Open access peer-reviewed chapter

Alkaloids and Their Pharmacology Effects from Zanthoxylum Genus

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

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

DOI: 10.5772/intechopen.91685

Downloaded: 294

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

Zanthoxylumgenus 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 Zanthoxylumgenus 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 Zanthoxylumspecies, many compounds have been isolated, including alkaloids, lignans, coumarins, flavonoids, terpenoids, steroids, etc.; they are the specific classes of compounds in Zanthoxylumgenus. 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 vitrobut also their ability to inhibit tumor in vivothrough 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 theZanthoxylumspecies. The images were obtained fromhttp://tropical.theferns.info.

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2. Alkaloids constituents from Zanthoxylumgenus

A total of 35 Zanthoxylumspecies 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 (151) were isolated from Zanthoxylumspecies. Of these, nitidine (1), chelerythrine (2), and arnottianamide (48) were found in almost Zanthoxylumspecies (Figure 2 and Table 1).

Figure 2.

The structures of alkaloids151.

No.Compound namesSourcesRef.
1NitidineZ. 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]
2ChelerythrineZ. 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]
3FagaridineZ. nitidum, Z. atchoum[6, 17]
4IsofagandineZ. nitidum[6]
5TerihanineZ. ovalifolium[10]
6IsoterihanineZ. ovalifolium[10]
711-NitronitidineZ. atchoum[17]
8SanguinarinZ. nitidum[11, 13]
9MethoxyfagaridineZ. atchoum[17]
109-Methoxy chelerythrine chlorideZ. rubescens[5]
118-MethoxynorchelerythrineZ. nitidum[9]
128-MethoxysanguinarineZ. nitidum[19]
13NorchelerythrineZ. nitidum, Z. simulans[17, 20, 21, 22, 23]
14DecarineZ. nitidum, Z. simulans[13, 20, 21, 22, 23, 24]
15N-NortidineZ. myriacanthum[23, 25]
167,9-Dimethoxy-2,3-methylen dioxybenzophenantridineZ. myriacanthum[25]
17ZanthoxylineZ. rhoifolium, Z. nitidum[18, 26]
18Noravicine[23]
19Rhoifoline AZ. rhoifolium, Z. nitidum[13, 26, 27]
20Rhoifoline BZ. rhoifolium[26]
216,7,8-Trimethoxy-2,3-methylen dioxybenzophenantridineZ. nitidum[11]
228-MethoxyisodecarineZ. nitidum[19]
23DihydronitidineZ. myriacanthum, Z. nitidum[3, 12]
24DihydrochelerythrineZ. coriaceum, Z. nitidum, Z. simulans[9, 11, 12, 13, 18, 20, 22, 28]
255,6-Dihydro-6-methoxynitidineZ. nitidum[29]
266-AcetonyldihydronitidineZ. rhoifolium, Z. nitidum[12, 26, 30]
276-AcetonyldihydroavicineZ. rhoifolium[26]
286-AcetonyldihydrochelerythrineZ. rhoifolium, Z. nitidum[12, 18, 22, 23, 26]
29(R)-8-(1-hydroxyethyl) dihydrochelerythrineZ. nitidum[9, 23, 31]
308-MethoxydihydrochelerythrineZ. nitidum, Z. bungeanum[9, 13, 23]
318-HydroxydihydrochelerythrineZ. nitidum[9, 13, 23]
32Dihydrochelerythrinyl-8-acetaldehydeZ. nitidum[13]
33BocconolineZ. nitidum[18]
34Carboxymethyl dihydrochelerythrineZ. nitidum[18, 23]
356-Methoxy-7-hydroxydihydro chelerythrineZ. nitidum[23]
366-Nitro-8-methoxy-7,8-dihydronitidineZ. atchoum[17]
378-(2′-Cyclohexanone)-7,8-dihydrochelerythrineZ. nitidum[31]
386-Acetonyl-N-methyl-dihydrodecarineZ. lemairei, Z. riedelianum, Z. nitidum[14, 18]
39EthoxychelerythrineZ. nitidum[32]
40ZanthomuurolanineZ. nitidum[33]
41epi-ZanthomuurolanineZ. nitidum[33]
42Zanthocadinanine AZ. nitidum[33]
43Zanthocadinanine BZ. nitidum[33]
44epi-Zanthocadinanine BZ. nitidum[33]
45epi-Zanthocadinanine AZ. nitidum[22]
46OxynitidineZ. nitidum[17, 22]
47OxyavicineZ. nitidum, Z. ailanthoides[9, 11, 13, 22, 23]
48ArnottianamideZ. nitidum, Z. simulans, Z. bungeanum, Z. ailanthoides, Z. austrosinense[13, 17, 20, 21, 22, 23]
49IsoarnottianamideZ. nitidum, Z. myriacanthum[13]
5010-O-demethyl-17-O-methylisoarnottianamideZ. lemairei[14]
51IntegriamideZ. nitidum[13]

