Phytomedicine 22 (2014) 183–202

Contents lists available at ScienceDirect

Phytomedicine

journal homepage: www.elsevier.com/locate/phymed

Naturally occurring plant isoquinoline N-oxide alkaloids: Their

pharmacological and SAR activities

Valery M. Dembitsky a,∗, Tatyana A. Gloriozova b, Vladimir V. Poroikov b

a Institute of Drug Discovery, P.O. Box 45289, Jerusalem 91451, Israelb Institute of Biomedical Chemistry, Russian Academy of the Medical Sciences, Moscow 119121, Russia

a r t i c l e i n f o

Article history:

Received 25 August 2014

Revised 21 September 2014

Accepted 12 November 2014

Keywords:

Alkaloids

Isoquinoline

Anticancer

Antibacterial

SAR

Activities

a b s t r a c t

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 antimicro-

bial, 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 ad-

ditional 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.

© 2014 Elsevier GmbH. All rights reserved.

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ntroduction

Isoquinoline alkaloids (IQA, see Fig. 1) are a small group of nat-

ral bioactive products with widespread occurrence in nature and

lso playing a very important role in the secondary metabolism of

umerous plant species. They encompass a diverse group of more

han 200 structures with restricted occurrence in certain higher plant

axa belonging to species Aristolochia, Argemone, Ceratocapnos, Cheli-

onium, Corydalis, Cynanchum, Dicentra, Fumaria, Papaver, Pergularia,

latycapnos, Rupicapnos, Sarcocapnos, Sanguinera, and Tylophora (Sato

013; Nakagawa, et al., 2013; Egydio et al., 2013; Dembitsky 2008;

darilova et al. 2006; Bentley 2005; Dembitsky 2004, 2005; Kartsev

004).

IQA are important components in chemical defense of the produc-

ng species, which are usually avoided by herbivores (Salmore and

unter 2001; Majak et al. 2003). The most significant human toxins

n this group are in the laburnum tree and the mescal bean. The labur-

um bears golden pea like pods. Mescal bean is the seed of a small

ree and often is used in ornamental jewelry. Cytisine, the alkaloid

ommon to these plants, has nicotine like effects on the gastroin-

estinal (GI) tract and the central nervous system (CNS). IQA papaver-

ne, sanguinarine, protoverine, and chelidonine are GI tract irritants

nd CNS stimulants (Ribeiro and Rodriguez de Lores Arnaiz 2000; Liu

t al. 1999; Prager et al. 1981; Matin 1970).

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

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

(

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ttp://dx.doi.org/10.1016/j.phymed.2014.11.002

944-7113/© 2014 Elsevier GmbH. All rights reserved.

IQA are found in varying quantities in the prickly poppy, blood-

oot, and celandine poppy. Many have varying degrees of neurologic

ffects, ranging from relaxation and euphoria to seizures. Isoquino-

ine alkaloids are a major group of pharmacologically important com-

ounds, and some isoquinoline alkaloids demonstrated antimicrobial,

ntibacterial, antifungal, antitumor and other biological active prop-

rties (Nepali et al. 2014; Bournine et al. 2013; Sinnett-Smith et al.

013; Gu and Kinghorn 2005; Dembitsky, 2004, 2005; D’Incalci et al.

004; Vicario et al. 2003; Garcia-Mateos et al. 2001; Waterman 1999).

soquinoline N-oxide alkaloids (Fig. 1) are structurally related to their

orresponding alkaloids, and these alkaloids showed high pharma-

ological active properties (Sato 2013; Nakagawa et al. 2013; Majak

t al. 2003). Heterocyclic N-oxides and N-imides, alkaloid N-oxides,

nd their synthesis of oxygen-containing heterocycles by intramolec-

lar oxypalladation has recently been reviewed (El Antri et al. 2004;

ummangura et al. 1982; Taylor 1960). Structure, pharmacological

nd SAR (structure–activity relationship) activities of IQA, modes of

ction, and future prospects are discussed.

rigin of isoquinoline N-oxide alkaloids

The first simple tetrahydroisoquinoline N-oxide alkaloids have

een isolated from the Cactaceae species more than 20 years ago

Pummangura et al. 1982). Tehuanine N-oxide (1) was isolated from

achycereus pringlei and deglucopterocereine N-oxide (2) was iso-

ated from Pterocereus gaumeri (Pummangura et al. 1992). Tehuanine

not N-oxide) was identified from other cacti species: Backebergia

184 V.M. Dembitsky et al. / Phytomedicine 22 (2014) 183–202

N

R5

R2

R3

R4

R

R1

N

R5

R2

R3

R4

R

R1

Me

O-

Isoquinoline N-oxide alkaloids Isoquinoline alkaloids

N

R4

R1

R2

R3

R5

Quinoline alkaloids

R

Fig. 1. Isoquinoline N-oxide alkaloids are a heterocyclic aromatic compounds, many

of these compounds have been found in nature. It is a structural isomer of quinoline.

Quinoline, isoquinoline and its N-oxide derivatives are benzopyridines, which are com-

posed of a benzene ring fused to a pyridine ring. Numbering of isoquinoline N-oxide

alkaloids shown in tables as (1–117), and numbering of isoquinoline alkaloids shown

in tables as (A1–A117). R, R1, R2, R3, R4, and R5 = H, OH, alkyl, and/or other moieties.

N

MeO

MeO O-

OH

OH

Me

2 DeglucopterocereineN-oxide

1 Tehuanine N-oxide

N

MeO

MeO

OMe

O-

Me+

+

N

OH

MeO

MeO

O-

3

4 Nigellimine N-oxide

NMeO

MeO

O-

NMeO

MeO

H O-

MeOOC

5 Jamtine N-oxide

+

+

+

i

c

a

e

c

d

p

p

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h

t

h

s

s

“

i

t

O

a

K

P

A

m

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t

Y

e

w

h

e

N

(

(

a

w

(

L

militaris, Giant cactus, Lophocereus schottii, Neobuxbaumia euphor-

biodes, Pachycereus hollianus, Pachycereus marginatus, Pachycereus

pectin-aboriginum, Pachycereus pringlei, 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 (±)-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 metabo-

lites isolated from plant species were evaluated by computer predic-

tion. 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 pre-

dicts about 2500 pharmacological effects, mechanisms of action,

mutagenicity, carcinogenicity, teratogenicity and embryotoxicity

on the basis of structural formulae of compounds. PASS predic-

tions 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, Pa and Pi values are calculated, which can be

nterpreted either as the probabilities of a molecule belonging to the

lasses of active and inactive compounds, respectively, or as the prob-

bilities of the first and second kind of errors in prediction. First kind

rror of prediction reflects the “false-positives”, when an inactive

ompound is predicted to be active; and second kind error of pre-

iction: reflects the “false-negatives”, when an active compound is

redicted to be inactive.

Interpretation of the predicted results and selection of the most

rospective compounds are based on flexible criteria, which depend

n the purpose of particular investigation. If the user chooses a rather

igh value of Pa as a threshold for selection of probable activities,

he chance to confirm the predicted activities by the experiment is

igh too, but many existing activities will be lost. Typically, there are

everal dozen biological activities in the predicted biological activity

pectra; activity that is predicted with the highest probability is called

focal”. Focal biological activities for isoquinoline N-oxide alkaloids

solated from plants are shown below in supplementary Tables 1–5.

