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Alkaloids and Their Pharmacology Effects from Zanthoxylum Genus

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Nguyen Xuan Nhiem, Pham Minh Quan and Nguyen Thi Hong Van

Submitted: 29 October 2019 Reviewed: 10 February 2020 Published: 12 March 2020

DOI: 10.5772/intechopen.91685

Bioactive Compounds in Nutraceutical and Functional Food for Good Human Health IntechOpen
Bioactive Compounds in Nutraceutical and Functional Food for Good... Edited by Kavita Sharma

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Bioactive Compounds in Nutraceutical and Functional Food for Good Human Health

Edited by Kavita Sharma, Kanchan Mishra, Kula Kamal Senapati and Corina Danciu

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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.

Keywords

  • Zanthoxylum
  • Rutaceae
  • alkaloids
  • 13C-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, antimalarial, anti-inflammatory, antioxidant, tuberculosis, cardiovascular, and liver protective 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 infections in hospital [1] and also shown anti-inflammatory activity [2] (Figure 1).

Figure 1.

Photographs of the Zanthoxylum species. The images were obtained from http://tropical.theferns.info.

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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).

Figure 2.

The structures of alkaloids 1–51.

No. Compound names Sources Ref.
1 Nitidine Z. myriacanthum, Z. williamsii, Z. clava-herculis, Z. americanum, Z. bouetense, Z. nitidum, Z. usambarense, Z. ovalifolium, Z. lemairei, Z. atchoum [3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18]
2 Chelerythrine Z. williamsii, Z. monophyllum, Z. clava-herculis, Z. americanum, Z. bouetense, Z. nitidum, Z. usambarense, Z. simulans, Z. lemairei, Z. atchoum [4, 5, 6, 7, 8, 11, 13, 14, 17]
3 Fagaridine Z. nitidum, Z. atchoum [6, 17]
4 Isofagandine Z. nitidum [6]
5 Terihanine Z. ovalifolium [10]
6 Isoterihanine Z. ovalifolium [10]
7 11-Nitronitidine Z. atchoum [17]
8 Sanguinarin Z. nitidum [11, 13]
9 Methoxyfagaridine 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, 21, 22, 23]
14 Decarine Z. nitidum, Z. simulans [13, 20, 21, 22, 23, 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, 12, 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]
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-(2′-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, 21, 22, 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.

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 3.

The structures of alkaloids 52–78.

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.

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).

Figure 4.

The structures of alkaloids 79–97.

No. Compound names Sources Ref.
uinolines
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]
uinolones
92 Flindersine Z. nitidum [22]
93 4-Methoxy-1-methyl-2-quinolone Z. nitidum [22, 24]
uinazolines
94 1-Methyl-3-(2′-phenylethyl)-lH,3Hquinazoline-2,4-dione Z. arborescens [34]
95 1-Methyl-3-[2′-(4″-methoxyphenyl) ethyl]-lH,3H quinazoline-2,4-dione Z. arborescens [34]
96 Arborine Z. budrunga [38]
97 2-(2′,4′,6′-Trimethyl-heptenyl)-4-quinozolone Z. budrunga [38]

Table 3.

Quinolines, quinolones, and quinazolines from Zanthoxylum species.

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). Until now, only a small number of this class of compounds have been published (Figure 5 and Table 4).

Figure 5.

The structures of alkaloids 98–107.

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.

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).

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 N′-demethylalfileramine Z. coriaceum [28]
117 N-demethylalfileramine Z. coriaceum [28]
118 N,N′-demethylalfileramine Z. coriaceum [28]
119 Culantraraminol Z. procerom, Z. colantrillo [45]
120 Culantraramine Z. coriaceum [28]
121 N,N′-demethylculantraramine Z. coriaceum [28]
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-d mannopyranoside 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.

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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 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 IC50 values of 73.06 and 42.22 μg/ml, respectively [53].

The methanol, hexane, and chloroform extracts from Z. usambarense were evaluated 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, 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 apoptotic 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 IC50 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 IC50 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 benzophenanthridines may become a valid alternative of potential basis for new anti-proliferative agents [23]. Methyl 7-(β-d-mannopyranosyloxy)-1H-indole-2-carboxylate (126), methyl 7-[(3-O-acetyl-β-d-mannopyranosyl)oxy]-1H-indole-2-carboxylate (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 IC50 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 IC50 values of 2.19, 2.38, and 3.19 μg/ml, respectively [22]. In addition, normelicopidine (101) from Z. simulans showed the cytotoxic activities against PC-3M, LNCaP, and Dd2 with the IC50 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 IC50 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 (IC50 values < 4 μg/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 volume, 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, 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 significantly 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 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 activation 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-1β production and oxidative LPS-induced [73]. Chelerythrine was found to inhibit NO production, pro-inflammatory IL-6 and TNF-α level 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-α and 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 antifungal 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-acetonyldihydroavicine (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-quinolone from Z. monophyllum exhibited significant inhibitory activity against MRSA bacteria with the IC50 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 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 EC50 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].

