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Naturally occurring plant isoquinoline N-oxide alkaloids: their pharmacological and SAR activities.

ABSTRACT

The present review describes research on novel natural isoquinoline alkaloids and their N-oxides isolated from different plant species. More than 200 biological active compounds have shown confirmed antimicrobial, antibacterial, antitumor, and other activities. The structures, origins, and reported biological activities of a selection of isoquinoline N-oxides alkaloids are reviewed. With the computer program PASS some additional SAR (structure-activity relationship) activities are also predicted, which point toward new possible applications of these compounds. This review emphasizes the role of isoquinoline N-oxides alkaloids as an important source of leads for drug discovery.

Keywords:

Alkaloids

Isoquinoline

Anticancer

Antibacterial

SAR

Activities

Introduction

Isoquinoline alkaloids (IQA, see Fig. 1) are a small group of natural bioactive products with widespread occurrence in nature and also playing a very important role in the secondary metabolism of numerous plant species. They encompass a diverse group of more than 200 structures with restricted occurrence in certain higher plant taxa belonging to species Aristolochia, Argemone, Ceratocapnos, Chelidonium, Corydalis, Cynanchum, Dicentra, Fumaria, Papaver, Pergularia, Platycapnos, Rupicapnos, Sarcocapnos, Sanguinera, and Tylophora (Sato 2013; Nakagawa, et al., 2013; Egydio et al., 2013; Dembitsky 2008; Zdarilova et al. 2006; Bentley 2005; Dembitsky 2004, 2005; Kartsev 2004).

IQA are important components in chemical defense of the producing species, which are usually avoided by herbivores (Salmore and Hunter 2001; Majak et al. 2003). The most significant human toxins in this group are in the laburnum tree and the mescal bean. The laburnum bears golden pea like pods. Mescal bean is the seed of a small tree and often is used in ornamental jewelry. Cytisine, the alkaloid common to these plants, has nicotine like effects on the gastrointestinal (GI) tract and the central nervous system (CNS). IQA papaverine, sanguinarine, protoverine, and chelidonine are GI tract irritants and CNS stimulants (Ribeiro and Rodriguez de Lores Arnaiz 2000; Liu et al. 1999; Prageret al. 1981; Matin 1970).

IQA are found in varying quantities in the prickly poppy, bloodroot, and celandine poppy. Many have varying degrees of neurologic effects, ranging from relaxation and euphoria to seizures. Isoquinoline alkaloids are a major group of pharmacologically important compounds, and some isoquinoline alkaloids demonstrated antimicrobial, antibacterial, antifungal, antitumor and other biological active properties (Nepali et al. 2014; Bournine et al. 2013; Sinnett-Smith et al. 2013; Gu and Kinghorn 2005; Dembitsky, 2004, 2005; D'Incalci et al. 2004; Vicario et al. 2003; Garcia-Mateos et al. 2001; Waterman 1999). Isoquinoline N-oxide alkaloids (Fig. 1) are structurally related to their corresponding alkaloids, and these alkaloids showed high pharmacological active properties (Sato 2013; Nakagawa et al. 2013; Majak et al. 2003). Heterocyclic N-oxides and N-imides, alkaloid N-oxides, and their synthesis of oxygen-containing heterocycles by intramolecular oxypalladation has recently been reviewed (El Antri et al. 2004; Pummangura et al. 1982; Taylor 1960). Structure, pharmacological and SAR (structure-activity relationship) activities of IQA, modes of action, and future prospects are discussed.

Origin of isoquinoline N-oxide alkaloids

The first simple tetrahydroisoquinoline N-oxide alkaloids have been isolated from the Cactaceae species more than 20 years ago (Pummangura et al. 1982). Tehuanine N-oxide (1) was isolated from Pachycereus pringlei and deglucopterocereine N-oxide (2) was isolated from Pterocereus gaumeri (Pummangura et al. 1992). Tehuanine (not N-oxide) was identified from other cacti species: Backebergia militaris, Giant cactus, Lophocereus schottii, Neobuxbaumia euphorbiodes, Pachycereus hollianus, Pachycereus marginatus, Pachycereus pectin-aboriginum, Pachycereuspringlei, and Pachycereus weberi (Mata and McLaughlin 1980a, b; Mata et al. 1983; Unger et al. 1980).

The isoquinoline N-oxide alkaloid, 1-hydroxymethyl-6,7-dimethoxyisoquinoline N-oxide (3) (yield, 0.023% from dried seeds) was for the first time isolated from the alkaloid fraction of a methanol extract of the seeds of Calycotome villosa subsp. intermedia (El Antri et al. 2004), and previously was obtained as an intermediate in the synthesis of ([+ or -])-calycotomine (Battersby and Edwards 1959). The minor isoquinoline alkaloid, nigellimine N-oxide (4), was isolated from the seeds of Nigella sativa (Battersby et al. 1985; Rehman 1985); and non-oxidized nigellimine also isolated from same seeds (Rahman et al. 1992; Khalil 1994). Jamtine N-oxide (5) was isolated from Cocculus hirsutus (Uddin et al. 1987), non-oxidized analog was identified from the same tree C. hirsutus (Rasheed et al. 1991). Activities N-oxides (1-5) are shown in supplementary Table 1.

SAR activities of metabolites isolated from plant species

Probable additional biological activities of isoquinoline metabolites isolated from plant species were evaluated by computer prediction. For this purpose we used computer program 'PASS' (Sergeiko et al. 2008; Poroikov and Filimonov 2005; Borodina et al 2003; Stepanchikova, Lagunin, Filimonov and Poroikov, 2003), which predicts about 2500 pharmacological effects, mechanisms of action, mutagenicity, carcinogenicity, teratogenicity and embryotoxicity on the basis of structural formulae of compounds. PASS predictions are based on SAR (structure-activity relationships) analysis of the training set consisting of about 60,000 drugs, drug-candidates and lead compounds. Algorithm of PASS predictions is described in detail in several publications (Sergeiko et al. 2008; Poroikov and Filimonov 2005). Using MOL or SD files as an input for the PASS program, user may get a list of probable biological activities for any drug-like molecule was also published recently (Sergeiko et al. 2008; Dembitsky et al. 2005,2007).

For each activity, [P.sub.a] and [P.sub.i] values are calculated, which can be interpreted either as the probabilities of a molecule belonging to the classes of active and inactive compounds, respectively, or as the probabilities of the first and second kind of errors in prediction. First kind error of prediction reflects the "false-positives", when an inactive compound is predicted to be active; and second kind error of prediction: reflects the "false-negatives", when an active compound is predicted to be inactive.