Several known isoquinoline alkaloids were isolated from Thalic-

rum foetidum: thalactamine, protopine, thalidezine, hernandezine,

-methylthalicberine, thaligosine, berberine, laudanine, fetidine,

rgemonine, and argemonine N-oxide (6) (Velcheva et al. 1991;

intsurashvili and Vachnadze 1983; Sargazakov and Yunusov 1963;

an et al. 1992). Argemonine and norargemonine were isolated from

rgemone hispida in 1951 (Schermerhorn and Soine 1951), and arge-

onine N-oxide was for the first time isolated from Argemone graci-

enta in 1969 (Stermitz and McMurtrey 1969). Argemonine showed

ntimicrobial activity, and retinoid X receptor, retinoic acid recep-

or modulator and neurokinin receptor NK1 antagonist (Mitchell and

u 2003; Shamma et al. 1969). Cryptocarya chinensis (Lauraceae) is an

vergreen tree and widely distributed in low-altitude forests of Tai-

an and southern China (Liao 1996). Some pavine N-oxide alkaloids

ave been isolated from the stem bark of Cryptocarya chinensis (Lin

t al. 2002; Wu et al. 1975; Lu and Lan 1966; Lu 1966): (−)-caryachine

-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 (−)-

rgemonine N-oxide (6), together with eleven known compounds

ere isolated and characterized from the stem bark of C. chinensis

Serkedjieva and Velcheva 2003; Lin et al. 2002; Chang et al. 1998;

ee and Chen 1993; Lee et al. 1990; Lu and Lan 1966; Lu 1966).

V.M. Dembitsky et al. / Phytomedicine 22 (2014) 183–202 185

8 (+)-Caryachine N-oxide

O

OMeO

HO

NO-

Me

9 (+)-Isocaryachine N-oxide

O

OMeO

HO

NO-

Me

O

OMeO

HO

NO-

Me

10 (-)-Isocaryachine N-oxide B

7 (-)-Caryachine N-oxide

O

OMeO

HO

NO-

Me

MeO

MeO

NO-

MeOMe

OMe

6 Argemonine N-oxide

+

+

+

+

+O

ON

O-

MeO

O

11 Eschscholtzine N-oxide

12 (-)-Thalimonine N-oxide A

MeO

MeO

NO-

MeO

O

OMe

13 (-)-Thalimonine N-oxide B

MeO

MeO

N

OO

OMeMe

O-

+

+

+

a

i

(

M

p

c

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S

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p

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1

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The in vitro anti-influenza virus effects of some isoquinoline

lkaloids, isolated from Thalictrum species (Ranunculaceae), grow-

ng in Mongolia and Sweden have been studied (Velcheva et al. 1995).

−)-Thalimonine and (−)-thalimonine N-oxide (12), isolated from the

ongolian plant T. simplex, inhibited markedly the influenza virus re-

roduction in vitro; thalictuberine N-oxide was less effective. At a

oncentration range between 0.1–6.4 μM of tested alkaloids, viral

eproduction was inhibited in a selective and specific way. Two new

pimeric isopavine N-oxides, amuresinine N-oxide A (14) and B (15),

ere isolated from Meconopsis horridula var. racemosa (Xie et al. 2001;

lavik 1960).

15 Amuresinine B N-oxide

14 Amuresinine A N-oxide

+

+

O

O

OMe

OMeN

Me

O-

O

O

OMe

OMeN

O-

Me

Investigation of the alkaloid content of the aerial parts from Thal-

ctrum simplex allowed the isolation and structural elucidation of the

soquinoline alkaloids: aporphines, (+)-thalicsimidine, (+)-ocoteine,

+)-preocoteine, (+)-ocoteine, (+)-preocoteine, (+)-thalicsimidine,

orthalicthuberine, thalihazine, and N-hydroxy-northalicthuberine

20), and also were isolated N-oxide alkaloids: aporphine N-oxide,

reococteine N-oxide (18), (+)-thalicsimidine N-oxide (17), thali-

azine N-oxide (19) together with the known (Khozhdaev et al.

972). N-Oxides of thalicimidine (16) and preocoteine (18) were

solated from roots of Thalictrum minus which growing in Middle Asia

Khozhdaev et al. 1972). The (+)-O,O-dimethyl-corytuberine N-oxide

21) was found in the Indian plant Berberis chitria (Hussaini and Shoeb

985).

N

MeO

HO

MeO

OMe

OMe

HMe

O-

N

HO

MeO

OMe

OMe

H Me

O-

17 Thalicimidine N-oxide

18 Preocoteine N-oxide

16 Thalicsmidine N-oxide

O-

N

MeO

MeO

OMe

OMe

MeOH Me

+

+

+

Me

N

MeO

MeO

OO

OH

Me

N

MeO

MeO

OO

OMe

Me

O-

19 Thalihazine N-oxide

20 N-OH-Northalicthuberine

N

MeO

MeO

MeMeO

MeOO-

21 (+)-O,O-Di-Me-Corytuberine N-oxide

+

+

Four aporphine N-oxide alkaloids, named O-methylbulbocapnine

-N-oxide (22), (+)-O-methylbulbocapnine β-N-oxide (23), and (+)-

-methylnandigerine β-N-oxide (24) were isolated from the leaves

f Polyalthia longifolia (Annonaceae) growing in Taiwan (Wu et al.

990). Oliveroline β-N-oxide (25) and other alkaloids such as nor-

uciferine, isopiline, O-methylisopiline, calycinine, duguevanine, and

ve 7-hydroxyaporphines; pachypodanthine, oliveroline, oliveridine,

nd duguetine were isolated from Brazilian plant Duguetia flagellaris

elonging to Annonaceae (Navarro et al. 2001; Fechine et al. 2002).

A new aporphine alkaloid, (+)-bulbocapnine β-N-oxide (26), was

solated from Glaucium fimbrilligerum from Iran. Its structure and

he stereochemistry at the N-oxide center were determined by spec-

roscopic methods and confirmed by synthesis (Shafiee et al. 1998;

hafiee and Mahmoudi 1997). Aporphine alkaloid, (+)-isocorydine

-N-oxide (27) was isolated from the ethanolic extract of the stem

ark of plant Miliusa velutina growing in Bangladesh (Hasan 2000).

socorydine was identified from many other plants (Ribar 2003;

l Sawi and Motawe 2003; Goeren et al. 2003; Mat 2000), and shown

ntiviral activity against HSV-1 (Nawawi et al. 1999). Alkaloid (27)

as found in plant Glaucium corniculatum from Egypt, and other glau-

entrine N-oxide (28) (known as (+)-corydine N-oxide) (Al-Wakeel

t al. 1995). Eight annual Turkish Papaver species from sections Arge-

onidium (P. argemone), Carinatae (P. macrostomum), Mecones (P.

racile) and Rhoeadium (P. commutatum subsp. euxinum, P. dubium

ubsp. dubium, subsp. laevigatum, subsp. lecoqii, P. lacerum, P. rhoeas,

. rhopalothece) have been investigated for their alkaloid contents.

186 V.M. Dembitsky et al. / Phytomedicine 22 (2014) 183–202

N

O

OO-

MeO

MeO

Me

22 (+)-O-Me-bulbocapnineα-N-oxide

23 (+)-O-Me-bulbocapnineβ-N-oxide

N

MeO

MeO

O

OO-

Me

+

+

26 (+)-Bulbocaprineβ-N-oxide

24 (+)-N-Me-bulbocapnineβ-N-oxide

N

HO

MeO

O

OO-

Me

25 Oliveroline β-N-oxide

N

O

O

OH

O-

H Me

N

HO

MeO

H

O

OMe

O-

+

+

+

N+

MeO

MeO

HO

MeO

O-

H Me

27 (+)-Isocorydine α-N-oxide

28 (+)-Corydine N-oxide

N+

MeO

HO

MeO

MeO

O-

H Me

29 Roemerine N-oxide

N+

O

OH

O-

Me

31 DesoxytylophorininN-oxide

N

MeO

MeO

OMe

O-

N

MeO

MeO

OMe

O-

H

30 (-)-7-DemethoxytylophorineN-oxide

+

+

b

l

c

H

a

a

t

a

w

F

c

t

f

p

l

(

c

S

t

s

t

m

d

c

f

1

N

e

β(

a

a

i

Types of proaporphine, aporphine (roemerine N-oxide 29,

rhopalotine), protopine, isopavine, protoberberine, phthalideiso-

quinoline, cularine, spirobenzyl-isoquinoline, and rhoeadine com-

pounds 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 iso-

lated from the aerial parts of Cynanchum komarovii (An et al. 2001;

