Current Pharmaceutical Analysis, 2009, 5, 47-68 47

Noteworthy Secondary Metabolites Naphthoquinones – their Occurrence,

Pharmacological Properties and Analysis

Petr Babula1, Vojtech Adam2,3, Ladislav Havel4 and Rene Kizek2,*

1
Department of Natural Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Palackeho
1-3, CZ-612 42 Brno, Czech Republic; 2Department of Chemistry and Biochemistry, 3Department of Animal Nutrition
and Forage Production, and 4Department of Plant Biology, Faculty of Agronomy, Mendel University of Agriculture and
Forestry, Zemedelska 1, CZ-613 00 Brno, Czech Republic

Abstract: Chemical investigation of many bacterial and fungal, as well as plant species has revealed the presence of in-
teresting compounds derived from naphthalene – 1,4-naphthoquinones and rarely also 1,2-naphthoquinones. They were
detected in many species of families Bignoniaceae, Droseraceae, Plumbaginace, Boraginaceae, Juglandaceae as well as
in species of small families, such as Dioncophyllaceae or Acanthaceae. Naphthoquinones have very interesting spectrum
of biological actions, including antibiotic, antiviral, anti-inflammatory, antipyretic, antiproliferative and cytotoxic effects.
Because of these properties the plants containing them are used in folk medicines, mainly by natives in Asia, where espe-
cially Chinese medicine uses aerial as well as subterranean parts of these plants for hundreds years, and South America.
The utilizing of naphthoquinones for medicinal purposes and their occurrence in nature is reviewed and discussed.
Moreover, we review analytical techniques using for their analysis.

Keywords: Naphthoquinones, Plants, Pharmacology, Liquid chromatography, Electrochemical detection, UV-VIS Spectrome-
try.

INTRODUCTION parasitic and cytotoxic activities emerge due to their ability

Naphthoquinones are one of the groups of secondary me-
tabolites widespread in nature. The most important higher
plant families containing naphthoquinones are Avicenniaceae
[1], Bignoniaceae [2, 3], Boraginaceae [4], Droseraceae [5,
6], Ebenaceae [7, 8], Juglandaceae [9], Nepenthaceae [10]
and Plumbagnaceae [11, 12], they have been determined as
secondary metabolism products of actinomycetes (Strepto-
myces) [13] and fungi (Fusarium, Marasmius, Verticillium)
[14] lichens and algae [15]. In plants, they commonly occur
in the reduced and glycosidic forms. In some species (e.g.
Diospyros, Ebenaceae) are naphthoquinones present as
monomers as well as dimers or trimers. They are biosynthe-
sized via a variety of pathways including acetate and
malonate pathway (plumbagin), shikimate/succinyl CoA
combined pathway (lawsone) and shikimate/mevalonate
pathway (alkannin). Napthoquinones have many physiologi-
cal roles – ubiquinone, plastoquinone and K vitamins are
functional constituents of biochemical systems. Naphthoqui-
nones are usually coloured, especially they are responsible
for yellow or brown colour and thus, they play important
roles as dyes in pigmentation. The interest of many investi-
gators in these compounds is due to their broad-range of bio-
logical activities: antibacterial, fungicidal, antiparasitic and
insecticidal. In addition, they have inhibitory effect on insect
larval development and sedative or toxic effect on aquatic
organisms and animals [16, 17]. Their antimicrobial, anti-
*Address correspondence to this author at the Department of Chemistry and
Biochemistry, Mendel University of Agriculture and Forestry, Czech Re-
public; Tel: +420-5-4513-3350; Fax: +420-5-4521-2044;
E-mail: kizek@sci.muni.cz
to act as potent inhibitors of electron transport, as uncouplers
of oxidative phosphorylation, as intercalating agents in the
DNA double helix, as bioreductive alkylating agents of bio-
molecules, and as producers of reactive oxygen radicals by
redox cycling under aerobic conditions. Naphthoquinones,
especially juglone, are widely studied for allelopathic activ-
ity. Plants with naphthoquinone content are world-wide used
in the traditional medicines of countries where they grow.
Naphthoquinones are highly toxic. Moreover, 1,4-naphtho-
quinone has been evaluated as a corrosion inhibitor in 0.5 M
NaCl solutions. This effect is a result of its adsorption on the
metal surface and blocking the corrosion process [18]. High
performance liquid chromatography with spectrometric de-
tection and electrochemical techniques are most suitable for
their determination in biological samples.
CHARACTERIZATION OF NAPHTHOQUINONES
Chemical structure of monomeric naphthoquinones is
based on bicyclic system – naphthalene skeleton substitute in
position C1 and C4 (1,4-naphthoquinones) or C1 and C2 (1,2-
naphthoquinones). Dimeric and trimeric naphthoquinones
are also known. Most of them are coloured compounds.
Their colours usually vary between yellow, orange and
brown.
Almost all naphthoquinones are soluble in alcohol, ace-
tone, chloroform, benzene, DMSO and acetic acid, plum-
bagin and juglone are slightly soluble in hot water. The sim-
plest, and in the nature the most widespread naphthoqui-
nones, are juglone, lawsone, plumbagin and lapachol (Table
1).

1573-4129/09 $55.00+.00 © 2009 Bentham Science Publishers Ltd.

48 Current Pharmaceutical Analysis, 2009, Vol. 5, No. 1 Babula et al.

Table 1. Structural Formulas, Systematic and Trivial Names and Physical Properties of the Certain 1,4-naphthoquinones

Substituent Systematic (Trivial) Name Molecular Weight Melting Point [°C]

- 1,4-naphthoquinone 158.15 119 – 122

5-hydroxy-1,4-naphthoquinone
R3 = -OH 174.14 155
(juglone)

2-hydroxy-1,4-naphthoquinone
R1 = -OH 174.15 192 – 195
(lawsone)

5-hydroxy-2-methy-1,4-
R1 = -CH3, R3 = -OH naphthoquinone 188.18 78 – 79

R6 O
(plumbagin)
R5 R1 2-methyl-1,4-naphthoquinone
R1 = -CH3 172.18 105 – 107
R4 R2
(menadion)
R3 O
5,8-dihydroxy-1,4-naphthoquinone
R3, R6 = -OH 190.16 237
(naphtazalin)

2,5,7-trihydroxy-1,4-naphthoquinone
R1, R3, R5 = -OH 206.17 164 – 168.5
(flaviolin)

R1 = - 5,8-dihydroxy-2-(1-hydroxy-4-methyl-
CHOHCH2CH=C(CH3) 2 pent-3-enyl)-1,4-naphthoquinone 288.30 Not available
R3, R6 – OH (shikonin)

2-hydroxy-3-(3-methyl-but-2-enyl)-1,4-
R1 = -OH
naphthoquinone 242.27 141 – 143
R2 = -CH2CH=C(CH3) 2
(lapachol)

OH O O OH O OH
OH
CH3O CH3 CH3O CH3 CH3O
CH3
N OH O
CH3
OH O O OH O OH
bostrycoidin solaniol fusarubin
OH O
OH O CH2OH
CH3O CH3 O
OH
O HO
O
OH O
O OH
novarubin biflaviolin

Fig. (1). Selected fungal naphthoquinone metabolites.

