Alkaloids and Their Pharmacology Effects from Zanthoxylum Genus

Abstract

Zanthoxylum genus (Rutaceae) comprises about 212 species distributed in warm temperature and subtropical areas in the worldwide. Zanthoxylum species have been used in traditional for the treatment of tooth decay, snakebites, blood circulation problems, stomach problems, inflammation, rheumatic, and parasitic diseases. The chemical investigations of Zanthoxylum have been studied by many scientists over the world. Several classes of compounds have been isolated from this genus such as alkaloids, coumarins, and monoterpenes. Of these, alkaloids are the main components and play an important role in Zanthoxylum species. Alkaloids have been shown the potential promise about biological activities: cytotoxic, antimalarial, leishmanicidal, anti-inflammatory, analgesic, antiviral, and antibacterial activities. This chapter will focus on the structure elucidation and pharmacological activities of alkaloids from Zanthoxylum species. In addition, the absolute configuration of some alkaloids from Zanthoxylum genus will be also discussed.

Full text

Selection of our books indexed in the Book Citation Index
in Web of Science™ Core Collection (BKCI)
Interested in publishing with us?
Contact book.department@intechopen.com
Numbers displayed above are based on latest data collected.
For more information visit www.intechopen.com
Open access books available
Countries delivered to Contributors from top 500 universities
International authors and editor s
Our authors are among the
most cited scientists
Downloads
We are IntechOpen,
the world’s leading publisher of
Open Access books
Built by scientists, for scientists
12.2%
120,000
135M
TOP 1%
154
4,700

Chapter
Alkaloids and Their Pharmacology
Effects from Zanthoxylum Genus
Nguyen Xuan Nhiem, Pham Minh Quan
and Nguyen Thi Hong Van
Abstract
Zanthoxylum genus (Rutaceae) comprises about 212 species distributed in warm
temperature and subtropical areas in the worldwide. Zanthoxylum species have been
used in traditional for the treatment of tooth decay, snakebites, blood circulation
problems, stomach problems, inflammation, rheumatic, and parasitic diseases. The
chemical investigations of Zanthoxylum have been studied by many scientists over
the world. Several classes of compounds have been isolated from this genus such as
alkaloids, coumarins, and monoterpenes. Of these, alkaloids are the main compo-
nents and play an important role in Zanthoxylum species. Alkaloids have been
shown the potential promise about biological activities: cytotoxic, antimalarial,
leishmanicidal, anti-inflammatory, analgesic, antiviral, and antibacterial activities.
This chapter will focus on the structure elucidation and pharmacological activities
of alkaloids from Zanthoxylum species. In addition, the absolute configuration of
some alkaloids from Zanthoxylum genus will be also discussed.
Keywords: Zanthoxylum, Rutaceae, alkaloids,
13
C-NMR, circular dichroism
1. Introduction
Zanthoxylum genus is one of the biggest genera belonging to the Rutaceae family,
including 212 species in the world and widely distributed in the warm or tropic
temperate zones. Research findings showed that Zanthoxylum genus have many
interesting biological activities such as antifungal, antibacterial, antiviral, antimalar-
ial, anti-inflammatory, antioxidant, tuberculosis, cardiovascular, and liver protec-
tive activities, especially cytotoxic activities. From the Zanthoxylum species, many
compounds have been isolated, including alkaloids, lignans, coumarins, flavonoids,
terpenoids, steroids, etc.; they are the specific classes of compounds in Zanthoxylum
genus. The main components presented in this genus are alkaloids and coumarins,
with significant biological activities, especially anticancer activities. In particular,
this genus contains high levels of benzophenanthridine alkaloids that not only shown
their potential cytotoxic in vitro but also their ability to inhibit tumor in vivo through
many mechanisms, resistant against many pathogenics including MRSA strain
(methicillin-resistant Staphylococcus aureus)—a bacterium caused dangerous infec-
tions in hospital [1] and also shown anti-inflammatory activity [2] (Figure 1).
1

2
Alkaloids

2. Alkaloids constituents from Zanthoxylum genus
A total of 35 Zanthoxylum species have been studied and showed the presence of
alkaloids: Z. acanthopodium,Z. ailanthoides,Z. americanum,Z. arborescens,Z.
atchoum,Z. austrosinense,Z. avicennae,Z. bouetense,Z. budrunga,Z. bungeanum,Z.
caribaeum,Z. chiloperone,Z. clava-herculis,Z. colantrillo,Z. coriaceum,Z. culantrillo,
Z. cuspidatum,Z. dimoncillo,Z. fagara,Z. integrifoliolum,Z. lemairei,Z.
monophyllum,Z. myriacanthum,Z. nitidum,Z. ovalfolium,Z. paracanthum,Z.
procerom,Z. rhoifolium,Z. riedelianum,Z. rubescens,Z. schinifolium,Z. simulans,Z.
tingoassuiba,Z. usambarense, and Z. williamsii.
2.1 Benzophenanthridine
Benzophenanthridine alkaloids (1–51) were isolated from Zanthoxylum species.
Of these, nitidine (1), chelerythrine (2), and arnottianamide (48) were found in
almost Zanthoxylum species (Figure 2 and Table 1).
2.2 Aporphines and benzylisoquinolines, and furoquinolines
Aporphines and benzylisoquinolines, and furoquinolines (52–75) were reported
from Zanthoxylum species. Magnoflorine (52), lauriforine (55), skimmianine (69),
γ-fagarine (70), and dictamnine (71) were found in Zanthoxylum species such as Z.
americanum,Z. bouetense,Z. budrunga,Z. caribaeum,Z. clava-herculis,Z.
cuspidatum,Z. dimoncillo,Z. fagara,Z. monophyllum,Z. nitidum,Z. ovalifolium,Z.
rubescens,Z. schinifolium,Z. simulans,Z. usambarense, and Z. williamsii (Figure 3
and Table 2).
Figure 1.
Photographs of the Zanthoxylum species. The images were obtained from http://tropical.theferns.info.
3
Alkaloids and Their Pharmacology Effects from Zanthoxylum Genus
DOI: http://dx.doi.org/10.5772/intechopen.91685

2.3 Quinolines, quinolones, and quinazolines
There were 19 quinolines, quinolones, and quinazolines (79–97) isolated from
Zanthoxylum species. They are mainly found in Z. simulans and Z. nitidum (Figure 4
and Table 3).
2.4 Indolopyridoquinazolines, acridones, and canthinones
There are 10 indolopyridoquinazolines, acridones, and canthinones (98–107)
isolated from Zanthoxylum plants (Z. atchoum,Z. simulans, and Z. ovalfolium).
Figure 2.
The structures of alkaloids 1–51.
4
Alkaloids

No. Compound names Sources Ref.
1Nitidine Z. myriacanthum,Z. williamsii,Z. clava-
herculis,Z. americanum,Z. bouetense,Z.
nitidum,Z. usambarense,Z. ovalifolium,Z.
lemairei,Z. atchoum
[3–18]
2Chelerythrine Z. williamsii,Z. monophyllum,Z. clava-herculis,
Z. americanum,Z. bouetense,Z. nitidum,
Z. usambarense,Z. simulans,Z. lemairei,
Z. atchoum
[4–8, 11,
13, 14, 17]
3Fagaridine Z. nitidum,Z. atchoum [6, 17]
4Isofagandine Z. nitidum [6]
5Terihanine Z. ovalifolium [10]
6Isoterihanine Z. ovalifolium [10]
711-Nitronitidine Z. atchoum [17]
8Sanguinarin Z. nitidum [11, 13]
9Methoxyfagaridine Z. atchoum [17]
10 9-Methoxy chelerythrine
chloride
Z. rubescens [5]
11 8-Methoxynorchelerythrine Z. nitidum [9]
12 8-Methoxysanguinarine Z. nitidum [19]
13 Norchelerythrine Z. nitidum,Z. simulans [17, 20–23]
14 Decarine Z. nitidum,Z. simulans [13, 20–24]
15 N-Nortidine Z. myriacanthum [23, 25]
16 7,9-Dimethoxy-2,3-methylen
dioxybenzophenantridine
Z. myriacanthum [25]
17 Zanthoxyline Z. rhoifolium,Z. nitidum [18, 26]
18 Noravicine [23]
19 Rhoifoline A Z. rhoifolium,Z. nitidum [13, 26, 27]
20 Rhoifoline B Z. rhoifolium [26]
21 6,7,8-Trimethoxy-2,3-methylen
dioxybenzophenantridine
Z. nitidum [11]
22 8-Methoxyisodecarine Z. nitidum [19]
23 Dihydronitidine Z. myriacanthum,Z. nitidum [3, 12]
24 Dihydrochelerythrine Z. coriaceum,Z. nitidum,Z. simulans [9, 11–13, 18,
20, 22, 28]
25 5,6-Dihydro-6-methoxynitidine Z. nitidum [29]
26 6-Acetonyldihydronitidine Z. rhoifolium,Z. nitidum [12, 26, 30]
27 6-Acetonyldihydroavicine Z. rhoifolium [26]
28 6-Acetonyldihydrochelerythrine Z. rhoifolium,Z. nitidum [12, 18,
22, 23, 26]
29 (R)-8-(1-hydroxyethyl)
dihydrochelerythrine
Z. nitidum [9, 23, 31]
30 8-Methoxydihydrochelerythrine Z. nitidum,Z. bungeanum [9, 13, 23]
31 8-Hydroxydihydrochelerythrine Z. nitidum [9, 13, 23]
32 Dihydrochelerythrinyl-8-
acetaldehyde
Z. nitidum [13]
5
Alkaloids and Their Pharmacology Effects from Zanthoxylum Genus
DOI: http://dx.doi.org/10.5772/intechopen.91685

