Noteworthy Secondary Metabolites Naphthoquinones - IngentaConnect

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teresting compounds derived from naphthalene – 1,4-naphthoquinones and rarely also 1,2-naphthoquinones. They were detected in many species of families ...
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 interesting 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 especially 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 Spectrometry. INTRODUCTION Naphthoquinones are one of the groups of secondary metabolites 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 (Streptomyces) [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 biosynthesized 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 physiological roles – ubiquinone, plastoquinone and K vitamins are functional constituents of biochemical systems. Naphthoquinones 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 investigators in these compounds is due to their broad-range of biological 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 Republic; Tel: +420-5-4513-3350; Fax: +420-5-4521-2044; E-mail: [email protected] 1573-4129/09 $55.00+.00

parasitic and cytotoxic activities emerge due to their ability 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 biomolecules, and as producers of reactive oxygen radicals by redox cycling under aerobic conditions. Naphthoquinones, especially juglone, are widely studied for allelopathic activity. Plants with naphthoquinone content are world-wide used in the traditional medicines of countries where they grow. Naphthoquinones are highly toxic. Moreover, 1,4-naphthoquinone 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 detection 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 (1,2naphthoquinones). 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, acetone, chloroform, benzene, DMSO and acetic acid, plumbagin and juglone are slightly soluble in hot water. The simplest, and in the nature the most widespread naphthoquinones, are juglone, lawsone, plumbagin and lapachol (Table 1).

© 2009 Bentham Science Publishers Ltd.

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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

174.14

155

174.15

192 – 195

188.18

78 – 79

172.18

105 – 107

190.16

237

206.17

164 – 168.5

288.30

Not available

242.27

141 – 143

5-hydroxy-1,4-naphthoquinone

R3 = -OH

(juglone) 2-hydroxy-1,4-naphthoquinone

R1 = -OH

(lawsone) 5-hydroxy-2-methy-1,4naphthoquinone

R1 = -CH3, R3 = -OH R6

(plumbagin)

O R1

R5

2-methyl-1,4-naphthoquinone

R1 = -CH3

(menadion)

R2

R4 R3

O

5,8-dihydroxy-1,4-naphthoquinone

R3, R6 = -OH

(naphtazalin) R1, R3, R5 = -OH

2,5,7-trihydroxy-1,4-naphthoquinone (flaviolin)

R1 = CHOHCH2CH=C(CH3) 2

5,8-dihydroxy-2-(1-hydroxy-4-methylpent-3-enyl)-1,4-naphthoquinone

R3, R6 – OH

(shikonin)

R1 = -OH

2-hydroxy-3-(3-methyl-but-2-enyl)-1,4naphthoquinone

R2 = -CH2CH=C(CH3) 2

OH

(lapachol)

O

O

O

OH CH3

CH3 CH3O

CH3O

O

OH

solaniol

OH fusarubin

OH O

CH3

CH3 O

O

bostrycoidin

OH

OH

O

OH

N OH

OH

CH3O

O

CH2OH O

CH3

CH3O O

OH

HO O

OH

O

novarubin

biflaviolin

O

OH

Fig. (1). Selected fungal naphthoquinone metabolites.

NAPTHOQUINONES IN NATURE Actinomycetes and Fungi The ability of naphthoquinone synthesis is widespread among fungal organisms. The complete list of fungi producers 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-

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

Current Pharmaceutical Analysis, 2009, Vol. 5, No. 1

O

O

5 malonyl-CoA

OH

O

S-CoA

S-CoA COOH

O

O

49

COOH

HO

O

O -CO2

OH

OH

O

flavioline

OH

HO

OH

HO

OH

naphthalene-1,3,6,8-tetraol

O

Fig. (2). Mevalonate pathway of flaviolin biosynthesis.