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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 1H-, 13C-NMR, DEPT, COSY, HSQC, HMBC, NOESY, and ROESY. The absolute configurations of these compounds were also determined by XRAY, and experimental 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 7 summarized 13C-NMR characteristics of benzophenanthridine as follows:

  1. When dioxymethylene group at C-2/C-3, 13C-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.

C 1 7 11 12 13 14 19 20 22 24
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-OCH2O 104.4 103.0 101.6 103.4 101.4 101.4 101.5 101.5 101.8 100.9
7,8-OCH2O 102.3
8,9-OCH2O 101.9
NCH3 52.2 53.0 50.1 41.2
6-OCH3 40.9 49.7 41.1 41.2 41.2
7-OCH3 61.8 61.5 61.1 60.9
8-OCH3 57.2 58.0 56.7 56.7 56.2 59.9 55.7
9-OCH3 57.9 58.0 56.1
Solv. m m m m d d c c m c
Ref. [71] [17] [9] [19] [72] [72] [26] [26] [19] [72]

Table 6.

13C-NMR data of benzophenanthridine alkaloids.

c, recorded in chloroform-d1; d, DMSO-d6; m, methanol-d4.

C 26 29 36 37 38 40 41 42 43 44
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-OCH2O 101.3 103.4 104.0 101.0 101.0 101.2 101.3 101.3 101.3 101.3
NCH3 42.4 44.2 40.0 42.3 42.4 43.3 43.2 43.2 43.1 43.2
6-OCH3 55.0
7-OCH3 62.8 60.8 60.0 60.9 60.9 61.0 61.0 61.0
8-OCH3 56.1 57.9 57.0 55.7 55.8 55.6 55.7 55.7 55.7
9-OCH3 56.0 57.0
1′ 148.4 69.3 53.3 47.2 48.2 42.6 50.7 47.9 47.3
2′ 207.9 20.4 211.9 206.1 21.7 21.6 23.6 23.4 23.6
3′ 31.5 41.8 30.0 30.8 30.8 29.9 29.5 29.4
4′ 28.9 135.7 134.6 135.5 136.4 136.3
5′ 23.8 128.2 128.2 126.0 125.2 125.9
6′ 30.4 35.2 35.0 38.0 40.3 40.3
7′ 44.6 44.6 46.7 46.5 47.1
8′ 20.0 20.0 20.4 17.7 22.3
9′ 32.4 32.8 34.5 36.3 36.2
10′ 76.1 76.1 74.3 76.3 76.3
11′ 43.1 43.0 44.1 44.2 43.4
12′ 27.4 27.3 26.6 26.2 26.4
13′ 15.9 15.8 15.6 15.4 15.4
14′ 22.4 22.2 21.8 21.8 22.0
15′ 23.0 23.1 23.2 22.3 18.2
10′-OCH3 48.1 48.3 48.7 48.4 48.3
Solv. c m m c d p p p p p
Ref. [30] [9] [17] [31] [14] [33] [33] [33] [33] [33]

Table 7.

13C-NMR data of benzophenanthridine alkaloids (continued).

c, recorded in chloroform-d1; d, DMSO-d6; m, methanol-d4; p, pyridine-d5.

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. Quantum mechanical calculations based on density functional theory (DFT) and its time-dependent formulation theory (TD-DFT) could be used to determine the theoretical chiroptical response of all the possible conformations of complexed-structures; 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 R and S, respectively.

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].

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 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 experimental 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 (8′R,9′R)-zanthonitidine A and (8′S,9′S)-zanthonitidine A [24] (Figure 8).

Figure 8.

Two possible stereochemical structures of 77; experimental ECD spectra of (+)-77/(−)-77 and calculated ECD spectra of (8′R, 9′R)/(8′S, 9′S) of 77. The figure was cited from Zhao et al [24].

Overall, experimental and calculated ECD spectra could play an important role for determine absolute configurations of alkaloids from Zanthoxylum species.

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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.

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Conflict of interest

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this book chapter.

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Written By

Nguyen Xuan Nhiem, Pham Minh Quan and Nguyen Thi Hong Van

Submitted: 29 October 2019 Reviewed: 10 February 2020 Published: 12 March 2020

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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