Post on 30-Mar-2023
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.
I
u
a
n
t
t
d
P
2
Z
2
i
H
i
n
t
c
t
i
a
e
r
e
l
p
a
e
2
2
I
c
c
e
a
u
P
a
a
O
b
h
0
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).
(
P
l
(
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
o
h
t
h
s
s
“
i
t
O
a
K
P
A
m
l
a
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
r
e
w
S
i
i
(
n
(
p
h
1
i
(
(
1
αN
o
1
n
fi
a
b
i
t
t
S
αb
I
E
a
w
c
e
m
g
s
P
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 ofSTZ-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
References
Abbasoglu, U., Sener, B., Gunay, Y., Temizer, H., 1991. Antimicrobial activity of some
isoquinoline alkaloids. Arch. Pharm. (Weinheim)., 324, pp. 379–380.Abidov, A.A., Abdukhakimov, A., Mukhamedov, S.M., Yuldashev, P.Kh, 1962. Antimicro-
bical properties of alkaloids isolated from plants of Central Asia. Uzbek. Biol. Zh. 6,84–89.
Abidov, A.A., Mukhamedov, S.M., Abdukhakimov, A., 1963. Bactericidal proper-ties of some alkaloids from plants of Middle Asia. Med. Zh. Uzbek. 2,
45–47.
Achenbach, H., Frey, D., Waibel, R., 1991. Constituents of tropical medicinal plants. Part47. 6α,7-Dehydro-2-hydroxy-4,5-dioxonoraporphine and other alkaloids from
Monocyclanthus vignei: 13C-NMR studies on 4,5-dioxoaporphines. J. Nat. Prod. 54,1331–1336.
Achenbach, H., Hemrich, H., 1991. Constituents of tropical medicinal plants. Part 40.Alkaloids, flavonoids and phenylpropanoids of the West African plant Oxymitra
velutina. Phytochemistry 30, 1265–1267.
Al-Wakeel, S.A.M., Moubasher, M.H., Roberts, M.F., 1995. Alkaloids from Glauciumcorniculatum (L.) of Egyptian origin. Biochem. Syst. Ecol. 23, 337–338.
An, T.-Y., Huang, R.-Q., Yang, Z., Zhang, D.-K., Li, G.-R., Yao, Y.-C., Gao, J., 2001. Alkaloidsfrom Cynanchum komarovii with inhibitory activity against the tobacco mosaic
virus. Phytochemistry 58, 1267–1269.Anselmi, E., Fayos, G., Blasco, R., Candenas, L., cortes, D., D’Ocon, P., 1992. Selective
inhibition of calcium entry induced by benzylisoquinolines in rat smooth musde.J. Pharm. Pharmacol. 44, 337–343.
Amer, M.E., 2001. Alkaloids of Erythrina lysistemon L. leaves. Alexandria J. Pharm. Sci.
15, 40–43.Arima, K., Imanaka, M., Kousaka, M., Fukuda, A., Tamura, G., 1964. Pyrrolnitrin,
a new antibiotic substance, produced by Pseudomonas. Agric. Biol. Chem. 28,575–576.
Aronson, J.K., 2014. Plant poisons and traditional medicines, 23rd edition, Manson’sTropical Infectious Diseases, pp. 1128–1150.
Barton, D.H.R., Jenkins, P.N., Letcher, R., Widdowson, D.A., Hough, E., Rogers, D., 1970.
Erythristemine, a new alkaloid from Erythrina lysistemon; spectroscopic and crys-tallographic study. J. Chem. Soc., Chem. Commun. 7, 391–392.
Battersby, A.R., Edwards, T.P., 1959. Synthesis of calycotomine. J. Chem. Soc.,1909–1910.
Battersby, A.R., Edwards, A.U., Sohail, M., Sultan, A., Iqbal, C., Rehman, H.U., 1985.Nigellimine N-oxide – a new isoquinoline alkaloid from the seeds of Nigella sativa.
Heterocycles 23, 953–955.
Bensky, D., Gamble, A., Kaptchuk, T., Bensky, L.L., 1993. Chinese Herbal Medicine:Materia Medica, revised ed. Eastland Press, Seattle, 136.
Bentley, K.W., 2005. β-Phenylethylamines and the isoquinoline alkaloids. Nat. Prod.Rep. 22, 249–268.
Berthou, S., Jossang, A., Guinaudeau, H., Leboeuf, M., Cave, A., 1988.Bis(benzylisoquinoline)biphenyl alkaloids from Guatteria guianensis. Tetrahe-
dron 44, 2193–2201.
Bhakuni, D.S., 1983. Alkaloid biosynthesis in plants. Biol. Mem. 8, 103–112.Bhakuni, D.S., 2002. Biosynthesis and synthesis of biologically active alkaloids of Indian
medicinal plants. J. Indian Chem. Soc. 79, 203–210.Boelsterli, U.A., Ho, H.K., Zhou, S., Leow, K.Y., 2006. Bioactivation and hepatotoxicity of
nitroaromatic drugs. Curr. Drug Metab. 7, 715–727.Borodina, Y., Sadym, A., Filimonov, D., Blnova, V., Dmitriev, A., Poroikov, V., 2003. Pre-
dicting biotransformation potential from molecular structure. J. Chem. Inform.
Comput. Sci. 43, 1636–1646.
ournine, L., Bensalem, S., Peixoto, P., Gonzalez, A., Maiza-Benabdesselam, F., Bedjou, F.,
Wauters, J.-N., Tits, M., Frédérich, M., Castronovo, V., Bellahcène, A., 2013. Revealingthe anti-tumoral effect of Algerian Glaucium flavum roots against human cancer
cells. Phytomedicine 20, 1211–1218.remner, J.B., Wiriyachitra, P., 1973. Photochemistry of papaverine N-oxide. Aust. J.
Chem. 26, 437–442.
udzikiewicz, H., Faber, L., Herrmann, E.G., Perrollaz, F.F., Schlunegger, U.P.,Wiegrebe, W., 1979. Vincetene, a benzopyrroloisoquinoline alkaloid , from Cy-
nanchum vincetoxicum (L.) Pers. (Asclepiadaceae). Liebigs Ann. Chem. 8, 1212–1231.ardillo, R., Fuganti, C., Ghiringhelli, D., Giangrasso, D., Grasselli, P., 1972. On the
biological origin of the nitroaromatic unit of the antibiotic aureotine. TetrahedronLett. 13, 4875–4878.
arter, G.T., Nietsche, J.A., Goodman, J.J., Torrey, M.J., Dunne, S., Borders, D.B., Testa, R.T.,1987. LL-F42248, a novel chlorinated pyrrole antibiotic. J. Antibiot. 40, 233–236.
atret, M., Ivorra, M.D., D’ocon, M.P., Anselmi, E., 1998. The 5-HT and α-adrenoceptor
antagonist effect of four benzylisoquinoline alkaloids on rat aorta. J. Pharm. Phar-macol. 50, 317–322.
espedes, C., Jakupovic, J., Silva, M., Tsichritzis, F., 1993. A quinoline alkaloid fromAristotelia chilensis. Phytochemistry 34, 881–882.
hang, W.T., Lee, S.S., Chueh, F.S., Liu, K.C.S., 1998. Formation of pavine alkaloids bycallus culture of Cryptocarya chinensis. Phytochemistry 48, 119–124.
haran, R.D., Schlingmann, G., Bernan, V.S., Feng, X., Carter, G.T., 2006.
