Xanthone Derivatives: New Insights in Biological Activities

Abstract

Xanthones or xanthen-9H-ones (dibenzo-gamma-pirone) comprise an important class of oxygenated heterocycles whose role is well-known in Medicinal Chemistry. The biological activities of this class of compounds are associated with their tricyclic scaffold but vary depending on the nature and/or position of the different substituents. In this review, an array of biological/pharmacological effects is presented for both natural and synthetic xanthone derivatives, with an emphasis on some significant studies on structure-activity relationships. The antitumor activity of some xanthones as well as the related targets, particularly PKC modulation studies, is also discussed in detail. Examples of the "hit" compounds involved in cancer therapy, namely DMXAA, psorospermin, mangiferin, norathyriol, mangostins, and AH6809, a prostanoid receptor antagonist, are also mentioned. Finally, a historical perspective of these xanthonic derivatives, their relevance as therapeutic agents and/or their uses as pharmacological tools and as extract components in folk medicine are also highlighted.

Full text

Current Medicinal Chemistry, 2005, 12, 2517-2538 2517
0929-8673/05 $50.00+.00 © 2005 Bentham Science Publishers Ltd.
Xanthone Derivatives: New Insights in Biological Activities
M.M.M. Pinto
*
, M.E. Sousa and M.S.J. Nascimento
Centro de Estudos de Química Orgânica, Fitoquímica e Farmacologia da Universidade do Porto, Laboratórios
de Química Orgânica e Microbiologia, Faculdade de Farmácia, Rua Aníbal Cunha 164, 4050-047 Porto,
Portugal
Abstract: Xanthones or 9H-xanthen-9-ones (dibenzo-γ-pirone) comprise an important class of oxygenated
heterocycles whose role is well-known in Medicinal Chemistry. The biological activities of this class of
compounds are associated with their tricyclic scaffold but vary depending on the nature and/or position of the
different substituents. In this review, an array of biological/pharmacological effects is presented for both
natural and synthetic xanthone derivatives, with an emphasis on some significant studies on structure-activity
relationships. The antitumor activity of some xanthones as well as the related targets, particularly PKC
modulation studies, is also discussed in detail. Examples of the "hit" compounds involved in cancer therapy,
namely DMXAA, psorospermin, mangiferin, norathyriol, mangostins, and AH6809, a prostanoid receptor
antagonist, are also mentioned. Finally, a historical perspective of these xanthonic derivatives, their relevance
as therapeutic agents and/or their uses as pharmacological tools and as extract components in folk medicine
are also highlighted.
Keywords: Xanthone, xanthenone, heterocycle, antitumor, PKC modulation, structure-activity relationship.
1. INTRODUCTION
The xanthone nucleus or 9H-xanthen-9-one (dibenzo-γ-
pirone 1, Fig. (1)) comprises an important class of the
oxygenated heterocycles [1]. Natural xanthones can be sub-
divided, depending on the nature of the substituents in the
dibenzo-γ-pirone scaffold, into: simple oxygenated
xanthones, glycosylated xanthones, prenylated xanthones
and their derivatives, xanthone dimers, xanthonolignoids
and miscellaneous [1-4]. On the other hand, the xanthones of
a synthetic origin can have simple groups such as hydroxyl,
methoxyl, methyl, carboxyl, as well as more complex
substituents such as epoxide, azole, methylidene-
butyrolactone, aminoalcohol, sulfamoyl, methylthio-
carboxylic acid, and dihydropyridine in their scaffold.
O
O
1
1
2
3
45
6
7
8
4a10a
8a
9
9a
10
Fig. (1). Xanthone.
Since the growing interest in this class of compounds
has been associated with the pharmacological properties
demonstrated by both natural and synthetic derivatives, this
aspect will be emphasized in this review.
*Address correspondence to this author at the Centro de Estudos de
Química Orgânica, Fitoquímica e Farmacologia da Universidade do Porto,
Faculdade de Farmácia, Laboratório de Química Orgânica, Rua Aníbal
Cunha, 164, 4050-047 Porto, Portugal; Tel: 351-222057358; Fax: 351-
222003977; E-mail: madalena@ff.up.pt
Pharmacological investigations of xanthones date back to
1968, when Bhattacharya’s group reported the diuretic and
cardiotonic actions of the natural glycoside mangiferin
[5]. Later, Da Re et al. described, for the first time,
central stimulating and analeptic activities of synthetic
aminoalkylxanthone derivatives [6,7]. Further examination
of this activity led to the report of a remarkable central
nervous system (CNS) stimulating effect of mangiferin
[8], and in vitro experiments have shown that the above
effect was caused by an inhibition of the enzyme monoamine
oxidase (MAO) [9]. Meanwhile, in a continuing study with
aminoalkylxanthones, new aminopropanoxy derivatives were
described in 1972 as β-adrenergic blocking agents [10,11]. In
the same year, xanthone derivatives developed by isosteric
substitution of benzo [b]acronycine were investigated for
their in vivo antitumor activity [12], while xanthone-2-
carboxylic acids were shown to be effective in allergy [13].
At the end of the 70s, much was achieved for the recognition
of biological activity with more than twenty
pharmacological studies being carried out for natural and
synthetic xanthones [5-28].
At present, xanthones are of documented relevance to
human diseases. The most remarkable example is
dimethylxanthenone-4-acetic acid or DMXAA (2, Fig. (2)).
This compound is currently undergoing clinical trials as an
antitumor agent. On the other hand, the aqueous extracts of
Mangifera indica (Vimang) and Garcinia mangostana
(Xango), commercialized as antioxidants with human
health promotion properties, were also found to contain
xanthones. Interestingly, the main constituent of Vimang
is mangiferin (13, Fig. (3)) [29], while Xango is rich in
oxygenated and prenylated xanthones (16-18, Fig. (3)) [30].
Though biological activities of several xanthones have
been previously reported in the generic reviews for natural
[1-4] and synthetic xanthones [73, 74], they were concerned
only with primary studies of these compounds. The more
recent reviews covering this subject were restricted only to

2518 Current Medicinal Chemistry, 2005, Vol. 12, No. 21 Pinto et al.
O
O
CH
2
COOH
CH
3
CH
3
O
COOH
O
O
O
OOH
OCH
2
CH
2
CH
2
N(CH
3
)
2
MeO
(H
3
C)
2
NH
2
CH
2
CH
2
CO
O
O
OH
OH
O
O
OH
OMe
CHO
O
OO
O
HOH
2
C
OH
OMe
O
OO
O
HOH
2
C
OH
OMe
O
O
O
CH
2
OH
O
OH
OMe
O
O
O
O
CH
2
OH
OH
MeO
O
O
O
O
HOH
2
C
OH
OM e
2
11
3
6
9
8
10
7
45
Fig. (2). Bioactive synthetic xanthones selected.
either the subfamilies of xanthones [75] or a particular
biological activity [37, 76-80]. Thus, the objective of the
present review is to make an update on the biological
activities reported by this class of compounds as well as to
relate them to the targets involved. As the activities
described herein cover a large number of xanthone
derivatives and represent a huge variety of pharmacological
actions, it is impracticable to fully discuss all of them in
this review.
Due to the importance of xanthones for their application
in folk medicine and for their clinical relevance, our group
has been focusing on the synthesis and evaluation of
biological activity of this class of compounds.
Consequently, the antitumor activity of xanthones
derivatives and their ability to modulate the enzyme protein
kinase C (PKC) will be outlined in this review. Moreover,
the synthetic and natural xanthones investigated as
chemotherapeutic agents are also discussed in detail.

Xanthone Derivatives Current Medicinal Chemistry, 2005, Vol. 12, No. 21 2519
O
O
OH
OHHO
HO
O
OOH
HO
O
O
OOH
OHHO
HO
OH
OH
OH
OH
O
OOH
OHHO
MeO
O
OOH
HO
MeO
OM e
O
O
OH
OHHO
HO
O
O
OH
OHHO
HO
O
O
O
O
CH
3
H
OH
OMe
OMeO
OH
OH OHO
O
O
O
OH
OH
OH
HO
OH
OH
HO
HO
14
15
13
16
17
18
19
12
20
Fig. (3). Bioactive natural xanthones selected.
2. BIOLOGICAL ACTIVITIES
As phenolic compounds, xanthones have been described
for their antioxidant properties [31-53]. They can act as
metal chelators [35], free radical scavengers [31-33,35,39-
41,49,51,54-67], as well as inhibitors of lipid peroxidation
[31,33-35, 39,43,64,66, 68-70]. These properties have been
implicated with their hepatoprotective [64,71,72], anti-
inflammatory [43,48,54], and cancer chemopreventive
actions [50,69].
Table 1 lists the effects of xanthonic derivatives on
crucial enzyme systems. The effects of xanthones on other
functional systems are also given in Table 2. A pleiad of
biological activities of xanthones showing the associated
targets with their chemical scaffolds is presented in Table 3.
In most cases, the xanthonic framework belongs to the
pharmacophoric moiety for the activity exhibited as in the
case of DMXAA (2, Fig. (4A)) [81]. However, the xanthone
nucleus is not solely restricted to a pharmacophoric moiety
role (Fig. (4B)), as the xanthonic backbone can also function
as a substituent group to modulate the biological responses.
This can be exemplified by the 1,4-dihydropyridines
derivatives with a xanthonic substituent [82-84].
It is interesting to point out that the emerging results
from the pharmacological activity evaluation of both natural
and synthetic compounds have resulted in the increasing
quest and optimization of "hit" and lead compounds. To this
end, the structure-activity relationship (SAR) studies are
currently available for the following activities:
tuberculostatic [16,85-87], antimycotic [88], antimalarial
[89, 90], antiplatelet [91-94], antithrombotic [95], anti-
inflammatory [54,96,97], antiallergic [13,22, 24], antitumor
[7,17,81,98-107], antimutagenic [108-110], and antioxidant
[38,43,55]. Furthermore, SAR studies have been also
developed in the field of adrenergic blocking agents [7,11],
calcium antagonists [82-84,111,119], P-glycoprotein

2520 Current Medicinal Chemistry, 2005, Vol. 12, No. 21 Pinto et al.
Table 1. Enzyme Systems Modulated by Xanthonic Derivatives
Enzyme Systems Effects Substituents/Analogues
Acetylcholinesterase inhibition aminoalkoxy/xanthostigmin analogs [116*,117*], oxygenated
b
, prenyl,
pyrano [323], unsubstituted [324]
Aldose Reductase inhibition carboxysulfamoyl [118*,325], carboxy [326], glycosyl [292*,293*]
Angiotensin-I-Converting Enzyme inhibition tetra-oxygenated [297*]
Aromatase inhibition imidazole, triazole [76*,119*]
Butyrylcholinesterase inhibition aminoalkoxy/xanthostigmin analogs [116*,117*]
Calcium-ATPase noncompetitive inhibition prenyl [184*,313*]
activation unsubstituted [298*]
Catalase activity decreased glycosyl [42*,279*], Swertia chirata extract (oxygenated
b
, dimer)
a
[69*]
Cyclooxygenases (COXs) inhibition epoxy [327], prenyl [308*], glycosyl [277*], oxygenated
b
[301*]
COX-2 gene expression inhibition glycosyl [277*,280*], prenyl [312*], Mangifera indica extract
(glycosyl)
a
[280*]
Cyclic AMP- Binding Phosphatase noncompetitive inhibition prenyl [125*]
Cyclic AMP-Phosphodiesterase inhibition oxygenated
b
[14*,328], prenyl, pyrano [329]
Cyclic GMP-Phosphodiesterase inhibition oxygenated
b
[328]
Diphosphoglycerate Phosphatase inhibition tetrazole [330]
DNA Polymerase inhibition xanthone-flavone [331*,332*]
Glutamic Oxaloacetic Transaminase release decreased oxygenated
b
[333]
Glutathione-S-Transferase activity enhanced Swertia chirata extract (oxygenated
b
, dimer)
a
[69*]
Glutathione Peroxidase activity enhanced /decreased Swertia chirata extract (oxygenated
b
, dimer)
a
[69*]
Glutamic Acid Decarboxylase activity decreased oxygenated
b
, chloro, aminoalkyl [7*]
αα
αα
-Glycosidase inhibition glycosyl [290*]
Isomaltase competitive inhibition glycosyl [292*]
Human DNA Ligase I inhibition xanthone-flavone [334]
17-
αα
αα
-Hydroxylase / C17,20-Lyase inhibition imidazole [119*,120*], triazole [119*]
Hypoxanthine-Xanthine Oxidase noncompetitive inhibition oxygenated
b
[40*,294*]
Kinases:
Calcium-Dependent Protein Kinase inhibition prenyl [125*]
Casein Kinase 2 ATP-binding site inhibition dihydroxy, nitro [335,336,337]
Creatine Kinase inhibition glycosyl [42*]
release in coronary effluent
decreased
tetrahydroxy [338,339]
Cyclic AMP-Dependent Protein Kinase competitive inhibition of the catalytic
subunit
prenyl [125*,206*]
modulators [112], leukotriene (LT) B4 receptors blocking
agents [113-115], as well as for effects on several enzymes,
such as acetylcholinesterase [116,117], aldose reductase
[118], aromatase [119], cyclic AMP-phosphodiesterase [14],
human cytochrome P450 17 α-hydroxylase-17, 20-lyase
[120], MAO [121, 122], sphingomyelinases [123, 124], and
protein kinases [125-127]. From the available SARs,
quantitative structure-activity relationship (QSAR) studies
are emerging for tuberculostatic agents [16,85-87] and MAO
inhibitors [121,122]. More recently, computational studies
have been developed in the field of antimalarial agents [128-
130] using docking studies to obtain a correlation between
xanthone derivatives and hematin/hemazoin targets [130].

Xanthone Derivatives Current Medicinal Chemistry, 2005, Vol. 12, No. 21 2521
(Table 1)contd....
.
Enzyme Systems Effects Substituents/Analogues
Jun N-terminal kinase/stress-activated
protein kinase (JNK/SAPK)
activation prenyl [184*]
IκB Kinase inhibition methylenecarboxy [224*], prenyl [312*], glycosyl [279*,281*]
Myosin Light Chain Kinase (MLCK) inhibition prenyl [125*]
Protein Kinase C (PKC) activation oxygenated
b
[208*,209*,126*]
inhibition formyl, dihydroxy [211*], xanthonolignoids [127*]
competitive inhibition prenyl [125*,206*]
noncompetitive inhibition tetra-oxygenated [36*,207*]
Pyruvate Kinase inhibition tetrazole [330]
Tyrosine Kinase inhibition trihydroxy [66*], dihydrobenzoxanthones [340]
Lactate Dehydrogenase release increased tetra-oxygenated [48*,116*,341,342]
release decreased tetra-oxygenated [338,333]
Lipoxygenase inhibition oxygenated
b
[301*]
Monoamine Oxidases (MAOs) A and B competitive, reversible, selective
inhibition
unsubstituted [343,344], glycosyl [9,345], oxygenated
b
[121*,344,346-
351], prenyl [345,347], chloro, bromo, alkyl [122*,348]
NAD(P)H Quinone Oxidoreductase inhibition methylenecarboxy [253,352]
Nitric Oxide Synthase inhibition oxygenated
b
[44*,341]
gene expression inhibition glycosyl [58*,277*,280*], Mangifera indica extract (glycosyl)
a
[280*]
endogenous inhibitor level decreased tetrahydroxy [48*]
Phospholipase C inhibition tetra-oxygenated [40*], xanthone-chromone [168*]
Proteases:
Aspartic inhibition oxygenated
b
, prenyl [353]
Caspase-3 activation prenyl [131*,142*,144*,147*,184*]
Caspase-9 activation prenyl [144*]
HIV-1 Protease inhibition prenyl [305,354]
Sphingomyelinases inhibition prenyl [123*,124*,314*]
Steroid 11-
ββ
ββ
-Hydroxylase inhibition xanthone-anthraquinone [185*]
Sucrase competitive inhibition glycosyl [292*]
Sulfotransferases inhibition
substrate mimicry
tetra-oxygenated [355]
hydroxy [356]
Superoxide Dismutase activity decreased glycosyl [42*], oxygenated
b
[70*,333] Swertia chirata extract
(oxygenated
b
, dimer)
a
[69*]
Topoisomerases I and II inhibition furano [265*,263*,264*,357,358], prenyl [358,359], oxygenated
b
,
pyrano, furano, xanthonolignoids [359], carboxamide [360]
Reductase inhibition Mangifera indica extract (glycosyl)
a
[72*], methylenecarboxy [253*]
Reverse transcriptases:
HIV-1 inhibition trihydroxy [66*], pyrano [361]
competitive inhibition xanthone-flavone [331,362]
MMLV competitive inhibition oxygenated
b
[332,363,364]
a
main xanthone component(s),
b
refers to simple hydroxy- and/or methoxy-xanthones, * references cited in the text.