Interpretation of the predicted results and selection of the most prospective compounds are based on flexible criteria, which depend on the purpose of particular investigation. If the user chooses a rather high value of [P.sub.a] as a threshold for selection of probable activities, the chance to confirm the predicted activities by the experiment is high too, but many existing activities will be lost. Typically, there are several dozen biological activities in the predicted biological activity spectra; activity that is predicted with the highest probability is called "focal". Focal biological activities for isoquinoline N-oxide alkaloids isolated from plants are shown below in supplementary Tables 1-5.

Several known isoquinoline alkaloids were isolated from Thalictrum foetidum: thalactamine, protopine, thalidezine, hernandezine, O-methylthalicberine, thaligosine, berberine, laudanine, fetidine, argemonine, and argemonine N-oxide (6) (Velcheva et al. 1991; Kintsurashvili and Vachnadze 1983; Sargazakov and Yunusov 1963; Pan et al. 1992). Argemonine and norargemonine were isolated from Argemone hispida in 1951 (Schermerhorn and Soine 1951), and argemonine N-oxide was for the first time isolated from Argemone gracilenta in 1969 (Stermitz and McMurtrey 1969). Argemonine showed antimicrobial activity, and retinoid X receptor, retinoic acid receptor modulator and neurokinin receptor NK1 antagonist (Mitchell and Yu 2003; Shamma et al. 1969). Cryptocarya chinensis (Lauraceae) is an evergreen tree and widely distributed in low-altitude forests of Taiwan and southern China (Liao 1996). Some pavine N-oxide alkaloids have been isolated from the stem bark of Cryptocarya chinensis (Lin et al. 2002; Wu et al. 1975; Lu and Lan 1966; Lu 1966): (-)-caryachine N-oxide (7), (+)-isocaryachine N-oxide (8), (-)-isocaryachine N-oxide (9), (-)-isocaryachine N-oxide B (10), (-)-eschscholtzine N-oxide (11), and (-)-thalimonine N-oxide A (12) and B (13), and (-)argemonine N-oxide (6), together with eleven known compounds were isolated and characterized from the stem bark of C. chinensis (Serkedjieva and Velcheva 2003; Lin et al. 2002; Chang et al. 1998; Lee and Chen 1993; Lee et al. 1990; Lu and Lan 1966; Lu 1966).

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The in vitro anti-influenza virus effects of some isoquinoline alkaloids, isolated from Thalictrum species (Ranunculaceae), growing in Mongolia and Sweden have been studied (Velcheva et al. 1995). (-)-Thalimonine and (-)-thalimonine N-oxide (12), isolated from the Mongolian plant T. simplex, inhibited markedly the influenza virus reproduction in vitro; thalictuberine N-oxide was less effective. At a concentration range between 0.1-6.4 [micro]M of tested alkaloids, viral reproduction was inhibited in a selective and specific way. Two new epimeric isopavine N-oxides, amuresinine N-oxide A (14) and B (15), were isolated from Meconopsis horridula var. racemosa (Xie et al. 2001; Slavik 1960).

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Investigation of the alkaloid content of the aerial parts from Thalictrum simplex allowed the isolation and structural elucidation of the isoquinoline alkaloids: aporphines, (+)-thalicsimidine, (+)-ocoteine, (+)-preocoteine, (+)-ocoteine, (+)-preocoteine, (+)-thalicsimidine, northalicthuberine, thalihazine, and N-hydroxy-northalicthuberine (20), and also were isolated N-oxide alkaloids: aporphine N-oxide, preococteine N-oxide (18), (+)-thalicsimidine N-oxide (17), thalihazine N-oxide (19) together with the known (Khozhdaev et al. 1972). N-Oxides of thalicimidine (16) and preocoteine (18) were isolated from roots of Thalictrum minus which growing in Middle Asia (Khozhdaev et al. 1972). The (+)-0,0-dimethyl-corytuberine N-oxide (21) was found in the Indian plant Berberis chitria (Hussaini and Shoeb 1985).

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Four aporphine N-oxide alkaloids, named O-methylbulbocapnine [alpha]-N-oxide (22), (+)-0-methylbulbocapnine [beta]-N-oxide (23), and (+)N-methylnandigerine [beta]-N-oxide (24) were isolated from the leaves of Polyalthia longifolia (Annonaceae) growing in Taiwan (Wu et al. 1990). Oliveroline [beta]-N-oxide (25) and other alkaloids such as nornuciferine, isopiline, O-methylisopiline, calycinine, duguevanine, and five 7-hydroxyaporphines; pachypodanthine, oliveroline, oliveridine, and duguetine were isolated from Brazilian plant Duguetia flagellaris belonging to Annonaceae (Navarro et al. 2001; Fechine et al. 2002).

A new aporphine alkaloid, (+)-bulbocapnine [beta]-N-oxide (26), was isolated from Claucium fimbrilligerum from Iran. Its structure and the stereochemistry at the N-oxide center were determined by spectroscopic methods and confirmed by synthesis (Shafiee et al. 1998; Shafiee and Mahmoudi 1997). Aporphine alkaloid, (+)-isocorydine [alpha]-N-oxide (27) was isolated from the ethanolic extract of the stem bark of plant Miliusa velutina growing in Bangladesh (Hasan 2000). Isocorydine was identified from many other plants (Ribar 2003; El Sawi and Motawe 2003; Goeren et al. 2003; Mat 2000), and shown antiviral activity against HSV-1 (Nawawi et al. 1999). Alkaloid (27) was found in plant Glaucium comiculatum from Egypt, and other glaucentrine N-oxide (28) (known as (+)-corydine N-oxide) (Al-Wakeel et al. 1995). Eight annual Turkish Papaver species from sections Argemonidium (P. argemone), Carinatae (P. macrostomum), Mecones (P. gracile) and Rhoeadium (P. commutatum subsp. euxinum, P. dubium subsp. dubium, subsp. laevigatum, subsp. lecoqii, P. lacerum, P. rhoeas, P. rhopalothece) have been investigated for their alkaloid contents.

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Types of proaporphine, aporphine (roemerine N-oxide 29, rhopalotine), protopine, isopavine, protoberberine, phthalideisoquinoline, cularine, spirobenzyl-isoquinoline, and rhoeadine compounds were found in the species (Sariyar et al. 2002).

A pyrroloisoquinoline alkaloid, 7-demethoxy-tylophorine N-oxide (30) with inhibitory activity against the tobacco mosaic virus, was isolated from the aerial parts of Cynanchum komarovii (An et al. 2001; Zhang and Wu 2004). Also this compound (30) and new desoxytylophorinin N-oxide (31) were isolated from the roots and stems of Cynanchum komarovii, and it exhibited cytotoxic effects to P-388 leukemia cell in vitro (Zhang et al. 1991).