OH

O

OH

CH3 O

H3C O

OH CH3

H3C

HO OH

O

naphthazarin

OH

O OH

O OH

OH O

OH

hybocarpone

Fig. (3). Naphthazarin and hybocarpone.

nones biosynthesis was investigated using 14C and 3H labelled acetate or methyl group of methionin. This data indicate that synthesis of naphthoquinones proceeds via the formation of a precursor. This precursor is product of the acetate/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 leukaemia and HeLa cells. Antibiotic activity is manifest especially against Gram-positive bacteria [26]. Antibacterial activity 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 biosynthesis of proteins, lipids and transport of glucose. Fungal naphthoquinones are capable of redox conversions, whereas their antibiotic, cytotoxic and phytotoxic effect are due to interactions 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 naphthoquinone toxicity by metabolic modification, such as phosphorylation or acetylation [29]. Many naphthoquinones exhibit the properties of mycotoxins (in Penicillium, Aspergillus, Microsporium and Trichophyton) [30]. Actinomycetes (genus Streptomyces) are the producers of substitute isoprene-derived naphthoquinones. Structurally

simple redish-brown pigment flaviolin (Fig. 2) originates in the presence of rppA gene via malonate pathway and represents 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. Aliphatic acids, pulvinic acid, depsides, depsidones, dibenzofurans, anthraquinones and also naphthoquinones were described as compounds responsible for these activities [4751]. 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 naphthoquinone 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 recorded in genera Catalpa [55], Heterophragma [56, 57], Kigelia [58-61], Macfadyena [62], Mansona [2], Markhamia [63, 64], Newbouldia [65-70], Oroxylum [71, 72], Radermachera [73], Stereospermum [74], Tabebuia [3, 75, 76] and

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O

O

O

O

O OH

O -lapachone

OH O

O

9-hydroxy--lapachone

lapachol

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

COOH

COOH

COOH COOH

COOH

+ HOOC HO

OH

-ketoglutaric acid

shikimic acid

O

O

O

OH

o-sukcinylbenzoic acid

droserone, juglone

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

O

OH

OH

O

plumbagin

OH

O

CH3 H3C

O

OH

7-methyljuglone

CH3

OH

OH OH

O

droserone

O

O diomuscione

O

H3C

OH O

O

hydroxydroserone

O O

O

CH3

CH3

CH3

OH muscipulone

OH

O

O

OH

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 carnivorous 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 7methyljuglone. 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. longifolia, D. peltata, D. ramentacea, D. rotundifolia and D. whitakeri [96, 97]. The other Drosera species contain alternative monomeric naphthoquinones, such as droserone, 7-methyljuglone and their glycosides and dimeric naphthoquinones (Fig. 5) [98]. They are also produced in in vitro cultures [99106]. Two compounds biosynthetically connected with plumbagine, diomuscione and muscipulone, were identified in Dionaea muscipula [107]. Droserone or juglone are naphthoquinones 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 synthesis of shikimic acid trough aromatic amino-acid L-

Noteworthy Secondary Metabolites Naphthoquinones COOH

Current Pharmaceutical Analysis, 2009, Vol. 5, No. 1 COOH

COOH COOH

shikimate kinase

+ HO

OH

HO

51

P

O

chorismate synthase

CH2

CH2

OP

O

OH

OH

shikimate

shikimate 3-phosphate

COOH

OH phosphoenolpyruvate

chorismate chorismate mutase

COOH

COOH

HOOC

prephenate aminotransferase

COOH

O NH2

HO

OH

glutamate

a-ketoglutarate

arogenate

prephenate

4-hydroxyphenylpyruvate arogenat dehydratase

NADPH+H

arogenatdehydrogenase phenylalanine

H2O, CO2

NADP Phenylalanine and Tyrosine, pathway in yeast and E. coli

alkaloids COOH

transamination

COOH

NH2

HO

O

L-tyrosine phenylpyruvate

O2 CO2 OH

OH COOH

OH homogentisate

H3C

CH3 +

OH CH3

C5

OH

O CH3

CH3 H3C

OH

O 1,4-naphthoquinone (droserone, 7-methyljuglone)