Table 1.

Benzophenanthridines from Zanthoxylumspecies.

2.2 Aporphines and benzylisoquinolines, and furoquinolines

Aporphines and benzylisoquinolines, and furoquinolines (5275) were reported from Zanthoxylumspecies. Magnoflorine (52), lauriforine (55), skimmianine (69), γ-fagarine (70), and dictamnine (71) were found in Zanthoxylumspecies 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 alkaloids5278.

No.Compound namesSourcesRef.
Aporphines
52MagnoflorineZ. fagara, Z. williamsii, Z. monophyllum, Z. clava-herculis, Z. americanum, Z. usambarense, Z. nitidum[4, 7, 8, 34]
53CocsarmineZ. tingoassuiba[4]
54XanthoplanineZ. tingoassuiba[4]
55LauriforineZ. fagara, Z. williamsii, Z. clava-herculis, Z. americanum[4, 34]
56N-methyl isocorydineZ. caribaeum, Z. coriaceum[28, 34]
57Zanthoxoaporphine AZ. paracanthum[35]
58Zanthoxoaporphine BZ. paracanthum[35]
59Zanthoxaporphine CZ. paracanthum[35]
60LiriodenineZ. nitidum[11, 13, 20, 22, 32, 36]
61(−)-N-acetylanonanineZ. simulans, Z. nitidum[21, 22]
62N-acetyldehydroanonaineZ. simulans, Z. nitidum[21, 22]
Benzylisoquinolines
63BerberineZ. caribaeum, Z. monophyllum, Z. clava-herculis[34, 4]
64BerberubineZ. nitidum[11, 13]
65CoptisineZ. nitidum[11, 13]
66(−)-UsambarineZ. usambarense[7]
67(−)-cis-N-methylcanadineZ. usambarense, Z. nitidum[7, 8]
68N-methylcanadineZ. coriaceum[28]
Furoquinolines
69SkimmianineZ. 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]
70γ-FagarineZ. americanum, Z. simulans, Z. nitidum, Z. cuspidatum[4, 21, 22, 24, 29, 37]
71DictamnineZ. budrunga, Z. ovalifolium, Z. nitidum, Z. schinifolium, Z. avicennae, Z. acanthopodium[10, 13, 29, 37, 38]
728-Methoxy dictamnineZ. rubescens[5]
73RobustineZ. simulans, Z. nitidum[21, 24]
745-MethoxydictamineZ. ovalifolium, Z. nitidum[10, 29]
75HaplopineZ. nitidum[37]
764-Methoxyfuro[2,3-b]quinoline-8-O-β-D-glucopyranosideZ. nitidum[24]
77Zanthonitidine AZ. nitidum[24]
78(+)-N-methylplatydesmineZ. usambarense[7]

Table 2.

Aporphines and benzylisoquinolines, and furoquinolines from Zanthoxylumspecies.

2.3 Quinolines, quinolones, and quinazolines

There were 19 quinolines, quinolones, and quinazolines (7997) isolated from Zanthoxylumspecies. They are mainly found in Z. simulansand Z. nitidum(Figure 4 and Table 3).

Figure 4.

The structures of alkaloids79–97.