Compound (32), (13[alpha]R, 14R)-14-hydroxyantofin-N-oxide, was isolated from the stems of Cynanchum komarovii (Yao et al. 2001). A phenanthroindolizidine alkaloid antofine was isolated and identified from the root of Cynanchum paniculatum (Asclepiadaceae), and showed inhibited the growth of human cancer cells in culture ([IC.sub.50] = 7.0 ng/ml for A549, human lung cancer cells; [IC.sub.50] = 8.6 ng/ml for Col2, human colon cancer cells) (Lee et al. 2003). Two phenanthroindolizidine N-oxides, namely 10[beta]-(-)-antofine N-oxide (34) and 10[alpha]-(-)-antofine N-oxide (35) were isolated from the stem bark and the root bark of Vincetoxicum hirundinaria (Eibler et al. 1995; Lavault et al. 1994; Budzikiewicz et al. 1979). Compounds (32,34 and a novel alkaloid, (-)-10[beta], 13a[alpha]-secoantofine N-oxide 33), were isolated from aerial parts of Cynanchum vincetoxicum (Strk et al. 2000; Haznagy et al. 1967; Pailer and Streicher 1965). Cytotoxic activity of these alkaloids was assessed in vitro using both a drug-sensitive KB-3-1 and a multi-drug-resistant KB-V1 cancer cell line. The antofine derivatives (32 and 34) showed pronounced cytotoxicity against the drug-sensitive cell line ([IC.sub.50] values about 100 nM, supplementary Table 2), whereas the secoantofine derivative (33) was considerably less active. The KB-V1 cell line showed a marginal resistance against all alkaloids, demonstrating that these compounds are poor substrates for the P-glycoprotein (P-170) efflux pump.

Ficus septica (Moraceae) is a subtropical tree, which occurs widely in low-altitude forests of Taiwan, and this species has been known for its detoxicant, purgative, and emetic effects. The leaves of this plant have been used in folk medicine to treat colds, fever, and fungal and bacterial diseases (Kucharski 1964; Hadi and Bremner 2001). Members of the phenanthroindolizidine alkaloid class are known to exhibit pronounced cytotoxicity and antiamebic, antifungal, antibacterial, and anti-inflammatory activities and to also inhibit enzymes involved in the synthesis of DNA and proteins, and several alkaloids and their N-oxides (32-35) were obtained from the extract of F. septica (Damu et al. 2005). Ficuseptines B-D (non N-oxides) and compounds (32-35) showed cytotoxic activities against two human cancer cell lines, NUGC (gastric adenocarcinoma) and HONE-1 (nasopharyngeal carcinoma). Fifty four isoquinoline alkaloids, isolated from Formosan annonaceous plants, and their N-oxide derivatives, aterosperminine N-oxide (36), L-(+)-laudanidine N-oxide (37), ([+ or -])-tetrahydropalmatine N-oxide (38), and D-(-)-armepavine N-oxide (39) were tested for antimicrobial activity against bacteria and yeasts: Pseudomonas aeruginosa, Staphylococcus aureus, Salmonella paratyphi B, Escherichia coli, Streptococcus hemolyticus, Candida albicans, and Cryptococcus neoformans served as test organisms (Damu et al. 2005). Predicted biological activities from N-oxide alkaloids (16-31) and (32-35) shown in supplementary Tables 1 and 2, respectively.

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Twenty-three of the isoquinoline alkaloids and their N-oxide derivatives exhibited antimicrobial activity. Apparently, there is a close relationship between the structures of alkaloids and the affinity for some sites in microbial cells (Abidov et al. 1962, 1963; Tsai et al. 1989; Wu et al. 1988).

Kreisigine (40), O-methylkreisigine (41), and merenderine N-oxides (42) were isolated from Merendera raddeana (Khozhdaev et al. 1972). Also aerial parts of M. raddeana afforded colchicine, [beta]-lumicolchicine, N-deacetyl-N-formylcolchicine, merenderine (bechuanine), kreisigine, O-methyl-kereisigine, cornigerine, and 2and 3-demethylcolchicines. Seasonal variation in M. raddeanea organ alkaloids was given (Yusupov et al. 1991).

Ungiminorine N-oxide (43) was isolated from Pancratium maritimum, and non-isoquinoline alkaloids homolycorine N-oxide and O-melycorenine N-oxide from Lapiedra martinezii (both belonging to Amaryllidaceae) (Suau et al. 1988), and Ungiminorine was identified from Ungernia minor, Ungemia severtzovii, Pancratium maritimum, and Stembergia sicula (Normatov et al. 1961,1962,1965; Vazquez et al. 1988; Richomme et al. 1989); it showed antiviral activity, and demonstrated acetylcholinesterase inhibitory effects, and hypertension properties (Ingkaninan et al. 2000; Renard-Nozaki et al. 1989; Zakirov 1967). From Ceratocapnos heterocarpa, have been isolated both trans- (44) and cis-cularidine N-oxides (45) that exhibit a different conformation at the dihydroxepine ring and a distinct chemical behavior (Suau et al. 1995).

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Six cularine alkaloids; cularicine, O-methyl-cularicine, celtisine, cularidine, cularine and celtine, three isocularine alkaloids; sarcophylline, sarcocapnine and sarcocapnidine, and five non-cularine alkaloids; glaucine, protopine, ribasine, dihydrosanguinarine and chelidonine, were identified from the genus Sarcocapnos (Fumariaceae): S. baetica ardalii, S. baetica baetica, S. crassifolia atlantis, S. crassifolia crassifolia, S. enneaphylla, S. integrifolia, S. pulcherrima, S. saetabensis, and S. speciosa (Suau et al. 2005).

Cularidine was also found in other families (Manske 1965,1968; Protais et al. 1992). Cularidine, celtisine, and breoganine were able to inhibit the binding at D-1 and D-2 dopaminergic sites at nanomolar concentrations. These data suggest that the presence of an oxepine system in the isoquinoline skeleton could lead to compounds which would be very active and possibly selective at dopaminergic receptor sites(Manske 1965,1968; Protais et al. 1992). More recently, two new alkaloids, (+)-cis-cularine N-oxide (46) and (+)-ris-sarcocapnine Noxide (47) were isolated from Ceratocapnos heterocarpa (Suau 1996), and (+)-sarcocapnidine N-oxide (48) was isolated from Sarcocapnos baetica subsp, integrifolia (Castedo et al. 1988).

Two new bisbenzylisoquinoline alkaloids, (+)-cocsoline 2'-[beta]-Noxide (49), and (+)-12-0-methylcocsoline 2'-[beta]-N-oxide (50), were isolated from polar fractions of the roots of Anisocycla cymosa, in addition to eight known bisbenzylisoquinoline, aporphine, protoberberine, and phenanthrene alkaloids (Kanyinda et al. 1993). More recently, compound (49) was identified from water extract of the root of Epinetrum villosum (Menispermaceae), and cocsoline displayed antibacterial and anti-fungal activities (MIC values of 1000-15.62 and 31.25 [micro]g/ml, respectively). Cycleanine acted against HIV-2 ([EC.sub.50] = 1.83 [micro]g/ml) but was at least 10-fold less active against HIV-1. Cycleanine N-oxide (51) showed no activity toward all tested microorganisms (Otshudi et al. 2005).