2522 Current Medicinal Chemistry, 2005, Vol. 12, No. 21 Pinto et al.
Table 2. Other Cellular Systems Modulated by Xanthonic Derivatives
Cellular Systems Effects Substituents/Analogues
ββ
ββ
-Adrenergic receptors antagonism aminopropoxy [10*,11*,365]
Albumin binding carboxy, tetrazole [366,367]
immunoreactive conjugates formation furano [368,369]
antioxidant effect prenyl [72*]
Calcium channels blocking unsubstituted [298*,370], tetra-oxygenated [298*],
metanofosfonic group [371], 1,4-dihydropyridine [82-
84*,111*,372-374,], aminopropoxy, ω-aminoalkoxy [365]
Glycoproteins:
CD4 binding polycyclic [375,376]
P glycoprotein modulation prenyl [77*,112*]
Haemoglobin complexation with heme oxygenated
b
[129*,377], nitro [378]
oxygen affinity decreased tetrazole [367,379,380]
Heat Shock Protein HSP-47 gene expression inhibiton policyclic [187*]
5-HT 2A Receptor antagonist methylenecarboxy [230*], prenyl [307*,310*,311*]
Human Complement System inhibition oxygenated
b
[381-383], prenyl [383]
Human Umbilical Vein Endothelial Cells
(HUVECs)
inhibition of the expression of cell
adhesion molecule-1, ICAM-1,
VCAM-1 and E-selectin
oxygenated
b
[43*,384]
Histamine H1 receptor competitive antagonism prenyl [306*,307*]
Leukotriene B4 (LT B4) Receptors blocking carboxy [113*,179*,385,386], biphenylcarboxy [115*,387,388]
Lymphocytes inhibition of proliferation oxygenated
b
[165*,166*,383], xanthonolignoids [165*], prenyl
[142*]
activation/inhibition of proliferation glycosyl [389]
activation of proliferation glycosyl [390]
specific cytolytic T-killers formation glycosyl [390]
Macrophages phagocytic activity inhibition
controlling the expression of genes for
primary inflammation mediators
glycosyl [41*,56*,58*,196*,278*], Mangifera indica extract
(glycosyl)
a
[56*]
lytic properties increased furano,carboxy [175*]
inibition of ROS and NO production glycosyl [41*,56*], hydroxy [391], Mangifera indica extract
(glycosyl)
a
[41*,56*,277*]
stimulation of NO production methylenecarboxy [231*]
Platelet Activating Factor Receptors antagonism prenyl [392-394]
Prostaglandin D2(DP), E1 and E2 Receptors blocking prenyl [308*], carboxy [179*,181*,315*,316*,320-322*]
a
main xanthone component(s),
b
refers to simple hydroxy- and/or methoxy-xanthones, * references cited in the text.
2.1. Antitumor Activity
Among a myriad of biological activities described for
xanthones, the in vitro growth inhibitory activity on tumor
cell lines appeared to be quite remarkable, since they exert
their effect on a wide range of different tumor cell lines such
as leukemia [106,131-157,146,154], multiple myeloma
[155], oral squamous cell carcinoma [98,99, 158-162],
melanoma [103,137,163-166], colon carcinoma [105,134,
135,137,145,146,148,156,160,167-175], breast adenocarci-
noma [46,106,107,134,135,145,155,164-166,170,176], ova-
rian carcinoma [137,155,172,175], uterine carcinoma [177],
prostate carcinoma [137,178], lung carcinoma [106,132,134,
137,141,145,148,149,154,164,178-180], liver carcinoma
[180], stomach carcinoma [174,180], renal carcinoma
[106,137], pancreatic carcinoma [155], CNS carcinoma [106,
164-166], glioma [181], colorectal carcinoma [145,152],
hepatoma [98,99,154,174,182], bladder carcinoma [182],
neuroblastoma [183], pheochromocytoma [184], adreno-
cortical carcinoma [185,186], fibroblasts tumor cells

Xanthone Derivatives Current Medicinal Chemistry, 2005, Vol. 12, No. 21 2523
Table 3. Biological Activities of Xanthones, Associated Targets and Scaffolds
Biological Activities Targets / Messengers / Associated Process Substituents/Analogues
Antimicrobial:
Antibacterial
[50*,66*,114*,167*,169*,177*,
190*,302*,353,395-414]
Actinobacillus actinomycetemcomitans [414], Bacillus brevis
[405], B. cereus [405,407], B. megaterium [66*], B. subtilis
[50*,407,410,412], Cladosporium herbarum [50*], Escherichia
coli [50*, 66*,405,411], Fusobacterium nucleatum [414],
Micrococcus luteus [412], Peptostreptococcus micros,
Porphyromonas gingivalis, Prevotella intermedia [414],
Pseudomonas aeruginosa [50*,405], Staphylococcus aureus
[50*,190*,403,405,410-412], Streptococcus pyogenes [405]
trihydroxy [66*], pyrano, prenyl
[177*,190*,403,411,412], methylenedioxy [410],
glycosyl [406,413,414], Mangifera indica extract
(glycosyl)
a
[414], essential oils
b
of Hypericum
scabrum, H. scabroides and H. triquetrifolium
[405], H. perforatum extract
b
[407], Garcinia
atroviridis extract
b
[50], extracts
b
of Mammea
americana and Calophyllum brasiliense [411]
antimycobacterial
[15*,16*,85-87*,176*,398,415-417]
Mycobacterium tuberculosis [15*,16*,86*,87*,176*,398,415-
417], M. lufu, M. smegmatis, M. avium [15*,16*,86*,398,415-
417]
polyhydroxy [15*,16*,85*,415], nitro
[87*,398,417], methyl, cyano, carboxy,
methylester, amide, amine [87*,417], dimeric
[176*]
Antiparasitic
[177*,404,406,413]
Philasterides dicentrarchi [413], Trichinella spiralis [406],
Typanosoma cruzi [177*,404,406]
tetrahydropyranylethoxy, thiocyanethoxy [404],
methyl, carboxy, methoxy [177*], Mangifera indica
extract (glycosyl)
a
[406], glycosyl [413]
antileishmanial [378,408] Leishmania mexicana [378], Leishmania amazonensis [408] diethylaminoalkoxy [378], methyl, carboxy,
methoxy [408]
antimalarial
[78*,89*,90*,128*,129*,176*,377,
418-426]
heme [89*,128*
c
,129*
c
,422], cyclic AMP-dependent protein
kinase [125*
c
], P. falsiparum [421,424-426], Plasmodium
berghei [176*,426]
prenyl [420,421,425], pyrano [425], oxygenated
[421,426] including polyhydroxy
[78*,89*,90*,128*,129*,377,418,419,425],
diethylaminoalkoxy [78*,422,423], dimeric [176*],
Garcinia kola extract
b
[424]
Antifungal
[47*,50*,66*,88*,114*,125*,167*,
303*,304*,347,353,405,409,427-
439]
protein kinase A [125*
c
], Candida albicans secreted aspartic
proteases [353], Alternaria sp [50*], Aspergillus
[114*,427,430,432], A. flavus [47*], A. fumigatus
[409,428,437,439], A. nidulans [439], A. niger [88*], A.
ochraceous [50*], Candida albicans
[50*,88*,114*,347,353,405,427-430,432,433], C. glabrata
[439], C. herbarum [50*], C. kruzei, C. tropicalis [172*],
Cladosporium cucunerinum [347,428,429,433], Cryptococcus
neoformans [88*,439], Dermatophytes [114*,427,430,432],
Eurotium repens [66*,438], Fusarium moniliforme [50*],
Microbotryum violaceum [66*], Trichophyton mentagrophytes
[428], Ustilago violacea [438]
prenyl [125*,347,353,409,429,433,437,439],
oxygenated [66*,353,409,428,433], chloro, fluor,
acetoxy, arylhydrazonomethyl [436], allylamine
[88*], methyl, hydroxymethyl [438], pyrano
[409,433,437], furano [429,437], polycyclic
[114*,427,430,432], Garcinia atroviridis [50*] and
G. indica extracts
b
[47*]
Antiviral [17*,282-284*,440] Herpes simplex virus replication [282-284*] furano [17*], glycosyl [282*,284*], Mangifera
indica extract (glycosyl)
a
[283*]
antiretroviral
[196*,305*,331*,332*,354,361-
364,441]
glycoprotein CD4 [375
c
], HIV-1 protease [305*
c
,354
c
], HIV-
1 reverse transcriptase [331*
c
,361
c
,362
c
,364], MMLV reverse
transcriptase [363]
tetrahydroxy [363,364], flavone-xanthone
[354,362,364], prenyl [305*,354,441], pyrano
[361], glycosyl [196*]
CNS Depressants
[15*,18*,26*,442,443]
oxygenated [7*,15*,443], glycosyl [18*,442],
prenyl [26*,443], chloro [7*], aminoalkyl [7*]
CNS Stimulants [6-8*,444] monoamine oxidase [9*
c
] aminopropanoloxy R-enantiomer [6*,7*,444],
glycosyl [8*]
Neurological disorders [445] action of the neurotrophic factor nerve growth factor
enhanced [445]
prenyl [445]
Anticonvulsants/
antiepileptics [19*,444,446-450]
decreasing γ-aminobutyric acid (GABA) level [446], in
induced seizures [19*,444,446-450]
oxygenated [19*], alkanolamides [446-450],
alkanoamines [448], aminopropanoloxy S-
enantiomer [444]
Analgesics [274*,451,452] bradykinin, P substance [452] hydroxyacetyl [451], oxygenated [452], glycosyl,
Mangifera indica extract
b
(glycosyl) [274*]
Antiarrhythmics
[111*,333,338,339,342,450,453,454]
calcium channel [111*,372-374], lipidic peroxidation
[333,339], TNF-α, ROS production [338]
aminoalkanolic [450,454], chiral aminopropanoloxy
[453], oxygenated [339,338,342,333], 1,4-
dihydropyridine [111*,372-374]
Antihypertensives
[230*,365,453,455,485]
calcium channel [111*
c
,298*
c
,365,370-373
c
], cyclic AMP
[370], AMP- and cyclic GMP-phosphodiesterase [328
c
], 5-HT
[230*], β-adrenergic receptors [11*
c
,365], platelet activating
factor [455], angiotensin-I-converting enzyme [297*
c
]
dimeric [455], 1,4-dihydropyridine [111*,372,373],
chiral aminopropanoloxy [453], methylenecarboxy
[230*], aminoalkoxy [365], unsubstituted [370],
oxygenated [485]

2524 Current Medicinal Chemistry, 2005, Vol. 12, No. 21 Pinto et al.
(Table 3)contd.....
Biological Activities Targets / Messengers / Associated Process Substituents/Analogues
Diuretics, Uricosurics [456-458] oxyacetoxy, dihydrofurocarboxy [456-458]
Antilipemic [289*,459] adrenaline- and theophylline-induced lipolysis [459], fat
metabolizing enzymes, lipolysis [289*]
glycosyl [289*], fenofibrate and fenofibric acid
analogs [459]
Anti-hypercholesterolemics [48*] NO synthase, lipidic peroxidation [48*] tetrahydroxy [48*]
Antiulcerogenic [6*,460,461] Helicobacter pylori [460] Garcinia cambogia extract [461]
Antiplatelet / Anticoagulants [91-
95*,327,392,455,462,463]
COX [327], platelet activating factor receptors [392,455], TX
[91*,95*], inositol phosphate [91*], thrombin-induced platelet
aggregation [94*], arachidonate-induced aggregation
[93*,95*,462,463]
epoxy [327], prenyl [392], glycosyl [91*],
aminoalkanolic [94*], dimeric [455], aminoalkoxy
[93*,95*,462], oxygenated [91*,92*,462,463]
Anti-Asthmatics
[20*,21*,27*,28*,464,465]
mast cells (degranulation) [21*
c
,465
c
], acetylcholine,
histamine, bradykinin, substance P, PG E2 , TX A2 analog
[464], LT B4 receptors [113*
c
,141*
c
,179*
c
,385
c
], exercise-
induced bronchospasm [27*,28*]
oxygenated [464], methylthio carboxy
[20*,21*,27*,28*,465]
Hepatoprotective
[64*,71*,72*,270*,272*]
lipid peroxidation [71*,72*,270*] oxygenated, xanthonolignoids [71*], Mangifera
indica extract (glycosyl)
a
[64*,72*], Polygala
elongata extract (glycosyl)
a
[272*], Salacia
reticulata extract (glycosyl)
a
[270*]
Antidiabetics
[42*,118*, 285-288*,
290*,291*,325, 326,466-470]
aldose reductase [118*,292*,293*,325,326], creatine
phosphokinase [42*], insulin [287*,467,469], glucose
[286*,468,469], cholesterol [285*,468], triglycerides
[285*,286*,288*], glycosylated haemoglobin [42*], α-
glycosidase [290*]
glycosyl [42*,287*,285*,286*,288*,290-293*],
carboxysulfamoyl [118*,325], carboxy [326],
oxygenated [466,467,470]
Antiosteoporotics [471,472] bone resorption [471,472] propoxy/ipriflavone analogs [471], glycosyl [472]
In Fibrotic Diseases [187*] HSP47 gene expression, inhibit collagen production on human
dermal fibroblast [187*]
polycyclic [187*]
In Erectile Dysfunction [473] corpus cavernosum [473] tri-oxygenated [473]
In Achondrogenesis [321*,320*] PKC, EP1 receptors [320*,321*] carboxy [320*,321*]
Antitumor
(see references in Section 2.1.)
see Table 5see Section 2.1. for natural products; see Table 4
for synthetic derivatives
Anti-inflammatory
[26*,54*,97*,273*,274*,277*,278*,
300*,301*,308*,312*,384,443,451,4
63,464,474,484]
PG E2 receptors, COX [301*,308*,312*], lysozyme,
histamine, β-glucuronidase, mast cells and neutrophils
(degranulation) [54*,300*,463], macrophages activation
[277*], acetylcholine, histamine, bradykinin, substance P
[300*,464], PG E2 [273*,464], TX A2 analog [464], PKC
[36*
c
,125*
c
,206*
c
,209*
c
,207*
c
], phospholipase C
[40*
c
,168*
c
], lipooxygenase [301*,312*], phospholipase A2
[273*], TNF-α, NO production [58*
c
, 278*]
oxygenated [54*,300*,301*,384,463,464,474],
hydroxyacetyl [451], carboxy [97*], prenyl
[26*,308*,443], glycosyl [273*,274*,277-279*],
Mangifera indica extract (glycosyl)
a
[273*,274*,277*,278*]
Antiallergics [13,22-
24,96,406,464,465]
macrophages activation [22*], mast cells (degranulation)
[465,474], acetylcholine, histamine, bradykinin, substance P,
PG E2, TX A2 analog [464], immunoglobulin E [22*,96*,406],
LT B4 receptors [113*
c
,179*
c
, 385
c
,387
c
]
oxygenated [464], methylthio carboxy [465],
dicarboxy [22*,23*], sulfoximide, alkyl, alkoxy,
carboxy [22*,24*,96*], glycosyl, Mangifera indica
extract (glycosyl)
a
[406]
Antianaphylatics
[22,25,96,300,328,451,474]
immunoglobulin E [25*,96*,474], immunoglobulin G [25*],
mast cells (degranulation) [300*], AMP- and cyclic GMP-
phosphodiesterase [328*]
oxygenated [300*,328*,474], hydroxyacetyl [451],
carboxy [22*,96*], methylsulphonimidoyl
carboxylic acids [25*]
Immunomodulators [275,276,
281,475]
antibodies production [275*,276*], immunoglobulin G
production [275*], JNK1, c-JUN [281*], interleukin-1β,
interleukin-6, interleukin-10, interferon-γ, TNF-α [475]
glycosyl, Mangifera indica extract (glycosyl)
a
[275*,276*, 281*], Swertia chirayita extract
(glycosyl)
a
[475]
a
main xanthone component,
b
rich in xanthones,
c
targets directly evaluated without inquiring the cited activity, * references cited in the text.
[149,168,176,187,188], fibrosarcoma [154], epithelial tumor
cells [114,188], nasopharynx epidermoid carcinoma
[176,178,189-191], and Friend tumor cells [139]. Moreover,
several in vivo studies in xenographic tumor models have
been carried out in colon adenocarcinoma [81,100-102,192-
194], lymphocytic leukemia [17,158,159,195], ovarian
[193], melanoma [163, 193], pancreatic [155], sarcoma
[12,190,195], Ehrlich's carcinoma [173,195], and glioma
[195]. Apart from the antitumor effect, some xanthones
containing substances and extracts have been described for
their antimutagenic properties [50,108,110,197-200] and for
their cancer chemopreventive effect, acting as inhibitors of

Xanthone Derivatives Current Medicinal Chemistry, 2005, Vol. 12, No. 21 2525
O
O
CH
2
COOHCH
3
H
3
CO
O
CH
2
COOH
O
O
CH
2
COOH
Fla voneacetic acid
Xanthoneacetic acid
DMXAA (2)
Pharmacophoric
moiety
Substituents
Fig. (4A). Example of the xanthonic backbone as part of the pharmacophore.
N
COOCH
3
H
3
COOC
NO
2
CH
3H
3
C
O
O
N
COORROOC
R
H
3
C
Nifedipine
Pharmacophoric
moiety
Substituent
Fig. (4B). Example of the xanthonic backbone as a substituent group in a bioactive compound.
tumoral promoters in vitro like 12-O-tetradecanoylphorbol-
13-acetate [109,201,202] and in vivo like dimethylbenz[a]
anthracene [69], azoxymethane [203], and 1,2-dimethyl-
hidrazine [204].
The xanthonic structures described as antitumor agents
include the xanthone molecule itself (1, Fig. (1)) [166,171],
as well as other natural and synthetic derivatives. Naturally
occurring xanthones with antitumor activity include simple
oxygenated xanthones [99,149,166,170,178,183,184,191],
glycosylated xanthones [157,184,196], a sulfonated
xanthone [143], prenylated xanthones [133,142,144,147,
156,158,160,162,167,172,174,177,184,188,189,191] and
their derivatives such as furanoxanthones [134,170,174,184],
dihydroxanthones [107,150,154] and pyranoxanthones
[156,160,161,174,177,184,189,190]. Moreover, other
xanthonic compounds such as xanthonolignoids [134],
bisxanthones [132,176], polycyclic xanthones [114,187],
xanthone-anthraquinone [185, 186] and xanthone-chromone
derivatives [168] have also been reported for this activity.
Additionally, several extracts from Garcinia mangostana
[46,151] and Mammea siamensis [178] have been described
to exhibit antitumor activity.
A number of synthetic xanthones have also been
evaluated for their antitumor activity. Table 4 lists the
molecular modifications undertaken on xanthonic nucleus
based on model antitumor agents. An increase in potency
and/or decrease in toxicity were often achieved from the
natural and/or synthetic parent compounds. Interestingly, the
stereochemistry of xanthonic derivatives was found to
greatly influence both the in vitro cytotoxic effect and the in
vivo antitumor activity. This effect is clearly seen in
psorospermin (12) and in DMXAA (2) analogs as will be
highlighted in sections 2.3.1. and 2.3.2. respectively.

2526 Current Medicinal Chemistry, 2005, Vol. 12, No. 21 Pinto et al.
Table 4. Molecular Modifications on Xantonic Nucleus Based on Antitumor Models
Molecular Modifications Models
Acetic acid [81*,100-102*,173*,175*,179*,192*] flavone-acetic acid, xanthenone acetic acid
Alkanediylbis(oxy)-xanthones [106*] hydrophilic bis-intercalators
Amides [107*] gambogic acid
2-(Aryloxymethyl)-5-oxygenated-pyridin-4-ones [164*] kojic acid, metal-chelators
Azapyranoxanthone, aminoderivatives [152*] mitoxanthrone, acronycine
Azathioxanthones [139*,195*,104*] with pyridinyl groups [195*,104*] lucanthone, azaellipticin, azaanthraquinone
Carboxamides [195*,360] aminoacridine-carboxamide
2-Dialkylaminoethylaminoxanthones and thioxanthones [146*] hycanthone, acronycine
Epoxy [98*,99*,138*,155*,182*] prenylflavones, psorospermin (3)
Furano [17*,155*,175*] 5-methoxysterigmatocystin, psorospermin (3)
4-Oxo-2-furanylbutenyloxy [103*,105*,136*], α-methylidene-γ-butyrolactone [137*]geiparvarin
Piperazinyl/fluoro [169*] fluoroquinolones
Pyrano [12*,138*,140*,145*] psorospermin (3), benzo[b] acronycine
Pyranothioxanthones [153*] acronycine, lucanthone, psorospermin (3)
Pyrazole [145*,148*], amino derivatives [145*,146*,148*]anthrapyrazoles, mitoxanthrone
Xanthonolignoids [165*] psorospermin (3)
* references cited in the text.
Table 5 summarizes the relationships between xanthone
derivatives with the cellular processes involved in
tumorigenesis. The overall results indicate that the planar
tricycle moiety in xanthonic derivatives serves as an
important feature for designing new DNA intercalators.
Furthermore, the antitumor mechanisms can also be
associated with other chemical moieties such as an epoxide
group, which is responsible for the presence of the covalent
adducts, or an azole function, which is associated with an
aromatase inhibitory effect.
2.2. PKC Modulation
Protein kinase C (PKC) is a multifunctional family of
kinases that phosphorylates serine and threonine residues in
very important target proteins [212]. PKC isoforms are
grouped into at least three families: the classical PKCs,
which includes the isoforms α, β I, β II and γ; the novel
PKCs, which include the isoforms δ, ε, η, θ , and µ; and
the atypical PKCs, which include the isoforms ζ and λ or ι
[205]. The PKC isoenzymes are distributed among selected
mammalian cells and tissues [212] and are related to very
important biological actions mainly in tumorigenesis (Table
6). Thus, the design and synthesis of drugs that can act at
the level of the pathology of cancer by PKC modulation
and/or can function as ligands to be used as probes for
detailed studies on the physiological and pathophysiological
roles of PKC isoforms are challenging perspectives.
It is only recently that the studies on PKC modulation
with xanthone derivatives have been reported. However, the
results obtained from these studies, although sparse, can be
considered relevant. Several prenylated xanthones including
α- and γ-mangostin (16 and 18, Fig. (3)), have been shown to
cause an effect compatible with PKC inhibition [125,206].
Interestingly, the most potent competitive inhibitor from the
prenylated xanthones evaluated was compound 3 (Fig. (2)),
which was described as having bulky/basic groups [125].
Norathyriol (14) and euxanthone (15), two natural xanthones
(Fig. (3)) with simple oxygenated xanthonic scaffolds, were
also investigated for their PKC modulation. The inhibition
of phorbol ester-induced respiratory burst and aggregation of
neutrophils by norathyriol (14) has been attributed to its
direct suppression of the PKC activity [36]. More recently,
norathyriol (14) was found to attenuate the serotonin-induced
permeability of rat heart endothelial cells to macromolecules,
an effect also associated with PKC inhibition [207]. The
decrease in endothelial cell permeability might be one of the
mechanisms responsible for the protective effects of
norathyriol (14) against edema formation in the in vivo
response to inflammatory agonists. On the other hand,
studies with euxanthone (15) indicated that this natural
product is a PKC activator [208,209] with a very high
potency to PKC ζ but lower potency for classic PKC
isoforms [208]. These results have raised the possibility that
neuroblastoma cells differentiation [183] may be associated
with a direct activation of PKC [208,209].