Zhang and Wu 2004). Also this compound (30) and new desoxyty-

lophorinin 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), (13αR,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

(IC50 = 7.0 ng/ml for A549, human lung cancer cells; IC50 = 8.6 ng/ml

for Col2, human colon cancer cells) (Lee et al. 2003). Two phenan-

throindolizidine N-oxides, namely 10β-(−)-antofine N-oxide (34)

and 10α-(−)-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, (−)-10β ,13aα-secoantofine N-oxide 33), were iso-

lated 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 (IC50 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

een known for its detoxicant, purgative, and emetic effects. The

eaves of this plant have been used in folk medicine to treat

olds, fever, and fungal and bacterial diseases (Kucharski 1964;

adi and Bremner 2001). Members of the phenanthroindolizidine

lkaloid class are known to exhibit pronounced cytotoxicity and

ntiamebic, antifungal, antibacterial, and anti-inflammatory activi-

ies and to also inhibit enzymes involved in the synthesis of DNA

nd proteins, and several alkaloids and their N-oxides (32–35)

ere obtained from the extract of F. septica (Damu et al. 2005).

icuseptines B–D (non N-oxides) and compounds (32–35) showed

ytotoxic activities against two human cancer cell lines, NUGC (gas-

ric adenocarcinoma) and HONE-1 (nasopharyngeal carcinoma). Fifty

our isoquinoline alkaloids, isolated from Formosan annonaceous

lants, and their N-oxide derivatives, aterosperminine N-oxide (36),

-(+)-laudanidine N-oxide (37), (±)-tetrahydropalmatine N-oxide

38), and d-(−)-armepavine N-oxide (39) were tested for antimi-

robial activity against bacteria and yeasts: Pseudomonas aeruginosa,

taphylococcus aureus, Salmonella paratyphi B, Escherichia coli, Strep-

ococcus hemolyticus, Candida albicans, and Cryptococcus neoformans

erved as test organisms (Damu et al. 2005). Predicted biological ac-

ivities from N-oxide alkaloids (16–31) and (32–35) shown in supple-

entary Tables 1 and 2, respectively.

Twenty-three of the isoquinoline alkaloids and their N-oxide

erivatives exhibited antimicrobial activity. Apparently, there is a

lose relationship between the structures of alkaloids and the affinity

or some sites in microbial cells (Abidov et al. 1962, 1963; Tsai et al.

989; Wu et al. 1988).

Kreisigine (40), O-methylkreisigine (41), and merenderine

-oxides (42) were isolated from Merendera raddeana (Khozhdaev

t al. 1972). Also aerial parts of M. raddeana afforded colchicine,

-lumicolchicine, N-deacetyl-N-formylcolchicine, merenderine

bechuanine), kreisigine, O-methyl-kereisigine, cornigerine, and 2-

nd 3-demethylcolchicines. Seasonal variation in M. raddeanea organ

lkaloids was given (Yusupov et al. 1991).

Ungiminorine N-oxide (43) was isolated from Pancratium mar-

timum, and non-isoquinoline alkaloids homolycorine N-oxide and

V.M. Dembitsky et al. / Phytomedicine 22 (2014) 183–202 187

N

MeO

MeO

OMe

O

H

N

MeO

MeO

OMe

O-

H

34 10β-(-)-Antofine N-oxide

35 10α-(-)-Antofine N-oxide

N

MeO

MeO

OMe

O-

HOH

32 14-Hydroxyantofine N-oxide

33 10β,13α-Secoantofine N-oxide

N

MeO

MeO

OMe

O-

H

+

+

+

+

37 L-(+)-Laudanidine N-oxide

N

OMe

OH

MeO

MeO

Me

O-

36 Aterosperminine N-oxide

MeO

OMe

NMeMe

O-

+

+

O

A

fi

a

e

d

s

Z

b

e

b

c

p

k

l

S

c

a

P

i

c

s

w

s

a

o

a

b

o

i

i

t

M

o

l

1

H

N

OH

MeO

MeOO-

Me

39 D-(-)-Armepavine N-oxide

38 Tetrahydropalmatine N-oxide

N

OMe

OMe

O-

OMe

MeO

+

+

41 O-Me-K

MeO

MeO

MeO

MeO

40 Kreis

MeO

HO

MeO

MeO

-melycorenine N-oxide from Lapiedra martinezii (both belonging to

maryllidaceae) (Suau et al. 1988), and Ungiminorine was identi-

ed from Ungernia minor, Ungernia severtzovii, Pancratium maritimum,

nd Sternbergia sicula (Normatov et al. 1961,1962,1965; Vazquez

t al. 1988; Richomme et al. 1989); it showed antiviral activity, and

emonstrated acetylcholinesterase inhibitory effects, and hyperten-

ion properties (Ingkaninan et al. 2000; Renard-Nozaki et al. 1989;

akirov 1967). From Ceratocapnos heterocarpa, have been isolated

oth trans- (44) and cis-cularidine N-oxides (45) that exhibit a differ-

nt conformation at the dihydroxepine ring and a distinct chemical

ehavior (Suau et al. 1995).

Six cularine alkaloids; cularicine, O-methyl-cularicine, celtisine,

ularidine, cularine and celtine, three isocularine alkaloids; sarco-

hylline, sarcocapnine and sarcocapnidine, and five non-cularine al-

aloids; glaucine, protopine, ribasine, dihydrosanguinarine and che-

idonine, were identified from the genus Sarcocapnos (Fumariaceae):

. baetica ardalii, S. baetica baetica, S. crassifolia atlantis, S. crassifolia

rassifolia, S. enneaphylla, S. integrifolia, S. pulcherrima, S. saetabensis,

nd S. speciosa (Suau et al. 2005).

Cularidine was also found in other families (Manske 1965, 1968;

rotais et al. 1992). Cularidine, celtisine, and breoganine were able to

nhibit the binding at D-1 and D-2 dopaminergic sites at nanomolar

oncentrations. These data suggest that the presence of an oxepine

ystem in the isoquinoline skeleton could lead to compounds which

ould be very active and possibly selective at dopaminergic receptor

ites (Manske 1965, 1968; Protais et al. 1992). More recently, two new

lkaloids, (+)-cis-cularine N-oxide (46) and (+)-cis-sarcocapnine N-

xide (47) were isolated from Ceratocapnos heterocarpa (Suau 1996),

nd (+)-sarcocapnidine N-oxide (48) was isolated from Sarcocapnos

aetica subsp, integrifolia (Castedo et al. 1988).

Two new bisbenzylisoquinoline alkaloids, (+)-cocsoline 2′-β-N-

xide (49), and (+)-12-O-methylcocsoline 2′-β-N-oxide (50), were

solated from polar fractions of the roots of Anisocycla cymosa,

n addition to eight known bisbenzylisoquinoline, aporphine, pro-

oberberine, and phenanthrene alkaloids (Kanyinda et al. 1993).

ore recently, compound (49) was identified from water extract

f the root of Epinetrum villosum (Menispermaceae), and cocso-

ine displayed antibacterial and anti-fungal activities (MIC values of

000–15.62 and 31.25 μg/ml, respectively). Cycleanine acted against

IV-2 (EC50 = 1.83 μg/ml) but was at least 10-fold less active against

reisigine N-oxide

N

OMe

O-

Me

igine N-oxide

N

OMe

O-

Me

+

+

N

O

O

HO OH

OMe

H

O-

H

43 Ungiminorine N-oxide

42 Merenderine N-oxide

N

MeO

HO

MeO

MeO

OH

O-

Me

+

+

188 V.M. Dembitsky et al. / Phytomedicine 22 (2014) 183–202

44 trans-Cularidine N-oxide

O

N

MeO

HO-

Me

HO

OMe

O

NHO

MeO OMe

H

O-

Me

O

N

MeO

HO-

Me

MeO

OMe

45 cis-Cularidine N-oxide

46 cis-Cularine N-oxide

+

+

+

O

NMeO

MeO

H

HO

O-

Me

O

NMeO

MeO

H

MeO

O-

Me

47 cis-Sarcocapnine N-oxide

48 cis-Sarcocapnidine N-oxide

+

+50 (+)-12'-O-Me-Cocsoline

2'-β-N-oxide

49 (+)-Cocsoline 2'-β-N-oxide

O

N

O

O

OMe

NH

OMe

H

HMe

-O

O

N

O

O

OMe

NH

OH

H

HMe

-O

+

+

N

MeO OMe

O-Me

N

MeO OMe

Me

O

O

N

MeO OMe

O-Me

N

MeO OMe

Me

O

O

52 Cycleanine β-N-oxide

53 Cycleanine α-N-oxide

51 Cycleanine N-oxide

N

MeO OMe

O-Me

N

MeO OMe

Me

O

O

+

+

+

a

h

t

d

a

l

i

(

(

p

1

w

i

m

t

e

i

1

f

i

1

n

2

l

o

f

(

(

l

i

G

(

8

HIV-1. Cycleanine N-oxide (51) showed no activity toward all tested

microorganisms (Otshudi et al. 2005).