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Cycleanine N-oxide (51) was isolated from the stems of Synclisia scabrida, along with the known bisbenzylisoquinoline alkaloids cycleanine, norcycleanine, cocsuline, and cocsoline (Ohiri et al. 1983). Oxidation of cycleanine with m-chloroperbenzoic acid gave two diastereomeric N-oxides [[beta]- and [alpha]-N-oxide), and their stereochemistry was unambiguously detected on the basis of spectroscopic evidence. The NMR spectra of synthetic cycleanine mono-N-oxides [[beta]- 52 and [alpha]-N-oxide 53) were significantly different from those of the natural product previously reported to be cycleanine N-oxide (51) (Kashiwaba et al. 1998).

A new bisbenzylisoquinoline N-oxide, (+)-2-norobaberine 2'-[beta]-N-oxide (54), along with six known alkaloids, 2-norobaberine, daphnandrine, coclobine, anisocycline, palmatine, and remrefidine, has been isolated from seeds of Aniswycla cymosa (Menispermaceae). The structure of (54) was determined by spectral data and reduction into (+)-norobaberine. This woody climber growing in Zaire, and it is used in Zairian traditional medicine as a tonic, antipyretic, analgesic, and anti-rheumatic (Kanyinda et al. 1993).

Investigation on Cocculus pendulus (Menispermaceae) resulted in the isolation of two new alkaloids, kurramine 2'-[beta]-N-oxide (55) and kurramine 2'-[alpha]-N-oxide (56), and three known bisbenzylisoquinoline alkaloids (Rahman et al. 2004; Rahman 1986; Bhakuni 2002). Compounds (55 and 56) were screened for their anticholinesterase activity in a mechanism-based assay. Compound (55, IC50 = 10 [micro]M) and (56, [IC.sub.50] = 150 [micro]M) have inhibited acetylcholinesterase, respectively. The cholinesterase inhibitory activities of these bisbenzylisoquinoline alkaloids are reported here for the first time (Rahman et al. 2004; Rahman 1986; Bhakuni 2002).

Six new alkaloids, (+)-ovigeridimerine, 4-methoxyoxohemandaline, 7-formyldehydro-hernangerine, 5,6-dimethoxy-N-methylphthalimide, 7-hydroxy-6-methoxy-L-methyl-isoquinoIine and (+)-vateamine 2'-[beta]-N-oxide (56), along with one new dialdehyde, hernandial, have been isolated and characterized from the trunk bark of Hemandia nymphaeifolia (Chen et al. 1996).

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Aporphine alkaloids from Formosan Hemandia nymphaeifolia demonstrated anti-platelet aggregation activity (Chen et al. 2000), and cytotoxic activity against the P388 lymphocytic leukemia cell line and human tumor cell lines (Pettit et al. 2004).

Some bisbenzylisoquinoline N-oxide alkaloids (58-61) were isolated from some plant species: limacusine 2'-[beta]-N-oxide (58) (Kanyinda et al. 1995), and 12-O-methylcocsoline 2'-[beta]-N-oxide (59) (Kanyinda et al. 1993) isolated from Anisocycla jollyana, and compounds (60 and 61) isolated from Cyalea sutchuenensis (Lai et al. 1993a,b) (both plants belonging to the family Menispermaceae).

Unusual homoproaporhine alkaloid, robustamine cis-N-oxide (62) was isolated from plant Merendera robusta (family Liliaceae) growing in Uzbekistan (Yusupov 1996). Robustamine (Yusupov and Chammadov 1995) was isolated from the same plant. It has been shown that the plant produced increased amounts of homoaporphine at the end of the growing season (Yusupov 1996).

A new alkaloid funiferine N-oxide (63) was isolated from medicinal plants (Costa Rica) Tiliacora funifera (Menispermaceae) (Lopez 1976), the same alkaloid also was isolated from the roots of Tiliacora funifera from the West Africa (Dwuma-Badu et al. 1977). Funiferine was detected in extracts of Tiliacora funifera (Tackie and Thomas 1965, 1968), Tiliacora dinklagei (Tackie et al. 1975), Cuatteria guianensis (Berthou et al. 1988), and Cuatteria boliviano (Mahiou et al. 2000). Triclisia patens, contained funiferine and bisbenzylisoquinoline alkaloids, that displayed activity against L. donovani promastigotes ([IC.sub.50] = 1.5 [micro]g/ml) and T. brucei blood stream trypomastigote forms ([IC.sub.50] = 31.25 [micro]g/ml) (Marshall et al. 1994).

Roemeria hybrida yielded proaporphine tryptamine N-oxides, (-)-roehybridine [alpha]-N-oxide (64) and (-)-roehybramine [beta]-N-oxide (65), and 4'-OMe-(-)-roehybramine [beta]-N-oxide (66). NMR data allowed a facile assignment of these proaporphine tryptamine dimers into different stereochemical subgroups (Gunes and Gozler 2001; Gozler et al. 1990). Roehybridine was identified from the same species (El Masry et al. 1990; Gozler et al. 1989; Slavik et al. 1974).

Two new 8-benzylberbine-type alkaloids, the N-oxide of 8-benzylberbine A (67), and an unusual N-oxide derivative, named 8-benzylberbine B N-oxide (68) have been isolated from Aristolochia gigantea (Aristolochiaceae) (Lopes and Humpfer 1997). Non N-oxide analogs of alkaloids 67 and 68 were also identified in the same plants (Cortes et al. 1987; Lopes 1992). The biological activities of the isoquinoline N-oxide alkaloids (36-61) and their non oxidized analogs (A36-A61) are shown in supplementary Tables 2 and 3.

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Different erythrinaline alkaloids have been isolated from the flowers and pods of Erythrina lysistemon, and among them the new compounds are (+)-11[beta]-hydroxyerysotramidine, (+)11[beta]-hydroxyerysotrine N-oxide (69), and two C-11 epimers (70 and 71), (+)-11[beta]-methoxyerysotramidine N-oxide (72), (+)-11[beta]-hydroxyerysotrine, and 11-dehydroerysotrine (73). The crude CH[Cl.sub.3]/MeOH extract showed moderate toxicity to brine shrimp ([LC.sub.50] 23 [micro]g/ml) and moderate ([IC.sub.50] 86 [micro]g/ml) radical scavenging properties against stable 2,2-diphenyl-l-picrylhydrazyl radical (Juma and Majinda 2004). The same non N-oxides were identified from the genus Erythrina (Amer 2001; Letcher 1971; Barton et al. 1970). Aqueous EtOH and EtOAc extracts of the bark and leaves of five South African Erythrina species: E. caffra, E. humeana, E. latissima, E. lysistemon and E. zeyheri, showed prostaglandin synthesis-inhibitory and antibacterial activities. The highest cyclooxygenase-inhibiting and antibacterial activity was found in the aqueous EtOH and EtOAc extracts of the bark of E. caffra, E. latissima and E. lysistemon (Pillay et al. 2001).