Xanthone Derivatives Current Medicinal Chemistry, 2005, Vol. 12, No. 21 2527
Table 5. Mechanisms of Action for Xanthonic Derivatives with Antitumor Activity
Mechanisms Xanthonic Derivatives/Substituents
Apoptosis induction via active caspase 3 pathways prenyl [107*,131*,142*,144*,147*,184*,476], glycosyl [157*],
methylenecarboxy [155*,477], Garcinia mangostana extract (prenyl)
a
[46*]
Aromatase inhibition imidazole, triazole [76*,119*]
DNA binding pyrano [145*,148*], amino [148*], oxygenated [149*]
DNA breaks and DNA-proteins cross-links furano/epoxy [265*]
DNA synthesis suppression epoxy [98*,155*], polycyclic [114*,182*], prenyl
b
[180*], dialkylamine [146*],
oxygenated [149*], furano [155*]
11-β-Hydroxylase inhibition xanthone-anthraquinone [185*]
17-α-Hydroxylase/C17,20-lyase inhibition imidazole [119*,120*], triazole [119*]
Immunomodulation, cytokines induction methylenecarboxy [193*,194*,223-227*,229-232*,478-481]
Kinases modulation:
Casein kinase 2 dihydroxy [335], dihydroxy/nitro [335-337]
IκBmethylenecarboxy [224*,233*], prenyl [312*], glycosyl [279*]
Mitogen-activated protein kinases (MAPKs) prenyl
a
[144*]
Protein kinase A prenyl [81*]
Protein kinase C prenyl [81*,206*], formyl, hydroxyl [211*], xanthonolignoids [127*],
oxygenated [36*,126*,208*,209*]
Phospholipase C inhibition xanthone-chromone [168*], tetra-oxygenated [40*]
Post-replication repair interference oxygenated [197*]
Prostaglandin (PG) E2 receptors blocking prenyl [308*], carboxy [179*,181*,320*,321*]
Protein synthesis suppression epoxy [98*,182*]
RNA synthesis suppression epoxy [98*,182*]
Signal transdution inhibition in Ha-ras oncogene epoxy [98*,182*]
Sphingomyelinases inhibition prenyl [123*,124*,314*]
Topoisomerases I and II inhibition furano [155*,263-265*,357,359], sterigmatocystins [358], prenyl [358,359],
oxygenated, pyrano, xanthonolignoids [359], carboxamide [360]
Transforming growth factor-β (TGF-β) gene expression increasing glycosyl [58*]
Vasculogenic mimicry inhibition methylenecarboxy [163*]
a
main xanthone component(s),
b
correlation between mechanism/compound not found, * references cited in the text.
Table 6. PKC Isoforms and Related Biological Actions
PKC Isoenzymes
a
Biological Actions
PKCα activity levels seem to be increased in breast cancers and malignant gliomas but under-expressed in colon cancers [482],
plays a role in cell-cell contact and in suppression of apoptosis [210*]
PKCβI plays a role in cellular proliferation and tumor suppression [212*]
PKCδretards cell cycle progression in G1 through an effect on cell cyclins in smooth muscle
[212*], tumor suppression [483] and
induces cellular differentiation and suppression of apoptosis [210*,484]
PKCη plays a role in epithelial differentiation [210*]
PKCζ plays a role in differentiation and cellular proliferation [212*]
a
PKC isoforms investigated for xanthonic derivatives [126*,127*,208*,211*], * references cited in the text.
Recently, our group has carried out a more extensive
study on PKC modulation by evaluating the effects of
twenty xanthonic derivatives on several PKC independent
isoforms using the in vivo yeast phenotypic assay [126]. It

2528 Current Medicinal Chemistry, 2005, Vol. 12, No. 21 Pinto et al.
was found that the xanthones tested differed in their efficacy
and potency towards individual PKC isoforms. Curiously,
some simple oxygenated xanthones have revealed high
selectivity for individual PKC isoforms. For example, 3,4-
dimethoxyxanthone for PKC-δ and 2-hydroxy, 2-methoxy,
3-hydroxy, 4-methoxy-, and 1,2-dyhydroxyxanthone for
PKC-ζ, these being isoforms of crucial importance in the
apoptotic process [212]. On the other hand, xanthone and
1,2-dimethoxyxanthone revealed high selectivity for PKC-η,
an isoform involved in growth, differentiation and
tumorigenesis of epithelial tissues [210]. Therefore, these
xanthones could become valuable research tools to elucidate
the physiological roles of these PKC isoforms.
In a further study, 3,4-dihydroxyxanthone (4) and 1-
formyl-4-hydroxy-3-methoxyxanthone (5) have also been
found to cause an effect compatible with PKC inhibition
[211]. For some isoforms, both compounds showed
potencies even higher than those presented by the standard
PKC inhibitors, chelerythrine and NPC 15437 [211]. It is
noteworthy that slight differences in the nature and position
of the substituents on the xanthone framework can
drastically influence the activity/selectivity on the PKC
modulation. The presence of a formyl group on C (1) caused
a change from a selective η isoform PKC activator, 4-
hydroxy-3-methoxyxanthone to a classical PKC isoforms
inhibitor, 1-formyl-4-hydroxy-3-methoxyxanthone (5). Thus,
3,4-dihydroxyxanthone (4) and 1-formyl-4-hydroxy-3-
methoxyxanthone (5) could be useful models to develop new
isoform-selective PKC modulators for simple oxygenated
xanthones.
Concerning xanthonolignoids, the same molecular
approach was investigated to shed light on the mechanism of
their growth inhibitory effect. Interestingly, it was found
that the effect of kielcorins 6-10 was compatible with PKC
inhibition, which is similar to that exhibited by the well-
established PKC inhibitor chelerythrine [127]. Most
remarkable is the fact that kielcorin 6 has been shown to
posses high selectivity for the PKC isoform ζ, recognized
for its role in differentiation and cellular proliferation [212].
The high potency and selectivity presented by these
compounds suggest that kielcorins may also be an important
model for developing potent and isoform-selective PKC
inhibitors.
2.3. Some "Hit"/Lead Xanthone Derivatives
New chemotherapeutic agents with new biochemical
mechanisms for the treatment of cancer in general, and tumor
resistance in particular, are a permanent necessity in the
therapeutic arsenal [213]. Thus, there is an urgent need to
develop a new class of antitumoral compounds with reduced
secondary effects when compared to those usually associated
with the current antitumor drugs [214, 215]. During recent
decades, investigations based on natural substances have
been particularly successful in this field [216, 217],
particularly from the plants of the Guttiferae family [218].
For this approach, a number of xanthone derivatives from
natural and synthetic origins have been evaluated for their
cytotoxic/antitumoral activity. From these large structural
groups, only some of the "hit"/lead compounds (Fig. (2) and
Fig. (3)) will be highlighted due to their well-recognized and
specific mode of action. These include DMXAA (2),
psorospermin (12) and AH6809 (11). On the other hand, the
use of some xanthone containing extracts in traditional
medicine makes imperative to have a detailed discussion of
some xanthones such as mangiferin (13), norathyriol (14),
α-mangostin (16) and the related prenyl xanthones (17-19),
as well as their effects on mammalian cellular systems.
2.3.1. DMXAA, an Antivascular Agent
With the role of angiogenesis in tumor growth and
progression firmly established, considerable efforts have
been directed to antiangiogenic therapy as a new modality to
treat human cancers [219]. 5,6-Dimethylxanthenone-4-acetic
acid or DMXAA (2) (Fig. (2)), a simple carboxylated
xanthone, can be highlighted in the field of antitumor drugs
for its advanced stage development [220,221]. DMXAA (2)
was discovered in a structure-activity relationship study
involving a series of xanthone-4-acetic acids related to the
parent drug flavone acetic acid [81]. DMXAA (2) was the
most effective analog and was then selected for detailed
evaluation. At the present time, phase I clinical trials have
been completed in the United Kingdom and New Zealand
[222].
DMXAA (2) causes a fast vascular collapse and tumor
necrosis by immunomodulation and cytokines induction,
particularly of tumor necrosis factor-α (TNF-α) [193,194,
223-228], γ-interferon [229] and interferon-induced protein
10 [194]. It possesses inductive effects in 5-
hydroxytryptamine (5-HT) [228,230], nitric oxide (NO)
[228,231,232], and in transcription factors STAT and
nuclear factor κB (NFκB) [224,229,233]. DMXAA (2) may
be applied in synergy not only with conventional cytotoxic
agents and other antivascular agents, but also with
immunomodulatory agents that increase host-mediated
responses such as cytokines and NO [220]. DMXAA (2) has
also demonstrated a synergic effect when combined with
chemotherapeutic agents [234-238] and with thermal or
radiation therapy [240-242]. For DMXAA (2 )
pharmacokinetic profile, extensive distribution-metabolism
studies have been carried out [243-251] and interactions with
other drugs evaluated [252-256]. It has been proposed that
the multiple actions of DMXAA (2) can be used as a basis
to improve antivascular therapy. The purpose of the phase I
dose-escalation study for DMXAA (2) has been to determine
the toxicity, maximum tolerated dose, pharmacokinetics,
and pharmacodynamic end points of DMXAA (2). Both
results of the pharmacokinetics and pharmacodynamic
studies concluded that DMXAA has antitumour activity at
well-tolerated doses [222].
It could be pointed out that two enantiomers of DMXAA
(2) analogue, 5-methyl-α-methyl-xanthone acetic acid, were
separated and tested: both were active, but the S-(+)-
enantiomer was much more dose-dependent than the R-(-)-
enantiomer in both the in vivo tumor necrosis assay and an
in vitro assay measuring the stimulation of nitric oxide
production by macrophages [101]. This study suggested that
the enantiomers have different intrinsic activities, rather than
differing in their metabolism.

Xanthone Derivatives Current Medicinal Chemistry, 2005, Vol. 12, No. 21 2529
2.3.2. PSOROSPERMIN, a Topoisomerase Poison
Psorospermin (12, Fig. (3 )) is a natural
dihydrofuranoxanthone isolated from the roots and bark of a
tropical African plant Psorospermum febrifugum [159,257]
in advanced preclinical development. This natural product
was shown to have both in vitro and in vivo (in mice
models) antileukaemic activity [159] and to be active against
several human tumor cell lines from different tumor types
such as breast, colon, lymphocytic leukemia [135,258,259],
drug-resistant leukemias, and in AIDS-related lymphoma
[159].
The structure and stereochemistry of psorospermin (12)
and its analogs and the importance of the configuration and
the functionality of the epoxydihydrofuran group for the in
vivo activity have also been determined [170,259-261].
Recent work has shown that the R,R-stereochemistry of
psorospermin (12) gives optimum DNA alkylation and
antitumor activity, although all four possible stereoisomers
show topoisomerase II-dependent alkylation. This different
intrinsic activity was rationalized in terms of the energy of
interaction with DNA and proximity of the CH
2
in the
epoxide ring to N (7) of guanine [259]. Only recently was
the total synthesis of psorospermin (12) with the natural
(2’R,3’R)-stereochemistry was achieved [258,262].
Mechanistic studies confirmed that psorospermin (12)
acted by intercalation into the DNA molecule and by the
alkylation of guanine at the topoisomerase II cleavage site
[263,264]. By placing the tricyclic xanthone chromophore
moiety in an orientation parallel to the adjacent base pairs,
psorospermin (12) can interact by a covalent binding to
guanine N (7) [265-267]. Psorospermin (12) is unique
among topoisomerase II poisons in two aspects: it
intercalates between the base pairs at the 11 to 12 position of
the gate site and it forms a covalent adduct [264].
Consequently, the topoisomerase II-cleaved complex
formation is trapped and the topoisomerase II is hindered
from catalyzing the breakage–rejoining reaction of DNA
strands [264,268]. To further understand the structural
requirements of psorospermin (12) mechanism of action,
ring-constrained analogs were design based on the skeleton
of bisfuranoxanthone natural products and evaluated for their
topoisomerase II dependence of DNA alkylation [259]. This
study pointed to topoisomerase II providing an energetically
favored binding site for psorospermin (12) analogs and
directing the molecules to a certain region of DNA, which
gives a higher probability of alkylation at this site.
Evaluation of psorospermin/quinobenzoxazine hybrids
[269] gave rise to the structurally novel antitumor agents,
which are even more potent than their parent compounds. A
similar situation occurred with the diastereomeric pair of O-
5-methyl-(±)-(2’R,3’R)-psorospermin that also exhibits a
unique mode of action [155,258].
2.3.3. MANGIFERIN and its Aglycon Norathyriol
Mangiferin (13, Fig. (3 )) or 1,3,6,7-
tetrahydroxyxanthone-C 2- β-D -glycoside is widely
distributed in higher plants. Mangiferin is a polyphenol
well-known for its antioxidant, anti-inflammatory,
immunomodulatory and antiviral effects. Interestingly,
mangiferin was the first xanthone to be investigated for
pharmacological purposes [5]. In studying Canscora
decussata extracts, a remarkable central nervous system
stimulating effect was observed for mangiferin. Its effect was
found to be higher than that of its aglycone norathyriol (14)
[8]. Subsequently, it was found that an MAO-inhibiting
activity of mangiferin was associated with this effect [9].
Some of the mangiferin containing extracts are used in
traditional medicine in many parts of the world as anti-
inflammatory, analgesic and antioxidant. Mangiferin (13)
was proven to be responsible for these effects, due to its
ability to scavenge free radicals [31,35,45,58,63] involved in
lipid peroxidation initiation [31,35,39], an activity
evidenced by redox properties [51]. The antioxidant activity
investigated in hepatic systems for several plant extracts
especially Mangifera indica [64,65,72], Salacia reticulata
[270], Cratoxylum cochinchinensis [271], and Polygala
elongata [272] revealed that the antioxidant profile of these
extracts was similar to that of mangiferin, their principal
polyphenolic component. Additionally, some of these
studies [64,72,270] have linked the antioxidant activity of
these extracts with their hepatoprotective effect. Furthermore,
mangiferin was also found to exert its protective effect on
cardiac [42], renal [42], liver [41], and brain tissues [41]
from oxidative damage caused by reactive oxygen species
(ROS), which are over-produced by peritoneal macrophages
[41].
Vimang, the aqueous extract of Mangifera indica L., is
used traditionally in Cuba as an anti-inflammatory, analgesic
and antioxidant [273,274]. Vimang has been subjected to a
broad set of toxicological tests, including acute and
subchronic toxicity and genotoxicity. The results obtained
were shown to be satisfactory and it was thus classified as a
nontoxic product [41]. Like mangiferin (13), Vimang was
shown to possess depressor effects on the phagocytic and
ROS production activities of murine macrophages [56,65].
These results could justify its value in the treatment of the
diseases of immunopathological origin, characterized by the
hyperactivation of phagocytic cells. The humoral immune
response modulation has also been demonstrated for
Vimang [275], as well as for an alcoholic extract of
Mangifera indica [276]. The anti-inflammatory and
immunomodulatory effects of Vimang and mangiferin (13)
were related to their reduction on the expression of
inflammation-related genes in macrophages such as TNF-α
[58,277,278], cytokines, interleukins 1β [275], transforming
growth factor-β (TGF-β) [58], colony-stimulating factor,
NFκB [275,279] and secondary mediators such as NO
synthase [58,277,278,280], cyclooxygenase-2 (COX-2)
[277,279,280], and intercellular adhesion molecule-1
(ICAM-1) [279]. In addition, mangiferin (13) can inhibit
TNF-induced p65 phosphorylation and translocation to
nucleus, TNF-induced reactive oxygen intermediate
generation, as well as NFκB activation induced by other
inflammatory agents [279]. Mangiferin (13) was also found
to enhance the glutathione (GS) level, but at the same time,
decrease the levels of GSSG; however, it did cause an
increase in catalase activity [279]. To further characterize the
immunomodulatory activity of mangiferin (13), its effects
on the expression, by activated mouse macrophages, of
diverse genes related to the NFκB signaling pathway have
been investigated [281]. The inhibition of the Jun N-
terminal kinase 1 (JNK1), together with stimulation of the
Jun oncogene (c-JUN) [281] and the previously reported