toluquinone

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. Antiinflammatory effect was found out too [108]. Nature medicine 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 rubefacient and vesicant [109]. Juglandaceae North temperate and subtropical family Juglandaceae extending 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 examined plants. Naphthoquinones, bisnaphthoquinones and trisnaphthoquinones (plumbagin, chitranone, maritinone, elliptinone and isoshinanolon) [115-118] and plumbagic acid with two glucosides [116] have been isolated from this semiclimbing subshrub (Fig. 8). The whole plant and the roots are used in folk medicine in Thailand for the treatment of carbuncle, ulcers, injuries,

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OH

O

O

O

CH3

H3C OH

O

OH

O

CH3 OH

O O

O

OH

O

CH3

CH3

CH3

O

OH

chitranone

O

O

elliptinone

maritinone

Fig. (8). Naphthoquinones of Plumbago zeylanica. OH

OH

O

O

O

O

OH

CH3 OH

O

H3C

H3C

O

O H3C

OH

O

O

H3C

O

O

diospyrin

O

O

isozeylanone CH3

OH

HO

OH

O

O

OH O

8´-hydroxyisodiospyrin O

OH H3C

CH3

CH3

OMe OH

O

OMe

O H3C

O

diosindigo A

OH

O CH3

3,3´- biplumbagin

O OH

O CH3 chitranone

O

OH

O

2,3-epoxyplumbagin

Fig. (9). Napthoquinones of different Diospyros species: 8´-hydroxyisodiospyrin, diospyrin (D. assimilis, D. montana, D. paniculata), diosindigo 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 diarrhoea, 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. scandens) as well as their in vitro cultures (callus, suspension, immobilised cells and hairy root cultures) produce plumbagin and other naphthoquinones too [11, 12, 122-133]. Plumbagin, its glycosides and derivates, shinanolon and epiisoshinanolon, have been detected in extracts of Ceratostigma 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-naphthoquinones 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 folklore 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 different Euclea species are used for various purposes, such as toothbrushes, hypnotic, for toothache and headache by people of South Africa. All naphthoquinones of genus Euclea have potent antituberculosis activity, especially 7-methyljuglone [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 +

Current Pharmaceutical Analysis, 2009, Vol. 5, No. 1

OH

OH

O

COOH

OH

O

53

OH

C10

COOH

p-hydroxybenzoic acid

alkannin

Fig. (10). Combined shikimate/mevalonate pathway of alkannin biosynthesis.

colouring matter – lawsone – and various phenolic compounds, 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 shikimate/mevalonate pathway (Fig. 10). The reported naphthoquinone constituent of genus Lithospermum is shikonin. Roots of L. erythrorhizon are widely used for shikonin isolation and are produced for cosmetic and pharmaceutical industries in Japan [4, 165]. In vitro plant cell suspension cultures stimulated by specific oligogalacturonides, ethylene [168, 169], ultrasound [170] and low-dose gamma irradiation [171]. Transformed organ cultures are used for shikonin production too [172-175]. Other species widely utilised in Chinese 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 hormonal 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 colouring 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,

CH3 OH

O

alkannan: R

H

OH

CH3 CH3

alkannin: H OH

O

OH

CH3 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 Macrotomia 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 confirmed. In addition to that larvicidal meroterpenoid naphthoquinones were isolated from roots of Cordia linnae [183]; roots of other species – Cordia corymbosa and C. curassavica – contain sesquiterpenic (meroterpenoid) napthoquinones – 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 (Rubiaceae with important genera Galium and Rubia) contain naphthoquinones or similar compounds [186, 187]? Nepenthaceae Family Nepenthaceae with 70 species at 2 genera includes carnivorous plants with specialized leaves as passive traps - pitchers. Naphthoquinones are characteristic compounds of these plants. Plumbagin, isoshinanolone, epishinanolone, shinanolone, quercetin and kaempferol were isolated 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 Lalanine 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