No.Compound namesSourcesRef.
uinolines
79EdulitineZ. simulans, Z. nitidum[21, 24, 37]
80LunacridineZ. budrunga[39]
81EdulinineZ. williamsii, Z. nitidum[4, 37]
82TembetarineZ. fagara, Z. usambarense, Z. nitidum[4, 7, 8]
83(R)-(+)-isotembetarineZ. nitidum[8]
84(−)-OblongineZ. usambarense[7]
85SimulenolineZ. simulans[21]
86PeroxysimulenolinZ. simulans[21]
87BenzosimulinZ. simulans[21]
88ZanthodiolineZ. simulans, Z. nitidum[21, 24, 37]
89ZanthosimulineZ. simulans[21]
90HuajiaosimulineZ. simulans[21]
91ZanthobisquinoloneZ. simulans[21]
uinolones
92FlindersineZ. nitidum[22]
934-Methoxy-1-methyl-2-quinoloneZ. nitidum[22, 24]
uinazolines
941-Methyl-3-(2′-phenylethyl)-lH,3Hquinazoline-2,4-dioneZ. arborescens[34]
951-Methyl-3-[2′-(4″-methoxyphenyl) ethyl]-lH,3H quinazoline-2,4-dioneZ. arborescens[34]
96ArborineZ. budrunga[38]
972-(2′,4′,6′-Trimethyl-heptenyl)-4-quinozoloneZ. budrunga[38]

Table 3.

Quinolines, quinolones, and quinazolines from Zanthoxylumspecies.

2.4 Indolopyridoquinazolines, acridones, and canthinones

There are 10 indolopyridoquinazolines, acridones, and canthinones (98107) isolated from Zanthoxylumplants (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 alkaloids98107.

No.Compound namesSourcesRef.
Indolopyridoquinazolines
983-HydroxydehydroevodiamineZ. atchoum[17]
99DehydroevodiamineZ. atchoum[17]
100EvodiamineZ. atchoum[17]
Acridones
101NormelicopidineZ. simulans[40]
102NormelicopineZ. simulans[40]
103MelicopineZ. simulans[40]
104MelicopidineZ. simulans[40]
105MelicopicineZ. simulans[40]
Canthinones
1066-CanthinoneZ. ovalfolium[10, 41]
1075-Methoxycanthin-6-oneZ. chiloperone[42]

Table 4.

Indolopyridoquinazolines, acridones, and canthinones from Zanthoxylumspecies.

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 alkaloids108131.

No.Compound namesSourcesRef.
108SynephrineZ. fagara, Z. culantrillo[4]
109CandicineZ. clava-herculis, Z. americanum[4]
110HordenineZ. coriaceum[28]
1114-(2-N-methyltyraminyl)-(Z)-1,2-epoxy-2-ethylbut-3-eneZ. coriaceum[28]
112FagaramideZ. rubescens[5]
113-(2-methoxyethyl)-N,N-dimethyl benzenamineZ. nitidum[43]
114(+)-AegilineZ. coriaceum[28]
115AlfileramineZ. coriaceum, Z. integrifoliolum[28, 44]
116N′-demethylalfileramineZ. coriaceum[28]
117N-demethylalfileramineZ. coriaceum[28]
118N,N′-demethylalfileramineZ. coriaceum[28]
119CulantraraminolZ. procerom, Z. colantrillo[45]
120CulantraramineZ. coriaceum[28]
121N,N′-demethylculantraramineZ. coriaceum[28]
122IntegramineZ. integrifoliolum[44]
123IsoalfileramineZ. coriaceum[28]
124N,N,N-trimethyltryptamineZ. nitidum[8]
125N-trimethyltryptamineZ. nitidum[8]
126Methyl 7-(β-d-mannopyranosyloxy)-1H-indole-2-carboxylateZ. nitidum[46]
127Methyl 7-[(3-O-acetyl-β-d-mannopyranosyl)oxy]-1H-indole-2-carboxylateZ. nitidum[46]
1282-Methyl-1H-indol-7-yl β-d mannopyranosideZ. nitidum[46]
1294,5-Dihydroxy-1-methyl-3-oxo-2-(trichloromethyl)-3H-indolium chlorideZ. nitidum[43]
130Zanthonitiside AZ. nitidum[47]
131Zanthonitiside BZ. nitidum[47]

Table 5.

Other alkaloids from Zanthoxylumspecies.

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 Zanthoxylumgenus have attracted the attention of many research scientists. The studies have shown that the extracts and alkaloids from Zanthoxylumspecies 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 Zanthoxylumare amides and alkaloids.