2530 Current Medicinal Chemistry, 2005, Vol. 12, No. 21 Pinto et al.
superoxide-scavenging activity of mangiferin (13)
[45,56,58,275,276], suggested that it might protect cells
against oxidative damage and mutagenesis. All of data
indicated that mangiferin (13) modulated the expression of a
large number of genes critical to the regulation of apoptosis,
viral replication, tumorigenesis, inflammation and various
autoimmune diseases, and therefore raised the possibility
that it might be of value in the treatment of inflammatory
diseases and/or cancer [281]. Mangiferin (13) has also been
suggested as a potential naturally-occurring cancer
chemopreventive agent [203] and a potent biological
response modifier with antitumor and antiviral effects [196].
The effect of mangiferin (13) in rat colon carcinogenesis
induced by the chemical carcinogen azoxymethane has been
successfully examined [203]. It was also shown to have an
antiproliferative effect on leukemia cells by induction of
apoptosis, probably through down regulation of the bcr/abl
gene expression [157]. Recently, a semi-purified extract from
Cratoxylum cochinchinense with antioxidant properties [271]
that mostly contains mangiferin (13) was found to be
selectively toxic to certain tumor cell types, causing intense
oxidative stress and ultimately cell death [53]. Furthermore,
mangiferin (13) has shown in vitro and in vivo, growth-
inhibitory activity against ascitic fibrosarcoma [196], and
enhanced tumor cell cytotoxicity of the splenic cells and
peritoneal macrophages of normal and tumor-bearing mice
[196]. In the same study, mangiferin was found to
antagonize the in vitro cytopathic effect of human
immunodeficiency virus (HIV) [196]. Mangiferin (13) was
found to be the active component in Mangifera indica
extract for its activity against Herpes simplex virus
[282,283], and it was suggested that mangiferin inhibited
the late event in this virus replication [282,284].
The antidiabetic activity has been recognized not only for
mangiferin (13) [285-290] but also for its glycoside
(mangiferin-7-O- β-glycoside) [285,288] as well as for the
extracts of Anemarrhena asphodeloides [288] and Salacia
oblonga [289,290], plants traditionally used in the
prevention and treatment of diabetes [290,291]. Both of the
extracts and mangiferin were found to lower blood glucose
level, and it was inferred that this antidiabetic activity was
caused by increasing insulin sensitivity [285] and/or
decreasing insulin resistance [288]. Mechanism studies
revealed the inhibitory activity of mangiferin (13) and its
glycoside against several carbohydrate-metabolizing enzymes
[290,292,293]. Nevertheless, mangiferin (13) has shown
much weaker effects than Salacia oblonga extract in
inhibiting α-glucosidase activity, suggesting that it was not
the most active constituent responsible for this effect
[290,291]. Additionally, mangiferin (13) and Salacia
reticulata extract have shown antiobesity/lipolytic effects,
thus explaining their use as a supplementary food in Japan
to prevent obesity and diabetes [289].
The aglycon of mangiferin, norathyriol (14) or 1,3,6,7-
tetrahydroxyxanthone, together with 1,3- and 1,6-
dihydroxyxanthones, 1,3,7-trihydroxyxanthone, 1,3,5,6-,
2,3,6,7-, and 3,4,5,6-tetrahydroxyxanthones have shown
potent inhibitory effects on superoxide formation by rat
neutrophils [40]. The reduction of superoxide anion
formation by norathyriol (14) was attributed to the
scavenging of the generated superoxide anion, which is
responsible for the blockade of the phospholipase C
pathway, the reduction of protein tyrosine phosphorylation,
and the suppression of NADPH oxidase activity through the
interruption of electrons transport at the FAD redox centre
[40]. Norathyriol (14) alone has been found to be a non-
competitive inhibitor of xanthine oxidase [294]. It was also
found to inhibit platelet aggregation [295], relax the rat
thoracic aorta [296], inhibit angiotensin-I-converting-enzyme
activity [297], induce calcium release from the sarcoplasmic
reticulum of skeletal muscle [298], and suppress pleurisy
and cutaneous plasma extravasation caused by inflammatory
mediators in mice [300]. Inhibition of thromboxane (TX) B2
and LT B4 formation by norathyriol (14) in stimulated
neutrophils was recently attributed to a direct inhibition of
COX and 5-lypoxygenase, respectively, but not to inhibition
of phospholipase A2 [301]. Overall results suggested that
norathyriol (14) might be a dual COX and lipoxygenase
pathway blocker and thus could be beneficial in the
treatment of inflammatory diseases [301].
2.3.4. PRENYLATED XANTHONES from the Extract
Garcinia Mangostana L.
The pericarps of mangosteen (Garcinia mangostana L.)
have been used for many years in traditional medicine for the
treatment of skin infection and wounds in Southeast Asia
[46,144,147]. In 1979, α-mangostin (16) and other
prenylated (17, 18) and glycosyl prenylated mangostins from
the extract of Garcinia mangostana were first screened for
various pharmacological effects [26]. With the exception of
γ-mangostin (18), all compounds produced CNS depression
and pronounced anti-inflammatory activity, although none of
them exhibited analgesic, antipyretic, anticonvulsant and
cardiovascular effects [26]. α-Mangostin (16) alone produced
significant antiulcer activity in vivo [26]. Consequently,
xanthones from the fruit pulp and pericarp of this plant have
become very attractive as useful sources of cancer
chemopreventive and therapeutic agents [46,147,151,
180,204]. Moreover, they have also been found in several
other applications such as antibacterial [26,302,303],
antifungal [304], antiretroviral [305], antiallergic [306,307],
antioxidant [38,67], anti-inflammatory [26,308], and for the
treatment of rosacea, telangiectasia and skin aging [309].
Some mechanistic aspects have already been investigated
for these xanthones. γ-Mangostin (18) was characterized as a
novel and specific 5-hydroxytryptamine (5-HT) 2A receptor
antagonist in vascular smooth muscle cells and platelets
[310,311]. Thus, γ-mangostin (18) is a non-nitrogenous 5-
HT 2A receptor antagonist and it might be a promising lead
compound in this field. γ-Mangostin (18) also inhibited
COX and prostaglandin (PG) E2 synthesis in rat glioma
cells [308,312] by direct inhibition of IκB activity and
thereby prevented COX-2 gene transcription, a NFκB target
gene. This probably decreases the inflammatory agent-
stimulated PG E2 production in vivo. γ-Mangostin (18) was
thereby considered a new useful lead compound for anti-
inflammatory drug development [312]. Moreover, xanthones
(16-19) have been found to exhibit growth inhibitory effects
in leukemia cell lines [147], especially garcinone E (19),
which has also shown a potent cytotoxic effect against
hepatocellular carcinoma, gastric, and lung tumor cell lines
[180]. Interestingly, the extract of Garcinia mangostana has
also revealed an antiproliferative effect on leukemia [151]
and breast tumor cell lines [46], in addition to short-term

Xanthone Derivatives Current Medicinal Chemistry, 2005, Vol. 12, No. 21 2531
cancer chemopreventive effects on putative preneoplastic
lesions involved in rat colon carcinogenesis [204]. Its crude
methanolic extract demonstrated apoptotic and antioxidative
properties by inhibiting intracellular ROS production [46]. It
was also found that α- (16) and γ-mangostins (18) could
induce apoptosis in leukemia cell lines [142,147] via
activation of caspase 3 pathways [142]. Moreover, α- (16),
β- (17), and γ-mangostins (18) have been shown to cause the
caspase-9 and -3 activation but not caspase-8. This fact has
led to the conclusion that compounds 16-18 probably
induced apoptosis through the mitochondrial pathway [144].
In the same manner, α- (16) and γ-mangostins (18) were
found to inhibit calcium-ATP synthase (ATPase) in rat
pheochromocytoma cells, thus causing apoptosis through the
mitochondrial pathway [184,313]. α-Mangostin (16) also
revealed itself to be a potent inhibitor of acidic
sphingomyelinase [123,124,314]. Structure-activity
relationship studies indicated that the prenyl groups might
be required to express the highly selective inhibitory activity
against acidic sphingomyelinase when compared to neutral
sphingomyelinase [124]. Both α- (16) and γ-mangostins
(18) also showed an effect compatible with cyclic AMP-
dependent protein kinase and PKC inhibition, as described
earlier [125].
2.3.5. AH6809, a Prostaglandin Receptor Antagonist
6-Isopropoxy-9-oxoxanthene-2-carboxylic acid or
AH6809 (11) is an EP [315] and DP [316] prostanoid
receptor antagonist with near-equal affinity for the cloned
human EP1, EP2, EP3-III, and DP1 receptors [317]. Thus,
it is a useful drug tool for characterization of PG E receptors
[318]. The effect of AH6809 (11) has been studied upon the
anti-aggregatory and aggregatory actions of various agents in
human blood platelets. AH6809 (11) appeared to be a weak
but specific DP-receptor blocking drug on human platelets
[316]. It blocked the accumulation of calcium in Xenopus
oocytes expressing the human EP1 receptor [319] and
behaved as an EP2 receptor antagonist by inhibiting the
increase in cyclic AMP caused by PG E2 [179,315]. It acted
as a cytostatic agent in cases when the growth inhibition was
overcome by exogenous PG E2 in non-small cell lung cancer
[179] and in glioma [181]. The effects of AH6809 (11) on
chondrogenesis [320] were recently compared with the
cytosine arabinoside, an established inhibitor of cell
proliferation and growth, giving evidence of the potent
inhibitory effects of AH6809 (11) observed on cartilage
differentiation [321]. Moreover, AH6809 (11) has been
shown to cause a decrease in the vitamin D metabolite, 1,25-
dihydroxy D3-stimulated PKC due to its effect on PG EP1
receptors [320]. It was also reported to block PG E–mediated
inhibition of lipopolysaccharide-induced TNF-α generation
[322].
From the biological activity perspective, it is evident
that some xanthone structures such as DMXAA (2) and
compounds (11-19) may serve as useful scaffolds for the
development of potential chemotherapeutic agents. However,
other novel structures still continue to emerge from the array
of xanthone derivatives for the treatment of widespread
diseases. The example of these is swertifrancheside (20), the
first flavone-xanthone C-glycoside isolated from Nature.
This compound has been found to be a strong inhibitor of
the HIV-1 reverse transcriptase [331,332].
3. CONCLUSION
Although natural products may undoubtedly correspond
to the original important source of bioactive compounds of
great interest in Medicinal Chemistry, the synthetic
pathways and the enzymes involved, condition their
structural diversity. Therefore, it is extremely important to
build new chemical structures by total synthesis or
molecular modifications using natural products as models.
For xanthone derivatives, both situations are contemplated
not only because Nature can afford a large variety of
structures, but also because the development of new
synthetic methodologies can furnish novel structures that can
serve as chemical clues to clinically useful drugs. This can
be achieved through drug design by computational
methodologies and/or lead refinement. On the other hand,
new insights in biological activities of xanthones in the last
decade, especially in the field of cancer, have provided
significant tools for drug development. We hope that the
emerged "hit" xanthone derivatives may constitute an
excellent starting material to the leads and could be
developed to the stage of efficient drugs in the near future.
4. ACKNOWLEDGEMENTS
We thank Fundação para a Ciência e a Tecnologia, (FCT,
Lisbon, Portugal) (I&D Nº 226/94) POCTI and FEDER for
financial support.
5. ABBREVIATIONS
5-HT = 5-Hydroxytryptamine
AIDS = Acquired Immune Deficiency Syndrome
AMP=Adenosine Monophosphate
ATPase = Adenosine Triphosphate Synthase
c-JUN = Jun oncogene
CD4 = Cluster of Differentiation 4
CNS = Central Nervous System
COX = Cyclooxygenase
DMXAA = 5,6-Dimethylxanthenone-4-acetic Acid
DNA = Deoxyribonucleic Acid
FAD = Flavin Adenine Dinucleotide
GMP=Guanylate Monophosphate
GS = Glutathione
HIV-1 = Human Immunodeficiency Virus Type 1
HUVECs = Human Umbilical Vein Endothelial Cells
ICAM-1 = Intercellular Adhesion Molecule-1
JNK/SAPK = Jun N-terminal kinase/stress-activated
protein kinase
LT B4 = Leukotriene B4
MAO=Monoamine Oxidase
MAPKs =Mitogen-Activated Protein Kinases
MMLV = Moloney Murine Leukemia Virus

2532 Current Medicinal Chemistry, 2005, Vol. 12, No. 21 Pinto et al.
MLCK = Myosin Light Chain Kinase
NAD(P)H = Nicotinamide Adenine Dinucleotide
(Phosphate), Reduced Form
NFκB=Nuclear Factor κB
NO = Nitric Oxide
PG = Prostaglandin
PKC = Protein Kinase C
QSAR = Quantitative Structure-Activity Relationship
ROS = Reactive Oxygen Species
SAR = Structure-Activity Relationship
STAT = Signal Transducer and Activator of
Transcription
TX = Thromboxane
TGF-β=Transforming Growth Factor-β
TNF-α=Tumor Necrosis Factor-α
VCAM-1 = Vascular Cell Adhesion Molecule-1
REFERENCES
[1] Sultanbawa, M.U.S. Tetrahedron, 1980, 36, 1465.
[2] Peres, V.; Nagem, T.J. Phytochemistry, 1997, 44, 191.
[3] Bennett, G.J.; Lee, H.H. Phytochemistry, 1989, 28, 967.
[4] Mandal, S.; Das, P.C.; Joshi, P.C. J. Indian Chem. Soc., 1992, 69,
611.
[5] Finnegan, R.A.; Stephani G.M.; Ganguli G.; Bhattacharya S.K. J.
Pharm. Sci., 1968, 57, 1039.
[6] Da Re, P.; Mancini, V.; Toth, E.; Cima, L. Arzneim.-Forsch./Drug.
Res., 1968, 18, 718.
[7] Da Re, P.; Sagramora, L.; Mancini, V.; Valenti, P.; Cima, L. J.
Med. Chem., 1970, 13, 527.
[8] Bhattacharya, S.K.; Ghosal, S.; Chaudhuri, R.K.; Sanyal, A.K. J.
Pharm. Sci., 1972, 61, 1838.
[9] Bhattacharya, S.K.; Sanyal, A.K.; Ghosal, S. Naturwissenschaften,
1972, 59(12), 651.
[10] Da Re, P.; Valenti, P.; Borraccini, A.; Primofiore, G.P. J. Med.
Chem., 1972, 15, 198.
[11] Da Re, P.; Primofiore, G.P.; Bertelli, A. J. Med. Chem., 1972, 15,
868.
[12] Schneider, J.; Evans, E.L.; Grunberg, E.; Fryer, R.I. J. Med.
Chem., 1972, 266.
[13] Pfister, J.R.; Ferraresi, R.W.; Harrison, I.T.; Rooks, W.H.;
Roszkowski, A.P.; Van Horn, A.; Fried, J.H. J. Med. Chem., 1972,
15, 1032
[14] Beretz, A.; Joly, M.; Stoclet, J.C.; Anton, R. Planta Med., 1979, 36,
193.
[15] Ghosal, S.; Chaudhuri, R.K. J. Pharm. Sci., 1975, 64, 888.
[16] Ghosal, S.; Biswas, K.; Chaudhuri, R.K. J. Pharm. Sci., 1978, 67,
721.
[17] Essery, J. M.; O'Herron, F.A.; McGregor, D.N.; Bradner, W.T. J.
Med. Chem., 1976, 19, 1339.
[18] Ghosal, S.; Sharma, P.V.; Chaudhuri, R.K. J. Pharm. Sci., 1974,
63, 1286.
[19] Ghosal, S.; Sharma, P.V.; Chaudhuri, R.K.; Bhattacharya, S.K. J.
Pharm. Sci., 1973, 62, 926.
[20] Chowhan, Z.T.; Amaro, A.A. J Pharm Sci., 1976, 65, 1669.
[21] Wuthrich, B.; Parrott, D. Respiration, 1976, 33, 231.
[22] Pfister, J.R.; Ferraresi, R.W.; Harrison, I.T.; Rooks, W.H.; Fried,
J.H. J. Med. Chem., 1978, 21, 669
[23] Jones, W.D., Jr.; Albrecht, W.L.; Munro, N.L.; Stewart, K.T. J.
Med. Chem., 1977, 20, 594.
[24] Barnes, A.C.; Hairsine, P.W.; Matharu, S.S.; Ramm, P.J.; Taylor,
J.B. J. Med. Chem., 1979, 22, 418.
[25] Miller, P.; James, G. W. Arch. Int. Pharmacodyn. Ther., 1978,
231, 328
[26] Shankaranarayan, D.; Gopalakrishnan, C.; Kameswaran, L. Arch.
Int. Pharmacodyn. Ther., 1979, 239, 257.
[27] Stenius, B.; Salorinne, Y.; Parrott, D. Scand. J. Respir. Dis., 1978,
59, 75.
[28] Sprenkle, A.C.; VanArsdel, P.P.; Biermann, C.W. Pediatrics,
1975, 56, 937.
[29] Alberto, J.N.S.; Herman, T.V.C.; Juan, A.; Johanes, G.; Fabio, N.;
Francesco, D.S.; Luca, R. J. Agr. Food Chem., 2002, 50, 762.
[30] Garrity, A.R.; Morton, G.A.R.; Morton, J.C. U.S. Patent 6,730,333,
2004.
[31] Sato, T.; Kawamoto, A.; Tamura, A.; Tatsumi, Y.; Fujii, T. Chem.
Pharm. Bull., 1992, 40, 721.
[32] Minami, H.; Kinoshita, M.; Fukuyama, Y.; Kodama, M.;
Yoshizawa T.; Sugiura, M.; Nakagawa, K.; Tago, Harumi.
Phytochemistry, 1994, 36, 501.
[33] Minami, H.; Takahashi, E.; Fukuyama, Y.; Kodama, M.;
Yoshizawa, T.; Nakagawa, K. Chem. Pharm. Bull., 1995, 43, 347.
[34] Minami, H.; Kuwayama, A.; Yoshizawa T.; Fukuyama, Y. Chem.
Pharm. Bull., 1996, 44, 2103.
[35] Ghosal, S.; Rao, G.; Saravana, V.; Misra, N.; Rana, D. Indian J.
Chem. B, 1996, 35, 561.
[36] Wang, J.P.; Raung, S.L.; Tsao, L.T.; Lin, C.N. Eur. J. Pharmacol.,
1997, 336, 81.
[37] Scartezzini, P.; Speroni, E. J. Ethnopharmacol., 2000, 71, 23.
[38] Mahabusarakam, W.; Proudfoot, J.; Taylor, W.; Croft, K. Free
Radic. Res., 2000, 33, 643.
[39] Born, M.; Carrupt, P.A.; Zini, R.; Brée, F.; Tillement, J.P.;
Hostettmann, K.; Testa, B. Helv. Chim. Acta, 1996, 79, 1147.
[40] Hsu, M.F.; Raung, S.L.; Tsao, L.T.; Lin, C.N.; Wang, J.P. Free
Radic. Biol. Med., 1997, 23, 1035.
[41] Sanchez, G.M.; Re, L.; Giuliani, A.; Nunez-Selles, A.J.; Davison,
G.P.; Leon-Fernandez, O.S. Pharmacol. Res., 2000, 42, 565.
[42] Muruganandan, S.; Gupta, S.; Kataria, M.; Lal, J.; Gupta, P.K.
Toxicology, 2002, 176, 165.
[43] Madan, B.; Singh, I.; Kumar, A.; Prasad, A.; Raj, H.; Parmar, V.;
Ghosh, B. Bioorg. Med. Chem., 2002, 10, 3431.
[44] Jiang, D.J.; Jiang, J.L.; Tan, G.S.; Du, Y.H.; Xu, K.P.; Li,Y.J.
Naunyn-Schmiedeberg’s Arch. Pharmacol., 2003, 367, 600.
[45] Calliste, C.A.; Trouillas, P.; Allais, D.P.; Simon, A.; Duroux, J.L. J.
Agr. Food Chem., 2001, 49, 3321.
[46] Moongkarndi, P.; Kosem, N.; Kaslungka, S.; Luanratana, O.;
Pongpan, N.; Neungton, N. J. Ethnopharmacol., 2004, 90, 161.
[47] Selvi, A.T.; Joseph, G.S.; Jayaprakasha, G.K. Food Microbiol.,
2003, 20, 455.
[48] Jiang, D.J.; Jiang, J.L.; Zhua, H.Q.; Tan, G.S.; Liu, S.Q.; Xu, K.P.;
Li, Y.J. J. Ethnopharmacol., 2004, 93, 295.
[49] Merza, J.; Aumond, M.C.; Rondeau, D.; Dumontet, V.; Le Ray,
A.M.; Seraphin, D.; Richomme, P. Phytochemistry, 2004, 65, 2915
[50] Mackeen, M.M.; Ali, A.M.; Lajis, N.H.; Kawazu, K.; Hassan, Z.;
Amran, M.; Habsah, M.; Mooi, L.Y.; Mohamed, S.M.; J.
Ethnopharmacol., 2000, 72, 395.
[51] Pauletti, P.M.; Castro-Gamboa, I.; Silva, D.H.S.; Young, M.C.;
Tomazela, D.M.; Eberlin, M.N.; Bolzani, V.S. J. Nat. Prod., 2003,
66, 1384.
[52] Soong, Y.-Y.; Barlow, P.J. Food Chem., 2004, 88, 411.
[53] Tang, S.Y.; Whiteman, M.; Jenner, A.; Peng, Z.F.; Halliwell, B.
Free Radic. Biol. Med., 2004, 36, 1588.
[54] Lin, C.N.; Chung, M.I.; Liou, S.J.; Lee, T.H.; Wang, J.P. J. Pharm.
Pharmacol., 1996, 48, 532.
[55] Takenaka, Y.; Tanahashi, T.; Nagakura, N.; Hamada, N. Z.
Naturforsch. [C], 2000, 55, 910.
[56] Garcia, D.; Delgado, R.; Ubeira, F. M.; Leiro, J. Int.
Immunopharmacol., 2002, 2, 797.
[57] Rusterucci, C.; Milat, M.-L.; Blein, J.-P. Phytochemistry, 1996, 42,
979.
[58] Leiro, J.M.; Álvarez, E.; Arranz, J.A.; Siso, I.G.; Orallo, F.
Biochem. Pharmacol., 2003, 65, 1361.
[59] Pauletti, P.M.;Gamboa, I.C.; Silva, D.H.S.; Young, M.C.M.;
Tomazela, D.M.; Eberlin, M.N.; Bolzani, V.S. J. Nat. Prod., 2003,
66, 1384.
[60] Masuda,T.; Inaba, Y.; Maekawa, T.; Takeda, Y.; Yamaguchi, H.;
Nakamoto, K.; Kuninaga, H.; Nishizato, S.; Nonaka, A. J. Agr.
Food Chem., 2003, 51, 1831.
[61] Hay, A.E.; Aumond, M.C.; Mallet, S.; Dumontet, V.; Litaudon, M.;
Rondeau, D.; Richomme, P. J. Nat. Prod., 2004, 67, 707.
[62] Cervellati, R.; Innocenti, G.; Acqua, S.D.; Costa, S.; Sartini, H.
ChemBiodiv., 2004, 1, 415.