NAPTHOQUINONES IN NATURE ticillium [14, 19-22]. Naphthoquinone metabolites of fungi

Actinomycetes and Fungi
The ability of naphthoquinone synthesis is widespread
among fungal organisms. The complete list of fungi produc-
ers includes about 63 species [14]. They are widespread in
genus Fusarium – 10 species. They can be also found in
other important genera such as Aspergillus, Cladosporium,
Microsporium, Mollisia, Penicillium, Trichophyton and Ver-
differ significantly in their chemical composition (Fig. 1).
The simplest naphthoquinone produces by a fungus is
juglone (Verticillium dahliae).
Fungal naphthoquinones may be produced in in vitro
conditions. Composition of produced naphthoquinones can
be affected by initial ratio of carbon and nitrogen sources
and pH of cultivation medium [23, 24]. Fungal naphthoqui-
Noteworthy Secondary Metabolites Naphthoquinones
O O
5 malonyl-CoA S-CoA
COOH
O HO
O O
OH O
HO OH
O naphthalene-1,3,6,8-tetraol
flavioline
Fig. (2). Mevalonate pathway of flaviolin biosynthesis.
OH O OH
H3C
HO
OH O OH
naphthazarin hybocarpone
Fig. (3). Naphthazarin and hybocarpone.
nones biosynthesis was investigated using 14C and 3H la-
belled acetate or methyl group of methionin. This data indi-
cate that synthesis of naphthoquinones proceeds via the for-
mation of a precursor. This precursor is product of the ace-
tate/malonate pathway [23, 25]. The fungal naphthoquinones
have a broad range of biological activities. They are active
against bacteria, yeasts and fungi. Cytotoxic properties of
fungal naphthoquinones were demonstrated on mouse leu-
kaemia and HeLa cells. Antibiotic activity is manifest espe-
cially against Gram-positive bacteria [26]. Antibacterial ac-
tivity of fungal naphthoquinones depends on their chemical
structure – the most important requirement is water solubility
because of penetration to cells trough cell membranes. The
toxicity of the naphthoquinones decreases in the presence of
metal ions (Cu, Fe, Al) [27]. Antibacterial effect is based on
inhibition of mitochondrial respiration (respiratory chain
interruption), suppress of RNA biosynthesis, and biosynthe-
sis of proteins, lipids and transport of glucose. Fungal naph-
thoquinones are capable of redox conversions, whereas their
antibiotic, cytotoxic and phytotoxic effect are due to interac-
tions with the oxidative systems of cells [28]. They are able
to accept the reducing equivalents from the redox enzymes
and transfer them to oxygen. Two basic systems providing
resistance of fungi to their own secondary metabolites –
naphthoquinones – is also known. The first one bases in
change of the sensitivity of the target or its absence in the
cells of producers and second one in change the naphthoqui-
none toxicity by metabolic modification, such as phosphory-
lation or acetylation [29]. Many naphthoquinones exhibit the
properties of mycotoxins (in Penicillium, Aspergillus, Mi-
crosporium and Trichophyton) [30].
Actinomycetes (genus Streptomyces) are the producers of
substitute isoprene-derived naphthoquinones. Structurally
Current Pharmaceutical Analysis, 2009, Vol. 5, No. 1 49
OH O
S-CoA
COOH
O
-CO2
OH OH
HO OH
H3C CH3
O O OH
CH3
O OH
O OH OH O OH
simple redish-brown pigment flaviolin (Fig. 2) originates in
the presence of rppA gene via malonate pathway and repre-
sents a precursor for other naphthoquinones [13]. Production
of mostly prenylated naphthoquinones, such as naphterpin,
naphthgeranines, fumaquinone, furaquinocins, marinone,
neomarinone hygrocins, chloroquinocins, napyradiomycin
and other naphthoquinone compounds, such as heterocyclic
naphthoquinones with significant anti-inflammatory efect is
also reported [31-46].
Lichens
Lichens were determined as producers of wide spectrum
of secondary metabolites that demonstrate many biological
actions, such as antioxidant, antimicrobial or cytotoxic. Ali-
phatic acids, pulvinic acid, depsides, depsidones, dibenzo-
furans, anthraquinones and also naphthoquinones were de-
scribed as compounds responsible for these activities [47-
51]. The best-known genera that produce them are Cetraria
and Cladonia [52, 53]. Naphthazarin and its derivates were
isolated from Cetraria islandica (Fig. 3). This naphthoqui-
none demonstrate in in vitro experiments strong cytotoxic
effect to human epidermal carcinoma cells. Dimer of this
naphthoquinone, hybocarpone, was isolated from Lecanora
hybocarpa [54].
Bignononiaceae (incl. Avicenniaceae)
Family Bignoniaceae includes about 120 genera and 650
species of tropical trees, shrubs or lianes, mainly abundant in
Brazil. The presence of naphthoquinone production was re-
corded in genera Catalpa [55], Heterophragma [56, 57],
Kigelia [58-61], Macfadyena [62], Mansona [2], Markhamia
[63, 64], Newbouldia [65-70], Oroxylum [71, 72], Rader-
machera [73], Stereospermum [74], Tabebuia [3, 75, 76] and
50 Current Pharmaceutical Analysis, 2009, Vol. 5, No. 1 Babula et al.

O O O

O O OH
O OH O O

-lapachone 9-hydroxy-
-lapachone lapachol

Fig. (4). Some naphthoquinones of Bignoniaceae family.

COOH O
COOH COOH COOH COOH
+
HOOC
HO OH
OH O O O

shikimic acid
-ketoglutaric acid o-sukcinylbenzoic acid droserone, juglone

Fig. (5). Some naphthoquinones of family Droseraceae.