Cycleanine N-oxide (51) was isolated from the stems of Synclisia

scabrida, along with the known bisbenzylisoquinoline alkaloids cy-

cleanine, norcycleanine, cocsuline, and cocsoline (Ohiri et al. 1983).

Oxidation of cycleanine with m-chloroperbenzoic acid gave two

diastereomeric N-oxides (β- and α-N-oxide), and their stereochem-

istry was unambiguously detected on the basis of spectroscopic

evidence. The NMR spectra of synthetic cycleanine mono-N-oxides

(β- 52 and α-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′-β-

N-oxide (54), along with six known alkaloids, 2-norobaberine, daph-

nandrine, 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’-β-N-oxide

(55) and kurramine 2′-α-N-oxide (56), and three known bisbenzyl-

isoquinoline alkaloids (Rahman et al. 2004; Rahman 1986; Bhakuni

2002). Compounds (55 and 56) were screened for their anti-

cholinesterase activity in a mechanism-based assay. Compound (55,

IC50 = 10 μM) and (56, IC50 = 150 μM) have inhibited acetyl-

cholinesterase, 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-methoxy-

oxohemandaline, 7-formyldehydro-hernangerine, 5,6-dimethoxy-N-

methylphthalimide, 7-hydroxy-6-methoxy-L-methyl-isoquinoline

nd (+)-vateamine 2′-β-N-oxide (56), along with one new dialde-

yde, hernandial, have been isolated and characterized from the

runk bark of Hernandia nymphaeifolia (Chen et al. 1996).

Aporphine alkaloids from Formosan Hernandia nymphaeifolia

emonstrated anti-platelet aggregation activity (Chen et al. 2000),

nd cytotoxic activity against the P388 lymphocytic leukemia cell

ine and human tumor cell lines (Pettit et al. 2004).

Some bisbenzylisoquinoline N-oxide alkaloids (58–61) were

solated from some plant species: limacusine 2’-β-N-oxide (58)

Kanyinda et al. 1995), and 12-O-methylcocsoline 2′-β-N-oxide (59)

Kanyinda et al. 1993) isolated from Anisocycla jollyana, and com-

ounds (60 and 61) isolated from Cyalea sutchuenensis (Lai et al.

993a,b) (both plants belonging to the family Menispermaceae).

Unusual homoproaporhine alkaloid, robustamine cis-N-oxide (62)

as isolated from plant Merendera robusta (family Liliaceae) growing

n Uzbekistan (Yusupov 1996). Robustamine (Yusupov and Cham-

adov 1995) was isolated from the same plant. It has been shown

hat the plant produced increased amounts of homoaporphine at the

nd of the growing season (Yusupov 1996).

A new alkaloid funiferine N-oxide (63) was isolated from medic-

nal plants (Costa Rica) Tiliacora funifera (Menispermaceae) (Lopez

976), the same alkaloid also was isolated from the roots of Tiliacora

unifera from the West Africa (Dwuma-Badu et al. 1977). Funifer-

ne was detected in extracts of Tiliacora funifera (Tackie and Thomas

965, 1968), Tiliacora dinklagei (Tackie et al. 1975), Guatteria guia-

ensis (Berthou et al. 1988), and Guatteria boliviana (Mahiou et al.

000). Triclisia patens, contained funiferine and bisbenzylisoquino-

ine alkaloids, that displayed activity against L. donovani promastig-

tes (IC50 = 1.5 μg/ml) and T. brucei blood stream trypomastigote

orms (IC50 = 31.25 μg/ml) (Marshall et al. 1994).

Roemeria hybrida yielded proaporphine tryptamine N-oxides,

−)-roehybridine α-N-oxide (64) and (−)-roehybramine β-N-oxide

65), and 4′-OMe-(−)-roehybramine β-N-oxide (66). NMR data al-

owed a facile assignment of these proaporphine tryptamine dimers

nto different stereochemical subgroups (Gunes and Gozler 2001;

ozler 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

-benzylberbine A (67), and an unusual N-oxide derivative, named

V.M. Dembitsky et al. / Phytomedicine 22 (2014) 183–202 189

NH

OMe

OMe

O

N

MeO

MeOMe

O-

O

54 (+)-2-Norobaberine 2'-β-N-oxide

N

OH

O

N

HO

O

OH

Me

O-

56 Kurramine 2'-α-N-oxide

+

+

N

HO

H

O-

Me

N

OH

OO

O

55 Kurramine 2'-β-N-oxide

NMe

OMe

OH

OMe

OH

N

MeO

H

O-

MeHO

MeO

O

57 (+)-Vateamine 2'-β-N-oxide

+

+

8

g

a

(

q

(

fl

t

1

a

h

C

2

e

M

E

E

E

z

a

t

o

e

4

-benzylberbine B N-oxide (68) have been isolated from Aristolochia

igantea (Aristolochiaceae) (Lopes and Humpfer 1997). Non N-oxide

nalogs of alkaloids 67 and 68 were also identified in the same plants

Cortes et al. 1987; Lopes 1992). The biological activities of the iso-

uinoline N-oxide alkaloids (36–61) and their non oxidized analogs

A36–A61) are shown in supplementary Tables 2 and 3.

Different erythrinaline alkaloids have been isolated from the

owers and pods of Erythrina lysistemon, and among them

he new compounds are (+)-11β-hydroxyerysotramidine, (+)-

1β-hydroxyerysotrine N-oxide (69), and two C-11 epimers (70

nd 71), (+)-11β-methoxyerysotramidine N-oxide (72), (+)-11β-

ydroxyerysotrine, and 11-dehydroerysotrine (73). The crude

HCl3/MeOH extract showed moderate toxicity to brine shrimp (LC50

58 Limacusine 2'-β-N-oxide

NMe

OMe

OMe

O

N

MeO

HO

O

O-

MeH

59 12-O-Methylcocsoline 2'-β-N-oxide

NH

OMe

O

N

MeO

O

O-

MeH

O +

+

3 μg/ml) and moderate (IC50 86 μg/ml) radical scavenging prop-

rties against stable 2,2-diphenyl-1-picrylhydrazyl radical (Juma and

ajinda 2004). The same non N-oxides were identified from the genus

rythrina (Amer 2001; Letcher 1971; Barton et al. 1970). Aqueous

tOH and EtOAc extracts of the bark and leaves of five South African

rythrina species: E. caffra, E. humeana, E. latissima, E. lysistemon and E.

eyheri, showed prostaglandin synthesis-inhibitory and antibacterial

ctivities. The highest cyclooxygenase-inhibiting and antibacterial ac-

ivity was found in the aqueous EtOH and EtOAc extracts of the bark

f E. caffra, E. latissima and E. lysistemon (Pillay et al. 2001).