Until now, only a small number of this class of compounds have been published
(Figure 5 and Table 4).
2.5 Other alkaloids
Amines were mainly found in Z. coriaceum. But tryptamines were only found in
Z. nitidum. 16 amines and 6 tryptamines have been reported (Figure 6 and
Table 5).
3. Biological activities of alkaloids
The abundance and diversity as well as the valuable properties in terms of
chemical compositions and biological activities of the Zanthoxylum genus have
attracted the attention of many research scientists. The studies have shown that the
extracts and alkaloids from Zanthoxylum species have many valuable biological
No. Compound names Sources Ref.
33 Bocconoline Z. nitidum [18]
34 Carboxymethyl
dihydrochelerythrine
Z. nitidum [18, 23]
35 6-Methoxy-7-hydroxydihydro
chelerythrine
Z. nitidum [23]
36 6-Nitro-8-methoxy-7,8-
dihydronitidine
Z. atchoum [17]
37 8-(20-Cyclohexanone)-7,8-
dihydrochelerythrine
Z. nitidum [31]
38 6-Acetonyl-N-methyl-
dihydrodecarine
Z. lemairei,Z. riedelianum,Z. nitidum [14, 18]
39 Ethoxychelerythrine Z. nitidum [32]
40 Zanthomuurolanine Z. nitidum [33]
41 epi-Zanthomuurolanine Z. nitidum [33]
42 Zanthocadinanine A Z. nitidum [33]
43 Zanthocadinanine B Z. nitidum [33]
44 epi-Zanthocadinanine B Z. nitidum [33]
45 epi-Zanthocadinanine A Z. nitidum [22]
46 Oxynitidine Z. nitidum [17, 22]
47 Oxyavicine Z. nitidum,Z. ailanthoides [9, 11,
13, 22, 23]
48 Arnottianamide Z. nitidum,Z. simulans,Z. bungeanum,Z.
ailanthoides,Z. austrosinense
[13, 17,
20–23]
49 Isoarnottianamide Z. nitidum,Z. myriacanthum [13]
50 10-O-demethyl-17-O-
methylisoarnottianamide
Z. lemairei [14]
51 Integriamide Z. nitidum [13]
Table 1.
Benzophenanthridines from Zanthoxylum species.
6
Alkaloids

activities: anticancer, antibacterial, antifungal, antiviral, anti-inflammatory, and
antioxidant activities. Many trials of biological properties of these species have been
studied and evaluated promising applications in medicine. However, the most
prominent compounds with cytotoxic activity in the genus Zanthoxylum are amides
and alkaloids.
3.1 Cytotoxic activities
In folk medicine, many species of Zanthoxylum are used as drugs to treat cancer,
such as: the people in Kakamega, Kenya use the leaves and roots of Z. gilletii to treat
breast and skin cancers [48]; fruits of Zanthoxylum species are used in Indians and
South Korea for chemopreventive effects [49, 50], while Cameron people use them
to treat anemia disease sickle erythrocytes [51] and Japanese people use as one of the
main components in the traditional medicine daikenchuto to treat gastrointestinal
and chronic diseases [52]. The chloroform-soluble fraction of Z. ailanthoides showed
cytotoxic activity against HL-60 and WEHI-3 cell lines with IC
50
values of 73.06
and 42.22 μg/ml, respectively [53].
The methanol, hexane, and chloroform extracts from Z. usambarense were eval-
uated for cytotoxicity against two breast cancer cell lines, MDA-MB-231 and MCF-7
and one brain tumor cell line, U251 using MTT assay [54]. The crude extract of Z.
setulosum collected in Monteverde, Costa Rica showed potent cytotoxic activity
(100% cells killed at 100 μg/ml) on three cancer cell lines, MCF-7, MDA-MB-231,
Figure 3.
The structures of alkaloids 52–78.
7
Alkaloids and Their Pharmacology Effects from Zanthoxylum Genus
DOI: http://dx.doi.org/10.5772/intechopen.91685

No. Compound names Sources Ref.
Aporphines
52 Magnoflorine Z. fagara,Z. williamsii,Z. monophyllum,Z. clava-
herculis,Z. americanum,Z. usambarense,Z. nitidum
[4, 7, 8, 34]
53 Cocsarmine Z. tingoassuiba [4]
54 Xanthoplanine Z. tingoassuiba [4]
55 Lauriforine Z. fagara,Z. williamsii,Z. clava-herculis,Z.
americanum
[4, 34]
56 N-methyl isocorydine Z. caribaeum,Z. coriaceum [28, 34]
57 Zanthoxoaporphine A Z. paracanthum [35]
58 Zanthoxoaporphine B Z. paracanthum [35]
59 Zanthoxaporphine C Z. paracanthum [35]
60 Liriodenine Z. nitidum [11, 13,
20, 22,
32, 36]
61 ()-N-acetylanonanine Z. simulans,Z. nitidum [21, 22]
62 N-acetyldehydroanonaine Z. simulans,Z. nitidum [21, 22]
Benzylisoquinolines
63 Berberine Z. caribaeum,Z. monophyllum,Z. clava-herculis [34, 4]
64 Berberubine Z. nitidum [11, 13]
65 Coptisine Z. nitidum [11, 13]
66 ()-Usambarine Z. usambarense [7]
67 ()-cis-N-methylcanadine Z. usambarense,Z. nitidum [7, 8]
68 N-methylcanadine Z. coriaceum [28]
Furoquinolines
69 Skimmianine Z. dimoncillo,Z. caribaeum,Z. fagara,Z. williamsii,
Z. americanum,Z. rubescens,Z. bouetense,Z.
simulans,Z. nitidum,Z. atchoum
[4, 5, 17, 21,
22, 29,
34, 37]
70 γ-Fagarine Z. americanum,Z. simulans,Z. nitidum,Z.
cuspidatum
[4, 21,
22, 24,
29, 37]
71 Dictamnine Z. budrunga,Z. ovalifolium,Z. nitidum,Z.
schinifolium,Z. avicennae,Z. acanthopodium
[10, 13,
29, 37, 38]
72 8-Methoxy dictamnine Z. rubescens [5]
73 Robustine Z. simulans,Z. nitidum [21, 24]
74 5-Methoxydictamine Z. ovalifolium,Z. nitidum [10, 29]
75 Haplopine Z. nitidum [37]
76 4-Methoxyfuro[2,3-b]
quinoline-8-O-β-D-
glucopyranoside
Z. nitidum [24]
77 Zanthonitidine A Z. nitidum [24]
78 (+)-N-methylplatydesmine Z. usambarense [7]
Table 2.
Aporphines and benzylisoquinolines, and furoquinolines from Zanthoxylum species.
8
Alkaloids