CoASH+NAD+

-ketoglutarate H3C

Babula et al.

glutamate

COOH

H3C

H3C

SCoA

pyruvate-dehydrogenase

alanine-aminotransferase

NH2

CO2+NADH

COOH O

O acetyl CoA

pyruvate

L-alanine

6x

OH

O

OH

O

OH

O

O

reduction,aldol condensation

oxidation

SCoA decarboxylation CH3

CH3

O O

O

CH3

O plumbagin

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

CH3

O

O

O

R

R O

OH

R O

O

balsaminol - R = -OH balsaminolate - R = -ONa

impatienol - R = -OH impatienolate - 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. balsamina, 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 several types of dermatitis including urticaria. The main active compounds were determined derivates of 1,4-naphthoquinone, 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], Annonaceae (roots of Goniothalamus cheliensis) [203], Dioncophyllaceae 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-1,4naphthoquinone) [209], Iridaceae (Aristea, Eleutherine bulbosa and E. americana – eleutherinon, eleutherin, isoeleutherin and their derivates) [210-212], Liliaceae (naphthol-naphthoquinone derivates such as imbricatonol isolated from Stypandra imbricata and Dianella revoluta) [213, 214], Malvaceae (genus Hibiscus with very rare derivates of 1,2naphthoquinones 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 (5,8dihydro-2,7-dimethyl-1,4-naphthoquinone from the roots of

Noteworthy Secondary Metabolites Naphthoquinones

pyruvate + CO2 2-oxoglutarate

COOH OH

Current Pharmaceutical Analysis, 2009, Vol. 5, No. 1

OH COOH

COOH

- H2O

COOH

COOH

COOH O

55

CH2 O 2-sukcinylbenzoate

O 6-hydroxy-2-sukcinylcyklohexa-2,4-dienkarboxylate

izochorismate

HS-CoA

OH

O

ATP + HS-CoA

H

AMP + PPi COOH

COOH

CO-S-CoA CH3 O

OH

O

1,4-dihydroxy-2-naphtoate

n = 2 - phylloquinone (vitamin K1) n = 1 - 13 - menaquinone (vitamin K2)

4-(2-karboxyphenyl)-4oxobutanoyl-CoA

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

NAD(P)H

OH

O H Any N

H

3.

2-RSH

N H

CH3

RS-SR OH

O

CO2H

vitamin K - quinol H

1. O2, CO2

protrombin precursor

CH3 O vitamin K O 2.

H O

2-RSH

CH3

RS-SR

O vitamin K - 2,3-epoxide

H Any N

O N H CO2H CO2H

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-naphthoquinone and the corresponding acetate, 2-acetoxy-3-(1,1dimethylprop-2-enyl)-1,4-naphthoquinone [222, 223]; Capraria biflora – biflorin [224], Paulownia tomentosa with the low content of plumbagin [94]), Verbenaceae (Lippia microphylla – prenylated naphthoquinone dimer, mixture of 6-methoxyand 7-methoxy-naphtho[2,3-b]-furan-4,9quinones and tecomaquinone from the roots) [225] and Zygophyllaceae (larreantin from the root of Larrea tridentata) [226]. VITAMINS OF K GROUP – A STRUCTURAL ANALOGUES 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 synthesized 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 (2methyl-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 -carboxyglutamate 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].

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1. karbamoyl-phosphate

dihydroorotate

orotate dTTP

2.