Dioxapyrrolomycin biosynthesis in Streptomyces fumanus. J. Nat. Prod. 69, 29–33.hawla, A.S., Sood, A., Kumar, M., Jackson, A.H., 1992. Alkaloid constituents from
Erythrina bidwillii flowers. Phytochemistry 31, 372–374.hen, C.-Y., Chang, F.-R., Wu, Y.-C., 1997. The constituents from the stems of Annona
cherimola. J. Chin. Chem. Soc. (Taipei) 44, 313–319.hen, J.J., Tsai, I.L., Ishikawa, T., Wang, C.J., Chen, I.S., 1996. Alkaloids from trunk bark of
Hernandia nymphaeifolia. Phytochemistry 42, 1479–1484.
hen, J.J., Chang, Y.L., Teng, C.M., Chen, I.S., 2000. Anti-platelet aggregation alkaloidsand lignans from Hernandia nymphaeifolia. Planta Med. 66, 251–256.
hen, J.J., Chang, Y.L., Teng, C.M., Lin, W.Y., Chen, Y.C., Chen, I.S., 2001. A new tetrahy-droprotoberberine N-oxide alkaloid and anti-platelet aggregation constituents of
Corydalis tashiroi. Planta Med. 67, 423–427.hen, J.-J., Duh, C.-Y., Chen, I.-S., 1999. New tetrahydroprotoberberine N-oxide alkaloids
and cytotoxic constituents of Corydalis tashiroi. Planta Med. 65, 643–647.
hen, K.S., Ko, F.N., Teng, C.M., Wu, Y.C., 1996. Antiplatelet and vasorelaxing actions ofsome aporphinoids. Planta Med. 62, 133–136.
hernin, L., Brandis, A., Ismailov, Z., Chet, I., 1996. Pyrrolnitrin production by an Enter-obacter agglomerans strain with a broad spectrum of antagonistic activity towards
fungal and bacterial phytopathogens. Curr. Microbiol. 32, 208–212.hulia, S., Ivorra, M.D., Lugnier, C., Vila, E., Noguera, M.A., D’Ocon, P., 1994. Mechanism
of the cardiovascular activity of laudanosine: comparison with papaverine and
other benzylisoquinolines. Br. J. Pharmacol. 113, 1377–1385.omer, F., Tiwari, H.P., Spenser, I.D., 1969. Biosynthesis of aristolochic acid. Can. J. Chem.
47, 481–487.orrea, J.E., Rios, C.H., Castillo, A.R., Romero, L.I., Ortega-Barria, E., Coley, P.D.,
Kursar, T.A., Heller, M.V., Gerwick, W.H., Rios, L.C., 2006. Minor alkaloids fromGuatteria dumetorum with antileishmanial activity. Planta Med. 72, 270–272.
ortes, D., Dadoun, H., Paiva, R.L.R., De Oliveira, A.B., 1987. New bisbenzylisoquinoline
alkaloids isolated from leaves of Aristolochia gigantea. J. Nat. Prod. 50, 910–914.ortes, D., Hocquemiller, R., Cave, A., Saez, J., 1986. Annonaceae alkaloids. Part 64. Minor
alkaloids from the bark of Pseudoxandra sclerocarpa. J. Nat. Prod. 49, 854–858.amu, A.G., Kuo, P.-C., Shi, L.-S., Li, C.-Y., Kuoh, C.-S., Wu, P.-L., Wu, T.-S., 2005.
Phenanthroindolizidine alkaloids from the stems of Ficus septica. J. Nat. Prod. 68,
1071–1075.V.M. Dembitsky et al. / Phytomedicine 22 (2014) 183–202 199
D
D
D
D
D
D
D
D
D
D
D
E
E
E
E
E
E
E
E
E
E
E
H
H
F
G
G
G
C
G
G
G
G
G
G
G
G
G
G
H
H
H
H
H
H
I
I
I
I
I
I
I
J
J
J
J
K
K
K
K
K
K
K
K
K
K
K
K
K
K
K
L
L
asgupta, S., Ray, A.B., Bhattacharya, S.K., Bose, R., 1979. Constituents of Pachygoneovata and pharmacological action of its major leaf alkaloid. J. Nat. Prod. 42,
399–406.embitsky, V.M., 2004. Chemistry and biodiversity of the biologically active natural
glycosides. Chem. Biodiver. 1, 673–781.embitsky, V.M., 2005. Astonishing diversity of natural surfactants: 6. Biologically
active marine and terrestrial alkaloid glycosides. Lipids 40, 1081–1105.embitsky, V.M., 2008. Bioactive a cyclobutane-containing alkaloids. J. Nat. Med.
(Tokyo) 62, 1-33.
embitsky, V.M., Gloriozova, T., Poroikov, V.V., 2005. Novel antitumor agents: marinesponge alkaloids, their synthetic analogues and derivatives (mini-review). Med.
Chem. 5, 319–336.embitsky, V.M., Gloriozova, T.A., Poroikov, V.V., 2007. Natural peroxy anticancer
agents. Mini Rev. Med. Chem. 7, 571–589.ias, K.L.G., Dias, C.D.S., Barbosa-Filho, J.M., Almeida, R.N., Correia, N.D.A., Medeiros, I.A.,
2004. Cardiovascular effects induced by reticuline in normotensive rats. Planta
Med. 70, 328–333.imant, M.I., Bardashevskaia, S.P., 1974. Glaucine treatment of hypertensive disease.
Vrachebnoe Delo 12, 24–26.’Incalci, M., Simone, M., Tavecchio, M., Damia, G., Garbi, A., Erba, E., 2004. New drugs
from the sea. J. Chemother., Suppl. 4, 86-89.onev, N.T., 1964. Pharmacology of glaucine and its methiodide. Farmatsiya (Sofia) 14,
49–54.
wuma-Badu, D., Okarter, T.U., Tackie, A.N., Lopez, J.A., Slatkin, D.J., Knapp, J.E.,Schiff Jr., P.L., 1977. Constituents of West African medicinal plants. XIX: funifer-
ine N-oxide, a new alkaloid from Tiliacora funifera (Menispermaceae). J. Pharm. Sci.66, 1242–1244.
gydio, A.P.M., Valvassoura, T.A., Santos, D.Y.A.C., 2013. Geographical variation of iso-quinoline alkaloids of Annona crassiflora Mart. From cerrado, Brazil. Biochem. Syst.
Ecol. 46, 145–151.
hrlich, J., Gottlieb, D., Burkholder, P.R., Anderson, L.E., Pridham, T.G., 1948. Streptomycesvenezuelae, n. sp., the source of chloromycetin. J. Bacteriol. 56, 467–477.
ibler, E., Tanner, U., Mayer, K.K., Wiegrebe, W., Reger, H.P., 1995. LC-analysis of alka-loids from Cynanchum vincetoxicum. Acta Pharm. (Zagreb) 45, 487–493.
l Antri, A., Messouri, I., Bouktaib, M., El Alami, R., Bolte, M., El Bali, B., Lachkar, M.,2004. Isolation and X-ray crystal structure of a new isoquinoline-N-oxide alkaloid
from Calycotome villosa subsp. intermedia. Fitoterapia 75, 774–778.
l Banna, N., Winkelmann, G., 1998. Pyrrolnitrin from Burkholderia cepacia: antibioticactivity against fungi and novel activity against streptomycetes. J. Appl. Microbiol.
85, 69–78.l Masry, S., Amer, M., Ghazy, N.M., El-Lakany, A.M., 1990. Alkaloids from Roemeria
hybrida L. growing in Egypt. Alexandria J. Pharm. Sci. 4, 90–93.l Sayed, K.A., 2000. Microbial transformation of papaveraldine. Phytochemistry 53,
675–678.
l Sawi, S.A., Motawe, H.M., 2003. Cytotoxic alkaloids and terpenes from the aerial partsof Diceratella elliptica D.C. Bull. Nat. Res. Centre (Egypt) 28, 163–170.
lander, R.P., Mabe, J.A., Hamill, R.H., Gorman, M., 1968. Metabolism of tryptophans byPseudomonas aureofaciens. VI. Production of pyrrolnitrin by selected Pseudomonas
species. Appl. Microbiol. 16, 753–758.zaki, N., Shomura, T., Koyama, M., Niwa, T., Kojima, M., Inouye, S., Ito, T., Niida, T.,
1981. New chlorinated nitro-pyrrole antibiotics, pyrrolomycin A and B (SF-2080 Aand B). J. Antibiot. 34, 1363–1365.
zaki, N., Koyama, M., Shomura, T., Tsuruoka, T., Inouye, S., 1983. Pyrrolomycins C, D,
and E, new members of pyrrolomycins. J. Antibiot. 36, 1263–1267.aznagy, A., Toth, L., Szendrei, K., 1967. Effective substances of the root of Cynanchum
vincetoxicum. III. Acta Pharm. Hung. 37, 186–190.sieh, T.-J., Chang, F.-R., Wu, Y.-C., 1999. The constituents of Cananga odorata. J. Chin.