and MDA-MB-468 [55]. The methanol extract of Z. avicennae inhibited the highly
metastatic HA22T liver cancer cell migration and invasion effects through PP2A
activation [56]. Most recently, the methanol extract of Z. alatum showed the apo-
ptotic activity on Ehrlich ascites tumor in Swiss albino mice [57].
A screening study of cytotoxic activity of the extracts from 11 species used as
salad in Korea showed that the methanol extract of Z. schinifolium had the strongest
cytotoxic against Calu-6 cell line with the IC
50
values <25.0 μg/ml, meanwhile the
methanol extract of Z. piperitum exhibited antioxidant effects through ability to
arrest radical DPPH. Through the results of this study, the authors suggested that
these salad vegetables can be used as functional foods to support cancer treatment
[58]. The linear fatty acid amides of the sandshool class are the major ingredient
found in seeds of Z. piperitum exhibited cytotoxicity in the A-549 cell line [59].
Glycoprotein from the seeds of Z. piperitum prevented damage to liver tissue caused
by N-nitrosodiethylamine in the experimental mouse model [49].
Thirteen benzophenanthridines were isolated from Z. nitidum by Wang et al.
[23]. The research indicated that 6-methoxy-7-hydroxydihydrochelerythrine
exhibited the moderate cytotoxic activity against A549, Hela, SMMC-7721 and EJ,
with the IC
50
values of 27.50, 37.50, 16.95 and 60.42 μM, respectively. 6-
Methoxydihydrochelerythrin and 8-(10-hydroxyethyl)-7,8-dihydrochelerythrine
also showed strong cytotoxicity when tested against the four human cancer cell
lines (A549, Hela, SMMC-7721 and EJ). These results suggested that benzophenan-
thridines may become a valid alternative of potential basis for new anti-
proliferative agents [23]. Methyl 7-(β-D-mannopyranosyloxy)-1H-indole-2-carbox-
ylate (126), methyl 7-[(3-O-acetyl-β-D-mannopyranosyl)oxy]-1H-indole-2-carbox-
ylate (127), and 2-methyl-1H-indol-7-yl β-D-mannopyranoside (128) were isolated
from the ethanol extract of Z. nitidum roots.Biological evaluation revealed that
these alkaloids possess significant cytotoxicities against all the tested tumor cell
lines with the IC
50
values of less than 30 μM [46]. Liriodenine (60) was the active
compound against the MCF-7, NCI-H460, and SF-268 cell lines with IC
50
values of
2.19, 2.38, and 3.19 μg/ml, respectively [22]. In addition, normelicopidine (101)
Figure 4.
The structures of alkaloids 79–97.
9
Alkaloids and Their Pharmacology Effects from Zanthoxylum Genus
DOI: http://dx.doi.org/10.5772/intechopen.91685

Figure 5.
The structures of alkaloids 98–107.
No. Compound names Sources Ref.
Quinolines
79 Edulitine Z. simulans,Z. nitidum [21, 24, 37]
80 Lunacridine Z. budrunga [39]
81 Edulinine Z. williamsii,Z. nitidum [4, 37]
82 Tembetarine Z. fagara,Z. usambarense,Z.
nitidum
[4, 7, 8]
83 (R)-(+)-isotembetarine Z. nitidum [8]
84 ()-Oblongine Z. usambarense [7]
85 Simulenoline Z. simulans [21]
86 Peroxysimulenolin Z. simulans [21]
87 Benzosimulin Z. simulans [21]
88 Zanthodioline Z. simulans,Z. nitidum [21, 24, 37]
89 Zanthosimuline Z. simulans [21]
90 Huajiaosimuline Z. simulans [21]
91 Zanthobisquinolone Z. simulans [21]
Quinolones
92 Flindersine Z. nitidum [22]
93 4-Methoxy-1-methyl-2-quinolone Z. nitidum [22, 24]
Quinazolines
94 1-Methyl-3-(20-phenylethyl)-lH,3Hquinazoline-2,4-dione Z. arborescens [34]
95 1-Methyl-3-[20-(4″-methoxyphenyl) ethyl]-lH,3H
quinazoline-2,4-dione
Z. arborescens [34]
96 Arborine Z. budrunga [38]
97 2-(20,40,60-Trimethyl-heptenyl)-4-quinozolone Z. budrunga [38]
Table 3.
Quinolines, quinolones, and quinazolines from Zanthoxylum species.
10
Alkaloids

from Z. simulans showed the cytotoxic activities against PC-3M, LNCaP, and Dd2
with the IC
50
values of 12.5, 21.1, and 18.9 μg/ml respectively.
Acridone alkaloid derivatives isolated from the roots and fruits of Z. leprieurii
showed the selective moderately active against two cancer cell lines, A549 and
DLD-1 in comparison to normal cell line, WS1 [60]. Liriodenine (60) was also
isolated from Z. nitidum and showed significant cytotoxic activity against three
human cancer cell lines, MCF-7, NCI-H460, and SF-268 with IC
50
values of 2.19,
2.38, and 3.19 μg/ml, respectively. A series of benzo[c]phenanthridine alkaloids
isolated from Zanthoxylum species showed significant cytotoxic activities:
huajiaosimuline (90) and zanthosimuline (89) isolated from Z. simulans showed
significant antiplatelet aggregation activity and induced terminal differentiation
with cultured HL-60 cells [61], 7,8-dehydro-1-methoxyrutaecarpine,
norchelerythrine (13), ethoxychelerythrine (39), 6-acetonyldihydrochelerythrine
(29), γ-fagarine (70), skimmianine (69), ()-matairesinol, and canthin-6-one
(106) isolated from the roots of Z. integrifoliolum exhibited cytotoxic activities on
two human cancer cell lines, P-388 and HT-29 (IC
50
values <4μg/ml) [62]. A new
benzophenanthridine-type alkaloid, rutaceline isolated from the stem bark powder
of Z. madagascariense and induced cell cycle arrest in the GO/G1 phase, decreased of
cells in S phase as well as induced DNA fragmentation in both cancer cell lines
(human colorectal adenocarcinoma (Caco-2) and the African green monkey kidney
(Vero) cell lines) [63]. Three others alkaloids isolated from the rhizome of Z. capense
exhibited strong anticancer activity in HCT-116 colon carcinoma cell line [64].
Nitidine (1), a specific compound in Zanthoxylum species: Z. myriacanthum,
Z. williamsii,Z. clava-herculis,Z. americanum,Z. bouetense,Z. nitidum,
Z. usambarense,Z. ovalifolium,Z. lemairei,Z. atchoum inhibited gastric tumor cell
growth, induced tumor cell apoptosis in vitro and effectively suppressed the vol-
ume, weight, and microvessel density of human SGC-7901 gastric solid tumors at a
dosage of 7 mg/kg/d (intraperitoneal injection) [15], suppressed the growth and
pro-apoptotic effects on renal cancer cells both in vitro and in vivo [16]. Nitidine
could inhibit breast cancer cell migration and invasion both in vitro and in vivo [65].
Chelerythrine (2) was found in Z. williamsii,Z. monophyllum,Z. clava-herculis,
No. Compound names Sources Ref.
Indolopyridoquinazolines
98 3-Hydroxydehydroevodiamine Z. atchoum [17]
99 Dehydroevodiamine Z. atchoum [17]
100 Evodiamine Z. atchoum [17]
Acridones
101 Normelicopidine Z. simulans [40]
102 Normelicopine Z. simulans [40]
103 Melicopine Z. simulans [40]
104 Melicopidine Z. simulans [40]
105 Melicopicine Z. simulans [40]
Canthinones
106 6-Canthinone Z. ovalfolium [10, 41]
107 5-Methoxycanthin-6-one Z. chiloperone [42]
Table 4.
Indolopyridoquinazolines, acridones, and canthinones from Zanthoxylum species.
11
Alkaloids and Their Pharmacology Effects from Zanthoxylum Genus
DOI: http://dx.doi.org/10.5772/intechopen.91685

Figure 6.
The structures of alkaloids 108–131.
No. Compound names Sources Ref.
108 Synephrine Z. fagara,Z. culantrillo [4]
109 Candicine Z. clava-herculis,
Z. americanum
[4]
110 Hordenine Z. coriaceum [28]
111 4-(2-N-methyltyraminyl)-(Z)-1,2-epoxy-2-ethylbut-
3-ene
Z. coriaceum [28]
112 Fagaramide Z. rubescens [5]
113 -(2-methoxyethyl)-N,N-dimethyl benzenamine Z. nitidum [43]
114 (+)-Aegiline Z. coriaceum [28]
115 Alfileramine Z. coriaceum,Z. integrifoliolum [28, 44]
116 N0-demethylalfileramine Z. coriaceum [28]
117 N-demethylalfileramine Z. coriaceum [28]
118 N,N0-demethylalfileramine Z. coriaceum [28]
119 Culantraraminol Z. procerom,Z. colantrillo [45]
120 Culantraramine Z. coriaceum [28]
121 N,N0-demethylculantraramine Z. coriaceum [28]
12
Alkaloids