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The genus Aristolochia (Aristolochiaceae) is found in wide areas, from the tropics to temperate zones and consists of about 400 species. Some species have been used in the form of crude drugs as anodynes, antiphlogistics, antitussives, expectorants, antiasthmatics and detoxicants, especially in China. Three N-oxide benzoyl benzyltetrahydroisoquinoline ether alkaloids, aristoquinoline A (74), aristoquinoline B (75), and aristoquinoline C (76) were isolated from Aristolochia elegans. The benzoyl benzyltetrahydroisoquinoline alkaloids have been identified for the first time from this plant, which can be considered as an immediate progenitors of bisbenzyltetrahydroisoquinoline alkaloids, important constituents of A. elegans (Shi et al. 2004). Aristoquinolines were isolated from the genus Aristolochia: A. australasica, A. chilensis, A. fruticosa, A. peduncularis, and A. serrata (Silva et al. 1996, 1997; Cespedes et al. 1993). Isoboldine [beta]-N-oxide (77) has been isolated from leaves of Cryptocarya chinensis (Velcheva et al. 1995; Lin et al. 2002), and isoboldine was found in Peumus boldus (Vanhaelen 1973; Genest et al. 1969), Corydalisgortschakovii (Israilov et al. 1977), Berberis integerrima (Karimov et al. 1978), Aconitum karakolicum (Sultankhodzhaev et al. 1979), Coccutus laurifolius, Galanthus caucasicus, Magnolia obovata, Cocculus laurifolius, and Veratrum lobelianum (Tsakadze et al. 2005, 1997).

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Erythristemine N-oxide (78) was isolated from flowers of Erythrina bidwillii (Chawla et al. 1992),E. mulungu (Sarragiotto et al. 1981), E. americana (Garcia-Mateos et al. 2004), and E. lysistemon (Juma and Majinda 2004). Erysotrine N-oxide (79) and erythrartine N-oxide (80), and other alkaloids: erysotrine, erythrartine, hypaphorine, were isolated from the flowers of Erythrina mulungu. Erysotrine N-oxide and erythrartine N-oxide, these two alkaloids have been isolated for the first time more than 20 years ago from Erythrina mulungu (Sarragiotto et al. 1981). The alkaloids present in the seeds or foliage of six Erythrina species, E. americana, E. coralloides, E. lepthoriza, E. mexicana, E. oaxacana and E. sousae have been screened by GC-MS (Garcia-Mateos et al. 1998).

The concentration of alkaloids was variable among species and organs, but highest in flowers and seeds. The composition of alkaloids in seeds, flowers, leaves and bark was different among species.

The alkaloids of the dienoid type were most abundant than alkenoid series. Erysotrine, erythraline and erythratidine were detected in E. lepthoriza, E. mexicana, E. oaxacana and E. sousae. 11-Hydroxylated, 11-methoxylated and 8-oxo-alkaloids (crystamidine and erysotramidine) and erybidine, not described previously in these species were also detected. Erysotrine N-oxide (79) has been isolated from E. leptorhiza for the first time. The erythroidines were the main alkaloids detected in E. americana and E. coralloides together with minor alkaloids which support their taxonomic differences (Garcia-Mateos et al. 1998).

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A series of 53 isoquinoline alkaloids isolated from different plant species, and including some N-oxides have been tested for their cytotoxicity against A-549, HCT-8, KB, P-388, and L-1210 cells. These alkaloids include two tetrahydroprotoberberines, two protoberberines, six aporphines (including 81 and 82), one morphinandienone, five oxoaporphines, seven phenanthrenes, one spirobenzyl-isoquinoline N-oxide (101), nine aporphine N-oxides (24, 27, 87, 88), (22 and 23 epimers), (89-83), seven benzyltetrahydro-isoquinoline N-oxides (37, 39, 94-98), one benzyl-isoquinoline N-oxide (99), one protopine N-oxide (102), three tetrahydro-protoberberine N-oxides (103-105), three pavine N-oxides (7, 11, 100), and four phenanthrene N-oxides (83-86) (Wu et al. 1989).

Some tested N-oxide alkaloids showed high activity against cancer cells: thus, dihydroochotensimine N-oxide (101) showed activity against KB cell line ([ED.sub.50] = 2.5 [micro]g/ml), (-)-dicentrine N-oxide (89) showed activity against KB cell line ([ED.sub.50] = 3.3 [micro]g/ml), (-)-armepavine N-oxide (39) and dicentrine methane N-oxide (84) showed same activities against KB cell line ([ED.sub.50] = 4.0 [micro]g/ml). The fact that all other tested isoquinoline N-oxide alkaloids showed only marginal activity against KB cells (Ioanoviciu et al. 2005; Mayr et al. 1997; Tan et al. 1991).

Inhibitory effects of isoquinoline-type alkaloids (37, 84, 94, 95 and 97) on leukemic cell growth were studied (Ohiri et al. 1983). The L-(+)-laudanidine N-oxide (37), dicentrine methine N-oxide (84), ([+ or -])-armepavine N-oxide (94), L-(+)-armepavine N-oxide (95), and ([+ or -])-N-methylcodaurine N-oxide (97) have been isolated from the indigenous plants of Taiwan, and they were studied for their potency in inhibiting precursor incorporation into DNA, RNA and protein. These compounds showed inhibitory activity against murine leukemic LI 210 and human leukemic CCRF-CEM and HL-60 cell ([IC.sub.50] < 10 [micro]M) (loanoviciu et al. 2005; Mayr et al. 1997; Tan et al. 1991).

Reticuline N-oxide (88) was isolated from aerial parts of flowering Corydalis pseudoadunca, and total alkaloid content was 1.39% dry weight (Israilov et al. 1985), and reticuline N-oxide (88) also was isolated from Pachygone ovata (Dasgupta et al. 1979); it showed central stimulant, hyperthermic, and spinal convulsant actions in mice, the activity profile closely resembling that of thebaine. Reticuline was identified from Argemone albiflora, A. ochroleuca (Israilov et al. 1986), and Cinnamomum camphora (Tomita and Kozuka 1964). The cardiovascular effects of reticuline, isolated in a pure form from the stem of Ocotea duckei was reported (Dias et al. 2004). Reticuline (3 x [10.sup.-6], 3 x [10.sup.-5], 3 x [10.sup.-4], 9 x [10.sup.-4] and 1.5 x [10.sup.-3] M) antagonized Ca[Cl.sub.2]-induced contractions, and also inhibited the intracellular calcium dependent transient contractions induced by norepinephrine (1 [micro]M), but not those induced by caffeine (20 mM). These results suggest that the hypotensive effect of reticuline was probably due to a peripheral vasodilation in consequence of; (A) muscarinic stimulation and NOS activation in the vascular endothelium, (B) voltage-dependent [Ca.sup.2+] channel blockade and/or (C) inhibition of [Ca.sup.2+] release from norepinephrine-sensitive intracellular stores (Dias et al. 2004).