Xanthone Derivatives Current Medicinal Chemistry, 2005, Vol. 12, No. 21 2533
[63] Salvi, A.; Brhlmann, C.; Migliavacca, E.; Carrupt, C.A.;
Hostettmann, K.; Testa, B. Helv. Chim. Acta, 2002, 85,867.
[64] Sánchez, G.M.; Rodríguez, M.A.; Giuliani, A.; Núñez Sellés, A.J.;
Rodríguez, N.P.; Fernández, H.; Leon, O.S.; Re, L. Phytother.
Res., 2003, 17, 197.
[65] Mart_nez, G.; Delgado, R.; Perez, G.; Garrido, G.; Nunez Selles,
A.J.; Leon, O.S. Phytother. Res., 2000, 14, 424.
[66] Abdel-Lateff, A.; Klemke, C.; Konig, G.M.; Wright, A.D. J. Nat.
Prod., 2003, 66, 706.
[67] Williams, P.; Ongsakul, M.; Proudfoot, J.; Croft, K.;, Beilin, L.
Free. Radic. Res., 1995, 23,175.
[68] Chang, C.H.; Lin, C.C.; Hattori, M.; Namba, T. J.
Ethnopharmacol., 1994, 44, 79.
[69] Saha, P.; Mandal, S.; Das, A.; Das, P.C.; Das, S. Phytother. Res.,
2004, 18, 373.
[70] Shi, G.-F.; Lu, R.-H.; Yang Y.-S; Li, C.-L., Yang, A.-M.; Cai, L.-
X. Chinese J. Struct. Chem., 2004, 23, 1014.
[71] Fernandes, E.R.; Carvalho, F.D.; Remião, F.G.; Bastos, M.L.;
Pinto, M.M.; Gottlieb, O.R. Pharm. Res., 1995, 12, 1756.
[72] Martinez, G.; Giuliani, A.; Leon, O.S.; Perez, G.; Nunez Selles,
A.J. Phytother. Res., 2001, 15, 581.
[73] Afzal, M.; Al-Hassan, J.M. Heterocycles, 1980, 14, 1173.
[74] Dean, F.M. In The Total Synthesis of Natural Products; Apsimon,
Ed.; 1973, Vol. 1, pp. 534-562.
[75] Pinto, M.M.M.; Sousa, E.P. Curr. Med. Chem., 2003, 10, 1.
[76] Recanatini, M.; Cavalli, A.; Valenti, P. Med. Res. Rev., 2002,
22,282.
[77] Boumendjel, A.; Di Pietro, A.; Dumontet, C.; Barron, D. Med. Res.
Rev., 2002, 22, 512.
[78] Go, ML. Med. Res. Rev., 2003, 23, 456.
[79] Vermani, K.; Garg, S. J. Ethnopharmacol., 2002, 80, 49.
[80] Cowan, M.M. Clin. Microbiol. Rev., 1999, 12, 564.
[81] Rewcastle, G.W.; Atwell, G.J.; Li, Z.A.; Baguley, B.C.; Denny,
W.A. J. Med. Chem., 1991, 34, 217.
[82] Bisi, A.; Budriesi, R.; Chiarini, A.; Rampa, A.; Valenti, P.
Farmaco, 1993, 48, 1491.
[83] Rampa, A.; Budriesi, R.; Bisi, A.; Fabbri, G.; Barili, P.L.; Chiarini,
A.; Valenti, P. Arzneim.-Forsch./Drug. Res., 1995, 45, 957.
[84] Budriesi, R.; Rampa, A.; Bisi, A.; Fabbri, G.; Chiarini, A.; Valenti,
P. Arzneim.-Forsch./Drug. Res., 1996, 46, 374.
[85] Ungwitayatorn, J.; Pickert, M.; Frahm, A.W. Pharm. Acta Helv.,
1997, 72, 23.
[86] Schaper, K. J.; Pickert, M.; Frahm, A.W. Arch. Pharm.
(Weinheim.), 1999, 332, 91.
[87] Pickert, M.; Frahm, W.A. Arch. Pharm. Pharm. Med. Chem.,
1998, 177.
[88] Salmoiraghi, I.; Rossi, M.; Valenti, P.; Da Re, P. Arch. Pharm.
(Weinheim.), 1998, 331, 225.
[89] Ignatushchenko, M.V.; Winter, R.W.; Bachinger, H.P.; Hinrichs,
D.J.; Riscoe, M.K. FEBS Lett., 1997, 409, 67.
[90] Ignatushchenko, M.V.; Winter, R.W.; Riscoe, M. Am. J. Trop.
Med. Hyg., 2000, 62, 77.
[91] Teng, C.M.; Lin, C.N.; Ko, F.N.; Cheng, K.L.; Huang, T.F.
Biochem. Pharmacol., 1989, 38, 3791.
[92] Lin, C.N.; Liou, S.S.; Ko, F.N.; Teng, C.M. J. Pharm. Sci., 1992,
81, 1109.
[93] Liou, S.S.; Teng, C.M.; Ko, F.N.; Lin, C.N. J. Pharm. Sci., 1994,
83, 391.
[94] Rajtar, G.; Zolkowska, D.; Kleinrok, Z.; Marona, H. Acta Pol.
Pharm., 1999, 56, 319.
[95] Lin, C.N.; Hsieh, H.K.; Liou, S.J.; Ko, H.H.; Lin, H.C.; Chung,
M.I.; Ko, F.N.; Liu, H.W.; Teng, C.M. J. Pharm. Pharmacol.,
1996, 48, 887.
[96] Byars, N.E.; Ferraresi, R.W. Agents Actions, 1980, 10, 252.
[97] Eckstein, M.; Marona, H.; Mazur, J. Pol. J. Pharmacol. Pharm.,
1983, 35, 159.
[98] Lin, C.N.; Liou, S.J.; Lee, T.H.; Chuang, Y.C.; Won, S.J. J. Pharm.
Pharmacol., 1996, 48, 539.
[99] Liou, S.S.; Shieh, W.L.; Cheng, T.H.; Won, S.J.; Lin, C.N. J.
Pharm. Pharmacol., 1993, 45, 791.
[100] Rewcastle, G.W.; Atwell, G.J.; Baguley, B.C.; Calveley, S.B.;
Denny, W.A. J. Med. Chem., 1989, 32, 793.
[101] Rewcastle, G.W.; Atwell, G.J.; Baguley, B.C.; Boyd, M.;
Thomsen, L.L.; Zhuang, L.; Denny, W.A. J. Med. Chem., 1991,
34, 2864.
[102] Rewcastle, G.W.; Atwell, G.J.; Palmer, B.D.; Boyd, P.D.; Baguley,
B.C.; Denny, W.A. J. Med. Chem., 1991, 34, 491.
[103] Valenti, P.; Da Re, P.; Rampa, A.; Montanari, P.; Carrara, M.;
Cima, L. Anticancer Drug. Des., 1993, 8, 349.
[104] Varvaresou, A; Tsotinis, A.; Valiraki, P.; Papastaikoudi, T.S. J.
Heterocyclic Chem., 1996, 33, 917.
[105] Valenti, P.; Rampa, A.; Recanatini, M.; Bisi, A.; Belluti, F.; Da Re,
P.; Carrara, M.; Cima, L. Anticancer-Drug Des., 1997, 12, 443.
[106] Wang, T.C.; Zhao, Y.-L.; Liou, S.-S. Helv. Chim. Acta, 2002, 85,
1382.
[107] Zhang, H.-Z.; Kasibhatla, S.; Wang, Y.; Herich, J.; Guastella, J.;
Tseng, B.; Drewe, J.; Cai, S.X. Bioorg. Med. Chem., 2004, 12,
309.
[108] Edenharder, R.; Tang, X. Food. Chem. Toxicol., 1997, 35, 357.
[109] Ito, C.; Itoigawa, M.; Furukawa, H.; Rao, K.S.; Enjo, F.; Bu, P.;
Takayasu, J.; Tokuda, H.; Nishino, H. Cancer Lett., 1998, 132,
113.
[110] Edenharder, R.; Speth, C.; Decker, M.; Platt, M.L. Z. Lebensm.
Unters. Forsch. A. 1998, 207, 464.
[111] Valenti, P.; Chiarini, A.; Gasperi, F.; Budriesi, R. Arzneim.-
Forsch./Drug. Res., 1990, 40, 122.
[112] Tchamo, D.N.; Dijoux-Franca, M.G.; Mariotte, A.M.; Tsamo, E.;
Daskiewicz, J.B.; Bayet, C.; Barron, D.; Conseil, G.; Di Pietro, A.
Bioorg. Med. Chem. Lett., 2000, 10, 1343.
[113] Chaney, M.O.; Froelich, L.L.; Gapinski, D.M.; Mallett, B.E.;
Jackson, W.T. Receptor, 1992, 2, 169.
[114] Kobayashi, K.; Nishino, C.; Ohya, J.; Sato, S.; Mikawa, T.;
Shiobara, Y.; Kodama, M. J. Antibiot., 1988, 41, 741.
[115] Sawyer, J.S.; Schmittling, E.A.; Bach, N.J.; Baker, S.R.; Froelich,
L.L.; Saussy Jr., D.L.; Marder, P.; Jackson, W.T. Bioorg. Med.
Chem. Lett., 1994, 4, 2077.
[116] Rampa, A.; Bisi, A.; Valenti, P.; Recanatini, M.; Cavalli, A.;
Andrisano, V.; Cavrini, V.; Fin, L.; Buruani, A.; Giusti, P. J. Med.
Chem., 1998, 41, 3976-3986.
[117] Rampa, A.; Piazzi, L.; Belluti, F.; Gobbi, S.; Bisi, A.; Bartolini, M.;
Andrisano, V.; Cavrini, V.; Cavalli, A.; Recanatini, M.; Valenti, P.
J. Med. Chem., 2001, 44, 3810.
[118] Pfister, J.R.; Wymann, W.E.; Mahoney, J.M.; Waterbury, L.D. J.
Med. Chem., 1980, 23, 1264.
[119] Recanatini, M.; Bisi, A.; Cavalli, A.; Belluti, F.; Gobbi, S.; Rampa,
A.; Valenti, P.; Palzer, M.; Palusczak, A.; Hartmann, R.W. J.
Med. Chem., 2001, 44, 672
[120] Clement, O.O.; Freeman, C.M.; Hartmann, R.W.; Handratta, V.D.;
Vasaitis, T.S.; Brodie, A.M.H.; Njar, V.C.O. J. Med. Chem., 2003,
46, 2345.
[121] Gnerre, C.; Thull, U.; Gaillar, P.; Carrupt, P.A.; Testa, B.;
Fernandes, E.; Silva, F.; Pinto, M.; Pinto, M.M.; Wolfender, J.L.;
Hostettman, K.; Cruciani, G. Helv. Chim. Acta, 2001, 84, 552.
[122] Núñez, M.B.; Maguna, F.P.; Okulik, N.B.; Castro; E.A.. Bioorg.
Med. Chem. Lett., 2004, 14, 5611.
[123] Okudaira, C.; Ikeda, Y.; Kondo, S.; Furuya, S.; Hirabayashi, Y.;
Koyano, T.; Saito, Y.; Umezawa, K. J. Enzyme Inhib., 2000, 15,
129.
[124] Hamada, M.; Iikubo, K.; Ishikawa, Y.; Ikeda, A.; Umezawa, K.;
Nishiyama, S. Bioorg. Med. Chem. Lett., 2003, 13, 3151.
[125] Lu, Z.X.; Hasmeda, M.; Mahabusarakam, W.; Ternai, B.; Ternai,
P.C.; Polya, G.M. Chem. Biol. Interact., 1998, 114, 121.
[126] Saraiva, L.; Fresco, P.; Pinto, E.; Sousa, E.; Pinto, M.; Gonçalves,
J. Bioorg. Med. Chem., 2002, 10, 3219.
[127] Saraiva, L.; Fresco, P.; Pinto, E.; Sousa, E.; Pinto, M.; Gonçalves,
J. J. Enzyme Inhib. Med. Chem., 2003, 18, 357.
[128] Portela, C.; Afonso, C.M.M.; Pinto, M.M.M.; Ramos, M.J. FEBS
Lett., 2003, 27435, 217.
[129] Portela, C.; Afonso,C.M.M.; Pinto,M.M.M.; Ramos, M.J. Bioor.
Med. Chem., 2004, 12, 3313.
[130] Portela, C.; Afonso, C.M.M.; Pinto, M.M.M.; Ramos, M.J. J.
Comp.-Aided Molec. Des., 2003, 17, 583.
[131] Wu, X.; Cao, S.; Goh, S.; Hsu, A.; Tan, B.K. Planta Med., 2002,
68, 198.
[132] Xu, Y.-J.; Cao, S.-G.; Wu, X.-H.; Lai, Y.-H.; Tan, B.H.K.;
Pereira, J.T.; Goh, S.H.; Venkatraman, G.; Harrison, L.J.; Sim,
K.Y. Tetrahedron Lett., 1998, 39, 9103.
[133] Proksa, B.; Uhrin, D.; Adamcova, J.; Fuska, J. Phytochemistry,
1992, 31, 1442.
[134] Abou-Shoer, M.; Habib, A.; Chang, C.; Cassady, J.M.
Phytochemistry, 1989, 28, 2483.
[135] Douros, J.; Suffness, M. Cancer Treat. Rev., 1981, 8, 63.
[136] Valenti, P.; Recanatini, M.; Da Re, P.; Galimbeni, W.; Avanzi, N.;
Filippeschi, S. Arch. Pharm. (Weinheim.), 1985, 318, 923.