O O O OH O
CH3 H3C CH3 CH3

OH OH
OH O OH O OH O OH O

plumbagin 7-methyljuglone droserone hydroxydroserone

O O O
O H3C CH3
OH
CH3
O
O OH OH O O OH
diomuscione muscipulone biramentaceone

Fig. (6). Droserone and juglone biosynthesis via shikimate pathway.

Zeyheria [77]. Majority naphthoquinone in this family is
lapachol and its derivates (Fig. 4). Kigelia pinata bark is
used in Nigerian medicine for antimicrobial, tripanocidal and
anticarcinogenic (mainly melanoma) activities [78-81]. Bark
and wood of Tabebuia species, namely T. avellanedae, T.
pentaphylla and T. ochracea, are widely used in traditional
medicines of South America countries against cancer and for
anti-inflammatory properties [82-89]. The root bark of
Stereospermum kunthianum is used by some tribes in
Uganda to treat fever. Naphthoquinones – sterekunthals and
pyranokunthones – with potent antiplasmodial effect were
found in liphophilic extract of root bark [90]. Derivates of
lapachol with cancer chemoprotective activity were recorded
in different parts of Avicennia alba and A. rumphiana [1, 91,
92].
Droseraceae
Family Droseraceae include about 105 species of car-
nivorous perennial or annual herbs with active trapping
mechanism in four genera (Aldrovanda, Dionaea, Drosera
and Drosophyllum). The majority naphthoquinones detected
in almost all species of this family are plumbagin and 7-
methyljuglone. Plumbagin is majority naphthoquinone of
Aldrovanda, Dionaea [93, 94], Drosophyllum [95] and some
Drosera species – D. anglica, D. auriculata, D. binata, D.
capensis, D. cistiflora, D. indica, D. intermedia, D. longifo-
lia, D. peltata, D. ramentacea, D. rotundifolia and D. whi-
takeri [96, 97]. The other Drosera species contain alternative
monomeric naphthoquinones, such as droserone, 7-methyl-
juglone and their glycosides and dimeric naphthoquinones
(Fig. 5) [98]. They are also produced in in vitro cultures [99-
106]. Two compounds biosynthetically connected with
plumbagine, diomuscione and muscipulone, were identified
in Dionaea muscipula [107]. Droserone or juglone are naph-
thoquinones biosynthetised via shikimate pathway. Molecule
of shikimic acid condenses with molecule of
-ketoglutaric
acid and forms naphthoquinones of droserone or juglone
type (Fig. 6). The second biosynthetic pathway includes syn-
thesis of shikimic acid trough aromatic amino-acid L-
Noteworthy Secondary Metabolites Naphthoquinones Current Pharmaceutical Analysis, 2009, Vol. 5, No. 1 51

COOH COOH COOH

shikimate kinase
COOH
chorismate synthase
+
P O CH2 CH2
HO OH HO OP O
OH OH OH COOH

shikimate shikimate 3-phosphate phosphoenolpyruvate chorismate

chorismate mutase

COOH HOOC COOH

COOH prephenate aminotransferase

O
NH2
HO

glutamate OH
arogenate a-ketoglutarate
prephenate
4-hydroxyphenylpyruvate
arogenat dehydratase
NADPH+H
arogenat-
dehydrogenase
phenylalanine
NADP H2O, CO2
Phenylalanine and Tyrosine,
pathway in yeast and E. coli
alkaloids

COOH
transamination COOH
NH2
HO O
L-tyrosine
O2 phenylpyruvate

CO2
OH OH OH O
H3C CH3
CH3 CH3 H3C CH3
COOH + C5

OH OH OH O
1,4-naphthoquinone
homogentisate toluquinone (droserone, 7-methyljuglone)

Fig. (7). 7-methyljuglone and plumbagin synthesis through L-tyrosine.

tyrosine. Plumbagin and 7-methyljuglone are two important
products of this pathway (Fig. 7). The European sundew,
Drosera rotundifolia, has been utilized in folk medicines for
long time and has been included in some pharmacopoeias. In
the Czech Republic it has been using from 13th century
against cold, cough, bronchitis and asthma. Anti-
inflammatory effect was found out too [108]. Nature medi-
cine in USA recommends extract from D. rotundifolia as
geriatric. In Italy, it is an ingredient of a liqueur. Drosera
burmanni is widely used in Chinese traditional medicine as
well as rubefacient in Indic folk medicine [109]. The crushed
leaves of Drosera indica and D. peltata are used as rubefa-
cient and vesicant [109].
Juglandaceae
North temperate and subtropical family Juglandaceae ex-
tending to India, Indochina, Malaysia and Andean South
America contains about 50 species in 8 genera. The most
important genus is Juglans (valuable source of edible nuts)
with majority naphthoquinone juglone. Juglone is present in
free as well as glucosidic form (1,5-dihydroxy-4-naftalenyl-

-D-glucopyranoside) [9, 110, 111]. This glucosidic form is
decomposing by hydrojuglone-
-D-glucopyranosid-
-gluco-
sidase to juglone. Naphthoquinones have been detected in
Juglans nigra [112] and J. regia [9, 113]. Extracts, as well as
miscellaneous parts of walnuts, have long traditions of use in
folk medicines for acne, allergies, gastrointestinal disorders
and intestinal parasitosis treatment. External use is reserved
for fungal, bacterial and viral infections (herpes) therapy.
Most recently published analyses demonstrate the presence
of juglone in other members of Juglandaceae family – genus
Pterocarya (P.fraxinifolia) [114].
Plumbaginaceae
Cosmopolitan-spread family Plumbaginaceae includes
about 775 species of herbs, shrubs or lianas in 24 genera.
Naphthoquinones, above all plumbagin and its derivates, are
reported in genera Ceratostigma, Limonium, Plumbago and
Plumbagella. Plumbago zeylanica is one of the most exam-
ined plants. Naphthoquinones, bisnaphthoquinones and tris-
naphthoquinones (plumbagin, chitranone, maritinone, ellipti-
none and isoshinanolon) [115-118] and plumbagic acid with
two glucosides [116] have been isolated from this semi-
climbing subshrub (Fig. 8).
The whole plant and the roots are used in folk medicine
in Thailand for the treatment of carbuncle, ulcers, injuries,
52 Current Pharmaceutical Analysis, 2009, Vol. 5, No. 1 Babula et al.