Z. americanum,Z. bouetense,Z. nitidum,Z. usambarense,Z. simulans,Z. lemairei,
and Z. atchoum. Chelerythrine increased cellular ROS level, leading to endoplasmic
reticulum stress, inactivating STAT3 activities and inducing apoptosis in RCC cells
which were suppressed by NAC, a special ROS inhibitor [66]. Chelerythrine signif-
icantly reduced the gastric ulcer index, myeloperoxidase activities, macroscopic and
histological score in a dose-dependent manner [67].
Magnoflorine (52) could inhibit the apoptosis of the cells stimulated with TNF-
α/IFN-γ. Further animal experiments confirmed that magnoflorine significantly
attenuated the AD-like symptom and inhibited the AD-induced increases in IgE/IL-
4, as compared with positive control [68]. Doxorubicin effects on the inhibition of
migration and invasion of breast cancer cells was significantly promoted by
magnoflorine. Doxorubicin-induced cell distribution in G2/M phase was markedly
elevated when co-treated with magnoflorine. It is observed that apoptosis process
were enhanced through doxorubicin/magnoflorine combinatory treatment rather
than using doxorubicin alone through inducing Caspase-3 cleavage. In addition,
magnoflorine markedly promoted the role of doxorubicin in autophagy induction
by elevating light chain 3 (LC3)-II expression [69].
Liriodenine (60) was commonly found in Zanthoxylum genus. The effect of
liriodenine induced significant apoptosis and suppression of cell growth of the
MCF-7 cell line. The results indicated that the anticancer effects of liriodenine
suppress cell growth and induce the apoptosis of human breast cancer MCF-7 cells
through inhibition of Bcl-2, cyclin D1 and VEGF expression, and upregulation of
p53 expression [70].
Skimmianine (69) significantly inhibit the growth of non-small cell lung cancer
cells and markedly induce apoptosis in non-small cell lung cancer cells [71].
3.2 Inflammatory effects
Inflammation defines as the immune system responses to injury or infection
with foreign organisms such as bacteria and viruses. However, excessive chronic
inflammation represents the basis of inflammatory diseases including rheumatoid
arthritis, diabetes, and chronic hepatitis. Several research groups have reported the
No. Compound names Sources Ref.
122 Integramine Z. integrifoliolum [44]
123 Isoalfileramine Z. coriaceum [28]
124 N,N,N-trimethyltryptamine Z. nitidum [8]
125 N-trimethyltryptamine Z. nitidum [8]
126 Methyl 7-(β-D-mannopyranosyloxy)-1H-indole-2-
carboxylate
Z. nitidum [46]
127 Methyl 7-[(3-O-acetyl-β-D-mannopyranosyl)oxy]-
1H-indole-2-carboxylate
Z. nitidum [46]
128 2-Methyl-1H-indol-7-yl β-Dmannopyranoside Z. nitidum [46]
129 4,5-Dihydroxy-1-methyl-3-oxo-2-(trichloromethyl)-
3H-indolium chloride
Z. nitidum [43]
130 Zanthonitiside A Z. nitidum [47]
131 Zanthonitiside B Z. nitidum [47]
Table 5.
Other alkaloids from Zanthoxylum species.
13
Alkaloids and Their Pharmacology Effects from Zanthoxylum Genus
DOI: http://dx.doi.org/10.5772/intechopen.91685

inflammatory activity of Zanthoxylum genus. In LPS-induced endotoxemic mice,
nitidine (1) increased IL-10 production, suppressed inflammatory responses, and
reduced mortality remarkably. In LPS-stimulated RAW264.7 cells and in peritoneal
macrophages from endotoxemic mice, nitidine significantly enhanced the activa-
tion of Akt, a critical signal transducer for IL-10 production, and inhibition of Akt
prevented nitidine from enhancing IL-10 production and ameliorating endotoxemia
[72]. Chelerythrine (2) markedly suppressed TNF-α, IL-6, and IL-1βproduction
and oxidative LPS-induced [73]. Chelerythrine was found to inhibit NO production,
pro-inflammatory IL-6 and TNF-αlevel in serum and gastric mucosal in the mice
exposed to ethanol induced ulceration in a dose-dependent manner [67].
Skimmianine (69) significanly decreased in the mRNA levels of TNF-αand IL-6,
which are upstream events of the inflammatory cascade. The levels of PGE2 and NO
and the activities of COX-2 and 5-LOX were also significantly reduced after
skimmianine treatment [71].
3.3 Antifungal and antibacterial activities
Besides cytotoxic activities, the Zanthoxylum species has also showed antifungal
and antibacterial activities. In traditional medicine, many Zanthoxylum species are
used commonly to treat skin diseases, purulent dermatitis, diarrhea, hepatitis and
nephritis. Aqueous-ethanol 90% extracts of leaves, roots, and stem barks of Z.
leprieurii and Z. xanthoxyloides inhibited the in vitro growth of Candida albicans,
Cryptococcus neoformans and seven filamentous fungi tested [74]. Ethanolic extracts
of the Z. fagara,Z. elephantiasis, and Z. martinicense showed antifungal activity [75].
Antifungal activity was also found in all extracts of leaves, fruits, twigs, bark, and
roots of Z. americanum [76, 77]. Canthin-6-one (106) and 5-methoxycanthin-6-one
(107) are major components in Z. chiloperone showed the broad-spectrum antifun-
gal activity [78, 79]. In addition, benzophenanthridines such as dictamnine (71),
γ-fagarine (70), 5-methoxydictamnine from Z. nitidum [29], liriodenine from
Z. tetraspermum showed significant antifungal activity [80].
The screening in vitro and in vivo activity against the tuberculosis bacterium of
compounds isolated from Z. capense showed that a benzophenanthridine alkaloid,
decarine (14) and a N-isobutylamide N-isobutyl-(2E,4E)-2,4-tetradecadienamide
exhibited antibacterial activity against Mycobacterium tuberculosis H37Rv (MIC
value of 1.6 μg/ml) [81]. 6-Acetonyldihydronitidine (26) and 6-acetonyldihy-
droavicine (27) isolated from the stem bark of Z. tetraspermum [80] and from the
bark and twigs of Z. rhoifolium and Z. tetraspermum [26], showed significant
antibacterial activity.
In particular, benzophenanthridine alkaloids from Zanthoxylum genus exhibited
strong activity against methicillin-resistant Staphylococcus aureus (MRAS) such as:
dihydrochelerythrine (24) from Z. rhetsa [82], decarine (14), norchelerythrine
(13), dihydrochelerythrine (24), 6-acetonyldihydrochelerythrine (28),
tridecanonchelerythrine, and 6-acetonyldihydronitidine (26) from Z. capense [83],
bis-[6-(5,6-dihydro-chelerythrinyl)] ether, 6-ethoxy-chelerythrine, and 4-
methoxy-N-methyl-2-quinolone from Z. monophyllum [83], chelerythrine (2) from
Z. clava-herculis [31]. The polymeric proanthocyanidins from Z. piperitum also
showed antibacterial activity against MRAS [84]. 4-Methoxy-N-methyl-2-quino-
lone from Z. monophyllum exhibited significant inhibitory activity against MRSA
bacteria with the IC
50
value of 1.5 μg/ml [1].
Chelerythrine showed strong antibacterial activities against Gram-(+) bacteria,
Staphylococcus aureus, Methicillin-resistant S. aureus, and extended spectrum
β-lactamase S. aureus. Chellerythrine experiments on three bacteria resulted in
14
Alkaloids

MICs were all 0.156 mg/ml. It suggest the primary anti-bacterial mechanism of this
compound could be originated from the destruction of the channels across the
bacterial cell membranes which lead to protein leakage to the outside of the cell and
its inhibition on protein biosynthesis [85].
3.4 Other biological effect
Besides above mentioned biological activities, the alkaloid from Zanthoxylum
plants also showed antivirus, cardioprotective, liver protective, antidiabetic, and
antimalarial activities. Benzophenanthridine alkaloids, 5,6-dihydro-6-methoxynitidine,
skimmianine, and 5-methoxydictamnine from Z. nitidum showed significant
antiviral activities against hepatitis B virus [29], decarine, γ-fagarine, (+)-
tembamide from the root bark of Z. ailanthoides against HIV with EC
50
values
<0.1 μg/ml [86]. Nitidine showed similar in vitro activity in CQ-sensitive and
resistant strains, and also a satisfying selectivity index (>10) when compared with
a non-cancerous cells line. Nitidine can be considered a potential anti-malarial lead
compound [87].
4. Structure elucidation of benzophenanthridine alkaloids from
Zanthoxylum genus
4.1 NMR methods
Benzophenanthridine alkaloids are the most popular class of compounds isolated
from Zanthoxylum genus. Structures of benzophenanthridines were elucidated by
1
H-,
13
C-NMR, DEPT, COSY, HSQC, HMBC, NOESY, and ROESY. The absolute
configurations of these compounds were also determined by XRAY, and experi-
mental CD as well as calculated CD.
Study on the structures of benzophenanthridine from Zanthoxylum genus, we
found some following specifics: dioxymethylene group at C-2 and C-3, unsaturated
and saturated bond at N/C-6; some substitutions at C-6 such as sesquiterpenes.
Tables 6 and 7summarized
13
C-NMR characteristics of benzophenanthridine as
follows:
1.When dioxymethylene group at C-2/C-3,
13
C-NMR chemical shift was about
102.0 ppm.
2.The N-methyl group at N was confirmed by chemical shift about 50.1–53.0
ppm when the presence of double bond at N/C-6; chemical shift about
41.1–41.2 ppm when the presence of single bond at N/C-6.
3.When C-substitution at C-6, chemical shifts at C-6 appeared around 57.3–66.7
ppm (methine carbon).
4.The positions of methoxy groups at benzophenanthridines normally appear at
C-6, C-7, C-8, and C-9 with chemical shift around 55.7–62.8 ppm. Especially
when the presence of single bond at N/C-6, the chemical shift of methoxy
group at C-6 as 40.9–41.2 ppm.
5.When substitution groups at C-6 appear, they will have additional signals such
as sesquiterpene.
15
Alkaloids and Their Pharmacology Effects from Zanthoxylum Genus
DOI: http://dx.doi.org/10.5772/intechopen.91685