Antimicrobial activity of isoquinoline N-oxide alkaloids: D-(-)-armepavine N-oxide (39), D-(+)-N-methylcoclaurine N-oxide (97), ([+ or -])-tetrahydro-palmatine N-oxide (103), (+)-laudanidine N-oxide (37); dicentrine methine N-oxide (84), eschscholtzine N-oxide (11, and 81) isolated from Formosan annonaceous plants against bacteria and yeasts; Pseudomonas aeruginosa, Staphylococcus aureus. Salmonella paratyphi B, Escherichia coli, Streptococcus hemolyticus, Candida albicans, and Cryptococcus neoformans has been reported (Letasiova et al. 2005; Tsai et al. 1989; Wu et al. 1988). The antimicrobial activity of 23 isoquinoline alkaloids from Turkish Fumaria and Corydalis species was detected, and many alkaloids displayed a significant activity against Gram-positive and Gram-negative bacteria at 1 [micro]g/ml concentration. Phthalideisoquinolines and tetrahydroprotoberberines were the most active groups (Abbasoglu et al. 1991).

A group of semi-synthetic structural analogs of glaucine, including glaucine N-oxide (93) inhibited the central nervous system, caused a decrease in blood pressure, and had spasmolytic activity in laboratory's animals (Todorov and Zamfirova 1991; Petkov et al. 1979; Dimant and Bardashevskaia 1974; Donev 1964). Dehydrogenation and N-oxide of glaucine reduced its spasmolytic action. Glaucine and six structural analogs including glaucine N-oxide (93) showed inhibitory activity of cyclic 3',5'-AMP-phosphodiesterase in homogenates from different organs of guinea pigs and rats (Petkov and Stancheva 1980). N-Methyl-bulbocapnine N-oxide (24), N-methyl-actinodaphnine Noxide (87), oxoglaucine, boldine, and actinodaphnine showed vasorelaxing action in rat thoracic aorta (Chen et al. 1996). Microbial transformation of papaveraldine has also been reported (Fig. 2) (El Sayed 2000).

Preparative-scale fermentation of papaveraldine, the known benzylisoquinoline alkaloid, with Mucor ramannianus 1939 (sih) has resulted in a stereoselective reduction of the ketone group and the isolation of S-papaverinol and S-papaverinol N-oxide (106). The structure elucidation of both metabolites was based primarily on NMR analyses and chemical transformations. These metabolism results were consistent with the previous plant cell transformation studies on papaverine and isopapaverine. Photochemical degradation of papaverine solutions and oxidation products that were papaverinol, papaveraldine, and papaverine N-oxide (106) under the influence of UV light, was reported (Girreser et al. 2003; Souto-Bachiller et al. 1999; Bremner and Wiriyachitra 1973). Papaverine hydrochloride, papaverinol, and papaveraldine chloroform solutions were exposed to UV light of 254 nm in atmospheric, aerobic and anaerobic (helium) condition, their photooxidation in chloroform solutions was studied (Piotrowska et al. 2002; Muller and Dorfman 1934). The same degradation products appear in the above papaverine hydrochloride chloroform solutions.

However, the rate of papaverine hydrochloride degradation processes is enhanced as a function of oxygen pressure. Papaverinol and papaveraldine photooxidation products are essentially not different from those observed in the above papaverine hydrochloride solutions (Fig. 2). However, the amount of an unknown brown degradation product (X) is the greatest in the papaverinol chloroform solution degraded. That brown compound was previously observed in papaverine either hydrochloride or sulfate injection solutions on their storage even when protected from daylight (Piotrowska et al. 2002; Muller and Dorfman 1934).

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Selective inhibition of calcium entry induced by benzylisoquinolines in rat smooth muscle was studied (Catret et al. 1998; Morales et al. 1998; Chulia et al. 1994; Anselmi et al. 1992). The mechanism of relaxant activity of six benzylisoquinolines was examined in order to determine the minimal structural requirements that enable these compounds to have either a non-specific action like papaverine or an inhibitory activity on calcium entry via potential-operated channels. All the alkaloids tested totally or partially relaxed KCl-depolarized rat uterus and inhibited oxytocin-induced rhythmic contractions. Only glaucine and laudanosine inhibited K+-induced uterine contractions more than oxytocin-induced uterine contractions. In [Ca.sup.+]-free medium, sustained contractions induced by oxytocin or vanadate were relaxed by the alkaloids tested except for glaucine and laudanosine indicating no inhibitory effect on intracellular calcium release. Those alkaloids containing an unsaturated heterocyclic ring (papaverine, papaverinol, papaveraldine, N-methylpapaverine and dehydro-papaverine) exhibited a more specific activity than those with a tetrahydroisoquinoline ring (Catret et al. 1998; Morales et al. 1998; Chulia et al. 1994; Anselmi et al. 1992).

A new tetrahydroprotoberberine N-oxides, (-)-cis-isocorypal mine N-oxide (107), (-)-cis-corydalmine N-oxide (109), (-)-transcorydalmine N-oxide (110), (-)-trans-isocorypalmine N-oxide (111), together with known compounds, 6-methoxydihydro-sanguinarine and norjuziphine, were isolated in continuing studies of the entire Formosan Corydalis tashiroi plant (Chen et al. 2001). The (-)-cis-corydalmine N-oxide (109), (-)-trans-corydalmine N-oxide (110),(-)-trans-isocorypalmine N-oxide (111), scoulerine, protopine, oxysanguinarine and corydalmine showed were anti-platelet aggregation activity (Chen et al. 2001).

The cytotoxic effects of the isolates were tested in vitro against P388, KB16, A549, and HT-29 cell lines. The cytotoxicity data are shown in supplementary Table 5, and the clinically applied anticancer agent mithramycin was used as reference compound (Chen et al. 1999), and predicted activities shown in supplementary Table 5.

By comparison, the 2,3,7,8-tetraoxygenated benzo[c]phenan thridine alkaloids exhibited more potent cytotoxic activities than the berberine-type alkaloids like (109 and 111) against P-388, KB16, A549, and HT-29 cell lines. Among them, norsanguinarine, dihydrosanguinarine, and ([+ or -])-scoulerine exhibited effective cytotoxicities ([ED.sub.50] < 4 [micro]g/ml) against P-388, KB16, A549, and HT-29 cell lines, and palmatine showed selective cytotoxicity ([ED.sub.50] < 4 [micro]g/ml) only against the P-388 cell line (Chen et al. 1999).