Chem. Soc. (Taipei) 46, 607–611.echine, I.M., Navarro, V.R., da-Cunha, E.V.L., Silva, M.S., Maia, J.G.S., Barbosa-Filho, J.M.,
2002. Alkaloids and volatile constituents from Duguetia flagellaris. Biochem. Syst.
Ecol. 30, 267–269.arcia-Mateos, R., Soto-Hernandez, M., Kelly, D., 1998. Alkaloids from six Erythrina
species endemic to Mexico. Biochem. Syst. Ecol. 26, 545–551.arcia-Mateos, R., Soto-Hernandez, M., Martinez, M., 2004. Variation in alkaloid
type and content during Erythrina americana seed development. EAAP Publ. 110,57-61.
arcia-Mateos, R., Soto-Hernandez, M., Vibrans, H., 2001. Erythrina americana Miller
("Colorin"; Fabaceae), a versatile resource from Mexico: a review. Econom. Bot. 55,391–400.
astedo, L., Lopez, S., Villaverde, C., 1988. New cularine-related alkaloids from Sarco-capnos baetica subsp. integrifolia. Heterocycles 27, 2783–2786.
enest, K., Lowry, L.J., Hughes, D.W., 1969. Microcrystalloptic test for some minoralkaloids of Peumus boldus. Microchem. J. 14, 249–260.
erth, K., Trowitzsch, W., Wray, V., Hofle, G., Irschik, H., Reichenbach, H., 1982. Pyrrolni-
trin from Myxococcus fulvus (Myxobacterales). J. Antibiot. (Tokyo) 35, 1101–1103.irreser, U., Hermann, T.W., Piotrowska, K., 2003. Oxidation and degradation products
of papaverine. Part II. Investigations on the photochemical degradation of papaver-ine solutions. Archiv Pharm. (Weinheim) 336, 401–405.
oeren, A.C., Zhou, B., Kingston, D.G., 2003. I. Cytotoxic and DNA damaging activity ofsome aporphine alkaloids from Stephania dinklagei. Planta Med. 69, 867–868.
ottlieb, D., Bhattacharyya, P.K., Anderson, H.W., Carter, H.E., 1948. Some properties of
an antibiotic obtained from a species of Streptomyces. J. Bacteriol. 55, 409–417.ozler, B., Freyer, A.J., Shamma, M., 1989. A new class of isoquinoline alkaloids: the
proaporphine–tryptamine dimers. Tetrahedron Lett. 30, 1165–1168.ozler, B., Freyer, A.J., Shamma, M., 1990. The ten proaporphine-tryptamine dimers. J.
Nat. Prod. 53, 675–685.
u, J.-Q., Kinghorn, A.D., 2005. Bioactive constituents of the genus Hernandia. Stud. Nat.Prod. Chem. 30, 559–602.
uinaudeau, H., Lin, L.Z., Ruangrungsi, N., Cordell, G.A., 1993. Traditional medicinalplants of Thailand. 25. Bisbenzylisoquinoline alkaloids from Cyclea barbata. J. Nat.
Prod. 56, 1989–1992.unes, H.S., Gozler, B., 2001. Two novel proaporphine-tryptamine dimers from Roeme-
ria hybrida. Fitoterapia 72, 875–886.adi, S., Bremner, J.B., 2001. Initial studies on alkaloids from Lombok medicinal plants.
Molecules 6, 117–129.
asan, C.M., Jumana, S., Rashid, M.A., 2000. (+)-Isocorydineα-N-oxide: a new aporphinealkaloid from Miliusa velutina. Nat. Prod. Lett. 14, 393–397.
irata, Y., Nakata, H., Yamada, K., Okuhara, K., Naito, T., 1961. The structure of aureothin,a nitro compound obtained from Streptomyces thioluteus. Tetrahedron 14, 252–274.
ou, D., 1996. Flora of Taiwan, 2nd ed., vol. 2. Editorial Committee of the Flora ofTaiwan, Taipei, pp. 636–642.
sieh, T.-J., Chang, F.-R., Chia, Y.-C., Chen, C.-Y., Chiu, H.-F., Wu, Y.-C., 2001. Cytotoxic
constituents of the fruits of Cananga odorata. J. Nat. Prod. 64, 616–619.ussaini, F.A., Shoeb, A., 1985. Isoquinoline derived alkaloids from Berberis chitria.
Phytochemistry 24, 633.ngkaninan, K., Hazekamp, A., de Best, C.M., Irth, H., Tjaden, U.R., van der Heijden, R.,
van der Greef, J., Verpoorte, R., 2000. The application of HPLC with on-line cou-pled UV/MS-biochemical detection for isolation of an acetylcholinesterase inhibitor
from Narcissus ’Sir Winston Churchill’. J. Nat. Prod. 63, 803–806.
oanoviciu, A., Antony, S., Pommier, Y., Staker, B.L., Stewart, L., Cushman, M., 2005.Synthesis and mechanism of action studies of a series of norindenoisoquinoline
topoisomerase I poisons reveal an inhibitor with a flipped orientation in the ternaryDNA–enzyme–inhibitor complex as determined by X-ray crystallographic analysis.
J. Med. Chem. 48, 4803–4814.srailov, I.A., Irgashev, Yunusov, T., Yunusov, M.S., Yu, S., 1977. Alkaloids of Corydalis
gortschakovii. Khim. Prirod. Soed. 6, 834–836.
srailov, I.A., Irgashev, T., Yunusov, M.S., 1985. Alkaloids of Corydalis pseudoadunca.Khim. Prirod. Soed. 6, 842–843.
srailov, I.A., Chelombit’ko, V.A., Nazarova, L.E., 1986. Argemone alkaloids. Khim. Prirod.Soed. 6, 798–799.
wasa, K., Kim, H.-S., Wataya, Y., Lee, D.-U., 1998. Antimalarial activity and structure–activity relationships of protoberberine alkaloids. Eur. J. Med. Chem. 33, 65–69.
wasa, K., Nishiyama, Y., Ichimaru, M., Moriyasu, M., Kim, H.-S., Wataya, Y., Yamori, T.,
Takashi, T., Lee, D.-U., 1999. Structure-activity relationships of quaternary pro-toberberine alkaloids having an antimalarial activity. Eur. J. Med. Chem. 34,
1077–1083.ordan, S.A., Perwaiz, S., 2014. Aristolochic acids, third ed., Encyclopedia of Toxicology,
pp. 298–301.ossang, A., Leboeuf, M., Cabalion, P., Cave, A., 1983. Alkaloids from Annonaceae. XLV.