The genus Aristolochia (Aristolochiaceae) is found in wide ar-

as, from the tropics to temperate zones and consists of about

00 species. Some species have been used in the form of crude

60 Insularine 2-β-N-oxide

N

OMe-O

MeH

OMe

O

ON

Me

MeO

O

H

N

OMe

MeH

OMe

O

ON

MeO

O

HO-

Me

61 Insularine 2'-β-N-oxide

+

+

190 V.M. Dembitsky et al. / Phytomedicine 22 (2014) 183–202

60 Insularine 2-β-N-oxide

N

OMe-O

MeH

OMe

O

ON

Me

MeO

O

H

N

OMe

MeH

OMe

O

ON

MeO

O

HO-

Me

61 Insularine 2'-β-N-oxide

+

+

+

+

HO

MeO

N

Me

MeO

N-O

Me

OMe

OMe

O

63 Funiferine N-oxide

62 Robustamine cis-N-oxide

N

O

OMe OMe

OH

HMeO-

+

+

HO

MeO

N

Me

MeO

N-O

Me

OMe

OMe

O

63 Funiferine N-oxide

62 Robustamine cis-N-oxide

N

O

OMe OMe

OH

HMeO-

+N

H

MeHO

MeO

NHNH

OMe

O-

OMe

+N

H

Me

O-HO

MeO

NHNH

OMe

MeO

N

H

O-

MeHO

MeO

NHNH

OMe

OMe

MeO

64 (-)-Roehybridineα-N-oxide

65 (-)-Roehybridineβ-N-oxide

66 (-)-Roehybramineβ-N-oxide

+

a

m

M

s

t

k

s

o

N

2

(

N

t

(

c

a

N

(

drugs as anodynes, antiphlogistics, antitussives, expectorants, an-

tiasthmatics and detoxicants, especially in China. Three N-oxide

benzoyl benzyltetrahydroisoquinoline ether alkaloids, aristoquino-

line A (74), aristoquinoline B (75), and aristoquinoline C (76) were

isolated from Aristolochia elegans. The benzoyl benzyltetrahydro-

isoquinoline 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. pedun-

cularis, and A. serrata (Silva et al. 1996, 1997; Cespedes et al. 1993).

Isoboldine β-N-oxide (77) has been isolated from leaves of Crypto-

carya chinensis (Velcheva et al. 1995; Lin et al. 2002), and isobol-

dine was found in Peumus boldus (Vanhaelen 1973; Genest et al.

1969), Corydalis gortschakovii (Israilov et al. 1977), Berberis integerrima

(Karimov et al. 1978), Aconitum karakolicum (Sultankhodzhaev et al.

1979), Cocculus laurifolius, Galanthus caucasicus, Magnolia obovata,

Cocculus laurifolius, and Veratrum lobelianum (Tsakadze et al. 2005,

1997).

Erythristemine N-oxide (78) was isolated from flowers of Eryth-

rina 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 iso-

lated 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 Ery-

thrina 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 al-

kaloids 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 de-

tected 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

lkaloids detected in E. americana and E. coralloides together with

inor alkaloids which support their taxonomic differences (Garcia-

ateos et al. 1998).

A series of 53 isoquinoline alkaloids isolated from different plant

pecies, and including some N-oxides have been tested for their cyto-

oxicity against A-549, HCT-8, KB, P-388, and L-1210 cells. These al-

aloids include two tetrahydroprotoberberines, two protoberberines,

ix aporphines (including 81 and 82), one morphinandienone, five

xoaporphines, seven phenanthrenes, one spirobenzyl-isoquinoline

-oxide (101), nine aporphine N-oxides (24, 27, 87, 88), (22 and

3 epimers), (89–83), seven benzyltetrahydro-isoquinoline N-oxides

37, 39, 94–98), one benzyl-isoquinoline N-oxide (99), one protopine

-oxide (102), three tetrahydro-protoberberine N-oxides (103–105),

hree 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

ancer cells: thus, dihydroochotensimine N-oxide (101) showed

ctivity against KB cell line (ED50 = 2.5 μg/ml), (−)-dicentrine

-oxide (89) showed activity against KB cell line (ED50 = 3.3 μg/ml),

−)-armepavine N-oxide (39) and dicentrine methane N-oxide (84)

V.M. Dembitsky et al. / Phytomedicine 22 (2014) 183–202 191

s

f

m

1

a

T

(

(

i

t

t

l

(

1

i

w

i

t

t

w

1

c

s

(

C

c

(

s

a

l

d

l

2

a

(

(

a

t

S

C

(

c

C

n

1

b

g

a

t

m

N

s

a

d

N

o

l

f

2

z

s

NMeO

MeO

OOMe

OMe

NMeO

MeO

HOOMe

OMe

Papaveraldine

Papaverinol

NMeO

MeO

HOOMe

OMe

O-

106 Papaverinol N-oxide

+

Fig. 2. Fermentation of papaveraldine with Mucor ramannianus has resulted in a stere-

oselective reduction of the ketone group and the oxidation of (S)-papaverinol to (S)-

papaverinol N-oxide (106). Papaverinol also could be oxidized to N-oxide under UV

conditions.

t

e

a

t

a

t

a

r

a

p

2

t

(

d

c

c

p

f

(

p

g

i

e

a

howed same activities against KB cell line (ED50 = 4.0 μg/ml). The

act that all other tested isoquinoline N-oxide alkaloids showed only

arginal activity against KB cells (Ioanoviciu et al. 2005; Mayr et al.

997; Tan et al. 1991).

Inhibitory effects of isoquinoline-type alkaloids (37, 84, 94, 95

nd 97) on leukemic cell growth were studied (Ohiri et al. 1983).

he l-(+)-laudanidine N-oxide (37), dicentrine methine N-oxide (84),

±)-armepavine N-oxide (94), l-(+)-armepavine N-oxide (95), and

±)-N-methylcoclaurine N-oxide (97) have been isolated from the

ndigenous plants of Taiwan, and they were studied for their po-

ency in inhibiting precursor incorporation into DNA, RNA and pro-

ein. These compounds showed inhibitory activity against murine

eukemic L1210 and human leukemic CCRF-CEM and HL-60 cell

IC50 < 10 μM) (Ioanoviciu et al. 2005; Mayr et al. 1997; Tan et al.

991).

Reticuline N-oxide (88) was isolated from aerial parts of flower-

ng Corydalis pseudoadunca, and total alkaloid content was 1.39% dry

eight (Israilov et al. 1985), and reticuline N-oxide (88) also was

solated from Pachygone ovata (Dasgupta et al. 1979); it showed cen-

ral stimulant, hyperthermic, and spinal convulsant actions in mice,

he activity profile closely resembling that of thebaine. Reticuline

as identified from Argemone albiflora, A. ochroleuca (Israilov et al.

986), and Cinnamomum camphora (Tomita and Kozuka 1964). The

ardiovascular effects of reticuline, isolated in a pure form from the

tem of Ocotea duckei was reported (Dias et al. 2004). Reticuline

3 × 10−6, 3 × 10−5, 3 × 10−4, 9 × 10−4 and 1.5 × 10−3 M) antagonized

aCl2-induced contractions, and also inhibited the intracellular cal-

ium dependent transient contractions induced by norepinephrine

1 μM), but not those induced by caffeine (20 mM). These results

uggest that the hypotensive effect of reticuline was probably due to

peripheral vasodilation in consequence of: (A) muscarinic stimu-

ation and NOS activation in the vascular endothelium, (B) voltage-

ependent Ca2+ channel blockade and/or (C) inhibition of Ca2+ re-

ease from norepinephrine-sensitive intracellular stores (Dias et al.

004).

Antimicrobial activity of isoquinoline N-oxide alkaloids: D-(−)-

rmepavine N-oxide (39), d-(+)-N-methylcoclaurine N-oxide (97),

±)-tetrahydro-palmatine N-oxide (103), (+)-laudanidine N-oxide

37); dicentrine methine N-oxide (84), eschscholtzine N-oxide (11,

nd 81) isolated from Formosan annonaceous plants against bac-

eria and yeasts: Pseudomonas aeruginosa, Staphylococcus aureus,

almonella paratyphi B, Escherichia coli, Streptococcus hemolyticus,

andida albicans, and Cryptococcus neoformans has been reported

Letasiova et al. 2005; Tsai et al. 1989; Wu et al. 1988). The antimi-

robial activity of 23 isoquinoline alkaloids from Turkish Fumaria and

orydalis species was detected, and many alkaloids displayed a sig-

ificant activity against Gram-positive and Gram-negative bacteria at

μg/ml concentration. Phthalideisoquinolines and tetrahydroproto-

erberines were the most active groups (Abbasoglu et al. 1991).