4.2 Circular dichlorism
Circular dichroism (CD), a spectroscopic technique based on differential
absorption of left- and right-handed circularly polarized light, is ideally disposed to
analyze molecular structure, composition and interactions of chiral systems. Quan-
tum mechanical calculations based on density functional theory (DFT) and its time-
dependent formulation theory (TD-DFT) could be used to determine the theoreti-
cal chiroptical response of all the possible conformations of complexed-structures;
C171112131419202224
1 107.3 108.0 104.7 106.2 104.4 104.4 104.7 104.7 104.5 104.2
2 151.0 154.0 147.6 150.4 148.2 147.9 147.6 147.4 147.4 147.1
3 150.5 153.5 147.1 150.3 148.2 148.1 147.0 147.0 145.9 147.7
4 103.9 106.0 102.6 104.7 100.7 100.8 100.6 102.6 101.4 100.6
4a 132.6 123.0 121.1 121.2 126.9 128.3 120.8 121.0 120.0 126.2
4b 152.2 138.0 135.7 132.7 136.9 138.7 152.4 135.8 128.0 142.6
6 134.6 155.0 162.7 163.4 145.5 145.7 164.0 164.3 162.7 48.6
6a 134.5 122.0 119.8 129.2 120.6 121.4 135.9 119.0 126.4 126.1
7 109.7 110.0 150.3 147.0 144.1 142.1 106.6 108.6 145.7 146.0
8 154.2 155.0 152.8 151.1 149.4 147.5 148.2 149.6 148.1 152.2
9 161.4 160.0 118.0 127.0 120.5 123.5 131.1 153.5 126.4 110.9
10 105.6 105.0 117.9 119.1 118.6 118.5 102.6 102.7 118.6 118.6
10a 121.6 133.0 129.0 120.2 127.3 126.4 132.0 128.9 118.1 126.2
10b 128.3 119.0 117.3 126.4 120.0 120.0 116.8 116.7 123.7 123.7
11 120.0 144.0 118.5 117.9 118.4 118.5 118.5 118.3 118.7 120.0
12 131.9 128.0 123.4 132.1 127.6 127.0 123.2 123.2 127.1 123.6
12a 122.3 132.0 131.8 133.9 129.5 129.2 120.9 131.8 129.1 130.8
2,3-OCH
2
O 104.4 103.0 101.6 103.4 101.4 101.4 101.5 101.5 101.8 100.9
7,8-OCH
2
O 102.3
8,9-OCH
2
O 101.9
NCH
3
52.2 53.0 50.1 41.2
6-OCH
3
40.9 49.7 41.1 41.2 41.2
7-OCH
3
61.8 61.5 61.1 60.9
8-OCH
3
57.2 58.0 56.7 56.7 56.2 59.9 55.7
9-OCH
3
57.9 58.0 56.1
Solv. mmmm d d c c m c
Ref. [71] [17] [9] [19] [72] [72] [26] [26] [19] [72]
c, recorded in chloroform-d
1
; d, DMSO-d
6
; m, methanol-d
4
.
Table 6.
13
C-NMR data of benzophenanthridine alkaloids.
16
Alkaloids

C26293637384041424344
1 123.3 106.9 106.0 101.2 104.0 105.2 105.1 105.0 104.9 105.0
2 148.7 149.9 152.5 147.6 147.5 148.4 148.4 148.3 148.3 148.4
3 149.0 150.9 152.0 147.9 146.5 148.9 148.8 148.5 148.5 148.8
4 104.3 101.6 101.0 104.2 99.3 101.9 102.0 102.6 102.7 102.4
4a 123.8 128.8 130.5 131.0 123.1 132.1 132.1 132.0 132.0 132.1
4b 130.9 140.0 141.0 140.0 137.8 141.3 141.1 141.1 141.1 141.1
6 60.0 66.7 92.0 56.2 54.3 58.5 57.4 56.6 56.3 57.4
6a 123.5 126.0 121.0 126.2 121.3 131.1 131.1 131.5 131.4 131.3
7 100.4 149.3 112.0 146.7 149.5 147.0 147.0 147.0 147.0 147.1
8 147.5 154.4 150.0 151.9 143.8 153.0 153.0 153.0 153.0 153.0
9 148.2 114.4 150.0 111.3 116.0 112.1 111.8 112.0 112.0 111.9
10 106.4 121.4 110.0 119.1 118.7 119.3 119.3 119.3 119.3 119.2
10a 139.0 127.2 127.0 125.3 130.1 125.8 125.8 125.9 125.9 125.8
10b 127.0 126.7 119.0 123.2 127.4 124.8 124.8 124.8 124.8 124.9
11 119.6 121.9 144.0 119.6 119.5 120.7 120.7 120.8 120.7 120.7
12 110.4 126.7 121.0 123.5 123.6 124.4 124.5 124.4 124.3 124.4
12a 127.3 133.4 130.0 127.4 126.4 128.7 128.7 128.7 128.7 128.6
2,3-OCH
2
O 101.3 103.4 104.0 101.0 101.0 101.2 101.3 101.3 101.3 101.3
NCH
3
42.4 44.2 40.0 42.3 42.4 43.3 43.2 43.2 43.1 43.2
6-OCH
3
55.0
7-OCH
3
62.8 60.8 60.0 60.9 60.9 61.0 61.0 61.0
8-OCH
3
56.1 57.9 57.0 55.7 55.8 55.6 55.7 55.7 55.7
9-OCH
3
56.0 57.0
10148.4 69.3 53.3 47.2 48.2 42.6 50.7 47.9 47.3
20207.9 20.4 211.9 206.1 21.7 21.6 23.6 23.4 23.6
3031.5 41.8 30.0 30.8 30.8 29.9 29.5 29.4
4028.9 135.7 134.6 135.5 136.4 136.3
5023.8 128.2 128.2 126.0 125.2 125.9
6030.4 35.2 35.0 38.0 40.3 40.3
7044.6 44.6 46.7 46.5 47.1
8020.0 20.0 20.4 17.7 22.3
9032.4 32.8 34.5 36.3 36.2
10076.1 76.1 74.3 76.3 76.3
11043.1 43.0 44.1 44.2 43.4
12027.4 27.3 26.6 26.2 26.4
13015.9 15.8 15.6 15.4 15.4
14022.4 22.2 21.8 21.8 22.0
15023.0 23.1 23.2 22.3 18.2
100-OCH
3
48.1 48.3 48.7 48.4 48.3
Solv. cmmc dppppp
Ref. [30] [9] [17] [31] [14] [33] [33] [33] [33] [33]
c, recorded in chloroform-d
1
; d, DMSO-d
6
; m, methanol-d
4
; p, pyridine-d
5
.
Table 7.
13
C-NMR data of benzophenanthridine alkaloids (continued).
17
Alkaloids and Their Pharmacology Effects from Zanthoxylum Genus
DOI: http://dx.doi.org/10.5772/intechopen.91685

by comparison with the experimental CD spectra. This approach can lead to the
elucidation of possible absolute structure in the absence of X-ray crystallography or
NMR data.
Van et al. isolated four new compounds from Z. nitidum. Of these compounds
130 and 131 have the same constitution. This suggested the aglycone could be
enantiomer. Thus, the absolute configuration at C-11 of 130 and 131 were elucidated
by the comparison of its experimental ECD spectra with those calculated spectra.
The TD-DFT calculated ECD spectra [47] of a pair of epimers (130a and 131a) are
shown in Figure 7. The CD spectra of 130 and 131 were found to be similar to 130a
and 131a indicating the absolute configuration at C-11 as Rand S, respectively.
Yang et al., isolated five novel dihydrobenzo[c]phenanthridine alkaloids,
zanthomuurolanine (40), epi-zanthomuurolanine (41), zanthocadinanine A (42),
zanthocadinanine B (43), and epi-zanthocadinanine B (44) from Z. nitidum [33].
The absolute configurations of these compounds were determined by XRAY and
also CD spectra.
Zhao et al. isolated a pair of new enantiomeric furoquinoline alkaloids,
zanthonitidine A (77) from Z. nitidum. There is no obvious absorption of electronic
circular dichroism indicated that zanthonitidine A was proposed to be a racemate
Figure 7.
Experimental CD and calculated ECD spectra of 130 and 131 (calculated spectra are shifted by 8 nm).
The figure was cited from Van et al [47].
Figure 8.
Two possible stereochemical structures of 77; experimental ECD spectra of (+)-77/()-77 and calculated
ECD spectra of (80R,9
0R)/(80S,9
0S)of77. The figure was cited from Zhao et al [24].
18
Alkaloids