Alkaloids of Polyalthia nitidissima. Planta Med. 49, 20–24.
u, K.S., Parales, R.E., 2010. Nitroaromatic compounds, from synthesis to biodegradation.Microbiol. Mol. Biol. Rev. 74, 250–272.
uma, B.F., Majinda, R.R.T., 2004. Erythrinaline alkaloids from the flowers and pods ofErythrina lysistemon and their DPPH radical scavenging properties. Phytochemistry
65, 1397–1404.akinuma, K., Hanson, C.A., Rinehart Jr., K.L., 1976. Spectinabilin, a new nitro-containing
metabolite isolated from Streptomyces spectabilis. Tetrahedron 32, 217–222.anyinda, B., Vanhaelen-Fastre, R., Vanhaelen, M., 1993. A new bisbenzylisoquinoline-
N-oxide alkaloid from seeds of Anisocycla cymosa. J. Nat. Prod. 56, 618–620.
anyinda, B., Vanhaelen-Fastre, R., Vanhaelen, M., Ottinger, R., 1993. Bisbenzyliso-quinoline alkaloids from Anisocycla cymosa roots. J. Nat. Prod. 56, 957–960.
anyinda, B., Vanhaelen-Fastre, R., Vanhaelen, M., 1995. Benzylisoquinoline alkaloidsfrom Anisocycla jollyana leaves. J. Nat. Prod. 58, 1587–1589.
anyinda, B., Vanhaelen-Fastre, R., Vanhaelen, M., Ottinger, R., 1993. Bisbenzyliso-quinoline alkaloids from Anisocycla cymosa roots. J. Nat. Prod. 56, 957–960.
arimov, A., Telezhenetskaya, Lutfullin, M.V., Yunusov, K.L., Yu, S., 1978. Alkaloids from
Berberis integerrima. Khim. Prirod. Soed. 3, 419.artsev, V.G., 2004. Natural compounds in drug discovery. Biological activity and new
trends in the chemistry of isoquinoline alkaloids. Med. Chem. Res. 13, 325–336.ashiwaba, N., Ono, M., Toda, J., Suzuki, H., Sano, T., 1998. Synthesis of cycleanine
mono-N-oxides. J. Nat. Prod. 61, 253–255.halil, A.T., 1994. Further isoquinoline alkaloids from Arthrocnemum glaucum.
Mansoura J. Pharm. Sci. 10, 96–102.
hozhdaev, V.G., Maekh, S.K., Yunusov, S., 1972. N-oxides of thalicimidine and preo-coteine from Thalictrum minus roots. Khim. Prirod. Soed. 5, 631–633.
ing, R.R., Calhoun, L.A., 2009. The thaxtomin phytotoxins: sources, synthesis,biosynthesis, biotransformation, and biological activity. Phytochemistry 70, 833–
841.intsurashvili, L.G., Vachnadze, V.Yu., 1983. Alkaloids from some species of Thalictrum
growing in Georgia (USSR). Khim. Prirod. Soed. 5, 658–659.
rumbiegel, G., Hallensleben, J., Mennicke, W.H., Rittmann, N., Roth, H.J., 1987. Studieson the metabolism of aristolochic acids I and II. Xenobiotica 17, 981–991.
ucharski, S., 1964. Composition of the fig tree cultivated in the Azerkaijani S.S.R.Farmacol. Polska 20, 581–586.
umar, V., Poonam, P.A.K., Parmar, V.S., 2003. Naturally occurring aristolactams, aris-tolochic acids and dioxoaporphines and their biological activities. Nat. Prod. Rep.
20, 565–583.
ai, S., Zhao, T., Wang, X., Shizuri, Y., Yamamura, S., 1993. Two new insularine-N-oxidesfrom the roots of Cyclea sutchuenensis Gagnep. Huaxue Xuebao 51, 1133–1138.
ai, S., Zhao, T.F., Wang, X.K., Shizuri, Y., Yamamura, S., 1993. Two novel bisbenzyliso-quinoline alkaloids from Cyclea sutchuenensis Gagnep. Yao Xue Xue Bao (Acta
Pharm. Sin.) 28, 599–603.
200 V.M. Dembitsky et al. / Phytomedicine 22 (2014) 183–202
M
M
M
M
M
M
M
M
N
N
N
N
N
N
N
N
O
O
O
O
O
O
P
P
P
P
P
P
R
P
P
P
Lavault, M., Richomme, P., Bruneton, J., 1994. New phenanthroindolizidine N-oxidesalkaloids isolated from Vincetoxicum hirundinaria Medic. Pharm. Acta Helvet. 68,
225–227.Lee, S.K., Nam, K.-A., Heo, Y.-H., 2003. Cytotoxic activity and G2/M cell cycle arrest
mediated by antofine, a phenanthroindolizidine alkaloid isolated from Cynanchumpaniculatum. Planta Med. 69, 21–25.
Lee, S.S., Liu, Y.C., Chen, C.H., 1990. Neocaryachine, a new pavine alkaloid from Crypto-carya chinensis, and NMR spectral properties of related alkaloids. J. Nat. Prod. 53,
1267–1271.
Lee, S.S., Chen, C.H., 1993. Additional alkaloids from Cryptocarya chinensis. J. Nat. Prod.56, 227–232.
Letasiova, S., Jantova, S., Horvathova, M., Lakatos, B., 2005. Toxicity and apoptosis in-duced by berberine – a potential anticancer drug.. Biologia (Bratislava, Slovakia)
60 (Suppl. 17), 97–100.Letcher, R.M., 1971. Alkaloids of Erythria lysistemon. 11-Methoxyerythraline, a new
alkaloid. J. Chem. Soc. C 4, 652–654.
Liao, J.C., 1996. Flora of Taiwan, 2nd ed., vol 2. Editorial Committee of the Flora ofTaiwan, Taiwan, 433.
Lin, F.-W., Wang, J.-J., Wu, T.-S., 2002. New pavine N-oxide alkaloids from the stem barkof Cryptocarya chinensis Hemsl. Chem. Pharm. Bull. 50, 157–159.
Lin, F.-W., Wang, J.-J., Wu, T.-S., 2002. New pavine N-oxide alkaloids from the stembark of Cryptocarya the berberine derivative 6-protoberberine in spontaneously
hypertensive rats. Pharmacology 59, 239–283.
Liu, J.C., Chan, P., Chen, Y.J., Tomlinson, B., Hong, S.H., Cheng, J.T., 1999. The antihyper-tensive effect of chinensis Hemsl. Chem. Pharm. Bull. 50, 157–159.
Liu, Y.Y., Tsutumi, T., Zhang, C., Matsumoto, I., 2002. The effects of a traditionalmedicine, fang-ji-huang-qi-tang (Boi-ogi-to), on urinary sugar and sugar alcohols
in streptozotocin-induced diabetic mice. J. Health Sci. 48, 168–172.Lively, D.H., Gorman, M., Haney, M.E., Mabe, J.A., 1966. Metabolism of tryptophans
by Pseudomonas aureofaciens. I. Biosynthesis of pyrrolnitrin. Antimicrob. Agents
Chemother. 6, 462–469.Lo, W.-L., Wu, Y.-C., Hsieh, T.-J., Kuo, S.-H., Lin, H.-C., Chen, C.-Y., 2004. Chemical con-
stituents from the stems of Michelia compressa. Chin. Pharm. J. (Taipei, Taiwan) 56,69–75.
Lopes, L.M.X., Nascimento, I.R., Da Silva, T., 2001. Phytochemistry of the Aristolochiaceae family. In: Mohan, R.M.M. (Ed.). Research Advances in Phytochemistry, vol 2.
Global Research Network, Kerala, pp. 19–108.
Lopez, J.A., 1976. The isolation and characterization of funiferine N-oxide. A new alka-loid from Tiliacora funifera Oliver (Menispermaceae). Alkaloid N-oxides: study of
the N-oxides of funiferine and pheanthine and chemical constituents of selectedmedicinal plants from Costa Rica. University of Pittsburgh, Pittsburgh, PA. Dissirt.
Abst. Int. B 37, 2168.Lopes, L.M.X., Humpfer, E., 1997. 8-Benzylberbine and N-oxide alkaloids from
Aristolochia gigantea. Phytochemistry 45, 431–435.
Lopes, L.M.X., 1992. 8-Benzylberbine alkaloids from Aristolochia gigantea. Phytochem-istry 31, 4005–4009.