A group of semi-synthetic structural analogs of glaucine, including

laucine N-oxide (93) inhibited the central nervous system, caused

decrease in blood pressure, and had spasmolytic activity in labora-

ory’s animals (Todorov and Zamfirova 1991; Petkov et al. 1979; Di-

ant and Bardashevskaia 1974; Donev 1964). Dehydrogenation and

-oxide of glaucine reduced its spasmolytic action. Glaucine and six

tructural analogs including glaucine N-oxide (93) showed inhibitory

ctivity of cyclic 3′,5′-AMP-phosphodiesterase in homogenates from

ifferent organs of guinea pigs and rats (Petkov and Stancheva 1980).

-Methyl-bulbocapnine N-oxide (24), N-methyl-actinodaphnine N-

xide (87), oxoglaucine, boldine, and actinodaphnine showed vasore-

axing action in rat thoracic aorta (Chen et al. 1996). Microbial trans-

ormation of papaveraldine has also been reported (Fig. 2) (El Sayed

000).

Preparative-scale fermentation of papaveraldine, the known ben-

ylisoquinoline alkaloid, with Mucor ramannianus 1939 (sih) has re-

ulted in a stereoselective reduction of the ketone group and the isola-

ion of S-papaverinol and S-papaverinol N-oxide (106). The structure

lucidation of both metabolites was based primarily on NMR analyses

nd chemical transformations. These metabolism results were consis-

ent with the previous plant cell transformation studies on papaverine

nd isopapaverine. Photochemical degradation of papaverine solu-

ions and oxidation products that were papaverinol, papaveraldine,

nd papaverine N-oxide (106) under the influence of UV light, was

eported (Girreser et al. 2003; Souto-Bachiller et al. 1999; Bremner

nd Wiriyachitra 1973). Papaverine hydrochloride, papaverinol, and

apaveraldine chloroform solutions were exposed to UV light of

54 nm in atmospheric, aerobic and anaerobic (helium) condi-

ion, their photooxidation in chloroform solutions was studied

Piotrowska et al. 2002; Muller and Dorfman 1934). The same

egradation products appear in the above papaverine hydrochloride

hloroform solutions.

However, the rate of papaverine hydrochloride degradation pro-

esses is enhanced as a function of oxygen pressure. Papaverinol and

apaveraldine photooxidation products are essentially not different

rom those observed in the above papaverine hydrochloride solutions

Fig. 2). However, the amount of an unknown brown degradation

roduct (X) is the greatest in the papaverinol chloroform solution de-

raded. That brown compound was previously observed in papaver-

ne either hydrochloride or sulfate injection solutions on their storage

ven when protected from daylight (Piotrowska et al. 2002; Muller

nd Dorfman 1934).

192 V.M. Dembitsky et al. / Phytomedicine 22 (2014) 183–202

+

+

68 8-Benzylberbine B N-oxide

67 8-Benzylberbine N-oxide

N

HOH

OGlc

MeO

HO

OH

O-

N

HOH

OGlc

HO

MeO

OH

O-

+

+

+

71

70 Erysotrine N-oxide

N

MeO

MeO

OH

O-

MeO

N

MeO

MeO

OH

O-

MeO

69 (+)-11β-OH-ErysotrineN-oxide

N

MeO

MeO

OH

O-

MeO

N

MeO

MeO

OMe

O-

MeO

N

MeO

MeO

O-

MeO

72 (+)-11β-MeO-ErysotramidineN-oxide

73 11-dehydro-Erysotrine

+

+

A

d

N

MeO

MeO

O

OMe

HOOC

Me

O-

H

74 Aristoquinoline A

75 Aristoquinoline B

N

MeO

MeO

O

OMe

HOOC

O-

MeH

+

+

76 Aristoquinoline C

N

MeO

MeO

O

OH

HOOC

O-

MeH

N

MeO

HO

MeO

MeH

O-

77 Isoboldine N-oxide

+

+

t

a

a

1

N

d

m

(

(

1

Selective inhibition of calcium entry induced by benzylisoquino-

lines 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 or-

der to determine the minimal structural requirements that enable

these compounds to have either a non-specific action like papaver-

ine 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 con-

tractions. Only glaucine and laudanosine inhibited K+-induced uter-

ine contractions more than oxytocin-induced uterine contractions.

In Ca+-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), (−)-trans-

corydalmine N-oxide (110), (−)-trans-isocorypalmine N-oxide (111),

together with known compounds, 6-methoxydihydro-sanguinarine

and norjuziphine, were isolated in continuing studies of the en-

tire 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 aggre-

gation activity (Chen et al. 2001).

The cytotoxic effects of the isolates were tested in vitro against P-

388, 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,

549, and HT-29 cell lines. Among them, norsanguinarine, dihy-

rosanguinarine, and (±)-scoulerine exhibited effective cytotoxici-

ies (ED50 < 4 μg/ml) against P-388, KB16, A549, and HT-29 cell lines,

nd palmatine showed selective cytotoxicity (ED50 < 4 μg/ml) only

gainst the P-388 cell line (Chen et al. 1999).

In addition, the tetrahydroprotoberberine N-oxides, (107, 108,

09, 110, and 111), were less active as (±)-tetrahydroberberine

-oxide, (±)-tetrahydro-jatrorrhizine N-oxide and (±)-tetrahy

ropalmatine N-oxide. Furthermore, norsanguinarine was the

ost cytotoxic isolate, and exhibited a more potent cytotoxicity

ED50 = 0.051 μg/ml) against the P-388 cell line than mithramycin

ED50 = 0.056 μg/ml) (Chen et al. 2001). N-Oxide alkaloids (108–

11), and (−)-cis-corydalmine N-oxide (112) have been isolated from

V.M. Dembitsky et al. / Phytomedicine 22 (2014) 183–202 193

+

+

+

N

MeO

O-

MeO

MeO

79 Erysotrine N-oxide

78 Erythristemine N-oxide

N

OMe

MeO

O-

MeO

MeO

N

MeO

O-

MeO

MeO

OH

80 Erythrartine N-oxide

N

O

OOH

Me

OMe

N

O

OOH

Me

OMe

MeO

81

82

N

O

OO-

Me

OMe

Me

83 N-Me-Xylopine methineN-oxide

+

85 Glaucine methineN-oxide

N

O-

Me

OMe

MeO

MeO

MeO

Me

84 Dicentrine methineN-oxide

N

O

OO-

Me

OMe

Me

MeO

N

O-

Me

MeO

MeO

Me

86 AtherosperminineN-oxide

+

+

+

t

c

s

g

f

s

3

u

t

Y

i

m

2

e

d

(

l

a

s

v

P

E

t

l

d

s

s

i

(

+

+

+N

O

OO-

Me

OH

MeO

87 N-Me-ActinodaphnineN-oxide

N

O

OO-

Me

MeO

MeO

88 (+)-O-Me-BulbocapnineN-oxide

N

O

OO-

Me

OMe

MeO

89 (-)-Dicentrine N-oxide

+N

O

OO-

Me

OMe

90 (-)-N-Me-XylopinineN-oxide

+

+

+

93 Glaucine N-oxide

N

O-

Me

OMe

MeO

MeO

MeO

92 (+)-Boldine N-oxide

N

O-

Me

OH

MeO

MeO

HO

91 (+)-N-Me-LaurotetanineN-oxide

N

O-

Me

OH

MeO

MeO

MeO

b

(

a

e

he herb Corydalis tashiroi (Berthou et al. 1988). The (−)-trans-

orydalmine N-oxide (110) and (−)-cis-corydalmine N-oxide (112)

howed stronger inhibitory activity than corydalmine on platelet ag-

regation induced by AA and collagen, due to the effect of N-oxide

unction. Three of the isolated compounds non-N-oxide alkaloids

howed significant cytotoxic activities (ED50 < 4 μg/ml) against P-

88, KB16, A549, and HT-29 cell lines.