OH O
O O
CH3 H3C
OH O OH O
CH3
O
OH O O OH
O
CH3 CH3
CH3
O O

OH O
chitranone elliptinone
maritinone
Fig. (8). Naphthoquinones of Plumbago zeylanica.
OH O OH O O O OH
CH3

OH O
H3C H3C
O O OH O O
H3C
H3C

O O diospyrin O O isozeylanone
CH3
HO OH OH O O OH
O OH

8´-hydroxyisodiospyrin
OH O
O H3C CH3
CH3 H3C
OMe OMe O O
OH O
diosindigo A CH3 3,3´- biplumbagin
O
OH O
CH3
OH O
O
chitranone 2,3-epoxyplumbagin

Fig. (9). Napthoquinones of different Diospyros species: 8´-hydroxyisodiospyrin, diospyrin (D. assimilis, D. montana, D. paniculata), dios-
indigo A (D. sylvatica), isozeylanone, 3,3´-biplumbagin, chitranone and 2,3-epoxyplumbagin (D. maritima).

elimination internal parasites and rheumatic pains [119].
Moreover in traditional medicine of India have a use for di-
arrhoea, digestion disorders and skin diseases treatment as
well as abortion induction [120] and in Nigerian (Africa) for
parasitic diseases, scabies and ulcers [121]. Other Plumbago
species (P. auriculata, P. europaea, P. rosea, and P. scan-
dens) as well as their in vitro cultures (callus, suspension,
immobilised cells and hairy root cultures) produce plum-
bagin and other naphthoquinones too [11, 12, 122-133].
Plumbagin, its glycosides and derivates, shinanolon and epi-
isoshinanolon, have been detected in extracts of Cerato-
stigma minus and Ceratostigma willmottianum in addition to
phenolic compounds [134-136].
Ebenaceae
Family Ebenaceae, containing about 500 species in two
genera, is mainly extended in subtropical and tropical areas,
especially Indomalayan. Some species are important sources
of timber (ebony) and fruits. The majority naphthoquinone of
genus Diospyros is plumbagin [7, 8, 137-150]. Some species
contains glycosides of plumbagin – diospyrosids A – D
[151]. Dimers (D. greeniwai) were determined too [152].
Fruits of Diospyros maritima contain very rare brominate
derivate of plumbagin – 3-bromoplumbagin [153]. Other
compounds biosynthetically connected with 1,4-naphtho-
quinones are naphthalene derivates and naphthaldehydes
(Fig. 9). These naphthoquinones exhibit very interesting
pharmacological properties – extracts of many species this
genus are widely used in African, Chinese and Indian folk-
lore medicine for whooping cough, leprosy, scabies, skin
diseases eye infections, menstrual troubles and parasitosis
[154]. 7-methyljuglon and other naphthoquinone derivates
were determined in parts of Euclea divinorum [155] and
Euclea natalensis subsp. natalensis [156]. Body parts of dif-
ferent Euclea species are used for various purposes, such as
toothbrushes, hypnotic, for toothache and headache by peo-
ple of South Africa. All naphthoquinones of genus Euclea
have potent antituberculosis activity, especially 7-methyl-
juglone [156].
Lythraceae
Lawsonia inermis, a shrub cultivated in North Africa,
Egypt, India and Ceylon, has been using from ancient world
to obtain henna. Henna (powder of dried leaves) consist of
Noteworthy Secondary Metabolites Naphthoquinones
OH OH
C10
+
COOH COOH
p-hydroxybenzoic acid
Fig. (10). Combined shikimate/mevalonate pathway of alkannin biosynthesis.
colouring matter – lawsone – and various phenolic com-
pounds, coumarins, xanthones, quinoids, flavonoids, fats,
resin and henna-tanin [157, 158]. In vitro cultivated plants as
well as hairy root cultures produce lawsone too [159].
Extracts from stem-bark are traditionally used in India for
the treatment of liver and spleen diseases, jaundice and skin
diseases. Isoplumbagin was determined as anti-inflammatory
agent comparable to phenylbutazone [157]. Hepatoprotective
activity of stem-bark compounds was determined too [160].
Application of henna can induce severe haemolytic anaemia;
lawsone was determined as causative agent [161].
Boraginaceae
This family includes annual to perennial herbs, shrubs,
small trees or lianas with 2000 species in 120 genera. The
most important plants containing naphthoquinones belongs
to genera Alkanna [162], Cordia [163, 164], Lithospermum
[165], Arnebia and Onosma [166, 167]. The most important
naphthoquinones detected in species of these genera are
shikonin, acetylshikonin, deoxyshikonin, isobutylshikonin
and isovalerylshikonin. The compounds of these family
members are biosynthesized via combined shiki-
mate/mevalonate pathway (Fig. 10). The reported naphtho-
quinone constituent of genus Lithospermum is shikonin.
Roots of L. erythrorhizon are widely used for shikonin isola-
tion and are produced for cosmetic and pharmaceutical in-
dustries in Japan [4, 165]. In vitro plant cell suspension cul-
tures stimulated by specific oligogalacturonides, ethylene
[168, 169], ultrasound [170] and low-dose gamma irradiation
[171]. Transformed organ cultures are used for shikonin pro-
duction too [172-175]. Other species widely utilised in Chi-
nese folk medicine are Arnebia guttata and A. euchroma –
these two species are listed in Chinese pharmacopoeia as
official sourcing of drug “zicao” [167, 176]. In the Far East,
preparations from the purple roots have long been used for
treatment of inflammations, burns, wounds and ulcers, but in
in vitro laboratory tests skinonin (alkannine too) have no
significant anti-inflammatory activity. Other species, such as
Lithospermum arvense, are used as oral contraceptive in
Central Europe and suppress the oestrus cycle. Similar North
American species, Lithospermum ruderale, has similar hor-
monal activity and Lithospermum canescens contains
shikonin derivates [177, 178].
Dried roots of Alkanna tinctoria, herb cultivated in
Southern Europe, Hungary and Turkey, are used for colour-
ing oil and tars. The tincture of these pigments is used for
microscopical detection of oils and fats. These coloured
compounds are naphthoquinone derivates too – alkannin,
Current Pharmaceutical Analysis, 2009, Vol. 5, No. 1 53
OH O OH
OH O
alkannin
CH3
OH O alkannan:
R CH3
H OH
CH3
alkannin:
H OH CH3
OH O CH3
shikonin
CH3
Fig. (11). Main napthoquinone derivates of Alkanna tinctoria roots.
alkannan and shikonin (Fig. 11) [179, 180]. Most of these
pigments are produced in plant cell suspension cultures [162,
181]. Other members of family Boraginaceae, such as Mac-
rotomia cephalotes, produce similar red pigment.
Derivates of shikonin were discovered in roots of Turkish
species Onosma argentatum, as well as Onosma armeniacum
[182]. Antifungal properties of these derivates were con-
firmed. In addition to that larvicidal meroterpenoid naphtho-
quinones were isolated from roots of Cordia linnae [183];
roots of other species – Cordia corymbosa and C. curas-
savica – contain sesquiterpenic (meroterpenoid) napthoqui-
nones – cordiaquinones – with activity against some fungal
pathogens like Cladosporium or Candida [163, 184]. Roots
of Arnebia densiflora, widespread plant in Anatolia, contain
alkannin derivates [185]. The latest report is the utilization of
roots of Rindera graeca (in vivo and in vitro as transgenic
roots) as source of shikonin and its derivates [175].
There is one important, but unanswered question, do
similar plant families closely related to Boraginaceae (Ru-
biaceae with important genera Galium and Rubia) contain
naphthoquinones or similar compounds [186, 187]?
Nepenthaceae
Family Nepenthaceae with 70 species at 2 genera in-
cludes carnivorous plants with specialized leaves as passive
traps - pitchers. Naphthoquinones are characteristic com-
pounds of these plants. Plumbagin, isoshinanolone, epishi-
nanolone, shinanolone, quercetin and kaempferol were iso-
lated from the leaves of Nepenthes gracilis [188], from roots
of N. rafflesiana droserone, hydroxydroserone, plumbagin
and the nepenthones A-C [189, 190]. Roots of N. thorelli
contain plumbagin, droserone, 2-methylnaphthazarin and
isoshinanolon [10]. By means of application of labelled L-
alanine to the pitchers the incorporation of L-alanine to
plumbagin was explained (Fig. 12) [191]. The closely related
54 Current Pharmaceutical Analysis, 2009, Vol. 5, No. 1 Babula et al.