O

mitochondrion

intercalation

ROS

DNA

O 3. cytochrome-c anti-apoptic genes Bcl-2, Bcl-xL

BAX

APAF-1

APOPTOSIS

caspase-3

caspase-9

p53

replication

IAP1,2

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 naphthoquinones has been reported for numerous plant species [229231]. Mechanisms of plant growth reduction by juglone basis in decrease of H +-ATP-ase activity in corn and soybean root microsomal fraction [232], inhibition of p-hydroxyphenylpyruvate dioxygenase (the crucial enzyme of plastoquinone synthesis), inhibition of electron transport in mitochondria and chloroplasts [233], decrement photosynthesis in leaf tissues and transpiration and stomatal conductance inhibition [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 disorders (root tips of Allium cepa) [236]. Pharmacological Properties of Napthoquinones Naphthoquinones, such as plumbagin, lapachol or bisnaphthoquinoid 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 induction. Plumbagin-induced apoptosis involved release of

mitochondrial cytochrome c and apoptosis inducing factor (AIF). Activation of caspase-dependent (especially caspase3) 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 Bregulated anti-apoptotic (IAP1, IAP2, Bcl-2, Bcl-xL, cFLIP, Bfl-1/A1, and survivin), proliferative (cyclin D1 and COX2), 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 signal 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], inhibition of dihydroorotate dehydrogenase [254, 255], oxidative DNA damage [256], intercalation to DNA and mammalian topoisomerase I or II DNA-cleavage (Fig. 16) [257-261]. Juglone in some work that has been recently published demonstrated ability to interfere with processes of mitosis. They

Noteworthy Secondary Metabolites Naphthoquinones

can inactivate cysteine-rich proteins (parvulins) that are essential in mitosis progression [262]. Inhibition role in mitosis has also plumbagin; this naphthoquinone disrupts microtubule network, in more details inhibits tubuline polymerization [263]. Various novel synthetic naphthoquinone derivates with interesting anticarcinogenic properties have been prepared [264-280]. Antimicrobial activities of naturally occurring naphthoquinones have been investigated. Plumbagin, juglone and lawsone demonstrated this effect on Streptococcus, Prevotella, Peptostreptococcus, Mycobacterium, Clostridium, Helicobacter and Escherichia [143, 281, 282], lapachol on Kleibsiella, Proteus, Helicobacter and Streptococcus [283, 284]. Other naphthoquinones have also antibiotic activity [285]. Shikonin and its derivates is potent antifungal compound against Candida and Saccharomyces [286]. Synthetic derivates can be potentially antibacterial and antifungal compounds [287-293]. Lapachol and furanonaphthoquinones has inhibitory effect on Epstein-Barr virus activation [1, 294, 295], some intricately substituted naphthoquinones have inhibitory activity against HIV [218, 296], inhibit HIV1 integrase [297] and RNAse-H activity associated with HIV-1 reverse transcriptase [298]. Monomer and dimeric, natural and synthetic naphthoquinones 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 naphthoquinones are anti-inflammatory [165, 306], cardiotonic and ionotropic [307, 308], antikoagulation [309, 310], hypolipidemic (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 conditions, 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 dichlormethane [183], chloroform [114, 156], petrol [137] or butanol [134], eventually ethanol [319]. Conventional methods, as maceration or hot extraction, are widely used to obtain plant extracts. Some articles compared 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 maceration [123]. Naphthoquinones juglone, plumbagin and synthetic 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 sonification also allows use of low volumes of the extraction solvents.

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57

The highest yield of naphthoquinones was obtained using methanol and the lowest using n-hexane. Chloroform was employed as suitable solvent for naphthoquinones extractions too [7, 104, 114, 321]. The yield of naphthoquinones depends on temperature – for example yield of juglone significantly 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 polymerization; these processes can importantly decrease the recovery of these naphthoquinones [322]. The solvent is often evaporated to obtain dry residue containing naphthoquinones, which is consequently dissolved in other solvent and analysed [114]. In addition, very simple methods of plumbagin isolation were developed – cold maceration of dry material by acetone in connection with precipitation 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 HPLCUV/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 columns, but some authors favour C8 column because of resolution advance [324, 326]. Some naphthoquinones, particularly isohexenyl-naphthoquinone derivatives (alkannin, acetylalkannin, deoxyalkannin etc.), can not be separated by normal-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 chloride and nonylamine as the ion-pair reagent. These naphthoquinones could not be eluted from the column by the normalphase and reverse-phase (various compositions of methanolwater and acetonitrile-water) [327]. Optical isomers shikonin and alkannin can be separated by chiral phase high performance liquid chromatography, high performance liquid chromatography in connection with atmospheric pressure chemical ionization quadrupole mass spectrometry [328], high performance liquid chromatography in connection with photodiode array/mass spectrometry method [329] or high-speed counter-current chromatography [182, 328, 330]; these techniques 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 conductivity detection for shikonin determination in biological samples [176]. HPLC is the effective method for detection of lapachol, -lapachone and other isomers too [331], but utilizing 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