2534 Current Medicinal Chemistry, 2005, Vol. 12, No. 21 Pinto et al.
[137] Chen, Y.-L.; Chen, I-L.; Tzeng, C.-C. Helv. Chim. Acta, 2000, 83,
989.
[138] Sittisombut, C.; Costes, N.; Michel, S.; Koch, M.; Tillequin, F.;
Pfeiffer, B.; Renard, P.; Pierre, A.; Atassi, G. Chem. Pharm. Bull.,
2001, 49, 675.
[139] Croisy-Delcey, M.; Bisagni, E. J. Med. Chem., 1983, 26, 1329.
[140] Ghirtis, K.; Pouli, N.; Marakos, P.; Skaltsounis, A.-L.; Leonce, S.;
Caignard, D. H.; Atassi, G. Heterocycles, 2000, 53, 93.
[141] Palmer, B.D.; Rewcastle, G.W.; Atwell, G.J.; Baguley, B.C.;
Denny, W.A. J. Med. Chem., 1988, 31, 707.
[142] About the Cytotoxic Activity of α- and γ-Mangostins from
Garcinia mangostana on Leukemia Cell Line, URL
http://www.nricm.edu.tw/icom12/postpdf/P-30.pdf (accessed
March 2005).
[143] Hong, D.; Yin, F.; Hu, L.H.; Lu, P. Phytochemistry, 2004, 65,
2595.
[144] Matsumoto, K.; Akao, Y.; Yi, H.; Ohguchi, K.; Ito, T.; Tanaka, T.;
Kobayashi, E.; Iinumac, M.; Nozawa, Y. Bioorg. Med. Chem.,
2004, 12, 5799.
[145] Kostakis, I.K.; Magiatis, P.M.; Pouli, N.; Marakos, P.; Skaltsounis,
A.-L.; Pratsinis, H.; Leonce, S.; Pierre, A. J. Med. Chem., 2002,
45, 2599.
[146] Kostakis, I.K.; Ghirtis, K.; Pouli, N.; Marakos, P.; Skaltsounis,
A.L.; Leonce, S.; Gaignard, D.H.; Atassi, G. Farmaco, 2000, 55,
455.
[147] Matsumoto, K.; Akao, Y.; Kobayashi, E.; Ohguchi, K.; Ito, T.;
Tanaka, T.; Iinuma, M.; Nozawa, Y. J. Nat. Prod., 2003, 66, 1124.
[148] Kolokythas, G.; Kostakis, I.K.; Pouli, N.; Marakos, P.; Skaltsounis,
A.L.; Pratsinis, H. Bioorg. Med. Chem. Lett., 2002, 12, 1443.
[149] Pessoa, C. ; Silveira, E.R.; Lemos, T.L.G.; Wetmore, L.A.;
Moraes, M.O.; Leyva, A. Phytother. Res., 2000, 14, 187.
[150] Makmur, L.;Syamsurizal; Tukiran; Syamsu, Y.; Achmad, S.A.;
Aimi, N.; Hakim, E.H.; Kitajima, M.; Mujahidin, D.; Takayama,
H. Proc. ITB, 1999, 31, 63.
[151] Chiang, L.-C.; Cheng, H.-Y.; Liu, M.-C.; Chiang, W.; Lin, C.-C.
Lebensm.-Wiss. Technol., 2004, 37, 539.
[152] Kolokythas, G.; Kostakis, I.K.; Pouli, N.; Marakos, P.; Kletsas, D.;
Pratsinis, H. Bioorg. Med. Chem., 2003, 11, 4591.
[153] Kostakis, I.K.; Pouli, N.; Marakos, P.; Mikros, E.; Skaltsounis, A.-
L.; Leonce, S.; Atassi, G.; Renard, P. Bioorg. Med. Chem., 2001,
9, 2793.
[154] Cao, S.-G.; Sng, V.H.L.; Wu, X.-H.; Sim, K.-Y.; Tan, B.H.K.;
Pereira, J.T.; Goh, S.H. Tetrahedron, 1998, 54, 10915.
[155] Gleason-Guzman, M.C.; Paine-Murrieta, G.D.; Taylor, C.W.;
Hurley, L.H. Eur. J. Cancer, 2002, 38, S31.
[156] Chen, J.J.; Chen, Y.-S.; Duh, C.-Y. Planta Med., 2004, 70, 1195.
[157] Peng, Z.G.; Luo, J.; Xia, L.H.; Chen, Y.; Song, S.J. Zhongguo Shi
Yan Xue Ye Xue Za Zhi, 2004, 12, 590.
[158] Seo, E.-K.; Kim, N.-C.; Wani, M.C.; Wall, M.E.; Navarro, H.A.;
Burgess, J.P.; Kawanishi; K.; Kardono, B.S.; Riswan, S.; Rose,
W.C.; Fairchild, C.R.; Farnsworth, N.R.; Kinghorn, A.D. J. Nat.
Prod., 2002, 65, 299.
[159] a) Kupchan, S.M.; Streelman, D.R.; Sneden, A.T. J. Nat. Prod.,
1980, 43, 296. b) About the Use of Psorospermin for Treatment of
Resistant Leukemia, URL http://techpartners.osu.edu/
Technologies/display.asp?TechID=32F (accessed January 2003).
[160] Thoison, O.; Fahy, J.; Dumontet, V.; Chiaroni, A.; Riche, C.; Tri,
M.V.; Sevenet, T. J. Nat. Prod., 2000, 63, 441.
[161] Lin, L.-J.; Lin, L.-Z.; Pezzuto, J.M.; Cordell, G.A. Magn. Reson.,
1993, 31, 340.
[162] Seo, E.-K.; Wall, M.E.; Wani, M.C.; Navarro, H.; Mukherjee, R.;
Farnsworth, N. R.; Kinghorn, A.D. Phytochemistry, 1999, 52, 669.
[163] Zhao, L.; Edgar, S.; Marshall, E.; Kelland, L.; Baguley, B. Eur. J.
Cancer Suppl., 2004, 2, 47.
[164] Chen, Y.-L.; Chen, P.-H.; Chung, C.-H.; Li, K.C.; Jeng, H.-Y.;
Tzeng, C.-C. Helv. Chim. Acta, 2003, 86, 778.
[165] Sousa, E.P.; Silva, A.M.S.; Pinto, M.M.M.; Pedro, M.M.;
Cerqueira, F.A.M.; Nascimento, M.S.J. Helv. Chim. Acta, 2002,
85, 2862.
[166] Pedro, M.M.; Cerqueira, F.; Sousa, M.E.; Nascimento, M.S.J.;
Pinto, M.M.M. Bioorg. Med. Chem., 2002, 10, 3725.
[167] Sordat-Diserens, I.; Rogers, C.; Sordat, B.; Hostettmann, K.
Phytochemistry, 1992, 31, 313.
[168] Aoki, M.; Itezono, Y.; Shirai, H.; Nakayama, N.; Sakai, A.;
Tanaka, Y.; Yamaguchi, A.; Shimma, N.; Yokose, K. Tetrahedron
Lett., 1991, 32, 4737.
[169] Mari, S.; Rossi, M.; Valenti, P.; Da Re, P. Farmaco, 1999, 54, 411.
[170] Abou-Shoer, M.; Suwanborirux, K.; Habib, A.A.M.; Chang, C.-J.;
Cassady, J.M. Phytochemistry, 1993, 34, 1413.
[171] Kamei, H.; Koide, T.; Kojima, T.; Hashimoto, Y.; Hasegawa, M.
Cancer Biother. Radiopharm., 1998, 13, 185.
[172] Gobi, S.; Rampa, A.; Bisi, A.; Bellutti, F.; Valenti, P.; Caputo, A.;
Zampiron, A.; Carrara, M. J. Med. Chem., 2002, 45, 4931.
[173] Valenti, P.; Fabbri, G.; Rampa, A.; Bisi, A.; Gobbi, S.; Da Re, P.;
Carrara, M.; Sgevana, A.; Cima, L. Anti-Cancer Drug Des., 1996,
11, 243.
[174] Zou, Y.-S.; Hou, A.J.; Zhu, G.F.; Chen, Y.F.; Sunc, H.D.; Zhao,
Q.-S. Bioor. Med. Chem., 2004, 12, 1947.
[175] Valenti P.; Bisi, A.; Rampa, A.; Belluti, F.; Gobbi, S.; Zampiron,
A.; Carrara, M. Bioorg. Med. Chem., 2000, 8, 239.
[176] Isaka, M.; Jaturapat, A.; Rukseree, K.; Danwisetkanjana, K.;
Tanticharoen, M.; Thebtaranonth, Y. J. Nat. Prod., 2001, 64,
1015.
[177] Abe, F.; Nagafuji, S.; Okabe, H.; Higo, H.; Akahane, H. Biol.
Pharm. Bull., 2003, 26, 1730.
[178] Poobrasert, O.; Constant, H.L.; Beecher, C.W.W.; Farnsworth,
N.R.; Kinghorn, A.D.; Pezzuto, J.M.; Cordell, G.A.; Santisuk, T.;
Reutrakul, V. Phytochemistry, 1998, 47, 1661.
[179] Casibang, M.; Moody, T.W. Lung Cancer, 2002, 36, 33.
[180] Ho, C.-K.; Huang, Y.-L.; Chen, C.-C. Planta Med., 2002, 68, 975.
[181] Matsuo, M.; Yoshida, N.; Zaitsu, M.; Ishii, K.; Hamasaki, Y. J.
Neuro-oncol., 2004, 66, 285.
[182] Liu, H.S.; Lin, C.N.; Won, S.J. Anticancer Res., 1997, 17, 1107.
[183] Mak, N.K.; Li, W.K.; Zhang, M.; Wong, R.N.; Tai, L.S.; Yung,
K.K.; Leung, H.W. Life Sci., 2000, 66, 347.
[184] Sato, A.; Fujiwara, H.; Oku, H.; Ishiguro, K.; Ohizumi, Y. J.
Pharmacol. Sci., 2004, 95, 33.
[185] Ding, G.; Maume, G.; Milat, M.-L.; Humbert, C.; Blein, J.-P.;
Maume, B. Cell Biol. Int., 1996, 20, 523.
[186] Goudet, C.; Benitah, J.-P; Milat, M.-L.; Sentenac, H.; Thibaud, J.-
B. Biophys. J., 1999, 77, 3052.
[187] Terui, Y.; Yiwen, C.; Jun-ying, L.; Ando, T.; Yamamoto, H.;
Kawamura, Y.; Tomishima, Y.; Uchida, S.; Okazaki, T.;
Munetomo, E.; Seki, T.; Yamamoto, K.; Murakami, S;
Kawashima, A. Tetrahedron Lett., 2003, 44, 5427.
[188] Asano, J.; Chiba, K.; Tada, M.; Yoshii, T. Phytochemistry, 1996,
41, 815.
[189] Nkengfack, A.E.; Mkounga, P.; Fomum, Z.T.; Meyer, M.; Bodo,
B. J. Nat. Prod., 2002, 65, 734.
[190] Yimdjo, M.C.;. Azebaze, A.G.; Nkengfack, A.E.; Meyer, A.M.;
Bodo, B.; Fomum, Z.T. Phytochemistry, 2004, 65, 2789.
[191] Nkengfack, A.E.; Azebaze, G.A.; Vardamides, J.C.; Fomum,
Z.T.; van Heerden, F.R. Phytochemistry, 2002, 60, 381.
[192] Atwell, G.J.; Rewcastle, G.W.; Baguley, B.C.; Denny, W.A. J.
Med. Chem., 1990, 33, 1375.
[193] Joseph, W.R.; Cao, Z.; Mountjoy, K.G.; Marshall, E.S.; Baguley,
B.C.; Ching, L.M. Cancer Res., 1999, 59, 633.
[194] Cao, Z.; Baguley, B.C.; Ching, L.M. Cancer Res., 2001, 61, 1517.
[195] Hirschberg, E.; Gellhorn, A.; Murray, M.R.; Elslager, E.F. J. Natl.
Cancer Inst., 1959, 22, 567.
[196] Guha, S.; Ghosal, S.; Chattopadhyay, U. Chemotherapy, 1996, 42,
443.
[197] Schimmer, O.; Mauthner, H. Planta Med., 1996, 62, 561.
[198] Matsushima, T.; Araki, A.; Yagame, O.; Muramatsu, M.; Koyama,
K.; Ohsawa, K.; Natori, S.; Tomimori, H. Mutat. Res.-Fund. Mol.
M., 1985, 150, 141.
[199] Wehner, F.C.; Thiel, P.G.; van Rensburg, S.J.; Demasius, I.P.C.
Mutat. Res.-Gen. Tox., 1978, 58, 193.
[200] Wong, J.J.; Singh, R.; Hsieh, D.P.H. Mutat. Res.-Fund. Mol. M.,
1977, 44, 447.
[201] Ito, C.; Itoigawa, M.; Mishina, Y.; Filho, V.C.; Mukainaka, T.;
Tokuda, H.; Nishino, H.; Furukawa, H. J. Nat. Prod., 2002, 65,
267.
[202] Ito, C.; Itoigawa, M.; Takakura, T.; Ruangrungsi, N.; Enjo, F.;
Tokuda, H.; Nishino, H.; Furukawa, H. J. Nat. Prod., 2003, 66,
200.
[203] Yoshimi, N.; Matsunaga, K.; Katayama, M.; Yamada, Y.; Kuno,
T.; Qiao, Z.; Hara, A.; Yamahara, J.; Mori, H. Cancer Lett., 2001,
163, 163.
[204] Nabandith, V.; Suzui, M.; Morioka, T.; Kaneshiro, T.; Kinjo, T.;
Matsumoto, K.; Akao, Y.; Iinuma, N. Asian Pac. J. Cancer Prev.,
2004, 5, 433.
[205] Spitaler, M.; Cantrell, D.A. Nat. Immunol., 2004, 5, 785.

Xanthone Derivatives Current Medicinal Chemistry, 2005, Vol. 12, No. 21 2535
[206] Jinsart, W.; Ternai, B.; Buddhasukh, D.; Polya, G.M.
Phytochemistry, 1992, 31, 3711.
[207] Lee, H.-Z.; Lin, W.-C.; Yeh, F.-T.; Lin, C.-N.; Wu, C.-H. N.-S.
Arch. Pharmacol., 1998, 353, 303.
[208] Saraiva, L.; Fresco, P.; Kijjoa, A.; Gonzalez, M.J.; Gonçalves, J.
Planta Med., 2002, 68, 1039.
[209] Mak, N.K.; Lung, H.L.; Wong, R.N.; Leung, H.W.; Tsang, H.Y.;
Leung, K.N. Planta Med., 2001, 67, 400.
[210] Hofmann, J. FASEB J., 1997, 11, 649.
[211] Saraiva, L.; Fresco, P.; Pinto, E.; Sousa, E.; Pinto, M.; Gonçalves,
J. Bioorg. Med. Chem., 2003, 11, 1215.
[212] Webb, B.L.J.; Hirst, S.J.; Giembyez, M.A. Br. J. Pharmacol.,
2000, 130, 1433.
[213] DeVita, V.T.; Hellman, S.; Rosenberg, S.A. Cancer: Principles
and Practice of Oncology, Lippincott-Raven: Philadelphia, 1997.
[214] Atkins, J.H.; Gershell, L.J. Nature Rev. Drug Discov., 2002, 1,
491.
[215] Rothenberg, M.L.; Carbone, D.P.; Johnson, D.H. Nat. Rev.
Cancer, 2003, 3, 303.
[216] Hostettmann, K.; Potterat, O.; Wolfender, J.-L. Chimia, 1998, 52,
10.
[217] Graham, J.G.; Quinn, M.L.; Fabbicant, D.S.; Farnsworth, N.R. J.
Ethnopharm., 2000, 73, 347.
[218] Martson, A.; Décosterd, L.A.; Hostettmann, K. In Bioactive
Natural Products: Detection, Isolation, and Structure
Determination; S.M. Colegate, R.J. Molyneux, Ed.; CRC Press:
Boca Raton, 1993, pp. 224.
[219] Tandle, A.; Blazer, D.G., Libutti, S.K. J. Transl. Med., 2004, 2, 22.
[220] Baguley, B.C. Lancet Oncol., 2003, 4, 141.
[221] Zhou, S.; Kestell, P.; Baguley, B.C.; Paxton, J.W. Invest. New
Drugs, 2002, 20, 281.
[222] a) Jameson, M.B.; Thompson, P.I.; Baguley, B.C.; Evans, B.D.;
Harvey, V.J.; Porter, D.J.; McCrystal, M.R.; Small, M.; Bellenger,
K.; Gumbrell, L.; Halbert, G.W.; Kestell, P. Br. J. Cancer, 2003,
88, 1844. b) Rustin, G.J.; Bradley, C.; Galbraith, S.; Stratford, M.;
Loadman, P.; Waller, S.; Bellenger, K.; Gumbrell, L.; Folkes, L.;
Halbert, G. Br. J. Cancer, 2003, 88, 1160.
[223] Pang, J.H.; Cao, Z.; Joseph, W.R.; Baguley, B.C.; Ching, L.M. Eur.
J. Cancer, 1998, 34, 1282.
[224] Philpott, M.; Ching, L.M.; Baguley, B.C. Eur. J. Cancer, 2001, 37,
1930.
[225] Philpott, M.; Baguley, B.C.; Ching, L.M. Cancer Chemoth. Pharm.,
1995, 36, 143.
[226] Ching, L.M.; Goldsmith, D.; Joseph, W.R.; Korner, H.; Sedgwick,
J.D.; Baguley, B.C. Cancer Res., 1999, 59, 3304.
[227] Wang L.C.; Reddy, C.B.; Baguley, B.C.; Kestell, P.; Sutherland, R.;
Ching, L.M.; Biochem. Pharmacol., 2004, 67, 937.
[228] Baguley, B.C.; Ching, L.M. Int. J. Radiat. Oncol., 2002, 54, 1503.
[229] Ching, L.M.; Young, H.A.; Eberly, K.; Yu, C.R. Biochem.
Pharmacol., 1999, 58, 1173.
[230] Kestell, P.; Zhao, L.; Jameson, M.B.; Stratford, M.R.; Folkes, L.K.;
Baguley, B.C. Clin. Chim. Acta, 2001, 314, 159.
[231] Thomsen, L.L.; Ching, L.M.; Baguley, B.C. Cancer Res., 1990, 50,
6966.
[232] Thomsen, L.L.; Ching, L.M.; Zhuang, L.; Gavin, J.B.; Baguley,
B.C. Cancer Res., 1991, 51, 77.
[233] Woon, S.T.; Zwain, S.; Schooltink, M.A.; Newth, A.L.; Baguley,
B.C.; Ching, L.M. Eur. J. Cancer, 2003, 39, 1176.
[234] Pruijn, F.B.; van Daalen, M.; Holford, N.H.; Wilson, W.R. Cancer
Chemoth. Pharm., 1997, 39, 541.
[235] Siemann, D.W.; Mercer, E.; Lepler, S.; Rojiani, A.M. Int. J.
Cancer, 2002, 99, 1.
[236] Siim, B.G.; Lee, A.E.; Shalal-Zwain, S.; Pruijn, F.B.; McKeage,
M.J.; Wilson, W.R. Cancer Chemoth. Pharm., 2003, 51, 43.
[237] Chung, F.; Wang, L.C.; Kestell, P.; Baguley, B.C.; Ching, L.M.
Cancer Chemoth. Pharm., 2004, 53, 377.
[238] Zhao, L.; Kestell, P.; Philpott, M.; Ching, L.M.; Zhuang, L.;
Baguley, B.C. Cancer Chemoth. Pharm., 2001, 47, 491.
[239] Kestell, P.; Zhao, L.; Baguley, B.C.; Palmer, B.D.; Muller, G.;
Paxton, J.W.; Ching, L.M. Cancer Chemoth. Pharm., 2001, 46,
135.
[240] Wilson, W.R.; Li, A.E.; Cowan, D.S.; Siim, B.G. Int. J. Radiat.
Oncol. Biol. Phys., 1998, 42, 905.
[241] Murata, R.; Horsman, M.R. Int. J. Hypertherm., 2004, 20, 393.
[242] Horsman, M.R.; Murata, R. Int. J. Radiat. Oncol. Biol. Phys.,
2002, 54, 1518.
[243] Zhou, S.; Paxton, J.W.; Tingle, M.D.; Kestell, P. J. Chromatogr. B
Biomed. Sci. Appl., 2001, 757, 343.
[244] Zhou, S.; Paxton, J.W.; Tingle, M.D.; Kestell, P. J. Chromatogr. B
Biomed. Sci. Appl., 2001, 757, 359.
[245] Zhou, S.; Paxton, J.W.; Tingle, M.D.; McCall, J.; Kestell, P. J.
Chromatogr. B Biomed. Sci. Appl., 1999, 734, 129.
[246] Zhou, S.; Kestell, P.; Paxton, J.W. J. Chromatogr. B Analyt.
Technol. Biomed. Life Sci., 2002, 776, 231.
[247] Zhou, S.; Kestell, P.; Baguley, B.C.; Paxton, J.W. Biochem.
Pharmacol., 2003, 65, 1853.
[248] Zhou, S.; Kestell, P.; Baguley, B.C.; Paxton, J.W. Biochem.
Pharmacol., 2003, 65, 109.
[249] Kestell, P.; Paxton, J.W.; Rewcastle, G.W.; Dunlop, I.; Baguley,
B.C. Cancer Chemoth. Pharm., 1999, 43, 323.
[250] Zhao, L.; Kestell, P.; Ching, L.M.; Baguley, B.C. Cancer Chemoth.
Pharm., 2002, 49, 20.
[251] Everett, S.A.; Dennis, M.F.; Patel, K.B.; Wardman, P.; Stratford,
M.R.L. J. Chromatogr. A, 1997, 770, 273.
[252] Zhou, S.; Chiang, D.; Chin, R.; Kestell, P.; Paxton, J. W. J.
Chromatogr. B. Analyt. Technol. Biomed. Life Sci., 2002, 767, 19.
[253] Phillips, R.M. Biochem. Pharmacol., 1999, 58, 303
[254] Zhou, S.; Paxton, J.W.; Kestell, P.; Tingle, M.D.; Ching, L.M.
Cancer Chemoth. Pharm., 2001, 47, 319.
[255] Zhou, S.; Kestell, P.; Tingle, M.D.; Ching, L.M. ; Paxton, J.W.
Cancer Chemoth. Pharm., 2001, 47, 541.
[256] Zhou, S.; Chin, R.; Kestell, P.; Tingle, M.D.; Paxton, J.W. Br. J.
Clin. Pharmacol., 2001, 52, 129.
[257] Pachuta, R.R.; Cooks, R.G.; Cassady, J.M.; Cong, P.; McCloud,
T.G.; Chang, C.J. J. Nat. Prod. 1986, 49, 412.
[258] Terrance, T.; Schwaebe, M.K.; Whitten, J.P. W.O. Patent
2004/019888, 2004.
[259] Heald, R.A.; Dexheimer, T.S.; Vankayalapati, H.; Siddiqui-Jain,
A.; Szabo, L.Z.; Gleason-Guzman, M.C.; Hurley, L.H. J. Med.
Chem., 2005, 48, 2993.
[260] Habib, A.M.; Ho, D.K.; Masuda, S.; McCloud, T.; Reddy, K.S.;
Aboushoer, M.; McKenzie, A.; Byrn, S.R.; Chang, C.-J.; Cassady,
J.M. J. Org. Chem., 1987, 52, 412.
[261] Abou-Shoer, M.; Boettner, F.E.; Chang, C-J.; Cassady, J.
Phytochemistry, 1988, 27, 2795.
[262] Schwaebe, M.K.; Moran, T.J.; Whitten, J.P. Tetrahedron Lett.,
2005, 46, 827.
[263] Kwok, Y.; Hurley, L.H. J. Biol. Chem., 1998, 273, 33020
[264] Kwok, Y.; Zeng, Q.; Hurley, L.H. Proc. Natl. Acad. Sci., 1998, 95,
13531.
[265] Permana, P.A.; Ho, D.K.; Cassady, J.M.; Snapka, R.M. Cancer
Res., 1994, 54, 3191.
[266] Hansen, M.; Seung-Joo, L.; Cassady, J.M.; Hurley, L. J. Am.
Chem. Soc., 1996, 118, 5553.
[267] Hansen, M.; Yun, S.; Hurley, L. Chem. Biol., 1995, 2, 229.
[268] Kwok, Y.; Zeng, Q.; Hurley, L.H. J. Biol. Chem., 1999, 274,
17226.
[269] Kim, M.Y.; Na, Y.; Vankayalapati, H.; Gleason-Guzman, M.;
Hurley, L.H. J. Med. Chem., 2003, 46, 2958.
[270] Yoshikawa, M.; Ninomiya, K.; Shimoda, H.; Nishida, N.; Matsuda,
H. Biol. Pharm. Bull., 2002, 25, 72.
[271] Tang, S.Y.; Whiteman, M.; Peng, Z.F.; Jenner, A.; Yong, E.L.;
Halliwell, B. Free Radic. Biol. Med., 2004, 36, 1575.
[272] Shirwaikar, A.; Padma, R.; Kumar, A.V.; Rao, L. Indian J.
Pharmac. Sci., 2002, 64, 345.
[273] Garrido, G.; González, D.; Lemus, Y.; García, D.; Lodeiro, L.;
Quintero, G.; Delporte, C.; Núñez-Sellés, A.J.; Delgado, R.
Pharmacol. Res., 2004, 50, 143.
[274] Garrido, G.; González, D.; Delporte, C.; Backhouse, N.; Quintero,
G.; Núñez-Sellés, A.J.; Morales, M.A. Phytother. Res., 2001, 15,
18.
[275] Garcia, D.; Leiro, J.; Delgado, R.; Sanmartin, M.L.; Ubeira, F.M.
Phytother. Res., 2003, 17, 1182.
[276] Makare, N.; Bodhankar, S.; Rangari, V., J. Ethnopharmacol.,
2001, 78, 133.
[277] Leiro, J.; Garcya, D.; Arranz, J.A.; Delgado, R.; Sanmartyn, M.L.;
Orallo, F. Int. Immunopharmacol., 2004, 4, 991.
[278] Garrido, G.; Delgado, R.; Lemus, Y.; Rodriguez, J.; Garcia, D.;
Nunez-Selles, A. J. Pharmacol. Res., 2004, 50, 165.
[279] Sarkar, A.; Sreenivasan, Y.; Ramesh, G.T.; Manna, S.K. J. Biol.
Chem., 2004, 279, 33768.