CoASH+NAD+

-ketoglutarate
glutamate
CO2+NADH
H3C COOH H3C COOH H3C SCoA

alanine-aminotransferase pyruvate-dehydrogenase
NH2 O O

L-alanine pyruvate acetyl CoA

6x

OH O OH OH O O O

oxidation reduction,aldol condensation

SCoA
decarboxylation
CH3 CH3 O CH3
O O
O
plumbagin

Fig. (12). Incorporation of L-alanine to plumbagin structure.

CH3
O O O
R

R R OH
O O O

impatienol - R = -OH balsaminol - R = -OH

impatienolate - R = -ONa balsaminolate - R = -ONa

Fig. (13). Naphthoquinones isolated from aerial parts of Impatiens balsamina.

families are Ancistrocladaceae and Dioncophyllaceae, both
with naphthoquinone contents.
Balsaminaceae
This family contains approximately 600 species in only 4
genera. Some species of genus Impatiens, such as I. balsa-
mina, one of the most known species, are widely used in
Chinese medicine for rheumatism, bruises, pain and swelling
treatment and in Japan topically as potent agent against sev-
eral types of dermatitis including urticaria. The main active
compounds were determined derivates of 1,4-naphthoqui-
none, e. g. lawsone, 2-methoxy-1,4-naphthoquinone and
other naphthoquinones, such as impatienol and balsaminol
and their derivates; plumbagin was determined later (Fig. 13)
[94, 192-194], and flavonoid compounds in addition.
Other Plant Families
Other plant families containing naphthoquinones are
Acanthaceae with the genus Rhinacathus nasutus containing
esteric naphthoquinones marked as rhinacathins (A-D) in
roots [195-198] using in Thai traditional medicine for cancer
treatment [199-201], Ancistrocladaceae with only genus
Ancistrocladus with derivates of plumbagin [202], Annona-
ceae (roots of Goniothalamus cheliensis) [203], Dioncophyl-
laceae with only genus Triphyophyllum peltatum (droseron,
plumbagin) [204], Eriocaulaceae (Paepalanthus –
semixanthomegnin and its methoxy derivates) [205, 206],
Euphorbiaceae – Pera benesis (plumbagin and its derivates)
used as leihsmanicidal agent in Bolivia [207], Fabaceae
(naphthoquinone juglone was isolated from heartwood of
tree Caesalpinia sappan) [208], Gencianaceae (antifungal
properties of Swertia calycina extracts – 2-methoxy-1,4-
naphthoquinone) [209], Iridaceae (Aristea, Eleutherine bul-
bosa and E. americana – eleutherinon, eleutherin,
isoeleutherin and their derivates) [210-212], Liliaceae (naph-
thol-naphthoquinone derivates such as imbricatonol isolated
from Stypandra imbricata and Dianella revoluta) [213, 214],
Malvaceae (genus Hibiscus with very rare derivates of 1,2-
naphthoquinones called hibiscones A-D) [215], Leguminosae
– Caesalpinioideae (heartwood of Caesalpinia sappan with
juglone content) [208], Pedaliaceae (Sesamum indicum, in
vitro production by roots transformed by Agrobacterium
rhizogenes) [216], Proteaceae (Conospermum incurvum, C.
sphacelatum and C. stocheadis) [217-220], Pyrolaceae (5,8-
dihydro-2,7-dimethyl-1,4-naphthoquinone from the roots of
Noteworthy Secondary Metabolites Naphthoquinones Current Pharmaceutical Analysis, 2009, Vol. 5, No. 1 55

COOH pyruvate + CO2 OH

2-oxoglutarate COOH COOH
OH - H2O
COOH
COOH COOH
O CH2
O O
izochorismate 6-hydroxy-2-sukcinyl- 2-sukcinylbenzoate
cyklohexa-2,4-dienkarboxylate
ATP + HS-CoA

HS-CoA
O OH AMP + PPi
H COOH COOH

CO-S-CoA
CH3
O OH O

n = 2 - phylloquinone (vitamin K1) 1,4-dihydroxy-2-naphtoate 4-(2-karboxyphenyl)-4-

n = 1 - 13 - menaquinone (vitamin K2) oxobutanoyl-CoA

Fig. (14). Biosynthesis of phylloquinone and menaquinone via isochorismate.

NAD(P)H NAD(P)+
OH O
H Any
H N
N
H
3. CH3
2-RSH RS-SR
OH CO2H
O
vitamin K - quinol protrombin
1.
H precursor
O2, CO2

CH3
O
vitamin K

O O
H Any
2. H N
N
O H
CO2H
CH3
2-RSH RS-SR
O CO2H
vitamin K - 2,3-epoxide protrombin
Fig. (15). The role of vitamin K in coagulation.