3.1 Cytotoxic activities

In folk medicine, many species of Zanthoxylumare used as drugs to treat cancer, such as: the people in Kakamega, Kenya use the leaves and roots of Z. gilletiito treat breast and skin cancers [48]; fruits of Zanthoxylumspecies 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. ailanthoidesshowed 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. usambarensewere 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. setulosumcollected 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. avicennaeinhibited the highly metastatic HA22T liver cancer cell migration and invasion effects through PP2A activation [56]. Most recently, the methanol extract of Z. alatumshowed 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. schinifoliumhad the strongest cytotoxic against Calu-6 cell line with the IC50 values < 25.0 μg/ml, meanwhile the methanol extract of Z. piperitumexhibited 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. piperitumexhibited cytotoxicity in the A-549 cell line [59]. Glycoprotein from the seeds of Z. piperitumprevented damage to liver tissue caused by N-nitrosodiethylamine in the experimental mouse model [49].

Thirteen benzophenanthridines were isolated from Z. nitidumby 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. nitidumroots. 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. simulansshowed 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. leprieuriishowed 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. nitidumand 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 Zanthoxylumspecies showed significant cytotoxic activities: huajiaosimuline (90) and zanthosimuline (89) isolated from Z. simulansshowed 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. integrifoliolumexhibited cytotoxic activities on two human cancer cell lines, P-388 and HT-29 (IC50 values < 4 μg/ml) [62]. A new benzophenanthridine-typealkaloid, rutaceline isolated from the stem bark powder of Z. madagascarienseand 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. capenseexhibited strong anticancer activity in HCT-116 colon carcinoma cell line [64].

Nitidine (1), a specific compound in Zanthoxylumspecies: Z. myriacanthum, Z. williamsii, Z. clava-herculis, Z. americanum, Z. bouetense, Z. nitidum, Z. usambarense, Z. ovalifolium, Z. lemairei, Z. atchouminhibited gastric tumor cell growth, induced tumor cell apoptosis in vitroand 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 vitroand in vivo[16]. Nitidine could inhibit breast cancer cell migration and invasion both in vitroand 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 Zanthoxylumgenus. 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 Zanthoxylumgenus. 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 Zanthoxylumspecies has also showed antifungal and antibacterial activities. In traditional medicine, many Zanthoxylumspecies 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. leprieuriiand Z. xanthoxyloidesinhibited the in vitrogrowth of Candida albicans, Cryptococcus neoformansand seven filamentous fungi tested [74]. Ethanolic extracts of the Z. fagara, Z. elephantiasis, and Z. martinicenseshowed 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. chiloperoneshowed 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. tetraspermumshowed significant antifungal activity [80].

The screening in vitroand in vivoactivity against the tuberculosis bacterium of compounds isolated from Z. capenseshowed that a benzophenanthridine alkaloid, decarine (14) and a N-isobutylamide N-isobutyl-(2E,4E)-2,4-tetradecadienamide exhibited antibacterial activity against Mycobacterium tuberculosisH37Rv (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. rhoifoliumand Z. tetraspermum[26], showed significant antibacterial activity.

In particular, benzophenanthridine alkaloids from Zanthoxylumgenus 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. piperitumalso showed antibacterial activity against MRAS [84]. 4-Methoxy-N-methyl-2-quinolone from Z. monophyllumexhibited 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 Zanthoxylumplants also showed antivirus, cardioprotective, liver protective, antidiabetic, and antimalarial activities. Benzophenanthridine alkaloids, 5,6-dihydro-6-methoxynitidine, skimmianine, and 5-methoxydictamnine from Z. nitidumshowed significant antiviral activities against hepatitis B virus [29], decarine, γ-fagarine, (+)-tembamide from the root bark of Z. ailanthoidesagainst HIV with EC50 values < 0.1 μg/ml [86]. Nitidine showed similar in vitroactivity 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 Zanthoxylumgenus

4.1 NMR methods

Benzophenanthridine alkaloids are the most popular class of compounds isolated from Zanthoxylumgenus. 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 Zanthoxylumgenus, 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.