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In addition, the tetrahydroprotoberberine N-oxides, (107, 108, 109, 110, and 111), were less active as ([+ or -])-tetrahydroberberine N-oxide, ([+ or -])-tetrahydro-jatrorrhizine N-oxide and ([+ or -])-tetrahy dropalmatine N-oxide. Furthermore, norsanguinarine was the most cytotoxic isolate, and exhibited a more potent cytotoxicity ([ED.sub.50] = 0.051 [micro]g/ml) against the P-388 cell line than mithramycin ([ED.sub.50] = 0.056 [micro]g/ml) (Chen et al. 2001). N-Oxide alkaloids (108-111), and (-)-cis-corydalmine N-oxide (112) have been isolated from the herb Corydalis tashiroi (Berthou et al. 1988). The (-)-transcorydalmine N-oxide (110) and (-)-cis-corydalmine N-oxide (112) showed stronger inhibitory activity than corydalmine on platelet aggregation induced by AA and collagen, due to the effect of N-oxide function. Three of the isolated compounds non-N-oxide alkaloids showed significant cytotoxic activities ([ED.sub.50] < 4 [micro]g/ml) against P-388, KB16, A549, and HT-29 cell lines.

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Sixteen compounds and including a new stereoisomer of (+)-ushinsunine-[beta]-N-oxide (113a) were isolated from the methanolic extract of the Cananga odorata (Hsieh et al. 1999; Yang and Huang 1988, Yang and Huang 1989). N-oxides of (113a) and lyscamine (113b) were identified from the same plant, and showed cytotoxic effects (supplementary Table 5) (Hsieh et al. 2001).

Ushinsunine was found in extracts of Michelia compressa (Lo et al. 2004), Armorta cherimola (Chen et al. 1997), Stephania epigaea (Peng et al. 1990), Oxymitra velutina (Achenbach and Hemrich 1991), Pseudoxandra sclerocarpa (Cortes et al. 1986), and Polyalthia nitidissima (Jossang et al. 1983). Ushinsunine, which was isolated from Michelia compressa var. formosana, showed strong bacteriostatic activity against Staphylococcus, and strong bactericidal action against Shigella sp., Mycobacterium sp. and Bacillus subtilis, and prevented decay in various named wood (Wright et al. 2000).

Twenty-one alkaloids have been assessed for activities against Plasmodium falciparum (multidrug-resistant strain K1) in vitro, and Entamoeba histolytica. Two protoberberine alkaloids, dehydrodiscretine and berberine, were found to have antiplasmodial [IC.sub.50] values less than 1 [micro]M, while seven alkaloids-allocrytopine, columbamine, dehydroocoteine, jatrorrhizine, norcorydine, thalifendine, and ushinsunine had values between 1 and 10 [micro]M. Compounds were also assessed for anti-amoebic and cytotoxic activities, but none was significantly active except for berberine, which was moderately cytotoxic (Villinski et al. 2003; Moody et al. 1995; Wu et al. 1994).

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Kampo medicine, Stephania tetrandra in Boi-Ogi-To increases the blood insulin level and falls the blood glucose level in streptozotocin (STZ)-diabetic ddY mice. These actions of S. tetrandra are potentiated by Astragalus membranaceus (Astragali) in Boi-Ogi-To (Tsutsumi et al. 2003; Liu et al. 2002). Actions of bis-benzylisoquinoline alkaloids isolated from S. tetrandra were investigated in the hyperglycemia of STZ-diabetic mice (Tsutsumi et al. 2003; Liu et al. 2002).

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Fangchinoline 2'-N-[alpha]-oxide (117) and 2'-N-norfangchinoline, which are substituted with 7-hydroxy side chain for 7-O-methyl side chain, decreased to near 50% of high blood glucose level (Ogino et al. 1987, 1990, 1998). In addition, tetrandrine 2'-N-[beta]-oxide (114), tetrandrine 2'-N-[alpha]-oxide (115), tetrandrine 2-N-[beta]-oxide (116), fangchinoline 2'-N-[alpha]-oxide (117), which were added to 2- or 2'-N-oxide side chain, also decreased to near 50% of the high blood glucose level. Fangchinoline but not tetrandrine from Stephania showed the antihyperglycemic action in the STZ-diabetic mice. The demethylation of 7-O-position and/or addition of 2- or 2'-N-oxide side chain in bisbenzylisoquinoline compounds in S. tetrandra have a role for the induction of the anti-hyperglycemic actions (Ogino et al. 1987, 1990, 1998).

Fangchinoline was also isolated from Stephania tetrandra, Cyclea barbata, Hypscrpa nitida, Stepahania cepharantha, Stephaniae hainanensis, and Menispermum dauricum (Zhang 2005). Derivatives from fangchinoline and tetrandrine to reverse P-glycoprotein (P-gp)-dependent multidrug resistance in vitro and in vivo were reported (Wang et al. 2005). All compounds enhanced the in vitro cytotoxic effect of vinblastin at 0.1 [micro]M as potent as 10 p.M verapamil against the resistant cell line P388/ADR. Reviewed and predicted biological activities for N-oxide alkaloids (69-95) are shown in supplementary Tables 3 and 4.

The alkaloidal fraction from the roots of Cyclea barbata contain two new bisbenzylisoquinoline alkaloids, namely, (-)-2'-norlimacine and (+)-cycleabarbatine (Guinaudeau et al. 1993). The known (+)-tetrandrine 2'-[beta]-N-oxide (114), for which the configuration of the N-oxide function was identified.

The 39 protoberberine derivatives were tested for antimalarial activity in vitro against Plasmodium fakiparum and structure-activity relationships was proposed (Silva et al. 1996, 1997). The activity of the protoberberine alkaloids was influenced by the type of the quaternary nitrogen atom, the nature and the size of the substituents at the C-13 position, and the type of O-alkyl substituents on rings A and D. The activity of the quaternary protoberberinium salts with an aromatic ring C such as berberine was higher than that of the quaternary salts such as the N-metho- salts or the N-oxides of tetrahydro- and dihydroderivatives as well as tertiary tetrahydroproto-berberines.

A positive effect on the activity might be exerted by the introduction of a more hydrophilic function into the C-13 position of the protoberberinium salts (Iwasa et al. 1998,1999). Reviewed and predicted activities for N-oxide alkaloids (96-108) showed in supplementary Tables 4 and 5.