Pyrola japonica) [221], Scrophulariaceae (Calceolaria
andina – 2-(1,1-dimethylprop-2-enyl)3-hydroxy-1,4-naphtho-
quinone and the corresponding acetate, 2-acetoxy-3-(1,1-
dimethylprop-2-enyl)-1,4-naphthoquinone [222, 223]; Ca-
praria biflora – biflorin [224], Paulownia tomentosa with
the low content of plumbagin [94]), Verbenaceae (Lippia
microphylla – prenylated naphthoquinone dimer, mixture of
6-methoxy- and 7-methoxy-naphtho[2,3-b]-furan-4,9-
quinones and tecomaquinone from the roots) [225] and Zy-
gophyllaceae (larreantin from the root of Larrea tridentata)
[226].
VITAMINS OF K GROUP – A STRUCTURAL ANA-
LOGUES OF 1, 4-NAPHTHOQUINONE
Vitamin K is a title for group of fat-soluble compounds
that have 2-methyl-1,4-naphthoquinone skeleton substituted
at the C3 position by side chain (Fig. 14). They are synthe-
sized by plants (phylloquinone, vitamin K1 with phytyl side
chain with 20 carbons) and by bacteria (menaquinones with
repeating unsaturated prenyl units (MK-n, where n is number
of prenyl units) and compounds where one or more double
bonds of side chain is saturated) [227]. Basic menadion (2-
methyl-1,4-naphthoquinone) is thought to be a provitamin
and can be converted by vertebrates to MK-4. Vitamin K is
important cofactor for a specific carboxylation reaction that
selectively transforms glutamate residues to
-carboxygluta-
mate residues. Four procoagulants depend on vitamin K –
(prothrombin – factor II and factors VII, IX and X). All of
them are serine proteases synthesized in the liver (Fig. 15).
Vitamin K is metabolized in the liver and excreted in the
urine and bill as a water soluble conjugates, mainly with
glucuronic acid [228].
56 Current Pharmaceutical Analysis, 2009, Vol. 5, No. 1
karbamoyl-phosphate dihydroorotate
mitochondrion ROS
cytochrome-c
anti-apoptic genes
Bcl-2, Bcl-xL
APOPTOSIS caspase-3
Fig. (16). Different mechanisms of 1,4-naphthoquinone derivates cytotoxic effect – inhibition of orotate synthesis (1), inhibition of
thymidine incorporation to DNA (2), inhibition of DNA replication by topoisomerase I and/or topoisomerase II cleavage (3), reactive oxygen
species (ROS) generation and mitochondrion damage with down-regulation of antiapoptic genes and releasing of apoptosis inducing factor.
Naphthoquinones and Interactions Between Plants
Naphthoquinones, especially juglone, are widely studied
for allelopathic activity. Massey in 1925 hypothesized that
inhibitory effect of black walnut (Juglans nigra L.) on
growth of some associated species caused compound exuded
by roots. This compound was determined in 1928 by Davis
as juglone. Juglone, as well as other naphthoquinones, is able
to release to environment through disintegration of necrotic
plant tissues, may persists in the soil and can be attributed to
phytotoxicity. Growth inhibition and interaction by naphtho-
quinones has been reported for numerous plant species [229-
231]. Mechanisms of plant growth reduction by juglone ba-
sis in decrease of H +-ATP-ase activity in corn and soybean
root microsomal fraction [232], inhibition of p-hydroxy-
phenylpyruvate dioxygenase (the crucial enzyme of plas-
toquinone synthesis), inhibition of electron transport in mito-
chondria and chloroplasts [233], decrement photosynthesis in
leaf tissues and transpiration and stomatal conductance inhi-
bition [234] and reduction of water reuptake by the roots
[232]. Induction of reactive oxygen species (ROS) may play
a critical role in the protection of plants against pathogens
[235]. Plumbagin tested in in vitro plant cell models induces
polyploidy, micronuclei formation and chromosomal disor-
ders (root tips of Allium cepa) [236].
Pharmacological Properties of Napthoquinones
Naphthoquinones, such as plumbagin, lapachol or bis-
naphthoquinoid diospyrin, have an interesting potential as a
cytostatic agents. Naphthoquinone-induced cell death has
been determined in many cell including cancer cell lines -
HEPA-3B, COLO-25, A-459, ME-180, HaCaT and HeLa
[237-242]. The cytotoxic effect of these compounds is based
on generation of reactive oxygen species and apoptosis in-
duction. Plumbagin-induced apoptosis involved release of
Babula et al.
CTP
1.
orotate
dTTP
2.
O
intercalation
DNA
O
3.
BAX p53
APAF-1 replication
caspase-9 IAP1,2
mitochondrial cytochrome c and apoptosis inducing factor
(AIF). Activation of caspase-dependent (especially caspase-
3) and caspase–independent pathways by plumbagin, but
also shikonin has been also demonstrated [241, 243, 244].
Plumbagin and shikonin inhibits activation of NF-kappa B
pathway by tumour necrosis factor (TNF), carcinogens and
other inflammatory stimuli (hydrogen peroxide, cigarette
smoke condensate etc.) [245, 246]. It was confirmed that
inhibition of tumour necrosis factor alpha by shikonin is
based on selective blocade of Pre-mRNA splicing [247].
Plumbagin down-regulates the expression of NF-kappa B-
regulated anti-apoptotic (IAP1, IAP2, Bcl-2, Bcl-xL, cFLIP,
Bfl-1/A1, and survivin), proliferative (cyclin D1 and COX-
2), and angiogenic (matrix metalloproteinase-9 and vascular
endothelial growth factor) gene products [248]. This may
explain its cell growth modulatory, anticarcinogenic, and
radiosensitizing effects previously described in Ref. No.
[248, 249]. A following essays indicate that plumbagin
blocks of cell cycle in association with increased levels of
p21 protein and reduced amounts of cyclinB1, Cdc2, and
Cdc25C. Treatment of tumour cells increases the activation
of apoptosis signal-regulating kinase 1 and extracellular sig-
nal regulate kinase 1/2 and c-Jun N-terminal kinase and also
enhances the levels of inactivated phosphorylated Cdc2 and
Cdc25C [250, 251]. Synergic antitumour effect of plumbagin
may be also connected with inhibion of efflux of cytostatic
drug mitoxanthrone by multidrug resistance-linked ATP
binding cassette drug transporter (ABCG2) [252]. Cytotoxic
properties of naphthoquinones can be enhanced by inhibition
of thymidin incorporation to DNA of cancer cells [253], in-
hibition of dihydroorotate dehydrogenase [254, 255], oxida-
tive DNA damage [256], intercalation to DNA and mammal-
ian topoisomerase I or II DNA-cleavage (Fig. 16) [257-261].
Juglone in some work that has been recently published dem-
onstrated ability to interfere with processes of mitosis. They
Noteworthy Secondary Metabolites Naphthoquinones
can inactivate cysteine-rich proteins (parvulins) that are es-
sential in mitosis progression [262]. Inhibition role in mitosis
has also plumbagin; this naphthoquinone disrupts microtu-
bule network, in more details inhibits tubuline polymeriza-
tion [263]. Various novel synthetic naphthoquinone derivates
with interesting anticarcinogenic properties have been pre-
pared [264-280].
Antimicrobial activities of naturally occurring naphtho-
quinones have been investigated. Plumbagin, juglone and
lawsone demonstrated this effect on Streptococcus,
Prevotella, Peptostreptococcus, Mycobacterium, Clostrid-
ium, Helicobacter and Escherichia [143, 281, 282], lapachol
on Kleibsiella, Proteus, Helicobacter and Streptococcus
[283, 284]. Other naphthoquinones have also antibiotic activ-
ity [285]. Shikonin and its derivates is potent antifungal
compound against Candida and Saccharomyces [286]. Syn-
thetic derivates can be potentially antibacterial and antifun-
gal compounds [287-293]. Lapachol and furanonaphthoqui-
nones has inhibitory effect on Epstein-Barr virus activation
[1, 294, 295], some intricately substituted naphthoquinones
have inhibitory activity against HIV [218, 296], inhibit HIV-
1 integrase [297] and RNAse-H activity associated with
HIV-1 reverse transcriptase [298].
Monomer and dimeric, natural and synthetic naphthoqui-
nones showed in in vitro and in in vivo tests activity against
Leishmania [299-304], Pneumocystis [3], Trypanosoma
[299, 301, 305], Trichomonas [301] and Plasmodium [10].
Other described pharmacological activities of naphthoqui-
nones are anti-inflammatory [165, 306], cardiotonic and
ionotropic [307, 308], antikoagulation [309, 310], hypolipi-
demic (the mechanisms is probably based on inhibition of
cholesterol acyltransferase) [311, 312], spasmolytic [313],
antifertility and antigonatropic [120, 314-317].