Sixteen compounds and including a new stereoisomer of (+)-

shinsunine-β-N-oxide (113a) were isolated from the methanolic ex-

ract of the Cananga odorata (Hsieh et al. 1999; Yang and Huang 1988,

ang and Huang 1989). N-oxides of (113a) and lyscamine (113b) were

dentified from the same plant, and showed cytotoxic effects (supple-

entary Table 5) (Hsieh et al. 2001).

Ushinsunine was found in extracts of Michelia compressa (Lo et al.

004), Annona cherimola (Chen et al. 1997), Stephania epigaea (Peng

t al. 1990), Oxymitra velutina (Achenbach and Hemrich 1991), Pseu-

oxandra sclerocarpa (Cortes et al. 1986), and Polyalthia nitidissima

Jossang et al. 1983). Ushinsunine, which was isolated from Miche-

ia compressa var. formosana, showed strong bacteriostatic activity

gainst Staphylococcus, and strong bactericidal action against Shigella

p., Mycobacterium sp. and Bacillus subtilis, and prevented decay in

arious named wood (Wright et al. 2000).

Twenty-one alkaloids have been assessed for activities against

lasmodium falciparum (multidrug-resistant strain K1) in vitro, and

ntamoeba histolytica. Two protoberberine alkaloids, dehydrodiscre-

ine and berberine, were found to have antiplasmodial IC50 values

ess than 1 μM, while seven alkaloids-allocrytopine, columbamine,

ehydroocoteine, jatrorrhizine, norcorydine, thalifendine, and ushin-

unine had values between 1 and 10 μM. Compounds were also as-

essed for anti-amoebic and cytotoxic activities, but none was signif-

cantly active except for berberine, which was moderately cytotoxic

Villinski et al. 2003; Moody et al. 1995; Wu et al. 1994).

Kampo medicine, Stephania tetrandra in Boi-Ogi-To increases the

lood insulin level and falls the blood glucose level in streptozotocin

STZ)-diabetic ddY mice. These actions of S. tetrandra are potenti-

ted by Astragalus membranaceus (Astragali) in Boi-Ogi-To (Tsutsumi

t al. 2003; Liu et al. 2002). Actions of bis-benzylisoquinoline alkaloids

194 V.M. Dembitsky et al. / Phytomedicine 22 (2014) 183–202

+

+

+

93 Glaucine N-oxide

NO-

Me

OMe

MeO

MeO

MeO

92 (+)-Boldine N-oxide

NO-

Me

OH

MeO

MeO

HO

91 (+)-N-Me-LaurotetanineN-oxide

NO-

Me

OH

MeO

MeO

MeO

+

+

+

96 (+)-ReticulineN-oxide

95 (+)-ArmepavineN-oxide

NO-

Me

HO

MeO

MeOH

94 ArmepavineN-oxide

NO-

Me

OH

MeO

MeO

HO

NO-

Me

HO

MeO

MeO

+

+

98 (+)-N-Me-CoclaurineN-oxide

97 N-Me-CoclaurineN-oxide

NO-

Me

HO

MeO

HOH

NO-

Me

HO

MeO

HO

N

MeO

MeO

MeO

OMe

O-

99 Papaverine N-oxide

+

+

+

+

102 Protopine N-oxide

O

O N

O

OO

O-Me

101 DihydroochotensiminN-oxide

N

O

O

MeO

MeO

Me

O-

100 (-)-Crychine N-oxide

O

OMeO

MeO

N-O

Mew

c

1

d

l

c

F

h

7

b

d

1

c

h

f

d

(

e

t

a

T

t

a

t

N

a

isolated from S. tetrandra were investigated in the hyperglycemia of

STZ-diabetic mice (Tsutsumi et al. 2003; Liu et al. 2002).

Fangchinoline 2′-N-α-oxide (117) and 2’-N-norfangchinoline,

hich are substituted with 7-hydroxy side chain for 7-O-methyl side

hain, decreased to near 50% of high blood glucose level (Ogino et al.

987, 1990, 1998). In addition, tetrandrine 2’-N-β-oxide (114), tetran-

rine 2’-N-α-oxide (115), tetrandrine 2-N-β-oxide (116), fangchino-

ine 2’-N-α-oxide (117), which were added to 2- or 2’-N-oxide side

hain, also decreased to near 50% of the high blood glucose level.

angchinoline but not tetrandrine from Stephania showed the anti-

yperglycemic action in the STZ-diabetic mice. The demethylation of

-O-position and/or addition of 2- or 2’-N-oxide side chain in bis-

enzylisoquinoline compounds in S. tetrandra have a role for the in-

uction of the anti-hyperglycemic actions (Ogino et al. 1987, 1990,

998).

Fangchinoline was also isolated from Stephania tetrandra, Cy-

lea barbata, Hypscrpa nitida, Stepahania cepharantha, Stephaniae

ainanensis, and Menispermum dauricum (Zhang 2005). Derivatives

rom fangchinoline and tetrandrine to reverse P-glycoprotein (P-gp)-

ependent multidrug resistance in vitro and in vivo were reported

Wang et al. 2005). All compounds enhanced the in vitro cytotoxic

ffect of vinblastin at 0.1 μM as potent as 10 μM verapamil against

he resistant cell line P388/ADR. Reviewed and predicted biological

ctivities for N-oxide alkaloids (69–95) are shown in supplementary

ables 3 and 4.

The alkaloidal fraction from the roots of Cyclea barbata contain

wo new bisbenzylisoquinoline alkaloids, namely, (−)-2′-norlimacine

nd (+)-cycleabarbatine (Guinaudeau et al. 1993). The known (+)-

etrandrine 2′-β-N-oxide (114), for which the configuration of the

-oxide function was identified.

The 39 protoberberine derivatives were tested for antimalarial

ctivity in vitro against Plasmodium falciparum and structure–activity

V.M. Dembitsky et al. / Phytomedicine 22 (2014) 183–202 195

NH

HO

HO

HO

HO

HO

COOH

NH2

Tyrosine

N

O

O

OMe

Me

Norlaudanosoline Stephanine

N

COOHO

O

R

118 Aristolochic acid I, R = OMe119 Aristolochic acid II, R = H

N

MeO

MeO

MeO

99 Papaverine N-oxide

O

O

O

NH

MeO

MeO

MeO

MeO

Tetrahydropapaverine

OMe

Fig. 3. A proposed biosynthetic pathway of papaverine N-oxide and aristolochic acids.

r

p

n

p

a

r

s

d

t

b

a

T

(

t

h

w

(

c

(

t

p

p

1

a

T

w

k

m

t

i

e

elationships was proposed (Silva et al. 1996,1997). The activity of the

rotoberberine alkaloids was influenced by the type of the quaternary

itrogen atom, the nature and the size of the substituents at the C-13

osition, and the type of O-alkyl substituents on rings A and D. The

ctivity of the quaternary protoberberinium salts with an aromatic

ing C such as berberine was higher than that of the quaternary salts

uch as the N-metho- salts or the N-oxides of tetrahydro- and dihydro-

erivatives as well as tertiary tetrahydroproto-berberines.

A positive effect on the activity might be exerted by the introduc-

ion of a more hydrophilic function into the C-13 position of the proto-

erberinium salts (Iwasa et al. 1998, 1999). Reviewed and predicted

ctivities for N-oxide alkaloids (96–108) showed in supplementary

ables 4 and 5.