(S)-Reticuline is the universal precursor to the majority of IQA (Sato 2005; Zenk 1989; Bhakuni 1983). The biosynthesis of this important intermediate starting from the primary metabolite, L-tyrosine, has been completely solved at the enzyme level. Reticuline N-oxide was isolated from aerial parts of flowering Corydalis pseudoadurtca (Israilov et al. 1985), Pachygone ovata (Dasgupta et al. 1979), Monocyclanthus vignei (Achenbach et al. 1991), and Glossocalyx brevipes (Montgomery et al. 1985). (+)-Reticuline from young leaves of Guatteria dumetorum showed the growth inhibitory activity against the parasite Leishmania mexicana (Correa et al. 2006); stimulated the proliferation of cultured cells from murine hair app (Nakaoji et al. 1997); and it was active against HSV-1 (herpes simplex virus), as well as HSV-1 thymidine kinase deficient (acyclovir resistant type, HSV-1 TK-) and HSV-2 ([IC.sub.50] values of 8.3, 7.7 and 6.7 [micro]g/ml, respectively), it was cytotoxic (Nawawi et al. 1999).

One of the most diverse structures in the class of isoquinoline alkaloids are the benzo[c]phenanthridines. The most highly oxidized member is macarpine, an alkaloid produced in considerable quantity in cell suspension cultures of Eschscholtzia californica and Thalictrum bulgaricum. This plant source was used to isolate all of the enzymes involved in this pathway. Twelve steps are necessary for the transformation of (S)-reticuline to macarpine, eleven of these are enzyme catalyzed, have recently been reviewed (Sato 2005; Zenk 1989; Bhakuni 1983).

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Reviewed and predicted activities for metabolites (112-117 and A112-A117) represented in supplementary Table 5, and demonstrated activities isomers (113a,b) isolated from Cananga odorata.

Nitro-containing metabolites

Nitro-containing compounds have been discovered as natural products from a variety of bacteria, fungi, and plants (Michl et al., 2014; Sanchez-Calvo et al" 2013; Parry et al. 2011). These compounds are organic molecules that consist of at least one nitro group (-N[O.sub.2]) attached to an aromatic ring, or alkyl moieties, and display great structural diversity, and a wide range of biological activities (Boelsterli et al., 2006). Several Gram-negative bacteria, including Burkholderia (El Banna and WinkelmannEl-Banna et al., 1998; Mendes et al., 2007; Roitman et al., 1990) strains, Corallococcus exiguus, Cystobacter ferrugineus, Myxococcus fulvus (Gerth et al., 1982), Enterobacter agglomerans (Chernin et al., 1996), Pseudomonas (Arima, et al., 1964; Elander et al., 1968; Lively et al., 1966), and the actinomycete Actinosporangium vitaminophilum produced nitro-containing antibiotics with antifungal activity (Arima, et al., 1964; Mendes et al., 2007), and also were active against some Gram-negative and Gram-positive bacteria (Ezaki et al., 1981, 1983). Members of the genus Streptomyces are known to produced a wide variety of nitro-containing metabolites such as: antibiotics (Ehrlich et al., 1948; Gottlieb et al., 1948; Smith et al., 1948), polyketides (Cardillo et al., 1972; Hirata et al., 1961; Kakinuma et al., 1976; Maeda 1953; Muller et al., 2006; Traitcheva et al., 2007), heterocyclic compounds (Carter et al., 1987; Charan et al. 2006; Osato et al., 1955), nitro-dipeptides(Loriaetal.,2008; King and Calhoun 2009), cyclic heptapeptides (Takita, et al., 1964), and other compounds Qu and Parales, 2010; Winkler and Hertweck 2007).

Among nitro-containing metabolites, the aristolochic acids are a family of substituted 10-nitro-1-phenantropic acids, biogenetically derived from benzylisoquinoline precursors, which in turn originate from tyrosine amino acid (Michl et al., 2014; Kumar et al., 2003). A proposed biosynthetic pathway of papaverine N-oxide (99) and aristolochic acids (118 and 119) showed in Fig. 3. The scientific details of aristolochic acids biosynthesis have been reported in several research papers (Schiitte et al., 1967; Comer et al., 1969; Sharma et al., 1982; Krumbiegel et al. 1987), and recently reviewed (Winkler and Hertweck 2007; Michl et al., 2014; Kumar et al., 2003). The plants of the genera Aristolochia and Asarum became the interesting topic for the phytochemical and pharmaceutical researchers since the discovery of aristolochic acid derivatives. Species of Aristolochia and Asarum were widely distributed in tropical, subtropical and temperate regions of the world (Hou, 1996). Various species of both genera have been used in the folk and traditional medicines (Lopes et al, 2001), especially in the traditional Chinese medicines (Bensky, et al., 1993).

At present time a lot of derivatives of aristolochic acids have been found and their structures also reported (Michl et al., 2014; Kumar et al., 2003). Biological activities and toxicology of aristolochic acids and derivatives have also been reported (Jordan and Perwaiz 2014; Michl et al., 2014; Aronson 2014.).

While papaverine N-oxide (99) and aristolochic acids (118 and 119) having a common biosynthetic pathway, but, from the standpoint of chemistry, it is a different class of organic compounds. This review is devoted to isoquinoline N-oxide alkaloids, which shows their reported and SAR activities. Nitro aromatic compounds are very also an interesting group of natural compounds, and this family of metabolites should be discussed in other review article. Nevertheless, using the program PASS, we provide SAR activities two most known nitro aromatic compounds such as aristolochic acid 1 (118) aristolochic acid II (119). Thus, aristolochic acid I (118) shown 397 of 3300, and aristolochic acid II (119) shown 762 of 3300 possible activities at [P.sub.a] > [P.sub.i], and in supplementary Table 6 shows only the 40 most probable activities.

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Concluding remarks

Some IQA such as papaverine, sanguinarine, protoverine, and chelidonine are gastrointestinal tract irritants and central nervous system stimulants. Isoquinoline alkaloids are found in varying quantities in the prickly poppy, bloodroot, and celandine poppy. Many have varying degrees of neurologic effects, ranging from relaxation and euphoria to seizures. Among many thousands of modern drugs, about 41% are of natural origin. The widest spectra of pharmacological activities are exhibited by isoquinoline alkaloids, and their N-oxides. Using the program PASS we have shown that many reported activities for isoquinoline N-oxides have been predicted, including some additional biological activities.

Supplementary materials

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.phymed.2014.11.002.

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ARTICLE INFO

Article history:

Received 25 August 2014

Revised 21 September 2014

Accepted 12 November 2014

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Valery M. Dembitskya (a) *, Tatyana A. Gloriozova (b), Vladimir V. Poroikov (b)

(a) Institute of Drug Discovery, P.O. Box 45289, Jerusalem 91451, Israel

(b) Institute of Biomedical Chemistry, Russian Academy of the Medical Sciences, Moscow 119121, Russia

* Corresponding author. Tel.: +972 52 687 7444; fax: +972 52 687 7444

E-mail address: iddrdo@gmx.com, devalery@gmail.com (V.M. Dembitsky).

http://dx.doi.org/10.1016/j.phymed.2014.11.002
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Title Annotation:structure-activity relationship
Author:Dembitskya, Valery M.; Gloriozova, Tatyana A.; Poroikov, Vladimir V.
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
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Date:Jan 15, 2015
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