NAPHTHOQUINONES ANALYSIS
Extraction of Naphthoquinones
Number of authors has extracted naphthoquinones by
various organic solvents using different extraction condi-
tions, such as temperature. The most frequent used solvent
for naphthoquinones extraction is methanol [167, 197]. Some
works indicate that methanol is the most suitable solvent to
obtain the highest extraction yields, but hexane provides high
recovery with highest degree of naphthoquinones purity
[318]. Other, less frequently used solvents are dichlor-
methane [183], chloroform [114, 156], petrol [137] or buta-
nol [134], eventually ethanol [319].
Conventional methods, as maceration or hot extraction,
are widely used to obtain plant extracts. Some articles com-
pared different available techniques. Extraction in Soxhlet
apparatus for 5 hours demonstrates the highest efficiency to
plumbagin isolation from dried roots of Plumbago scandens
in the confrontation with static maceration or dynamic mac-
eration [123]. Naphthoquinones juglone, plumbagin and syn-
thetic 1,4-naphthoquinone demonstrate good solubility in
supercritical CO2 [320]. Sonification can be an extraordinary
technique for naphthoquinone extraction from plant material
because some naphthoquinones are heat-labile. The sonifica-
tion also allows use of low volumes of the extraction sol-
vents.
Current Pharmaceutical Analysis, 2009, Vol. 5, No. 1 57
The highest yield of naphthoquinones was obtained using
methanol and the lowest using n-hexane. Chloroform was
employed as suitable solvent for naphthoquinones extrac-
tions too [7, 104, 114, 321]. The yield of naphthoquinones
depends on temperature – for example yield of juglone sig-
nificantly decrease with increasing temperature [7, 104,
321]. Very important problem may be the ability of some
naphthoquinones, such as alkannin or shikonin, to subject to
some transformations during extraction processes, such as
photochemical or thermal degradation and especially polym-
erization; these processes can importantly decrease the re-
covery of these naphthoquinones [322].
The solvent is often evaporated to obtain dry residue con-
taining naphthoquinones, which is consequently dissolved in
other solvent and analysed [114]. In addition, very simple
methods of plumbagin isolation were developed – cold mac-
eration of dry material by acetone in connection with precipi-
tation by water, redissolution in chloroform and separation
using column chromatography. In addition, plubagin ability
to sublime at 90°C can be used in its isolation from plant
material [323].
Analytical Techniques for Detection of Napthoquinones
High performance liquid chromatography with UV/VIS
detection (HPLC-UV/VIS), especially normal-phase HPLC-
UV/VIS or eventually liquid chromatography-tandem mass
spectroscopy is one of the most commonly used techniques
for naphthoquinone determination and characterization in
biological samples [324, 325]. Optimization of detecting
conditions of naphthoquinone derivates depends on kind of
compound. The most used analytical columns are C18 col-
umns, but some authors favour C8 column because of resolu-
tion advance [324, 326]. Some naphthoquinones, particularly
isohexenyl-naphthoquinone derivatives (alkannin, acetyl-
alkannin, deoxyalkannin etc.), can not be separated by nor-
mal-phase or reverse-phase because of the fact that the pair
of isomers coeluted as a mixture or as single component, but
only by ion-pair method with tetramethylammonium chlo-
ride and nonylamine as the ion-pair reagent. These naphtho-
quinones could not be eluted from the column by the normal-
phase and reverse-phase (various compositions of methanol-
water and acetonitrile-water) [327]. Optical isomers shikonin
and alkannin can be separated by chiral phase high perform-
ance liquid chromatography, high performance liquid chro-
matography in connection with atmospheric pressure chemi-
cal ionization quadrupole mass spectrometry [328], high
performance liquid chromatography in connection with pho-
todiode array/mass spectrometry method [329] or high-speed
counter-current chromatography [182, 328, 330]; these tech-
niques may be used also in purification of alkannin and
shikonin [328]. They have usually UV absorption at 214, 275
and 520 nm [185]. There was also described technique based
on capillary electrophoresis with high freequency conductiv-
ity detection for shikonin determination in biological sam-
ples [176]. HPLC is the effective method for detection of
lapachol,
-lapachone and other isomers too [331], but utiliz-
ing the chiral columns for quality resolution is necessary
[332]; some advantages brings using of counter-current
chromatography in lapachol and its derivates determination
[333]. Normal-phase liquid chromatography is a simple and
rapid method for the determination for pharmacological im-
58 Current Pharmaceutical Analysis, 2009, Vol. 5, No. 1
Fig. (17). HPLC-UV/VIS and electrochemical chromatograms standards (left) and Nepenthes real samples (right). HPLC conditions were as
follows: mobile phase: 0.1 mol.l-1 acetic acid:methanol in ratio of 35:65 (%,v/v) except; flow rate: 0.75 ml.min -1; temperature: 42°C. Chroma-
tograms were registered at 260 nm and at applied potential 900 mV.
portant plumbagin and other naphthoquinones, such as
juglone and lawsone. As the mobile phase mixtures n-
hexane, chloroform and 2-propanol [334, 335] or methanol
and acetic acid are used [94, 336]. Typical HPLC-UV/VIS
chromatogram of naphthoquinones is shown in Fig. (17).
The compounds of interest are well separated and analysed
within 30 minutes. Moreover, detection limits of the tech-
nique enable us to employ it for analysing of a real sample
(Table 2). This fact is well demonstrated on chromatogram
of extract from Nepenthes plant, where we can easily identi-
fied and quantified plumbagin. Rapid techniques of plum-
bagin determination in plant and soil samples by thin layer
chromatography were developed [337] or high performance
thin layer chromatography [338].
The electrochemical techniques have been utilizing
mainly to study of naphthoquinones chemical interactions
(particularly naphthoquinone-amino acid or protein interac-
tion) [339-345], but not for determination in biological sam-
ples or plant material. Electrochemistry, such as cyclic volt-
ammetry, is also good tool to study menadione (vitamin K3)
and its chemical interactions [346, 347]. Cyclic voltammetry,
chronoamperometry and chronopotentiometry at the surface
of Au, Pt and glassy carbon electrodes are good tools to
study of some naphthoquinones (such as plumbagin) in
Babula et al.
aprotic solvents [348]. Cyclic voltammetry was used in one
study to determine the toxicity of different alkannin derivates
by monitoring of their ability to induce reactive oxygen spe-
cies [349]. Some naphthoquinones, such as plumbagin,
juglone or lawsone, may be analysed very sensitively by
differential pulse voltammetry coupled with hanging mer-
cury drop and carbon paste electrodes and by injection
analysis coupled with carbon printed electrode. Electro-
chemical methods are suitable for the construction of the
miniaturized sensors and biosensors [350-352]. Besides this
electrochemical detector coupled with liquid chromatogra-
phy (HPLC-ED) is an attractive alternative method for elec-
troactive species detection, because of its inherent advan-
tages of simplicity, ease of miniaturization, high sensitivity
and relatively low cost. HPLC-ED has been many times suc-
cessfully utilized for determination of plant secondary me-
tabolites as flavonoids [353, 354]. The electrochemical de-
tector is also suitable for determination of naphthoquinones
not only as standards but also in real samples (Table 2 and
Fig. 17). Therefore, we employed this technique to quantify
plumbagin in extracts from Nepenthes plants (Fig. 18). Con-
tent of plumbagin varied in different plant tissues. The high-
est content was determined in apex and the lowest ones in
petiole. There have been also used for analysis of naphtho-
quinones micellar electrokinetic chromatography [355],
Noteworthy Secondary Metabolites Naphthoquinones Current Pharmaceutical Analysis, 2009, Vol. 5, No. 1 59