mixture. Thus, they used Chiralpak ID column chromatography to separate the
mixtures to obtain the enantiomers, (+) and (-)-zanthonitidine A. The absolute
configurations of the enantiomers were then determined by comparing the experi-
mental CD to the calculated ECD using TD-DFT of the Gaussian 9.0. By analyzing
ECD spectra at the same theory level, the absolute configurations of (+) and ()-
zanthonitidine A were evaluated as (80R,90R)-zanthonitidine A and (80S,90S)-
zanthonitidine A [24] (Figure 8).
Overall, experimental and calculated ECD spectra could play an important role
for determine absolute configurations of alkaloids from Zanthoxylum species.
5. Conclusions
Alkaloids are the main constituents of Zanthoxylum species, present in the fruits,
leaves, bark and root of plants. There are different types of skeletons of these
alkaloids, including benzophenanthridines, aporphines, benzylisoquinolines,
furoquinolines, quinolines, quinolones, quinazolines, indolopyridoquinazolines,
acridones, canthinones, amines and tryptamines; in which benzophenanthridines
are the main ingredient. Alkaloids from Zanthoxylum species have been displayed a
variety of valuable biological activities, such as antibacterial, antifungal, antiviral,
anti-inflammatory, antioxidant, cardiovascular protect and especially anti-cancer
effects. Some alkaloids of which shown their potential to become natural healing
agents, this has increasingly attracted scientists’interest in the genus Zanthoxylum.
The data collected in this chapter has clearly shown that Zanthoxylum alkaloids with
abundance of chemical structures and a wide range of cytotoxic activities on many
the cancer cell lines. These could be good sources of potential cancer chemo-
preventive agents. Further studies should be carried out to know more clearly the
anticancer mechanisms of these alkaloids.
Conflict of interest
The authors declared no potential conflicts of interest with respect to the
research, authorship, and/or publication of this book chapter.
19
Alkaloids and Their Pharmacology Effects from Zanthoxylum Genus
DOI: http://dx.doi.org/10.5772/intechopen.91685

Author details
Nguyen Xuan Nhiem
1
, Pham Minh Quan
2
and Nguyen Thi Hong Van
2
*
1 Institute of Marine Biochemistry, Vietnam Academy of Science and Technology,
Hanoi, Vietnam
2 Institute of Natural Products Chemistry, Vietnam Academy of Science and
Technology, Hanoi, Vietnam
*Address all correspondence to: van762004@yahoo.com
© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms
of the Creative Commons Attribution License (http://creativecommons.org/licenses/
by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,
provided the original work is properly cited.
20
Alkaloids

References
[1] Rodriguez-Guzman R, Radwan MM,
Burandt CL, Williamson JS, Ross SA.
Xenobiotic biotransformation of
4-methoxy-N-methyl-2-quinolone,
isolated from Zanthoxylum
monophyllum. Natural Product
Communications. 2010;5:1463-1464
[2] Hu J, Zhang WD, Liu RH, Zhang C,
Shen YH, Li H-L, et al.
Benzophenanthridine alkaloids from
Zanthoxylum nitidum (ROXB.) DC, and
their analgesic and anti-inflammatory
activities. Chemistry & Biodiversity.
2006;3:990-995
[3] Waterman PG. Alkaloids from the
root bark of Zanthoxylum myriacanthum.
Phytochemistry. 1975;14:2530
[4] Stermitz FR, Caolo MA,
Swinehart JA. Chemistry of
Zanthoxylum. Part 5. Alkaloids and other
constituents of Zanthoxylum williamsii,
Z. monophyllum, and Z. fagara.
Phytochemistry. 1980;19:1469-1472
[5] Moody JO, Sofowora A. Leaf
alkaloids of Zanthoxylum rubescens.
Planta Medica. 1984;50:101-103
[6] Fang SD, Wang LK, Hecht SM.
Inhibitors of DNA topoisomerase I
isolated from the roots of Zanthoxylum
nitidum. Journal of Organic Chemistry.
1993;58:5025-5027
[7] Kato A, Moriyasu M, Ichimaru M,
Nishiyama Y, Juma FD, Nganga JN,
et al. Examination of alkaloidal
constituents of Zanthoxylum
usambarense by a combination of ion-
pair extraction and ion-pair
chromatography using sodium
perchlorate. Phytochemical Analysis.
1995;6:89-95
[8] Moriyasu M, Ichimaru M,
Nishiyama Y, Kato A, Wang J, Zhang H,
et al. (R)-(+)-Isotembetarine, a
quaternary alkaloid from Zanthoxylum
nitidium. Journal of Natural Products.
1997;60:299-301
[9] Patino-Ladino OJ, Cuca-Suarez LE.
Benzophenanthridine alkaloids from
Zanthoxylum quinduensis. Actualidades
Biologicas. 2005;27:53-58
[10] Halstead CW, Forster PI,
Waterman PG. Alkaloids from the stem
bark of an Australian population of
Zanthoxylum ovalifolium. Natural
Product Research. 2006;20:940-945
[11] Liang M, Zhang W, Hu J, Liu R,
Zhang C. Simultaneous analysis of
alkaloids from Zanthoxylum nitidum by
high performance liquid
chromatography-diode array detector-
electrospray tandem mass spectrometry.
Journal of Pharmaceutical and
Biomedical Analysis. 2006;42:178-183
[12] Cai M, Zhou Y, Wang X, Li R,
Liao X, Ding L. Rapid structural
characterization of isomeric benzo[c]
phenanthridine alkaloids from the roots
of Zanthoxylum nitidium by liquid
chromatography combined with
electrospray ionization tandem mass
spectrometry. Rapid Communications
in Mass Spectrometry. 2007;21:
1931-1936
[13] Hu J, Zhang W-D, Shen Y-H,
Zhang C, Xu L, Liu R-H, et al. Alkaloids
from Zanthoxylum nitidum (Roxb.) DC.
Biochemical Systematics and Ecology.
2007;35:114-117
[14] Talontsi FM, Matasyoh JC,
Ngoumfo RM, Chepkorir R. Mosquito
larvicidal activity of alkaloids from
Zanthoxylum lemairei against the
malaria vector Anopheles gambiae.
Pesticide Biochemistry and Physiology.
2011;99:82-85
[15] Chen J, Wang J, Lin L, He L, Wu Y,
Zhang L, et al. Inhibition of STAT3
signaling pathway by nitidine chloride
21
Alkaloids and Their Pharmacology Effects from Zanthoxylum Genus
DOI: http://dx.doi.org/10.5772/intechopen.91685

suppressed the angiogenesis and growth
of human gastric cancer. Molecular
Cancer Therapeutics. 2012;11:277-287
[16] Fang Z, Tang Y, Jiao W, Xing Z,
Guo Z, Wang W, et al. Nitidine chloride
induces apoptosis and inhibits tumor
cell proliferation via suppressing ERK
signaling pathway in renal cancer. Food
and Chemical Toxicology. 2014;66:
210-216
[17] Akoua Yao-Kouassi P, Caron C,
Ramiarantsoa H, Prost E, Harakat D,
Le Magrex-Debar E, et al. New
nitro-benzo[c]phenanthridine and
indolopyridoquinazoline alkaloids from
Zanthoxylum atchoum. Comptes Rendus
Chimie. 2015;18:891-897
[18] Tuyen TT, Van NTH, Quan PM,
Inh CT, Minh PTH, Thuy TTT, et al.
Non-alkaloid compounds isolated from
Zanthoxylum nitidum plant. Vietnam
Journal of Chemistry. 2018;56:396-400
[19] Cui XG, Zhao Q J, Chen QL, Xu L,
Song Y, Jin YS, et al. Two new
benzophenanthridine alkaloids from
Zanthoxylum nitidum. Helvetica
Chimica Acta. 2008;91:155-158
[20] Deyun K, Gray AI, Hartley TG,
Waterman PG. Alkaloids from an
Australian accession of Zanthoxylum
nitidum (Rutaceae). Biochemical
Systematics and Ecology. 1996;24:87-88
[21] Chen I-S, Tsai I-W, Teng C-M, Chen
J-J, Chang Y-L, Ko F-N, et al.
Pyranoquinoline alkaloids from
Zanthoxylum simulans. Phytochemistry.
1997;46:525-529
[22] Yang CH, Cheng MJ, Lee SJ,
Yang CW, Chang HS, Chen IS.
Secondary metabolites and cytotoxic
activities from the stem bark of
Zanthoxylum nitidum. Chemistry &
Biodiversity. 2009;6:846-857
[23] Wang CF, Fan L, Tian M, Du SS,
Deng ZW, Feng JB, et al. Cytotoxicity of
benzophenanthridine alkaloids from the
roots of Zanthoxylum nitidum (Roxb.)
DC. var. fastuosum How ex Huang.
Natural Product Research. 2015;29:
1380-1383
[24] Zhao L-N, Guo X-X, Liu S, Feng L,
Bi Q-R, Wang Z, et al. ()-
Zanthonitidine A, a pair of enantiomeric
furoquinoline alkaloids from
Zanthoxylum nitidum with antibacterial
activity. Natural Products and
Bioprospecting. 2018;8:361-367
[25] Sukari MA, Salim WSW,
Ibrahim NH, Rahmani M, Aimi N,
Kitajima M. Phenantridine alkaloids
from Zanthoxylum myriacanthum.
Fitoterapia. 1999;70:197-199
[26] Gonzaga WA, Weber AD,
Giacomelli SR, Dalcol II, Hoelzel SCS,
Morel AF. Antibacterial alkaloids from
Zanthoxylum rhoifolium. Planta Medica.
2003;69:371-374
[27] Hu J, Shi X, Mao X, Chen J, Zhu L,
Zhao Q. Antinociceptive activity of
Rhoifoline A from the ethanol extract of
Zanthoxylum nitidum in mice. Journal of
Ethnopharmacology. 2013;150:828-834
[28] Marcos M, Villaverde MC,
Riguera R, Castedo L, Stermitz FR.
Zanthoxylum coriaceum alkaloids related
to bishordeninyl terpenes.
Phytochemistry. 1990;29:2315-2319
[29] Yang G, Chen D. Alkaloids from the
roots of Zanthoxylum nitidum and their
antiviral and antifungal effects.
Chemistry & Biodiversity. 2008;5:
1718-1722
[30] Wang XL, Yu KB, Li QF, Peng SL,
Ding LS. 8-Acetonyldihydronitidine.
Archive of Acta Crystallographica
Section E. 2006;62:o2247-o2248
[31] Geng D, Li D-X, Shi Y, Liang J-Y,
Min Z-D. A new benzophenanthridine
alkaloid from Zanthoxylum nitidum.
Zhongguo Tianran Yaowu. 2009;7:
274-277
22
Alkaloids