2536 Current Medicinal Chemistry, 2005, Vol. 12, No. 21 Pinto et al.
[280] Beltran, A.E.; Alvarez, Y.; Xavier, F.E.; Hernanz, R.; Rodriguez,
J.; Nunez, A.J.; Alonso, M.J.; Salaices, M. Eur. J. Pharmacol.,
2004, 499, 297.
[281] Leiro, J.; Arranz, J.A.; Yanez, M.; Ubeira, F.M.; Sanmartin, M.L.;
Orallo, F. Int. Immunopharmacol., 2004, 4, 763.
[282] Zhu, X.M.; Song, J.X.; Huang, Z.Z.; Wu, Y.M.; Yu, M.J.
Zhongguo Yao Li Xue Bao, 1993, 14, 452.
[283] Yoosook, C.; Bunyapraphatsara, N.; Boonyakiat, Y.; Kantasuk, C.
Phytomedicine, 2000, 6, 411.
[284] Zheng, M.S.; Lu, Z.Y. Chin. Med. J. (Engl), 1990, 103, 160.
[285] Ichiki, H.; Miura, T.; Kubo, M.; Ishihara, E.; Komatsu, Y.;
Tanigawa, K.; Okada, M. Biol. Pharm. Bull., 1998, 21, 1389.
[286] Miura, T.; Iwamoto, N.; Kato, M.; Ichiki, H.; Kubo, M.; Komatsu,
Y.; Ishida, T.; Okada, M.; Tanigawa, K. Biol. Pharm. Bull., 2001,
24, 1091.
[287] Miura, T.; Ichiki, H.; Hashimoto, I.; Iwamoto, N.; Kato, M.; Kubo,
M.; Ishihara, E.; Komatsu, Y.; Okada, M.; Ishida, T.; Tanigawa,
K. Phytomedicine, 2001, 8, 85.
[288] Miura, T.; Ichiki, H.; Iwamoto, N.; Kato, M.; Kubo, M.; Sasaki,
H.; Okada, M.; Ishida, T.; Seino, Y.; Tanigawa, K. Biol. Pharm.
Bull., 2001, 24, 1009.
[289] Yoshikawa, M.; Shimoda, H.; Nishida, N.; Takada, M.; Matsuda,
H. J. Nutr., 2002, 132, 1819.
[290] Li, Y.; Peng, G.; Li, Q.; Wen, S.; Huang, T.H.-W.; Roufogalis,
B.D.; Yamahara, J. Life Sci., 2004, 75, 1735.
[291] Li, W.L.; Zheng, H.C.; Bukuru, J.; De Kimpe, N. J.
Ethnopharmacol., 92, 2004, 1.
[292] Yoshikawa, M.; Nishida, N.; Shimoda, H.; Takada, M.;
Kawahara, Y.; Matsuda, H. Yakugaku Zasshi, 2001, 121, 371.
[293] Morikawa, T.; Kishi, A.; Pongpiriyadacha, Y.; Matsuda, H.;
Yoshikawa, M. J. Nat. Prod., 2003, 66, 1191.
[294] Noro, T.; Ueno, A.; Mizutani, M.; Hashimoto, T.; Miyase, T.;
Kuroyanagi, M.; Fukushima, S. Chem. Pharm. Bull., 1984,
32,:4455.
[295] Teng, C.M.; Lin, C.N.; Ko, F.N.; Cheng, K.L.; Huang, T.F.
Biochem. Pharmacol., 1989, 38,3791.
[296] Ko, F.N.; Lin, C.N.; Liou, S.S.; Huang, T.F.; Teng, C.M. Eur. J.
Pharmacol., 1991, 192, 133.
[297] Chen, C.H.; Lin, J.Y.; Lin, C.N.; Hsu, S.Y. J. Nat. Prod., 1992, 55,
691.
[298] Kang, J.J.; Cheng, Y.W.; Ko, F.N.; Kuo, M.L.; Lin, C.N.; Teng,
C.M. Br. J. Pharmacol., 1996, 118, 1736
[299] Wang J.P.; Ho, T.F.; Lin, C.N.; Teng, C.M. N.-S. Arch.
Pharmacol., 1994, 350, 90.
[300] Wang, J.P.; Raung, S.L.; Lin, C.N.; Teng, C.M. Eur. J.
Pharmacol., 1994, 251, 35.
[301] Hsu, M.-F.; Lin, C.-N.; Lu, M.-C.; Wang, J.-P. Naunyn-
Schmiedeberg’s Arch. Pharmacol., 2004, 369, 507.
[302] Iinuma, M.; Tosa, H.; Tanaka, T.; Asai, F.; Kobayashi, Y.;
Shimano, R.; Miyauchi, K. J. Pharm. Pharmacol., 1996, 48, 861.
[303] Sundaram, B.M.; Gopalakrishnan, C.; Subramanian, S.;
Shankaranarayanan, D.; Kameswaran, L. Planta Med., 1983, 48,
59.
[304] Gopalakrishnan, G.; Banumathi, B.; Suresh, G. J. Nat. Prod., 1997,
60, 519.
[305] Chen, S.X.; Wan, M.; Loh, B.N. Planta Med., 1996, 62, 381.
[306] Chairungsrilerd, N.; Furukawa, K.I.; Ohta, T.; Nozoe, S.,
Ohizumi, Y. Eur. J. Pharmacol., 1996, 314, 351.
[307] Chairungsrilerd, N.; Furukawa, K.I.; Ohta, T.; Nozoe, S.,
Ohizumi, Y. Planta Med., 1996, 62, 471.
[308] Nakatani, K.; Nakahata, N.; Arakawa, T.; Yasuda, H.; Ohizumi,
Y. Biochem. Pharmacol., 2002, 63, 73.
[309] Ptchelintsev, D. U.S Patent 2003/0138467, 2003.
[310] Chairungsrilerd, N.; Furukawa, K.; Tadano, T.; Kisara, K.;
Ohizumi, Y. Br. J. Pharmacol., 1998, 123, 855.
[311] Chairungsrilerd, N.; Furukawa, K.I.; Ohta, T.; Nozoe, S.,
Ohizumi, Y. N.-S. Arch. Pharmacol., 1998, 357, 25.
[312] Nakatani, K.; Yamakuni, T.; Kondo, N.;Arakawa, T.; Oosawa,
K.; Shimura, S.; Inoue, H.; Ohizumi, Y. Mol. Pharmacol., 2004,
66, 667.
[313] Furukawa, K.; Shibusawa, K.; Chairungsrilerd, N.; Ohta, T.;
Nozoe, S.; Ohizumi, Y. Jpn. J. Pharmacol., 1996, 71, 337.
[314] Iikubo, K.; Ishikawa, Y.; Ando, N.; Umezawa, K.; Nishiyama, S.
Tetrahedron Lett., 2002, 43, 291.
[315] Woodward, D.F.; Pepperl, D.J.; Burkey, T.H.; Regan, J.W.
Biochem. Pharmacol., 1995, 50, 1731.
[316] Keery, R.J.; Lumley, P. Br. J. Pharmacol., 1988, 94, 745.
[317] Abramovitz, M.; Adam, M.; Boie, Y. Biochim. Biophys. Acta,
2000, 1483, 285.
[318] Daray F.M.; Minvielle A.I.; Puppo, S.; Rothlin, R.P. Br. J.
Pharmacol., 2003, 139, 1409.
[319] Funk, C.D.; Furci, L.; Fitzgerald, G.A. J. Biol. Chem., 1993, 268,
26767.
[320] Sylvia, V.L.; Del Toro, F. Jr.; Hardin, R.R.; Dean, D.D.; Boyan,
B.D.; Schwartz, Z. J. Steroid Biochem., 2001, 78, 261.
[321] Biddulph; D.M.; Capehart, A.A.; Beasley, T.C. Exp. Cell Res.,
1991, 196, 131.
[322] Hillock, C.J.; Crankshaw, D.J. Eur. J. Pharmacol., 1999, 378,99.
[323] Bruehlmann, C.; Marston, A.; Hostettmann, K.; Carrupt, P.A.;
Testa, B. ChemBiodiv, 2004, 1, 819.
[324] Kang, J.-J.; Fang, H.-W. Biochem. Biophys. Res. Comm., 1997,
238,367.
[325] Gervasi, G.B.; Bartoli, C.; Catalani, R.; Farina, C.; Carpita, G.;
Caccia, G.; Ammannati, P. Arzneim.-Forsch./Drug. Res., 1991, 41,
1160.
[326] Beyer-Mears, A.; Cruz, E.; Nicolas-Alexandre, J.; Varagiannis,
E. Arch. Int. Pharmacodyn. Ther., 1982, 259, 166.
[327] Chen, W.Y.; Ko, F.N.; Lin, C.N.; Teng, C.M. Thromb. Res., 1994,
75, 81.
[328] Ruckstuhl, M.; Landry, Y. Biochem. Pharmacol, 1981, 30, 697.
[329] Chairungsrilerd, N.; Takeuchi, K.; Ohizumi, Y.; Nozoe, S.; Ohta,
T. Phytochemistry, 1996, 43, 1099.
[330] Beutler, E.; Forman, L.; West, C.; Gelbart, T. Biochem.
Pharmacol., 1988, 37, 1057.
[331] Pengsuparp, T.; Cai, L.; Constant, H.; Fong, H.H.; Lin, L.Z.;
Kinghorn, A.D.; Pezzuto, J.M.; Cordell, G.A.; Ingolfsdottir, K.;
Wagner, H. J. Nat. Prod., 1995, 58, 1024.
[332] Matthée, G.; Wright, A.D.; Konig, G.M. Planta Med., 1999, 65,
493.
[333] He, Q.; Xu, S.; Peng, B. Zhongguo Zhong Yao Za Zhi., 1998, 23,
556.
[334] Tan, G.T.; Lee, S.; Lee, I.S.; Chenã, J.; Leitnerã, P.; Bestermanã,
J.M.; Kinghorn, A.D.; Pezzuto, J.M. Biochem. J., 1996, 314, 993.
[335] Moliner, E.D.; Moro, S.; Sarno, S.; Zagotto, G.; Zanotti, G.; Pinna,
L.A.; Battistutta, R. J. Biol. Chem., 2003, 278, 1831.
[336] Sarno, S.; Moro, S.; Meggio, F.; Zagotto, G.; Ben, D.D.; Ghisellini,
P.; Battistutta, R.; Zanotti; G.; Pinna, L.A. Pharmacol. Therapeut.,
2002, 93, 159.
[337] Pinna. L.A. Acc. Chem. Res., 2003, 36, 378.
[338] Dai1, Z.; Jiang, D.J.; Hu, G.Y.; Du, Y.H.; Yu, J.; Hu, C.P.; Luo,
D.; Li, Y.J. Cardiovasc. Drug. Ther., 2004,18, 279.
[339] Jiang, D.-J.; Tan, G.-S.; Ye, F.; Du, Y.-H.; Xu, K.-P.; Li, Y.-J.
Acta Pharmacol. Sin., 2003, 24, 175.
[340] Croisy-Delcey, M.; Croisy, A.; Mousset, S.; Letourneur, M.;
Bisagni, E.; Jacquemin-Sablon, A.; Pierre, J. Biomed.
Pharmacother., 1997, 51, 286.
[341] Jiang, D.J.; Hu, G.Y.; Jiang, J.L.; Xiang, H.L.; Denga, H.W.; Lia,
Y.J. Bioorg. Med. Chem., 2003, 11, 5171.
[342] He, Q.; He, L.; Xu, S.; Deng, Q. Zhong. Yao Cai., 2000, 23, 399.
[343] Suzuki, O.; Katsumata, Y.; Oya, M.; Chari, V.M.; Vermes, B.;
Wagner, H.; Hostettmann, K. Planta Med., 1981, 42, 17.
[344] Thull, U.; Testa, B. Biochem. Pharmacol., 1994, 47, 2307.
[345] Suzuki, O.; Katsumata, Y.; Oya, M.; Chari, V.M.; Klapfenberger,
R.; Wagner, H.; Hostettmann, K. Planta Med., 1980, 39, 19.
[346] Harfenist, M.; McGee, D.P.; White, H.L. J. Med. Chem., 1991,
34, 2931.
[347] Rocha, L.; Marston, A.; Kaplan, M.A.; Stoeckli-Evans, H.; Thull,
U.; Testa, B.; Hostettmann, K. Phytochemistry, 1994, 36, 1381.
[348] Thull, U.; Kneubuhler, S.; Testa, B.; Borges, M.F.; Pinto, M.M.
Pharmacol. Res., 1993, 10, 1187.
[349] Fujimoto, H.; Satoh, Y.; Yamaguchi, K.; Yamazaki, M. Chem.
Pharm. Bull., 1998, 46, 1506.
[350] Ohishi, N.; Susuki, T.; Ogasawara, T.; Yagi, K. J. Molecular
Catalysis B: Enzimatic, 2000, 10, 291.
[351] Kalgutkar, A.S.; Dalvie, D.K.; Castagnoli Jr., N.; Taylor, T.J.
Chem. Res. Toxicol., 2001, 14, 1139.
[352] Loadman, P.M.; Phillips, R.M.; Lim, L.E.; Bibby, M.C. Biochem.
Pharmacol., 2000, 59, 831.
[353] Zhang, Z.; ElSohly, H.N.; Jacob, M.R.; Pasco, D. S.; Walker, L.A.;
Clark, A.M. Planta Med., 2002, 68, 49.
[354] Vlietinck, A.J.; Bruyne, T.D.; Apers, S.; Pieters, L.A. Planta Med.,
1998, 64, 97.