Loria, R., Bignell, D.R., Moll, S., Huguet-Tapia, J.C., Joshi, M.V., Johnson, E.G., Seipke, R.F.,Gibson, D.M., 2008. Thaxtomin biosynthesis: the path to plant pathogenicity in the
genus Streptomyces. Antonie Van Leeuwenhoek 94, 3–10.Lu, S.-T., Lan, P.-K., 1966. The alkaloids of Fomosan lauraceous plants. VIII. Alkaloids of
Cryptocarya chinensis. 1. Structure of the new alkaloids crychine and caryachine.Yakugaku Zasshi 86, 177–184.
Lu, S.-T., 1966. Alkaloids of Formosan lauraceous plants. IX. Alkaloids of Cryptocarya
chinensis and C. konishii. Yakugaku Zasshi 86, 296–299.Maeda, K., 1953. Chemical studies on antibiotic substances. IV. A crystalline toxic
substance of Streptomyces thioluteus producing aureothricin. J. Antibiot. 6,137–138.
Mahiou, V., Roblot, F., Fournet, A., Hocquemiller, R., 2000. Bisbenzylisoquinoline alka-loids from Guatteria boliviana (Annonaceae). Phytochemistry 54, 709–716.
Majak, W., Bai, Y., Benn, M.H., 2003. Phenolic amides and isoquinoline alkaloids from
Corydalis sempervirens. Biochem. Syst. Ecol. 31, 649–651.Manske, R.H.F., 1965. The alkaloids of fumariaceous plants. LII. A new alkaloid, cular-
icine, and its structure. Can. J. Chem. 43, 989–991.Manske, R.H.F., 1968. Cularine alkaloids. Alkaloids, vol 10. Academic Press, pp. 463–465.
Marshall, S.J., Russell, P.F., Wright, C.W., Anderson, M.M., Phillipson, J.D., Kirby, G.C.,Warhurst, D.C., Schiff Jr., P.L., 1994. In vitro antiplasmodial, antiamoebic, and cy-
totoxic activities of a series of bisbenzylisoquinoline alkaloids. Antimicrob. Agents
Chemother., 96–103.Mat, A., Sariyar, G., Unsal, C., Deliorman, A., Atay, M., Ozhatay, N., 2000. Alkaloids and
bioactivity of Papaver dubium subsp. dubium and P. dubium subsp. laevigatum. Nat.Prod. Lett. 14, 205–210.
Mata, R., McLaughlin, J.L., 1980. Cactus alkaloids. XLV. Tetrahydroisoquinolines fromthe Mexican cereoid Pachycereus pringlei. Planta Med. 38, 180–182.
Mata, R., McLaughlin, J.L., 1980. Cactus alkaloids. Part 44. Tetrahydroisoquinoline al-
kaloids of the Mexican columnar cactus, Pachycereus weberi. Phytochemistry 19,673–678.
Mata, R., Chang, C.J., McLaughlin, J.L., 1983. Cactus alkaloids. Part 54. Carbon-13 NMR analysis of some simple tetrahydroisoquinolines. Phytochemistry 22,
1263–1270.Matin, S.B., 1970. Stereochemical aspects of centrally active compounds. Univ ersity of
California, San Francisco, CA.
Mayr, C.A., Sami, S.M., Dorr, R.T., 1997. In vitro cytotoxicity and DNA damageproduction in Chinese hamster ovary cells and topoisomerase II inhibition by
2-[2′-(dimethylamino)ethyl]-1,2-dihydro-3H-dibenz[de,h] isoquinoline-1,3-diones with substitutions at the 6 and 7 positions (azonafides). Anti-cancer Drugs 8,
245–256.
endes, R., Pizzirani-Kleiner, A.A., Araujo, W.K., Raaijimakers, J.M., 2007. Diversity ofcultivated endophytic bacteria from sugarcane: genetic and biochemical charac-
terization of Burkholderia cepacia complex isolates. Appl. Environ. Microbiol. 73,7259–7567.
ichl, J., Ingrouille, M.J, Simmonds, M.S., Heinrich, M., 2014. Naturally occurring aris-tolochic acid analogues and their toxicities. Nat. Prod. Rep. 31, 676–693.
itchell, D., Yu, H., 2003. Synthetic applications of palladium-catalyzed hydroarylationand related systems. Curr. Opin. Drug Discov. Dev. 6, 876–883.
ontgomery, C.T., Freyer, A.J., Guinaudeau, H., Shamma, M., Fagbule, M.O., Olatunji, G.,
1985. (+)-N-Methyllaurotetanine β-N-oxide from Glossocalyx brevipes. J. Nat. Prod.48, 833–834.
oody, J.O., Hylands, P.J., Bray, D.H., 1995. In vitro evaluation of Enantia chloranthaconstituents and derivatives for antiplasmodial and anticandidal activity. Pharm.
Pharmacol. Lett. 5, 80–82.orales, M.A., Bustamante, S.E., Brito, G., Paz, D., Cassels, B.K., 1998. Cardiovascular ef-
fects of plant secondary metabolites norarmepavine, coclaurine and norcoclaurine.
Phytother. Res. 12, 103–109.uller, A., Dorfman, M., 1934. Photoovrddot oxidation of 2-benzylpyridine and pa-
paverine. J. Am. Chem. Soc. 56, 2787–2788.uller, M., Kusebauch, B., Liang, G., Beaudry, C.M., Trauner, D., Hertweck, C.,
2006. Photochemical origin of the immunosuppressive SNF4435C/D and forma-tion of orinocin through “polyene splicing”. Angew. Chem. Int. Ed. Engl. 45,
7835–7838.
akagawa, A., Matsumura, E., Sato, F., Minami, H., 2013. Bioengineering of isoquinolinealkaloid production in microbial systems. Adv. Bot. Res. 68, 183–203.
akaoji, K., Nayeshiro, H., Tanahashi, T., 1997. Norreticuline and reticuline as possiblenew agents for hair growth acceleration. Biol. Pharm. Bull. 20, 586–588.
avarro, V.R., Sette, I.M.F., Da-Cunha, E.V.L, Silva, M.S., Barbosa-Filho, J.M., Maia, J.G.S.,2001. Alkaloids from Duguetia flagellaris Huber (Annonaceae). Rev. Bras. Plant. Med.
3, 23–29.
awawi, A., Ma, C.-M., Nakamura, N., Hattori, M., Kurokawa, M., Shiraki, K.,Kashiwaba, N., Ono, M., 1999. Anti-herpes simplex virus activity of alkaloids iso-
lated from Stephania cepharantha. Biol. Pharm. Bull. 22, 268–274.epali, U., Sharma, S., Sharma, M., Bedi, P.M.S., Dhar, K.L., 2014. Rational approaches,
design trategies, structure activity relationship and mechanistic insights for anti-cancer hybrids. Eur. J. Med. Chem. 77, 422–487.
ormatov, M., Abduazimov, Yunusov, Kh.A., Yu, S., 1961. Investigation on the alkaloids
of Ungernia minor. Dokl. Akad. Nauk UzSSR 9, 23–24.ormatov, M., Abduazimov, Yunusov, Kh.A., Yu, S., 1962. Structure of ungminorine..
Dokl. Akad. Nauk UzSSR 19, 27–29.ormatov, M., Abduazimov, Yunusov, Kh.A., Yu, S., 1965. Alkaloids of Ungernia minor.