(S)-Reticuline is the universal precursor to the majority of IQA

Sato 2005; Zenk 1989; Bhakuni 1983). The biosynthesis of this impor-

ant intermediate starting from the primary metabolite, L-tyrosine,

as been completely solved at the enzyme level. Reticuline N-oxide

as isolated from aerial parts of flowering Corydalis pseudoadunca

Israilov et al. 1985), Pachygone ovata (Dasgupta et al. 1979), Mono-

yclanthus vignei (Achenbach et al. 1991), and Glossocalyx brevipes

Montgomery et al. 1985). (+)-Reticuline from young leaves of Guat-

eria dumetorum showed the growth inhibitory activity against the

arasite Leishmania mexicana (Correa et al. 2006); stimulated the

roliferation of cultured cells from murine hair app (Nakaoji et al.

997); and it was active against HSV-1 (herpes simplex virus), as well

s HSV-1 thymidine kinase deficient (acyclovir resistant type, HSV-1

K-) and HSV-2 (IC50 values of 8.3, 7.7 and 6.7 μg/ml, respectively), it

as cytotoxic (Nawawi et al. 1999).

One of the most diverse structures in the class of isoquinoline al-

aloids are the benzo[c]phenanthridines. The most highly oxidized

ember is macarpine, an alkaloid produced in considerable quan-

ity in cell suspension cultures of Eschscholtzia californica and Thal-

ctrum bulgaricum. This plant source was used to isolate all of the

nzymes involved in this pathway. Twelve steps are necessary for the

196 V.M. Dembitsky et al. / Phytomedicine 22 (2014) 183–202

+

+N

MeO

MeO

OMe

OMe

H

O-

103 TetrahydropalmatineN-oxide

N

MeO

HO

OMe

OMe

H

O-

104 TetrahydrojatrorrhizineN-oxide

105 TetrahydroberberineN-oxide

N

OMe

OMe

H

O-O

O+ N

MeO

MeO

OMe

OMe

O-

H

109 EpicorynoxidineN-oxide

NHO

MeO

OMe

OMe

O-

H

108 (-)-cis-IsocorypalmineN-oxide

107 (-)-trans-IsocorypalmineN-oxide

NMeO

MeO

OMe

OMe

O-

H

+

+

+

f

d

f

A

a

t

r

1

H

o

f

c

A

a

h

2

1

f

e

a

M

1

p

r

t

a

m

l

k

a

transformation of (S)-reticuline to macarpine, eleven of these are en-

zyme catalyzed, have recently been reviewed (Sato 2005; Zenk 1989;

Bhakuni 1983).

Reviewed and predicted activities for metabolites (112–117 and

A112–A117) represented in supplementary Table 5, and demon-

strated 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; Sánchez-Calvo et al., 2013; Parry et al. 2011). These compounds

are organic molecules that consist of at least one nitro group (–NO2)

attached to an aromatic ring, or alkyl moieties, and display great struc-

tural diversity, and a wide range of biological activities (Boelsterli

et al., 2006). Several Gram-negative bacteria, including Burkholde-

ria (El Banna and WinkelmannEl-Banna et al., 1998; Mendes et al.,

2007; Roitman et al., 1990) strains, Corallococcus exiguus, Cystobac-

ter 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 Acti-

nosporangium vitaminophilum produced nitro-containing antibi-

otics 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 (Loria et al., 2008; King and

Calhoun 2009), cyclic heptapeptides (Takita, et al., 1964), and other

compounds (Ju and Parales, 2010; Winkler and Hertweck 2007).

Among nitro-containing metabolites, the aristolochic acids are a

amily of substituted 10-nitro-1-phenantropic acids, biogenetically

erived from benzylisoquinoline precursors, which in turn originate

rom tyrosine amino acid (Michl et al., 2014; Kumar et al., 2003).

proposed biosynthetic pathway of papaverine N-oxide (99) and

ristolochic acids (118 and 119) showed in Fig. 3. The scientific de-

ails of aristolochic acids biosynthesis have been reported in several

esearch papers (Schütte et al., 1967; Comer et al., 1969; Sharma et al.,

982; Krumbiegel et al. 1987), and recently reviewed (Winkler and

ertweck 2007; Michl et al., 2014; Kumar et al., 2003). The plants

f the genera Aristolochia and Asarum became the interesting topic

or the phytochemical and pharmaceutical researchers since the dis-

overy of aristolochic acid derivatives. Species of Aristolochia and

sarum were widely distributed in tropical, subtropical and temper-

te regions of the world (Hou, 1996). Various species of both genera

ave been used in the folk and traditional medicines (Lopes et al,

001), especially in the traditional Chinese medicines (Bensky, et al.,

993).

At present time a lot of derivatives of aristolochic acids have been

ound and their structures also reported (Michl et al., 2014; Kumar

t al., 2003). Biological activities and toxicology of aristolochic acids

nd derivatives have also been reported (Jordan and Perwaiz 2014;

ichl et al., 2014; Aronson 2014.).

While papaverine N-oxide (99) and aristolochic acids (118 and

19) having a common biosynthetic pathway, but, from the stand-

oint of chemistry, it is a different class of organic compounds. This

eview is devoted to isoquinoline N-oxide alkaloids, which shows

heir reported and SAR activities. Nitro aromatic compounds are very

lso an interesting group of natural compounds, and this family of

etabolites should be discussed in other review article. Neverthe-

ess, using the program PASS, we provide SAR activities two most

nown nitro aromatic compounds such as aristolochic acid I (118)

ristolochic acid II (119). Thus, aristolochic acid I (118) shown 397

V.M. Dembitsky et al. / Phytomedicine 22 (2014) 183–202 197

105 TetrahydroberberineN-oxide

N

OMe

OMe

H

O-O

O+

NMeO

MeO

OMe

OMe

O-

H

109 EpicorynoxidineN-oxide

NHO

MeO

OMe

OMe

O-

H

108 (-)-cis-IsocorypalmineN-oxide

107 (-)-trans-IsocorypalmineN-oxide

NMeO

MeO

OMe

OMe

O-

H

+

+

+

110 (-)-trans-CorydalmineN-oxide

NHO

MeO

OMe

OMe

O-

H

+

111 (-)-Corynoxidine N-oxide

NMeO

MeO

OMe

OMe

O-

H

+

113a (+)-Ushinsunineβ-N-oxide, α = H, β = OH113b LyscamineN-oxide, β = H, α = OH

O

O N

OH

Me

HO-

NMeO

MeO

OMe

OH

O-

H

112 (-)-cis-Corydalmine N-oxide

+

+

o

a

m

C

l

s

t

i

r

a

a

p

q

b

S

i

f 3300, and aristolochic acid II (119) shown 762 of 3300 possible

ctivities at Pa > Pi, and in supplementary Table 6 shows only the 40

ost probable activities.

oncluding remarks

Some IQA such as papaverine, sanguinarine, protoverine, and che-

idonine are gastrointestinal tract irritants and central nervous system

timulants. Isoquinoline alkaloids are found in varying quantities in

he prickly poppy, bloodroot, and celandine poppy. Many have vary-

ng degrees of neurologic effects, ranging from relaxation and eupho-

ia to seizures. Among many thousands of modern drugs, about 41%

re of natural origin. The widest spectra of pharmacological activities

re exhibited by isoquinoline alkaloids, and their N-oxides. Using the

rogram PASS we have shown that many reported activities for iso-

uinoline N-oxides have been predicted, including some additional

iological activities.

upplementary materials

Supplementary material associated with this article can be found,

n the online version, at doi:10.1016/j.phymed.2014.11.002.

198 V.M. Dembitsky et al. / Phytomedicine 22 (2014) 183–202

115 Tetrandrine 2'-N-α-oxide

NMe

OMe

OMe

OMe

NO-

MeO

O

O

Me

114 Tetrandrine 2'-N-β-oxide

NMe

OMe

OMe

OMe

NO-

MeO

O

O

Me+

+

116 Tetrandrine 2-N-β-oxide

N

OMe

OMe

OMe

N

MeO

O

O

Me

Me-O

117 Fangchinoline 2'-N-α-oxide

NMe

OMe

OH

OMe

NO-

MeO

O

O

Me

+

+

B

B

B

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

C

D

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