Xanthone Derivatives Current Medicinal Chemistry, 2005, Vol. 12, No. 21 2537
[355] Mesia-Vela, S.; Sanchez, R.I.; Estrada-Muniz, E.; Alavez-Solano,
D.; Torres-Sosa, C.; Jimenez, M.; Estrada; Reyes-Chilpa, R.;
Kauffman, F.C. Phytomedicine, 2001, 8(6), 481.
[356] Koizumi, M.; Shimizu, M.; Kobashi, K. Chem. Pharm. Bull., 1990,
38, 794.
[357] Froelich-Ammon, S.J.; Osheroff, N. J. Biol. Chem., 1995, 270,
21429.
[358] Zhu, F.;Lin, Y.C.;Zhou S.N.;Vrijmoed, L.L.P. Nat. Prod. Res.
Dev., 2004, 16, 406.
[359] Tosa, H.; Iinuma, M.; Tanaka, T.; Nozaki, H.; Ikeda, S.; Tsutsui,
K.; Tsutsui, K.; Yamada, M.; Fujimori, S. Chem. Pharm. Bull.,
1997, 45, 418.
[360] Wakelin, L.P.G.; Adams, A.; Denny, W.A. J. Med. Chem., 2002,
45, 894.
[361] Dharmaratne, H.R.; Tan, G.T.; Marasinghe, G.P.; Pezzuto, J.M.
Planta Med., 2002, 68, 86.
[362] Wang, J.N.; Hou, C.Y.; Liu, Y.L.; Lin, L.Z.; Gil, R.R.; Cordell,
G.A. J. Nat. Prod., 1994, 57, 211.
[363] Chang, C.C.; Lin, C.N.; Lin, J.Y. Antiviral Res., 1992, 19, 119.
[364] Ng, T.B.; Huang, B.; Fong, W.P.; Yeung, H.W. Life Sci., 1997, 61,
933.
[365] Wang, L.W.; Kang, J.J.; Chen, I.J.; Teng, C.M.; Lin, C.N. Bioorg.
Med. Chem., 2002, 10, 567.
[366] Hersey, A.; Hyde, R.M.; Livingstone, D.J.; Rahr, E. J. Pharm.
Sci., 1991, 80, 333.
[367] Paterson, R.A.; Dawson, J.; Hyde, R.M.; Livingstone, D.J.; Parry,
E.S.; Nash, S.; Boyce, I.M. Transfusion, 1988, 28, 34.
[368] Burkin, A.A.; Kononenko, G.P.; Soboleva, N.A. Appl. Biochem.
Micro., 2003, 39, 202.
[369] Kononenko, G.P.; Burkin, A.A.; Soboleva, N.A. Appl. Biochem.
Micro., 2003, 39, 105.
[370] Cheng, Y.W.; Kang, J.J. Eur. J. Pharmacol., 1997, 336, 23.
[371] Chiarini, A.; Valenti, P.; Fabbri, G.; da Re, P. Acta Pharm. Suec.,
1987, 24, 257.
[372] Bisi, A.; Budriesi, R.; Rampa, A.; Fabbri, G.; Chiarini, A.; Valenti,
P.Arzneim.-Forsch./Drug Res., 1996, 46, 848.
[373] Rampa, A.; Chiarini, A.; Bisi, A.; Budriesi, R.; Valenti, P.
Arzneim.-Forsch./Drug Res., 1991, 41, 705.
[374] Chiarini, A.; Rampa, A.; Bisi, A.; Budriesi, R.; Valenti, P.
Arzneim.-Forsch./Drug Res., 1992, 42, 797.
[375] Gammon, G.; Chandler, G.; Depledge, P.; Elcock, C.; Wrigley, S.;
Moore, J.; Cammarota, G.; Sinigaglia, F.; Moore, M. Eur. J.
Immunol., 1994, 24, 991.
[376] Wrigley, S.K.; Latif, M.A.; Gibson, T.M.; Chicarelli-Robinson,
M.I.; Williams, D.H. Pure Appl. Chem., 1994, 66, 2383.
[377] Kelly, J.X.; Winter, R.; Riscoe, M.; Peyton, D.H. J. Inorg.
Biochem., 2001, 86, 617.
[378] Kelly, J.X.; Ignatushchenko, M.V.; Bouwer, H.G.; Peyton, D.H.;
Hinrichs, D.J.; Winter, R.W.; Riscoe, M. Mol. Biochem. Parasitol.,
2003, 126, 43.
[379] Hyde, R.M.; Livingstone, D.J.; Patterson, R.A.; Batchelor, J.F.;
King, W.R. Lancet, 1984, 2, 15.
[380] Livingstone, D.J.; Hyde, R.M.; Batchelor, J.F. U.S. Patent
4,626,432, 1986.
[381] Pinto, M.; Nascimento, M.S.J. Pharm. Pharmacol. Lett., 1997, 7,
125.
[382] Pinto, M.; Nascimento, M.S.J.; Gonzalez, M.J.; Mondranondra,
I.O. Pharm. Pharmacol. Lett., 1997, 7, 128.
[383] Gonzalez, M.J.; Nascimento, M.S.J.; Cidade, H.M.; Pinto,
M.M.M.; Kijjoa, A.; Anantachoke, C.; Silva, A.M.S.; Herz, W.
Planta Med., 1999, 65, 368.
[384] Madan, B.; Prasad, A.K.; Parmar, V.S.; Ghosh, B. Bioorg. Med.
Chem., 2004, 12, 1431.
[385] Jackson, W.T.; Boyd, R.J.; Froelich, L.L.; Gapinski, D.M.; Mallett,
B.E.; Sawyer, J.S. J. Med. Chem., 1993, 36, 1726.
[386] Sawyer, J.S.; Baldwin, R.F.; Froelich, L.L.; Saussy Jr., D.L.;
Jackson, W.T. Bioorg. Med. Chem. Lett., 1993, 3, 1981.
[387] Sawyer, J.S.; Baldwin, R.F.; Sofia, M.J.; Floreancig, P.; Marder, P.;
Saussy, D.L., Jr.; Froelich, L.L.; Silbaugh, S.A.; Stengel, P.W.;
Cockerham, S.L.; Jackson, W.T. J. Med. Chem., 1993, 36, 3982.
[388] Jackson, W.T.; Froelich, L.L.; Boyd, R.J.; Schrementi, J.P.; Saussy,
Jr.; D.L.; Schultz, I.M.; Sawyer, J.S.; Sofia, M.J.; Herron, D.K.;
Goodson, Jr.; T.K., Snyder, D.W.; Pechous, P.A.; Spaethe, S.M.;
Roman, C.R.; Fleisch, J.H. J. Pharmacol. Exp. Ther., 1999, 288,
286.
[389] Chattopadhyay, U.; Das, S.; Guha, S.; Ghosal, S. Cancer Lett.,
1987, 37, 293.
[390] Nikolaeva, G.G.; Sergeev, A.V.; Nikolaev, S.M.; Glyzin, V.I.;
Dargaeva, T.D.; Sambueva, Z.G.; Tsyrenzhapov, A.V. Pharm.
Chem. J., 2004, 38, 25.
[391] Cerqueira, F.; Ufford, L. Q.; Beukelman, C.; Sousa, M.E.;
Nascimento, M.S.J. Drugs Fut., 2002, 27, 168.
[392] Jantan, I.; Juriyati, J.; Warif, N.A. J Ethnopharmacol., 2001, 75,
287.
[393] Jantan, I.; Pisar, M.M.; Idris, M.S.; Taher, M.; Ali, R.M. Planta
Med., 2002, 68, 1133.
[394] Jantan, I.; Jalil, J.; Warif, N.M.A. Pharmacut. Biol., 2001, 39, 243.
[395] Nakagawa, A.; Omura, S.; Kushida, K.; Shimizu, H.; Lukacs, G.
J. Antibiot., 1987, 40, 301.
[396] Carter, G.T.; Nietsche, J.A.; William, D.R.; Borders, D.B. J.
Antibiot., 1990, 43, 504.
[397] Pattalung, P.; Thongtheeraparp, W.; Wiriyachitra, P.; Taylor,
W.C. Planta Med., 1994, 60, 365.
[398] Ibrom, W.G.; Schaper, K.J.; Frahm, A.W. Arzneim.-Forsch./Drug.
Res., 1997, 47, 767.
[399] Dharmaratne, H.R.; Wijesinghe, W.M.; Thevanasem, V. J.
Ethnopharmacol., 1999, 66, 339.
[400] Rukachaisirikul, V.; Kaewnok, W.; Koysomboon, S.;
Phongpaichit, S.; Taylor, W.C. Tetrahedron, 2000, 56, 8539.
[401] Malmstrom, J.; Christophersen, C.; Barrero, A.F.; Oltra, J.E.;
Justicia, J.; Rosales, A. J. Nat. Prod., 2002, 65, 364.
[402] Nkengfack, A.; Mkounga, P.; Meyer, M.; Fomum, Z.; Bodo, B.
Phytochemistry, 2002, 61, 181.
[403] Azebaze, A.G.B.; Meyer, M.; Bodo, B.; Nkengfack, A.E.
Phytochemistry, 2004, 65, 2561.
[404] Szajnman, S.H.; Yan, W.; Bailey, B.N.; Docampo, R.; Elhalem, E.;
Rodriguez, J.B. J. Med. Chem., 2000, 43, 1826.
[405] Kyzyl, G.; Toker, Z.; Özen, H.C.; Aytekin, C. Phytother. Res.,
2004, 18, 339.
[406] Garcia, D; Escalante, M; Delgado, R; Ubeira, F.M.; Leiro, J.
Phytother. Res., 2003, 17, 1203.
[407] Avato, P.; Raffo, F.; Guglielmi, G.; Vitali C.; Rosato, A. Phytother.
Res., 2004, 18, 230.
[408] Éckeli, I.W.; Machado, D.S.B.; Simon, R.F.; Persuhn,
D.C.;Pinheiro, T.R.; Yunes, R.A.; Calixto, J.B.; Steindel,
M.;Grisard, E.C.; Santos, A.R.S.; Eger-Mangrich, Rev. Inst. Med.
Trop. S. Paulo, 2003, 45, 111.
[409] Morel, C.; Hay, A.E.; Litaudon, M.; Sévenet, T., Séraphin, D.;
Bruneton, J.; Richomme, P. Molecules, 2002, 7, 38.
[410] Oliveira, M.C.F.; Silveira, E.R. Phytochemistry, 2000, 55, 847
[411] Yasunaka, K.; Abe, F.; Nagayama, A.; Okabe, H.; Lozada-Perez,
L.; Lopez-Villafranco, E.; Muniz, E.E.; Aguilar, A.; Reyes-
Chilpa, R. J. Ethnopharmacol., 2005, 97, 293.
[412] Fukai, T.; Oku, Y.; Hou, A.J., Yonekawa, M.; Terada, S.
ChemBiodiv, 2004, 1, 1385.
[413] Leiro, J.; Arranz, J.A.; Parama, A.; Alvarez, M.F.; Sanmartin,
M.L. Dis. Aquat. Organ., 2004, 59, 171.
[414] Bairy, I.; Reeja, S.; Siddharth; Rao, P.S.; Bhat, M.; Shivananda,
P.G. Indian J. Pathol. Microbiol., 2002, 45, 307.
[415] Hambloch, H.; Frahm, A.W. Eur. J. Med. Chem., 1985, 20, 71.
[416] Pickert, M.; Schaper, K. J.; Frahm, A.W. Arch. Pharm.
(Weinheim.), 1998, 331, 193.
[417] Pickert, M.; Schaper, K.J.; Frahm, W. Eur. J. Pharm. Sci., 1998, 6,
S10.
[418] Winter, R.W.; Cornell, K.A.; Johnson, L.L.; Ignatushchenko, M.;
Hinrichs, D.J.; Riscoe, M.K. Antimicrob. Agents Chemother.,
1996, 40, 1408.
[419] Winter, R.W.; Ignatushchenko, M.; Ogundahunsi, O.A.; Cornell,
K.A.; Oduola, A.M.; Hinrichs, D.J.; Riscoe, M.K. Antimicrob.
Agents Chemother., 1997, 41, 1449.
[420] Likhitwitayawuid, K.; Chanmahasathien, W.; Ruangrungsi, N.;
Krungkrai, J. Planta Med., 1998, 64, 281.
[421] Likhitwitayawuid, K.; Phadungcharoen, T.; Krungkrai, J. Planta
Med,. 1998, 64, 70.
[422] Kelly, J.X.; Winter, R.; Peyton, D.H.; Hinrichs, D.J.; Riscoe, M.
Antimicrob. Agents Chemother., 2002, 46, 144.
[423] Kelly, J.; Winter, R.; Cornea, A.; Peyton, D.; Hinrichs, D.; Riscoe,
M. Mol. Biochem. Parasitol., 2002, 123, 47.
[424] Tona, L.; Cimanga, R.K.: Mesia, K.; Musuamba, C.T.; De Bruyne,
T.; Apers, S.; Hernans, N.; Van Miert, S.; Pieters, L.; Totté, J.;
Vlietinck, A.J. J. Ethnopharmacol., 2004, 93, 27.
[425] Hay, A.-E.; Hélesbeux, J.-J.; Duval, O.; Labaïed, M.; Grellier, P.;
Richomme, P. Life Sci., 2004, 75, 3077.

2538 Current Medicinal Chemistry, 2005, Vol. 12, No. 21 Pinto et al.
[426] Dua, V.K.; Ojha, V.P.; Roy, R.; Joshi, B.C.; Valecha, N.; Devi,
C.U.; Bhatnagar, M.C.; Sharma, V.P.; Subbarao, S.K. J.
Ethnopharmacol., 2004, 95, 247.
[427] Cooper, R.; Truumees, I.; Gunnarsson, I.; Loebenberg, D.; Horan,
A.; Marquez, J.; Patel, M.; Gullo, V.; Puar, M.; Das, P.; Mittelman,
S. J. Antibiot., 1992, 45, 444.
[428] Pinto, D.C.; Fuzzati, N.; Pazmino, X.C.; Hostettmann, K.
Phytochemistry, 1994, 37, 875.
[429] Rath, G.; Potterat, O.; Mavi, S.; Hostettmann, K. Phytochemistry,
1996, 43, 513.
[430] Chu, M.; Truumees, I.; Mierzwa, R.; Terracciano, J.; Patel, M.;
Loebenberg, D.; Kaminski, J.J.; Das, P.; Puar, M.S. J. Nat. Prod.,
1997, 60, 525.
[431] Reyes-Chilpa, R.; Jimenez-Estrada, M.; Estrada-Muñiz, E. J.
Chem. Ecology, 1997, 23, 1901.
[432] Chu, M.; Truumees, I.; Mierzwa, R.; Terracciano, J.; Patel, M.;
Das, P.R.; Puar, M.S.; Chan, T.-M. Tetrahedron Lett., 1998, 39,
7649.
[433] Cortez, D.A.G.; Young, M.C.M.; Marston, A.; Wolfender, J.-L.;
Hostettmann, K. Phytochemistry, 1998, 47, 1367.
[434] Bilia, A. R.; Yusuf, A. W.; Braca, A.; Keita, A.; Morelli, I. J. Nat.
Prod., 2000, 63, 16.
[435] Morel, C.; Seraphin, D.; Teyrouz, A.; Larcher, G.; Bouchara, J.P.;
Litaudon, M.; Richomme, P.; Bruneton, J. Planta Med., 2002, 68,
41.
[436] Moreau, S.; Varache-Lembege, M.; Larrouture, S.; Fall, D.;
Neveu, A.; Deffieux, G.; Vercauteren, J.; Nuhrich, A. Eur. J.
Med. Chem., 2002, 37, 237.
[437] Hay, A.E.; Guilet, D.; Morel, C.; Larcher, G.; Macherel, D.; Le
Ray, A.M.; Litaudon, M.; Richomme, P. Planta Med., 2003, 69,
1130.
[438] Höller, U.; König, G.M.; Wright, A.D. Eur. J. Org. Chem., 1999,
2949.
[439] Fukai, T.; Yonekawa, M.; Hou, A.-J.; Nomura, T.; Sun, H.-D.;
Uno, J. J. Nat. Prod., 2003, 66, 1118.
[440] Parmar, V.S.; Bisht, K.S.; Jain, R.; Singh, S.; Sharma, S.K.; Gupta,
S.; Malhotra, S.; Tyagi, O.D.; Vardhan, A.; Pati, H.N.; Berghe,
D.V.; Vlietinck, A.J. Indian J. Chem., 1996, 35, 220.
[441] Groweiss, A.; Cardellina, J.H.; Boyd, M.R. J. Nat. Prod., 2000, 63,
1537.
[442] Chen, I.J.; Lin, C.N.; Wu, B.N.; Cheng, K.L. Am. J. Chin. Med.,
1993, 21, 79.
[443] Gopalakrishnan, C.; Shankaranarayanan, D.; Nazimudeen, S.K.;
Viswanathan, S; Kameswaran, L. Ind. J. Pharmac., 1980, 12, 181.
[444] Jastrzebska-Wiesek, M.; Librowski, T.; Czarnecki, R.; Marona,
H.; Nowak, G. Pol. J. Pharmacol., 2003, 55, 461.
[445] Li, Y.; Ohizumi, Y. Yakugaku Zasshi, 2004, 124, 417.
[446] Rajtar, G.; Zolkowska, D.; Kleinrok, Z.; Marona, H. Acta Pol.
Pharm., 1999, 56, 311.
[447] Marona, H. Pharmazie, 1998, 53, 672.
[448] Marona, H. Pharmazie, 1998, 53, 405.
[449] Marona, H.; Gorka, Z.; Szneler, E. Pharmazie, 1998, 53, 219.
[450] Marona, H.; Pekala, E.; Filipek, B.; Maciag, D.; Szneler, E.
Pharmazie, 2001, 56, 567.
[451] Bianco, A.; Passacantilli, P.; Righi, G.; Brufani, M.; Cellai, L.;
Marchi, E.; Milani, M. R. Farmaco, 1989, 44, 547.
[452] Campos, R.O.; Santos, A.R.; Vaz, Z.R.; Pinheiro, T.R.; Pizzolatti,
M.G.; Cechinel Filho, V.; Delle Monache, F.; Yunes, R.A.;
Calixto, J.B. Life Sci., 1997, 61, 1619.
[453] Librowski, T.; Czarnecki, R.; Jastrzebska, M. Acta Pol. Pharm.,
1999, 56, 87.
[454] Marona, H.; Szneler, E.; Filipek, B.; Sapa, J. Acta Pol. Pharm.,
1997, 54, 63.
[455] Ishiguro, K.; Nagata, S.; Oku, H.; Yamaki, M. Planta Med., 2002,
68, 258.
[456] Sato, H.; Dan, T.; Onuma, E.; Tanaka, H.; Koga, H. Chem.
Pharm. Bull., 1990, 38, 1266.
[457] Hiroshi, K.; Takashi, D.; Mutsuji, M.; Michioka, A. Jpn. Patent
63010722, 1988.
[458] Hiroshi, K.; Mutsuji, M.; Takashi, D.; Michio, A. Jpn. Patent
61076476, 1986.
[459] Gaion, R.M.; Valenti, P.; Montanari, P.; Da Re, P. Arzneim.-
Forsch./Drug. Res. 1982, 32, 499.
[460] Hasegawa, H.; Sasaki, S.; Aimi, N.; Takayama, H.; Koyano, T.
Jpn. Patent, 08231396, 1996.
[461] Mahendran, P.; Vanisree, A.J.; Devi, C.S.S. Phytother. Res., 2002,
16, 80.
[462] Lin, C.N.; Liou, S.S.; Ko, F.N.; Teng, C.M. J. Pharm. Sci., 1993,
82, 11.
[463] Chung, M.I.; Weng, J.R.; Wang, J.P.; Teng, C.M.; Lin, C.N. Planta
Med., 2002, 68, 25.
[464] El Sayah, M.; Cechinel-Filho, V.; Pinheiro, T.R.; Yunes, R.A.;
Calixto, J.B. Inflamm. Res., 1999, 48, 218.
[465] Gonzalez-Alvarez, R.; Kazimierczak, W. Arch. Immunol. Ther.
Exp., 1982, 30, 333.
[466] Bajpai, M.B.; Asthana, R.K.; Sharma, N.K.; Chatterjee, S.K.;
Mukherjee, S.K. Planta Med., 1991, 57, 102.
[467] Basnet, P.; Kadota, S.; Shimizu, M.; Namba, T. Planta Med., 1994,
60, 507.
[468] Saxena, A.M.; Bajpai, M.B.; Mukherjee, S.K. Indian J. Exp. Biol.,
1991, 29, 674.
[469] Wang, H.X.; Ng, T.B. Life Sci., 1999, 65, 2663.
[470] Basnet, P.; Kadota, S.; Shimizu, M.; Takata, Y.; Kobayashi, M.;
Namba, T. Planta Med., 1995, 61, 402.
[471] Pifferi, G.; Da Re, P.; Valenti, P.; Bisi, A.; Malandrino, S. Arch.
Pharm. (Weinheim.), 1997, 330, 233.
[472] Li, H.; Miyahara, T.; Tezuka, Y.; Namba, T.; Nemoto, N.;
Tonami, S.; Seto, H.; Tada, T.; Kadota, S. Biol. Pharm. Bull., 1998,
21, 1322.
[473] Rakuambo, N.C.; Meyer; J.J.M.; Hussein, A. Fitoterapia, 2004, 75,
497.
[474] Banerjee, S.; Sur, T. K.; Mandal, S.; Das, P. C.; Sikdar, S. Indian J.
Pharmacol., 2000, 32, 21.
[475] Kumar, I.V.; Paul, B.N.; Asthana, R.; Saxena, A.; Mehrotra, S.;
Rajan, G. Immunopharmacol. Immunotoxicol., 2003, 25, 573.
[476] Cai , S.X.; Zhang H.-Z.; Wang Y.; Tseng B.; Kasibhatla S.; Drewe
J.A. W.O. Patent 00/44216, 2000.
[477] Ching, L.M.; Zwain, S.; Baguley, B.C. Br. J. Cancer, 2004, 90,
906.
[478] Bellnier, D.A.; Gollnick, S.O.; Camacho, S.H.; Greco, W.R.;
Cheney, R.T. Cancer Res., 2003, 63, 7584.
[479] Chung, F.; Palmer, B.D.; Muller, G.W.; Man, H.W.; Kestell, P.;
Baguley, B.C.; Ching, L.M. Oncol. Res., 2003, 14, 75.
[480] Zhao, L.; Ching, L.M.; Kestell, P.; Baguley, B.C. Br. J. Cancer,
2002, 87, 465.
[481] Woon, S.T.; Baguley, B.C.; Palmer, B.D.; Fraser, J.D.; Ching, L.M.
Oncol. Res., 2002, 13, 95.
[482] Rocha, A. B.; Mans, D. R. A.; Regner, A.; Schwatsmann, G.
Oncologist, 2002, 7, 17-33.
[483] Way, K. J.; Chou, E.; King, G. L. Trends Pharmacol. Sci., 2000,
21, 181-187.
[484] Gschwendt, M. Eur. J. Biochem., 1999, 259, 555-564.
[485] Chericoni, S.; Testai, L.; Calderone, V.; Flamini, G.; Nieri, P.;
Morelli, I.; Martinotti, E.; Planta Med., 2003, 69, 770.