Structure of ungrminorine and ungeremine. Uzbek. Khim. Zh. 9, 25–30.gino, T., Sato, S., Chin, M., Kawashima, K., 1990. Antihypertensives containing new
alkaloids. Jpn. Kokai Tokkyo Koho, 9 pp. Japanese Patent: JP 02078681 A2 19900319
Heisei.gino, T., Sato, S., Sasaki, H., Chin, M., 1987. Isolation of new alkaloids from Stephania
tetrandra as antihypertensives. Jpn. Kokai Tokkyo Koho, 5 pp. Japanese Patent: JP62205084 A2 19870909 Showa.
gino, T., Sato, T., Sasaki, H., Sugama, K., Okada, M., Mitsuhashi, H., Maruno, M., 1998.Four new bisbenzylisoquinoline alkaloids from the root of Stephania tetrandra (Fen-
Fang-Ji). Nat. Med. (Tokyo) 52, 124–129.hiri, F.C., Verpoorte, R., Svendsen, A.B., 1983. Cycleanine N-oxide, a new alkaloid from
Synclisia scabrida. Planta Med. 47, 87–89.
sato, T., Ueda, M., Fukuyama, S., Yagishita, K., Okami, Y., Umezawa, H., 1955. Produc-tion of tertiomycin (a new antibiotic substance), azomycin, and eurocidin by S.
eurocidicus. J. Antibiot. (Tokyo) 8, 105–109.tshudi, A.L., Apers, S., Pieters, L., Claeys, M., Pannecouque, C., De Clercq, E., Van Zee-
broeck, A., Lauwers, S., Frederich, M., Foriers, A., 2005. Biologically active bisben-zylisoquinoline alkaloids from the root bark of Epinetrum villosum. J. Ethnopharm.
102, 89–94.
ailer, M., Streicher, W., 1965. Alkaloids from Vincetoxicum officinale. Monatsh. Chem.96, 1094–1102.
an, J., Liu, S., Jiang, T., Wang, Y., Han, G., 1992. Calcium antagonistic principles from rootof glandularhairy meadowrue (Thalictrum foetidum). Zhongcaoyao 23, 453–455.
eng, S., Chen, L., Zhang, G., Pan, W., Chen, W., 1990. Medicinal isoquinoline alkaloids.II. Alkaloids of Stephania epigaea. Tianran Chanwu Yanjiu Yu Kaifa 2, 37–42.
etkov, V., Stancheva, S., 1980. In vitro inhibition of cyclic 3′ ,5′-AMP phosphodiesterase
by a group of structural analogs of glaucine. Acta Physiol. Pharmacol. Bulg. 6,38–47.
etkov, V., Todorov, S., Georgiev, V., Petkova, B., Donev, N., 1979. Pharmacologicalstudies of a group of semi-synthetic structural analogs of glaucine. Acta Physiol.
Pharmacol. Bulg. 5, 3–12.oroikov, V., Filimonov, D., 2005. PASS: Prediction of Biological Activity Spectra for
Substances. In: Helma, Ch. (Ed.). Predictive Toxicology. Taylor & Francis, pp. 459–
478.enard-Nozaki, J., Kim, T., Imakura, Y., Kihara, M., Kobayashi, S., 1989. Effect of al-
kaloids isolated from Amaryllidaceae on herpes simplex virus. Res. Virol. 140,115–128.
ettit, G.R., Meng, Y., Gearing, R.P., Herald, D.L., Pettit, R.K., Doubek, D.L., Chapuis, J.-C.,Tackett, L.P., 2004. Antineoplastic agents. 522. Hernandia peltata (Malaysia) and
Hernandia nymphaeifolia (Republic of Maldives). J. Nat. Prod. 67, 214–220.
iotrowska, K., Hermann, T.W., Augustyniak, W., 2002. Photooxidation of papaverine,papaverinol and papaveraldine in their chloroform solutions. Acta Polon. Pharm.
59, 359–364.rager, R.H., Tippett, J.M., Ward, A.D., 1981. Central nervous system active compounds.
VIII. New syntheses of phthalide isoquinolines. Aust. J. Chem. 34, 1085–1093.
V.M. Dembitsky et al. / Phytomedicine 22 (2014) 183–202 201
P
P
R
R
R
R
R
R
R
R
R
P
P
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
T
T
T
T
T
TT
T
T
T
T
T
T
U
U
V
V
V
V
V
V
W
W
W
W
W
rotais, P., Cortes, D., Pons, J.L., Lopez, S., Villaverde, M.C., Castedo, L., 1992. Displace-ment activity of some natural cularine alkaloids at striatal 3H-SCH 23390 and
3H-raclopride binding sites. Experientia 48, 27–30.ummangura, S., Mohamed, Y.A.H., Chang, C.-J., McLaughlin, J.L., 1982. Two simple
tetrahydroisoquinoline alkaloid N-oxides from cacti. Phytochemistry 21, 2375–2377.
ahman, A.U., Sohail, M., Khurshid, Z., 1992. Nigellimine: a new isoquinoline alkaloidfrom the seeds of Nigella sativa. J. Nat. Prod. 55, 676–678.
ahman, A.U., 1986. Isolation, structural and synthetic studies on the chemical con-
stituents of medicinal plants of Pakistan. Pure Appl. Chem. 58, 663–673.ahman, A.U., Wahab, A.T., Nawaz, S.A.M.I., 2004. New cholinesterase inhibiting
bisbenzyl-isoquinoline alkaloids from Cocculus pendulus. Chem. Pharm. Bull. 52,802–806.
asheed, T., Khan, M.N.I., Zhadi, S.S.A., Durrani, S., 1991. Hirsutine: a new alkaloid fromCocculus hirsutus. J. Nat. Prod. 54, 582–584.
ehman, H.U., 1985. Nigellimine N oxide, a new isoquinoline alkaloid from the seeds
of Nigella sativa. Heterocycles (Tokyo) 23, 953–956.ibar, B., 2003. Molecular structure of alkaloids isolated from Corydalis plants. Bull.
Acad. Serbe Sci. Arts Classe des Sci. Math. Nat.: Sci. Nat. 40, 95–106.ibeiro, R.A., Rodriguez de Lores Arnaiz, G., 2000. Nantenine and papaverine differen-
tially modify synaptosomal membrane enzymes. Phytomedicine 7, 313–323.ichomme, P., Pabuccuoglu, V., Gozler, T., Freyer, A.J., Shamma, M., 1989. (−)-Siculinine:
a lycorine-type alkaloid from Sternbergia sicula. J. Nat. Prod. 52, 1150–1152.
oitman, J.N., Mahoney, N.E., Janisiewicz, W.J., Benson, M., 1990. A new chlorinatedphenylpyrrole antibiotic produced by the bacterium Pseudomonas cepacia. J. Agric.
Food Chem. 38, 538–541.arry, R., Nishino, S., Spain, J., 2011. Naturally-occurring nitro compounds. Nat. Prod.
Rep. 28, 152–167.illay, C.C.N., Jager, A.K., Mulholland, D.A., van Staden, J., 2001. Cyclooxygenase-
inhibiting and antibacterial activities of South African Erythrina species. J.
Ethnopharm. 74, 231–237.almore, A.K., Hunter, M.D., 2001. Elevational trends in defense chemistry, vegetation,
and reproduction in Sanguinaria canadensis. J. Chem. Ecol. 27, 1713–1727.ánchez-Calvo, B., Barroso, J.B., Corpas, F.J., 2013. Hypothesis: Nitro-fatty acids play a
role in plant metabolism. Plant Sci. 199–200, 1–6.argazakov, Dzh., Ismailov, Z.F., Yunusov, S.Yu., 1963. The investigation of alkaloids
of Thalictrum foetidum. The structure of fetidine. Dokl. Akad. Nauk UzSSR 20,
28–31.ariyar, G., Mat, A., Unsal, C., Ozhatay, N., 2002. Biodiversity in the alkaloids of annual
Papaver species of Turkish origin. Acta Pharm. Turcica 44, 159–168.ato, F., 2013. Improved production of plant isoquinoline alkaloids by metabolic engi-
neering. Adv. Bot. Res. 68, 163–181.ato, F., 2005. RNAi silencing of alkaloid biosynthetic enzyme in plants for isoquinoline
alkaloid biosynthesis intermediate production: silencing Eschscholtzia berberine
bridge enzyme for reticuline accumulation. PCT Int. Appl., 32 pp. WO 2005033305A1 20050414.
