diabe-

tes Care, 2007, 30, 1039-43.

[104] Bernacki, R.J.; Niedbala, M.J.; Korytnyk, W. Glycosidases in can-

cer and invasion. Cancer Metastasis Rev., 1985, 4, 81-101.

[105] Seo, E.J.; Curtis-Long, M.J.; Lee, B.W.; Kim, H.Y.; Ryu, Y.B.;

Jeong, T-S.; Lee, W.S.; Parka, K.H. Xanthones from Cudrania tri-

cuspidata displaying potent -glucosidase inhibition. Bioorg. Med.

Chem. Lett., 2007, 17, 6421-24.

[106] Klabunde, T.; Petrassi, H.M.; Oza, V.B.; Raman, P.; Kelly, J.W.;

Sacchettini, J.C. Rational design of potent human transthyretin

amyloid disease inhibitors. Nat. Struct. Biol., 2000, 7, 312-21.

[107] Maia, F.; Almeida, M.R.; Gales, L.; Kijjoa, A.; Pinto, M.M.M.;

Saraiva, M.J.; Damas, A.M. The binding of xanthone derivatives to

transthyretin. Biochem. Pharmacol., 2005, 70, 1861-69.

[108] Reyes-Chilpa, R.; Baggio, C.H.; Alavez-Solano, D.; Estrada-

Muniz, E.; Kauffmanc, F.C.; Sanchez, R.I.; Mesia-Vela, S. Inhibi-

tion of gastric H+,K+-ATPase activity by flavonoids, coumarins and

xanthones isolated from Mexican medicinal plants. J. Ethnophar-

macol., 2006, 105, 167-72.

[109] Carvalho, A.C.S.; Guedes, M.M.; de Souza, A.L.; Trevisan,

M.T.S.; Lima, A.F.; Santos, F.A.; Rao, V.S.N. Gastroprotective ef-

fect of mangiferin, a xanthonoid from Mangifera indica, against

gastric injury induced by ethanol and indomethacin in rodents.

Planta Med., 2007, 73, 1372-76.

[110] Chen, J-J.; Chen, J-S.; Duh, C-Y. Cytotoxic xanthones and biphen-

yls from the root of Garcinia linii. Planta Med., 2004, 70, 1195-

200.

[111] Hong, D.; Yin, F.; Hum, L-H.; Ping, L.P. Sulfonated xanthones

from Hypericum sampsonii. Phytochemistry, 2004, 65, 2595-98.

[112] Chiang, Y-M.; Kuo, Y-H.; Oota, S.; Fukuyama, Y. Xanthones and

benzophenones from the stems of Garcinia multiflora. J. Nat.

Prod., 2003, 66, 1070-73.

[113] Tanaka, N.; Takaishi, Y.; Shikishima, Y.; Nakanishi, Y.; Bastow,

K.; Lee, K-H.; Honda, G.; Ito, M.; Takeda, Y.; Kodzhimatov, O.K.;

Ashurmetov, O. Prenylated benzophenones and xanthones from

Hypericum scabrum. J. Nat. Pord. 2004, 67, 1870-75.

[114] Shadid, K.A.; Shaari, K.; Abas, F.; Israf, D.A.; Hamzah, A.S.;

Syakroni, N.; Saha, K.; Lajis, N.H. Cytotoxic caged-polyprenylated

xanthonoids and a xanthone from Garcinia cantleyana. Phytochem-

istry, 2007, 68, 2537-44.

[115] Yang, N-Y.; Han, Q-B.; Cao, X-W.; Qiao, C-F.; SONG, J-Z.;

Chen, S-L.; Yang, D-J.; Yiu, H.; XU, H-X. Two new xanthones

isolated from the stem bark of Garcinia lancilimba. Chem. Pharm.

Bull., 2007, 55, 950-52.

[116] Nakagawa, Y.; Iinuma, M.; Naoe, T.; Nozawaa, Y.; Akaoa, Y.

Characterized mechanism of –mangostin induced cell death:

Caspase-independent apoptosis with release of endonuclease-G

from mitochondria and increased miR-143 expression in human co-

lorectal cancer DLD-1 cells. Bioorg. Med. Chem., 2007, 15, 5620-

28.

[117] Matsumoto, K.; Akao, Y.; Kobayashi, E.; Ohguchi, K.; Ito, T.;

Tanaka, T.; Iinuma, M.; Nozawa, Y. Induction of apoptosis by xan-

thones from mangosteen in human leukemia cell lines. J. Nat.

Prod., 2003, 66, 1124-27.

[118] Han, Q-B.; Wang, Y-L.;Yang, L.; Tso, T-F.; Qiao, C-F.; Song, J-

Z.; Xu, L-J.; Chen, S-L.; Yang, D-J.; Xu, H-X. Cytotoxic

polyprenylated xanthones from the resin of Garcinia hanburyi.

Chem. Pharm. Bull., 2006, 54, 265-67.

[119] Han, Q-B.; Cheung, S.; Tai, J.; Qiao, C-F.; Song, J-Z.; Xu, H-X.

Stability and cytotoxicity of gambogic acid and its derivative, gam-

bogoic acid. Biol. Pharm. Bull., 2005, 28, 2335-37.

[120] Krick, A.; Kehraus, S.; Gerhäuser, C.; Klimo, K.; Nieger, M.;

Maier, A.; Fiebig, H-H.; Atodiresei, I.; Raabe, G.; Fleischhauer, J.;

König, G.M. Potential cancer chemopreventive in vitro activities of

monomeric xanthone derivatives from the marine algicolous fungus

Monodictys putredinis. J. Nat. Prod., 2007, 70, 353-60.

[121] Cao, S.; Brodie, P.J.; Miller, J.S.; Randrianaivo, R.; Ratovoson, F.;

Birkinshaw, C.; Andriantsiferana, R.; Rasamison, V.E.; Kingston,

D.G.I. Antiproliferative xanthones of Terminalia calcicola from the

Madagascar rain forest. J. Nat. Prod., 2007, 70, 679-81.

[122] Pattanaprateeb, P.; Ruangrungsi, N.; Cordell, A.C. Cytotoxic Con-

stituents from Cratoxylum araborescens. Planta Med., 2005, 71,

181-83.


[123] Wilairat, R.; Manosroi, J.; Manosroi, A.; Kijjoa, A.; Nascimento,

M.; Pinto, M.; Silva, A.M.; Eaton, G.; Herz, W. Cytotoxicities of

xanthones and cinnamate esters from Hypericum hookerianum.

Planta Med., 2005, 71, 680-82.

[124] Nkengfack, A.; Azebaza, G.; Vardamides, J.; Fomum, Z.; Heerden,

F. A prenylated xanthone from Allanblackia floribunda. Phyto-

chemistry, 2002, 60, 381-84.

[125] Matsumoto, K.; Akao, Y.; Ohguchi, K.; Ito, T.; Tanaka, T.; Iinu-

mad, M.; Nozawa, Y. Xanthones induce cell-cycle arrest and apop-

tosis in human colon cancer DLD-1 cells. Bioorg. Med. Chem.,

2005, 13, 6064-69.

[126] Ito, C.; Itoigawa, M.; Takakura, T.; Ruangrungsi, N.; Enjo, F.;

Tokuda, H.; Nishino, H.; Furukawa, H. Chemical constituents of

Garcinia fusca: structure elucidation of eight new xanthones and

their cancer chemopreventive activity. J. Nat. Prod., 2003, 66, 200-

05.

Received: October 28, 2009 Revised: January 22, 2010 Accepted: January 23, 2010

Documents

Recent Insights into the biosynthesis and biological activites of natural Xanthones