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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. Chromatograms 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 nhexane, 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 technique 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 identified and quantified plumbagin. Rapid techniques of plumbagin 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 interaction) [339-345], but not for determination in biological samples or plant material. Electrochemistry, such as cyclic voltammetry, 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

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 species [349]. Some naphthoquinones, such as plumbagin, juglone or lawsone, may be analysed very sensitively by differential pulse voltammetry coupled with hanging mercury drop and carbon paste electrodes and by injection analysis coupled with carbon printed electrode. Electrochemical methods are suitable for the construction of the miniaturized sensors and biosensors [350-352]. Besides this electrochemical detector coupled with liquid chromatography (HPLC-ED) is an attractive alternative method for electroactive species detection, because of its inherent advantages of simplicity, ease of miniaturization, high sensitivity and relatively low cost. HPLC-ED has been many times successfully utilized for determination of plant secondary metabolites as flavonoids [353, 354]. The electrochemical detector 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). Content of plumbagin varied in different plant tissues. The highest content was determined in apex and the lowest ones in petiole. There have been also used for analysis of naphthoquinones 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)

a b c d

e * **

Naphthoquinone

tR (min) a

Lawsone

3.05

1,4-naphthoquinone

3.78

Juglone

4.27

Plumbagin

7.49

2,2-(3-hydroxy)-1,4naphthoquinone

9.51

… … … … … … …

Equationb,c

R2

LOD (ng.ml-1) d

LOQ (ng.ml-1) d

R.S.D. (%)e

y = 0.5185x + 0.1097*

1.0000*

10*

33*

2.9*

y = 1.4701x + 2.8418**

0.9965**

1**

3**

3.9**

y = 0.7451x + 0.0882*

0.9999*

15*

50*

2.3*

y = 0.0334x - 22.669**

0.9901**

2**

7**

4.2**

y = 0.8126x - 0.5371*

0.9971*

10*

33*

2.0*

y = 0.5235x + 3.3759**

0.9933**

1**

3**

4.1**

y = 0.5141x - 0.3141*

0.9996*

40*

133*

1.1*

y = 0.4196x + 0.7479**

0.9974**

5**

17**

3.6**

y = 0.5141x - 0.3141*

0.9996*

90*

300*

4.6*

y = 0.006950x + 0.3329**

0.9965**

15**

50**

6.9**

Retention time. The concentration range was from 50 to 5,000 μg.ml-1. The equation was derived from the dependence of the peak area on the naphthoquinone concentration. 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. 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 processing of data [356] and enzyme-linked immunosorbent assay using highly-specific monocloal antibodies against

plumbagin [357]. There is one work utilizing plumbagin for glassy carbon electrode modification for determination of electrocatalytic oxygen reduction [358].

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ACKNOWLEDGEMENTS Financial support from the grant IGA MZ 1A/8666-3, 1M06030 and FRVS A No. 280371 are greatly acknowledged.

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Noteworthy Secondary Metabolites Naphthoquinones [45]

[46]

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Noteworthy Secondary Metabolites Naphthoquinones [135]

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[139]

[140]

[141]

[142]

[143]

[144]

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Revised: 25 August, 2008

Accepted: 14 October, 2008