chermerhorn, J.W., Soine, T.O., 1951. Further studies on the alkaloids of Argemonehispida. J. Am. Pharm. Assoc. 40, 19–23.
chütte, H.R., Orban, U., Mothes, K., 1967. Biosynthesis of aristolochic acid. Eur. J.Biochem. 1, 70–72.
ergeiko, A., Poroikov, V.V., Hanus, L.O., Dembitsky, V.M., 2008. Cyclobutane-containingalkaloids: origin, synthesis, and biological activity. Open Med. Chem. J. 2,
26–37.
erkedjieva, J., Velcheva, M., 2003. In vitro anti-influenza virus activity of isoquinolinealkaloids from Thalictrum species. Planta Med. 69, 153–154.
hafiee, A., Morteza-Semnani, K., Amini, M., 1998. (+)-Bulbocapnine β-N-oxide fromGlaucium fimbrilligerum. J. Nat. Prod. 61, 1564–1565.
hafiee, A., Mahmoudi, Z., 1997. Alkaloids of Papaveraceae. XIV. Alkaloids of Glauciumfimbrilligerum Boiss., population Gaduk. J. Sci. Islamic Rep. Iran 8, 42–44.
hamma, M., Jones, C.D., Weiss, J.A., 1969. Applications of rates of methiodide formation
to alkaloid structural determination. Tetrahedron 25, 4347–4355.harma, V., Jain, S., Bhakuni, D.S., Kapil, R.S., 1982. Biosynthesis of aristolochic acid. J.
Chem. Soc., Perkin Trans 1, 1153–1155.hi, L.-S., Kuo, P.-C., Tsai, Y.-L., Damu, A.G., Wu, T.-S., 2004. The alkaloids and other
constituents from the root and stem of Aristolochia elegans. Bioorg. Med. Chem. 12,439–446.
ilva, M., Bittner, M., Cespedes, C., Jakupovic, J., 1997. The alkaloids of the genus Aris-
totelia. Aristotelia chilensis (Mol.) Stuntz. Bol. Soc. Chil. Quim. 42, 39–47.ilva, M., Bittner, M., Cespedes, C., Jakupovic, J., 1996. Chemistry of Chilean Elaeo-
carpaceae. Aristotelia chilensis (Mol.) Stuntz. Rev. Latin. Quim. 24, 85–92.lavik, J., 1960. Alkaloids of the Papaveraceae. XVI. Alkaloids of some Meconopsis
species. Coll. Czechosl. Chem. Commun. 25, 1663–1666.lavik, J., Dolejs, L., Slavikova, L., 1974. Alkaloids from Roemeria hybrida. Coll. Czechosl.
Chem. Commun. 39, 888–894.
mith, R.M., Joslyn, D.A., Gruhzit, O.M., Mclean, I.W., Penner, M.A., Ehrlich, J., 1948.Chloromycetin: biological studies. J. Bacteriol. 55, 425–448.
tepanchikova, A.V., Lagunin, A.A., Filimonov, D.A., Poroikov, V.V., 2003. Prediction ofbiological activity spectra for substances: Evaluation on the diverse set of drugs-like
structures. Current Med. Chem. 10, 225–233.termitz, F.R., McMurtrey, K.D., 1969. Alkaloids of the Papaveraceae. X. New alkaloids
from Argemone gracilenta. J. Org. Chem. 34, 555–559.
trk, D., Christensen, J., Lemmich, E., Duus, J.O., Olsen, C.E., Jaroszewski, J.W., 2000. Cyto-toxic activity of some phenanthroindolizidine N-oxide alkaloids from Cynanchum
vincetoxicum. J. Nat. Prod. 63, 1584–1586.uau, R., Gomez, A.I., Rico, R., Vazquez Tato, M.P., Castedo, L., Riguera, R., 1988. Alkaloid
N-oxides of Amaryllidaceae. Phytochemistry 27, 3285–3287.
uau, R., Segura, R.G., Silva, M.V., Valpuesta, M., Cominguez, D., Castedo, L., 1995. Struc-tural and conformational analysis of naturally occurring cularine N-oxide alkaloids.
Heterocycles 41, 2575–2585.uau, R., Cabezudo, B., Valpuesta, M., Posadas, N., Diaz, A., Torres, G., 2005. Identification
and quantification of isoquinoline alkaloids in the genus Sarcocapnos by GC–MS.Phytochem. Anal. 16, 322–327.
uau, R., Garcia-Segura, R., Silva, M.V., Valpuesta, M., 1996. Cularine N-oxide alkaloidsfrom Ceratocapnos heterocarpa. Phytochemistry 43, 1389–1391.
arragiotto, M.H., Filho, H., Marsaioli, A.J., 1981. Erysotrine N-oxide and erythrartine-
N-oxide, two novel alkaloids from Erythrina mulungu. Can. J. Chem. 59,2771–2775.
outo-Bachiller, F.A., Perez-Inestrosa, E., Suau, R., Rico-Gomez, R., Rodriguez-Rodriguez, L.A., Coronado-Perez, M.E., 1999. Photochemistry and photophysics of
papaverine N-oxide. Photochem. Photobiol. 70, 875–881.innett-Smith, J., Kisfalvi, K., Young, S.H., Hines, O.J., Eibl, G., Rozengurt, E., 2013. Tu1889
the isoquinoline alkaloid berberine inhibits the growth of human pancreatic cancer
cells in vitro and in vivo. Gastroenterology 144 (1), S–873.ultankhodzhaev, M.N., Beshitaishvili, L.V., Yunusov, M.S., Yunusov, S.Yu., 1979. Alka-
loids from the aboveground part of Aconitum karakolicum. Khim. Prirod. Soed. 6,826–829.
ackie, A.N., Thomas, A., 1965. Characterization of a new alkaloid (funiferine) fromTiliacora funifera. Ghana J. Sci. 5, 11–18.
ackie, A.N., Thomas, A., 1968. Alkaloids of Tiliacora funifera. Planta Med. 16,
158–165.ackie, A.N., Dwuma-Badu, D., Ayim, J.S.K., Dabra, T.T., Knapp, J.E., Slatkin, D.J.,
Schiff, P.L., Jr., 1975. Constituents of West African medicinal plants. VII. Alkaloidsof Tiliacora dinklagei. Lloydia 38, 210–212.
akita, T., Naganawa, H., Maeda, K., Umezawa, H., 1961. The structures of ilamycin andilamycin B2. J. Antibiot. (Tokyo) 17, 129–131.
an, G.T., Kinghorn, A.D., Hughes, S.H.J.M., 1991. Psychotrine and its o-methyl ether are
selective inhibitors of human immunodeficiency virus-1 reverse transcriptase. J.Biol. Chem. 266, 23529–23536.
aylor, W.M., 1960. Organic N-oxides. Swiss Patent: CH 346552 19600715.odorov, S., Zamfirova, R., 1991. Comparative study of the hypotensive effect of a
group of structural derivatives of glaucine. Acta Physiol. Pharmacol. Bulg. 17,98–103.
omita, M., Kozuka, M., 1964. Alkaloids of Cinnamomum camphora. Yakugaku Zasshi
84, 365–367.raitcheva, N., Jenke-Kodama, H., He, J., Dittmann, E., Hertweck, C., 2007. Non-colinear
polyketide biosynthesis in the aureothin and neoaureothin pathways: an evolu-tionary perspective. Chembiochem 8, 1841–1849.
sai, I.L., Liou, Y.F., Lu, S.T., 1989. Screening of isoquinoline alkaloids and their deriva-tives for antibacterial and antifungal activities. Gaoxiong Yi Xue Ke Xue Za Zhi
(Kaohsiung J. Med. Sci.) 5, 132–145.
sakadze, D., Sturua, M., Kupatashvili, N., Vepkhvadze, T., Ziaev, R., Samsonia, Sh.,Abdusamatov, A., 1997. Alkaloids of Cocculus laurifolius D.C. Bull. Georgian Acad.