Table 2. HPLC with UV/VIS and Electrochemical Detection (ED) Characteristics of Analysed Naphthoquinones (n = 5)

LOD LOQ R.S.D.

Naphthoquinone tR (min) a Equationb,c R2
(ng.ml-1) d (ng.ml-1) d (%)e

y = 0.5185x + 0.1097* 1.0000* 10* 33* 2.9*

Lawsone 3.05
y = 1.4701x + 2.8418** 0.9965** 1** 3** 3.9**

y = 0.7451x + 0.0882* 0.9999* 15* 50* 2.3*

1,4-naphthoquinone 3.78
y = 0.0334x - 22.669** 0.9901** 2** 7** 4.2**

y = 0.8126x - 0.5371* 0.9971* 10* 33* 2.0*

Juglone 4.27
y = 0.5235x + 3.3759** 0.9933** 1** 3** 4.1**

y = 0.5141x - 0.3141* 0.9996* 40* 133* 1.1*

Plumbagin 7.49
y = 0.4196x + 0.7479** 0.9974** 5** 17** 3.6**

2,2-(3-hydroxy)-1,4- y = 0.5141x - 0.3141* 0.9996* 90* 300* 4.6*

9.51
naphthoquinone y = 0.006950x + 0.3329** 0.9965** 15** 50** 6.9**
a
… Retention time.
b
… The concentration range was from 50 to 5,000 μg.ml-1.
c
… The equation was derived from the dependence of the peak area on the naphthoquinone concentration.
d
… The detection limits (LOD, 3 S/N) and quantification limits (LOQ, 10 S/N) were calculated according to Long [359], whereas N was expressed as
standard deviation of noise determined in the signal domain.
e
… Relative standard deviation (R.S.D.).
*
… HPLC-UV/VIS.
**
… HPLC-ED.

Fig. (18). Content of plumbagin in tissues of Nepenthes plants. The tissues were processed according to [336]. Particularly, the tissues were
extracting for 24 hours in methanol, then centrifuged and filtered prior to HPLC-ED analysis. Plumbagin content 140
M corresponds to
100 %.

spectrophotometric methods coupled with mathematical plumbagin [357]. There is one work utilizing plumbagin for
processing of data [356] and enzyme-linked immunosorbent glassy carbon electrode modification for determination of
assay using highly-specific monocloal antibodies against electrocatalytic oxygen reduction [358].
60 Current Pharmaceutical Analysis, 2009, Vol. 5, No. 1
ACKNOWLEDGEMENTS
Financial support from the grant IGA MZ 1A/8666-3,
1M06030 and FRVS A No. 280371 are greatly acknowl-
edged.
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Accepted: 14 October, 2008