[32] Liu H, Feng J, Feng K, Lai M.
Optimization of the extraction
conditions and quantification by RP-LC
analysis of three alkaloids in
Zanthoxylum nitidum roots. Pharmaceu-
tical Biology. 2014;52:255-261
[33] Yang CH, Cheng MJ, Chiang MY,
Kuo YH, Wang CJ, Chen IS.
Dihydrobenzo[c]phenanthridine
alkaloids from stem bark of
Zanthoxylum nitidum. Journal of Natural
Products. 2008;71:669-673
[34] Dreyer DL, Brenner RC.
Chemotaxonomy of the Rutaceae.
Part XIII. Alkaloids of some Mexican
Zanthoxylum species. Phytochemistry.
1980;19:935-939
[35] Samita FN, Sandjo LP, Ndiege IO,
Hassanali A, Lwande W.
Zanthoxoaporphines A-C: Three new
larvicidal dibenzo[de,g]quinolin-7-one
alkaloids from Zanthoxylum
paracanthum (Rutaceae). Beilstein
Journal of Organic Chemistry. 2013;9:
447-452, No. 447
[36] Liu Y-C, Chen Z-F, Liu L-M,
Peng Y, Hong X, Yang B, et al. Divalent
later transition metal complexes of the
traditional chinese medicine (TCM)
liriodenine: Coordination chemistry,
cytotoxicity and DNA binding studies.
Dalton Transactions. 2009:10813-10823
[37] Yang Z-D, Zhang D-B, Ren J,
Yang M-J. Skimmianine, a furoquinoline
alkaloid from Zanthoxylum nitidum as a
potential acetylcholinesterase inhibitor.
Medicinal Chemistry Research. 2012;21:
722-725
[38] Ruangrungsi N, Tantivatana P,
Borris RP, Cordell GA. Traditional
medicinal plants of Thailand. III.
Constituents of Zanthoxylum budrunga
(Rutaceae). Journal of the Science
Society of Thailand. 1981;7:123-127
[39] Ahmad MU, Rahman MA, Huq E,
Chowdhury R. Alkaloids of Zanthoxylum
budrunga. Fitoterapia. 2003;74:191-193
[40] Wang C, Wan J, Mei Z, Yang X.
Acridone alkaloids with cytotoxic and
antimalarial activities from Zanthoxylum
simulans Hance. Pharmacognosy
Magazine. 2014;10:73-76, 76a
[41] Talapatra SK, Dutta S, Talapatra B.
Alkaloids and terpenoids of
Zanthoxylum ovalifolium.
Phytochemistry. 1973;12:729-730
[42] Ferreira ME, Rojas de Arias A,
Torres de Ortiz S, Inchausti A,
Nakayama H, Thouvenel C, et al.
Leishmanicidal activity of two canthin-
6-one alkaloids, two major constituents
of Zanthoxylum chiloperone var.
angustifolium. Journal of
Ethnopharmacology. 2002;80:199-202
[43] Hu J, Zhang W-D, Shen Y-H,
Zhang C, Liu R-H, Xu X-K, et al. Two
novel alkaloids from Zanthoxylum
nitidum. Helvetica Chimica Acta. 2007;
90:720-722
[44] Liu S-L, Tsai I-L, Ishikawa T,
Harayama T, Chen I-S. Bishordeninyl
terpene alkaloids from Zanthoxylum
integrifoliolum. Journal of the Chinese
Chemical Society. 2000;47:571-574
[45] Schroeder DR. 1985
[46] Hu J, Shi X, Mao X, Chen J, Li H.
Cytotoxic mannopyranosides of indole
alkaloids from Zanthoxylum nitidum.
Chemistry & Biodiversity. 2014;11:
970-974
[47] Van NTH, Tuyen TT, Quan PM,
Long PQ, Nhiem NX, Tai BH, et al.
Alkaloid glycosides and their cytotoxic
constituents from Zanthoxylum nitidum.
Phytochemistry Letters. 2019;32:47-51
[48] Ochwang'i DO, Kimwele CN,
Oduma JA, Gathumbi PK, Mbaria JM,
Kiama SG. Medicinal plants used in
treatment and management of cancer in
Kakamega County, Kenya. Journal of
Ethnopharmacology. 2014;151:
1040-1055
23
Alkaloids and Their Pharmacology Effects from Zanthoxylum Genus
DOI: http://dx.doi.org/10.5772/intechopen.91685

[49] Lee J, Lim KT. Inhibitory effect of
phytoglycoprotein (24 kDa) on
hepatocarcinogenesis in N-
nitrosodiethylamine-treated ICR mice.
Journal of Pharmacy and Pharmacology.
2011;63:840-848
[50] Rajamani P, Banerjeet S, Rao AR.
Chemoprotective influence of
Zanthoxylum sps. on hepatic carcinogen
metabolizing and antioxidant enzymes
and skin papillomagenesis in murine
model. Indian Journal of Experimental
Biology. 2011;49:857-863
[51] Misra LN, Wouatsa NAV, Kumar S,
Venkatesh Kumar R,
Tchoumbougnang F. Antibacterial,
cytotoxic activities and chemical
composition of fruits of two
Cameroonian Zanthoxylum species.
Journal of Ethnopharmacology. 2013;
148:74-80
[52] Tokita Y, Yuzurihara M,
Sakaguchi M, Satoh K, Kase Y. The
pharmacological effects of daikenchuto,
a traditional herbal medicine, on
delayed gastrointestinal transit in rat
postoperative Ileus. Journal of
Pharmacological Sciences. 2007;104:
303-310
[53] Chou ST, Chan HH, Peng HY,
Liou MJ, Wu TS. Isolation of substances
with antiproliferative and apoptosis-
inducing activities against leukemia cells
from the leaves of Zanthoxylum
ailanthoides Sieb. & Zucc.
Phytomedicine. 2011;18:344-348
[54] Ozkan M, Mutiso PB, Nahar L,
Liu P, Brown S, Wang W, et al.
Zanthoxylum usambarense (Engl.)
Kokwaro (Rutaceae) extracts inhibit the
growth of the breast cancer cell lines
MDA-MB-231 and MCF-7, but not the
brain tumour cell line U251 in vitro.
Phytotherapy Research. 2013;27:787-790
[55] Walker TM, Vogler B,
Moriarity DM, Haber WA, Setzer WN.
A phytochemical investigation of
Zanthoxylum setulosum. Natural Product
Communications. 2011;6:1807-1808
[56] Dung TD, Feng CC, Kuo WW,
Pai P, Chung LC, Chang SH, et al.
Suppression of plasminogen activators
and the MMP-2/-9 pathway by a
Zanthoxylum avicennae extract to inhibit
the HA22T human hepatocellular
carcinoma cell migration and invasion
effects in vitro and in vivo via
phosphatase 2A activation. Bioscience,
Biotechnology, and Biochemistry. 2013;
77:1814-1821
[57] Karmakar I, Haldar S,
Chakraborty M, Chaudhury K,
Dewanjee S, Haldar PK. Regulation of
apoptosis through bcl-2/bax proteins
expression and DNA damage by
Zanthoxylum alatum. Pharmaceutical
Biology. 2016;54:503-508
[58] Chon SU, Heo BG, Park YS,
Kim DK, Gorinstein S. Total phenolics
level, antioxidant activities and
cytotoxicity of young sprouts of some
traditional Korean salad plants. Plant
Foods for Human Nutrition. 2009;64:
25-31
[59] Jang KH, Chang YH, Kim DD,
Oh KB, Oh U, Shin J. New
polyunsaturated fatty acid amides
isolated from the seeds of Zanthoxylum
piperitum. Archives of Pharmacal
Research. 2008;31:569-572
[60] Ngoumfo RM, Jouda JB, Mouafo FT,
Komguem J, Mbazoa CD, Shiao TC,
et al. In vitro cytotoxic activity of
isolated acridones alkaloids from
Zanthoxylum leprieurii Guill. et Perr.
Bioorganic & Medicinal Chemistry.
2010;18:3601-3605
[61] Chen I-S, Wu S-J, Tsai I-L, Wu T-S,
Pezzuto JM, Lu MC, et al. Chemical and
bioactive constituents from
Zanthoxylum simulans. Journal of
Natural Products. 1994;57:1206-1211
[62] Chen JJ, Fang HY, Duh CY, Chen IS.
New indolopyridoquinazoline, benzo[c]
24
Alkaloids