Sci. 155, 372–374.sakadze, D.M., Samsoniya, S.A., Ziaev, R., Abdusamatov, A., 2005. Alkaloid and pheno-
lic compounds of Galanthus caucasicus, Magnolia obovata, Cocculus laurifolius, andVeratrum lobelianum grown in Georgia. Mol. Divers. 9, 41–44.
sutsumi, T., Kobayashi, S., Liu, Y.Y., Kontani, H., 2003. Anti-hyperglycemic effect offangchinoline isolated from Stephania tetrandra Radix in streptozotocin-diabetic
mice. Biol. Pharm. Bull. 26, 313–317.
ddin, A.V., Rahman, A.U., Tahir, R., Rehman, H.U., 1987. Jamtine N-oxide. A new iso-quinoline alkaloid from Cocculus hirsutus. Heterocycles 26, 1251–1255.
nger, S.E., Cooks, R.G., Mata, R., McLaughlin, J.L., 1980. Chemotaxonomy of columnarMexican cacti by mass spectrometry/mass spectrometry. J. Nat. Prod. 43, 288–293.
anhaelen, M., 1973. Spectrophotometric determination of alkaloids in Peumus boldus.J. Pharm. Belg. 28, 291–299.
azquez Tato, M.P., Castedo, L., Riguera, R., 1988. New alkaloids from Pancratium
maritimum L.. Heterocycles 27, 2833–2838.elcheva, M.P., Danghaaghiin, S., Samdanghin, Z., Yansanghiin, Z., Hesse, M., 1995.
Epimeric pavine N-oxides from Thalictrum simplex. Phytochemistry 39, 683–687.elcheva, M., Duchevska, Kh., Kuzmanov, B., Dangaagiin, S., Samdangiin, Z.,
Yansangiin, Z., 1991. Alkaloids of Mongolian Thalictrum foetidum. Dokl. Bulg. Akad.Nauk 44, 33–36.
icario, J.L., Badia, D., Carrillo, L., Etxebarria, J., 2003. α-Amino acids and derivatives in
the asymmetric synthesis of tetrahydroisoquinoline alkaloids. Curr. Org. Chem. 7,1775–1792.
illinski, J.R., Dumas, E.R., Chai, H.-B., Pezzuto, J.M., Angerhofer, C.K., Gafner, S., 2003.Antibacterial activity and alkaloid content of Berberis thunbergii, Berberis vulgaris
and Hydrastis canadensis.. Pharm. Biol. (Lisse, Netherlands) 41, 551–557.ang, F.-P., Wang, L., Yang, J.-S., Nomura, M., Miyamoto, K.-I., 2005. Reversal of
P-glycoprotein-dependent resistance to vinblastine by newly synthesized bisben-
zylisoquinoline alkaloids in mouse leukemia P388 cells. Biol. Pharm. Bull. 28,1979–1982.
aterman, P.G., 1999. The chemical systematics of alkaloids: a review emphasising thecontribution of Robert Hegnauer. Biochem. Syst. Ecol. 27, 395–406.
inkler, R., Hertweck, C., 2007. Biosynthesis of nitro compounds. Chembiochem 8,973–977.
right, C.W., Marshall, S.J., Russell, P.F., Anderson, M.M., Phillipson, J.D., Kirby, G.C.,
Warhurst, D.C., Schiff Jr., P.L., 2000. In vitro antiplasmodial, antiamoebic, and cy-totoxic activities of some monomeric isoquinoline alkaloids. J. Nat. Prod. 63,
1638–1640.u, J., Chen, C.-H., Shaath, N.A., Soine, T.O., 1975. The structures of (±)-caryachine and
sevanine. Taiwan Yaoxue Zazhi 27, 105–107.
202 V.M. Dembitsky et al. / Phytomedicine 22 (2014) 183–202
Y
Y
Y
Z
Z
Z
Z
Z
Z
Wu, Y.-C., Chang, F.-R., Chen, K.-S., Ko, F.-N., Teng, C.-M., 1994. Bioactive alkaloids fromAnnona squamosa. Chin. Pharm. J. (Taipei, Taiwan) 46, 439–446.
Wu, Y.C., Duh, C.Y., Wang, S.K., Chen, K.S., Yang, T.H., 1990. Two new natural azafluorenealkaloids and a cytotoxic aporphine alkaloid from Polyalthia longifolia. J. Nat. Prod.
53, 1327–1331.Wu, Y.C., Liou, Y.F., Lu, S.T., 1988. Antimicrobial activity of isoquinoline alkaloids and
their N-oxide derivatives. Gaoxiong Yixue Kexue Zazhi (Taiwan, Kaohsiung J. Med.Sci.) 4, 336–344.
Wu, Y.C., Liou, Y.F., Lu, S.T., Chen, C.H., Chang, J.J., Lee, K.H., 1989. Antitumor agents.
103. Cytotoxicity of isoquinoline alkaloids and their n-oxides. Planta Med. 55,163–165.
Xie, H., Xu, J., Teng, R., Li, B., Wang, D., Yang, C., 2001. Two new epimeric isopavineN-oxides from Meconopsis horridula var. racemosa. Fitoterapia 72, 120–123.
Yang, T.H., Huang, W.Y., 1988. The alkaloid of Cananga odorata. (I). Isolation of a newbase, ushinsunine N-oxide. J. Chin. Chem. Soc. (Taipei, Taiwan) 35, 305–307.
Yang, T.H., Huang, W.Y., 1989. The alkaloids of Cananga odorata. II. Synthesis of
O-methylushinsunine and O-methylmichelalbine. Zhonghua Yaoxue Zazhi (China)41, 279–287.
Yao, Y.-C., An, T.-Y., Gao, J., Yang, Z., Yu, X.-S., Jin, Z., Li, G.-R., Huang, R.-Q., Zhu,C.-X., Wen, F.-J., 2001. Research of chemistry and bioactivity of active compounds
antiphytovirus in Cynanchum komarovii. Youji Huaxue 21, 1024–1028.
usupov, M.K., 1996. cis-N-Oxide of robustamine and merenderine from Merenderarobusta. Khim. Prirod. Soed. 5, 734–738.
usupov, M.K., Chammadov, B., 1995. Robustamine, a new homoproaporphine basefrom Merendera robusta. Khim. Prirod. Soed. 1, 109–114.
usupov, M.K., Chommadov, B.Ch., Aslanov, Kh.A., 1991. Homoaporphine alkaloid N-oxides from Merendera raddeana. Khim. Prirod. Soed. 1, 86–91.
akirov, U.B., 1967. Hypotensive properties of indophenanthridine alkaloids and theirderivatives. Med. Zh. Uzbek 9, 42–44.
hang, R., Fang, S., Chen, Y., Lu, S., 1991. The chemical constituents in Cynanchum
komarovii Al. Iljinski. (continued). Zhiwu Xuebao 33, 870–875.hang, Y., 2005. Application of tetrandine and fangchinoline to prepare the drug de-
livery systems or health-care food for improving hypnosis. Faming Zhuanli Shen-qing Gongkai Shuomingshu, 9 pp. Chinese Patent: CN 1666740 A 20050914 AN
2006:278915.hang, W., Wu, W., 2004. Development of chemical constituents and bioactivity for
Cynanchum komarovii. Tianran Chanwu Yanjiu Yu Kaifa 16, 273–276.
darilova, A., Malikova, J., Dvorak, Z., Ulrichova, J., Simanek, V., 2006. Quaternary iso-quinoline alkaloids sanguinarine and chelerythrine. In vitro and in vivo effects.
Chem. Listy 100, 30–41.enk, M.H., 1989. Biosynthesis of alkaloids using plant cell cultures. Recent Adv. Phy-
tochem. 23, 429–457.