phenanthridines and cytotoxic
constituents from Zanthoxylum
integrifoliolum. Planta Medica. 2005;71:
470-475
[63] Pachon G, Rasoanaivo H,
Azqueta A, Rakotozafy JC,
Raharisololalao A, De Cerain AL, et al.
Anticancer effect of a new
benzophenanthridine isolated from
Zanthoxylum madagascariense
(Rutaceline). In Vivo. 2007;21:417-422
[64] Mansoor TA, Borralho PM, Luo X,
Mulhovo S, Rodrigues CM, Ferreira MJ.
Apoptosis inducing activity of
benzophenanthridine-type alkaloids and
2-arylbenzofuran neolignans in HCT116
colon carcinoma cells. Phytomedicine.
2013;20:923-929
[65] Pan X, Han H, Wang L, Yang L,
Li R, Li Z, et al. Nitidine chloride
inhibits breast cancer cells migration
and invasion by suppressing c-Src/FAK
associated signaling pathway. Cancer
Letters. 2011;313:181-191
[66] He H, Zhuo R, Dai J, Wang X,
Huang X, Wang H, et al. Chelerythrine
induces apoptosis via ROS-mediated
endoplasmic reticulum stress and
STAT3 pathways in human renal cell
carcinoma. Journal of Cellular and
Molecular Medicine. 2020;24:50-60
[67] Li WF, Hao DJ, Fan T, Huang HM,
Yao H, Niu XF. Protective effect of
chelerythrine against ethanol-induced
gastric ulcer in mice. Chemico-
Biological Interactions. 2014;208:18-27
[68] Wu S, Yu D, Liu W, Zhang J, Liu X,
Wang J, et al. Magnoflorine from Coptis
chinese has the potential to treat DNCB-
induced Atopic dermatits by inhibiting
apoptosis of keratinocyte. Bioorganic &
Medicinal Chemistry. 2019;28:115093
[69] Wei T, Xiaojun X, Peilong C.
Magnoflorine improves sensitivity to
doxorubicin (DOX) of breast cancer
cells via inducing apoptosis and
autophagy through AKT/mTOR and p38
signaling pathways. Biomedicine &
Pharmacotherapy. 2020;121:109139
[70] Li ZH, Gao J, Hu PH, Xiong JP.
Anticancer effects of liriodenine on the
cell growth and apoptosis of human
breast cancer MCF-7 cells through the
upregulation of p53 expression.
Oncology Letters. 2017;14:1979-1984
[71] Ratheesh M, Sindhu G, Helen A.
Anti-inflammatory effect of quinoline
alkaloid skimmianine isolated from Ruta
graveolens L. Inflammation Research.
2013;62:367-376
[72] Yang N, Yue R, Ma J, Li W, Zhao Z,
Li H, et al. Nitidine chloride exerts anti-
inflammatory action by targeting
Topoisomerase I and enhancing IL-10
production. Pharmacological Research.
2019;148:104368
[73] Fan L, Fan Y, Liu L, Tao W, Shan X,
Dong Y, et al. Chelerythrine attenuates
the inflammation of lipopolysaccharide-
induced acute lung inflammation
through NF-kappaB signaling pathway
mediated by Nrf2. Frontiers
in Pharmacology. 2018;9:1047
[74] Ngane AN, Biyiti L, Zollo PH,
Bouchet P. Evaluation of antifungal
activity of extracts of two Cameroonian
rutaceae: Zanthoxylum leprieurii Guill.
et Perr. and Zanthoxylum
xanthoxyloides Waterm. Journal of
Ethnopharmacology. 2000;70:335-342
[75] Dieguez-Hurtado R, Garrido-
Garrido G, Prieto-Gonzalez S, Iznaga Y,
Gonzalez L, Molina-Torres J, et al.
Antifungal activity of some Cuban
Zanthoxylum species. Fitoterapia. 2003;
74:384-386
[76] Smith ML, Gregory P, Bafi-Yeboa
NF, Arnason JT. Inhibition of DNA
polymerization and antifungal
specificity of furanocoumarins present
in traditional medicines.
Photochemistry and Photobiology.
2004;79:506-509
25
Alkaloids and Their Pharmacology Effects from Zanthoxylum Genus
DOI: http://dx.doi.org/10.5772/intechopen.91685

[77] Bafi-Yeboa NF, Arnason JT, Baker J,
Smith ML. Antifungal constituents of
northern prickly ash, Zanthoxylum
americanum mill. Phytomedicine. 2005;
12:370-377
[78] Ferreira ME, Cebrian-Torrejon G,
Corrales AS, Vera de Bilbao N, Rolon M,
Gomez CV, et al. Zanthoxylum
chiloperone leaves extract: First
sustainable Chagas disease treatment.
Journal of Ethnopharmacology. 2011;
133:986-993
[79] Thouvenel C, Gantier JC, Duret P,
Fourneau C, Hocquemiller R,
Ferreira ME, et al. Antifungal
compounds from Zanthoxylum
chiloperone var. angustifolium.
Phytotherapy Research. 2003;17:
678-680
[80] Nissanka AP, Karunaratne V,
Bandara BM, Kumar V, Nakanishi T,
Nishi M, et al. Antimicrobial alkaloids
from Zanthoxylum tetraspermum and
caudatum. Phytochemistry. 2001;56:
857-861
[81] Luo X, Pires D, Ainsa JA, Gracia B,
Duarte N, Mulhovo S, et al.
Zanthoxylum capense constituents with
antimycobacterial activity against
Mycobacterium tuberculosis in vitro and
ex vivo within human macrophages.
Journal of Ethnopharmacology. 2013;
146:417-422
[82] Tantapakul C, Phakhodee W,
Ritthiwigrom T, Yossathera K,
Deachathai S, Laphookhieo S.
Antibacterial compounds from
Zanthoxylum rhetsa. Archives of
Pharmacal Research. 2012;35:1139-1142
[83] Luo X, Pedro L, Milic V, Mulhovo S,
Duarte A, Duarte N, et al. Antibacterial
benzofuran neolignans and
benzophenanthridine alkaloids from the
roots of Zanthoxylum capense. Planta
Medica. 2012;78:148-153
[84] Hatano T, Kusuda M, Inada K,
Ogawa TO, Shiota S, Tsuchiya T, et al.
Effects of tannins and related
polyphenols on methicillin-resistant
Staphylococcus aureus. Phytochemistry.
2005;66:2047-2055
[85] He N, Wang P, Wang P, Ma C,
Kang W. Antibacterial mechanism of
chelerythrine isolated from root of
Toddalia asiatica (Linn) Lam. BMC
Complementary Medicine and
Therapies. 2018;18:261
[86] Cheng MJ, Lee KH, Tsai IL, Chen IS.
Two new sesquiterpenoids and anti-HIV
principles from the root bark of
Zanthoxylum ailanthoides. Bioorganic &
Medicinal Chemistry. 2005;13:
5915-5920
[87] Bouquet J, Rivaud M, Chevalley S,
Deharo E, Jullian V, Valentin A.
Biological activities of nitidine, a
potential anti-malarial lead compound.
Malaria Journal. 2012;11:67
26
Alkaloids