C171112131419202224
1107.3108.0104.7106.2104.4104.4104.7104.7104.5104.2
2151.0154.0147.6150.4148.2147.9147.6147.4147.4147.1
3150.5153.5147.1150.3148.2148.1147.0147.0145.9147.7
4103.9106.0102.6104.7100.7100.8100.6102.6101.4100.6
4a132.6123.0121.1121.2126.9128.3120.8121.0120.0126.2
4b152.2138.0135.7132.7136.9138.7152.4135.8128.0142.6
6134.6155.0162.7163.4145.5145.7164.0164.3162.748.6
6a134.5122.0119.8129.2120.6121.4135.9119.0126.4126.1
7109.7110.0150.3147.0144.1142.1106.6108.6145.7146.0
8154.2155.0152.8151.1149.4147.5148.2149.6148.1152.2
9161.4160.0118.0127.0120.5123.5131.1153.5126.4110.9
10105.6105.0117.9119.1118.6118.5102.6102.7118.6118.6
10a121.6133.0129.0120.2127.3126.4132.0128.9118.1126.2
10b128.3119.0117.3126.4120.0120.0116.8116.7123.7123.7
11120.0144.0118.5117.9118.4118.5118.5118.3118.7120.0
12131.9128.0123.4132.1127.6127.0123.2123.2127.1123.6
12a122.3132.0131.8133.9129.5129.2120.9131.8129.1130.8
2,3-OCH2O104.4103.0101.6103.4101.4101.4101.5101.5101.8100.9
7,8-OCH2O102.3
8,9-OCH2O101.9
NCH352.253.050.141.2
6-OCH340.949.741.141.241.2
7-OCH361.861.561.160.9
8-OCH357.258.056.756.756.259.955.7
9-OCH357.958.056.1
Solv.mmmmddccmc
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.

C26293637384041424344
1123.3106.9106.0101.2104.0105.2105.1105.0104.9105.0
2148.7149.9152.5147.6147.5148.4148.4148.3148.3148.4
3149.0150.9152.0147.9146.5148.9148.8148.5148.5148.8
4104.3101.6101.0104.299.3101.9102.0102.6102.7102.4
4a123.8128.8130.5131.0123.1132.1132.1132.0132.0132.1
4b130.9140.0141.0140.0137.8141.3141.1141.1141.1141.1
660.066.792.056.254.358.557.456.656.357.4
6a123.5126.0121.0126.2121.3131.1131.1131.5131.4131.3
7100.4149.3112.0146.7149.5147.0147.0147.0147.0147.1
8147.5154.4150.0151.9143.8153.0153.0153.0153.0153.0
9148.2114.4150.0111.3116.0112.1111.8112.0112.0111.9
10106.4121.4110.0119.1118.7119.3119.3119.3119.3119.2
10a139.0127.2127.0125.3130.1125.8125.8125.9125.9125.8
10b127.0126.7119.0123.2127.4124.8124.8124.8124.8124.9
11119.6121.9144.0119.6119.5120.7120.7120.8120.7120.7
12110.4126.7121.0123.5123.6124.4124.5124.4124.3124.4
12a127.3133.4130.0127.4126.4128.7128.7128.7128.7128.6
2,3-OCH2O101.3103.4104.0101.0101.0101.2101.3101.3101.3101.3
NCH342.444.240.042.342.443.343.243.243.143.2
6-OCH355.0
7-OCH362.860.860.060.960.961.061.061.0
8-OCH356.157.957.055.755.855.655.755.755.7
9-OCH356.057.0
1′148.469.353.347.248.242.650.747.947.3
2′207.920.4211.9206.121.721.623.623.423.6
3′31.541.830.030.830.829.929.529.4
4′28.9135.7134.6135.5136.4136.3
5′23.8128.2128.2126.0125.2125.9
6′30.435.235.038.040.340.3
7′44.644.646.746.547.1
8′20.020.020.417.722.3
9′32.432.834.536.336.2
10′76.176.174.376.376.3
11′43.143.044.144.243.4
12′27.427.326.626.226.4
13′15.915.815.615.415.4
14′22.422.221.821.822.0
15′23.023.123.222.318.2
10′-OCH348.148.348.748.448.3
Solv.cmmcdppppp
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 130and 131have the same constitution. This suggested the aglycone could be enantiomer. Thus, the absolute configuration at C-11 of 130and 131were 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 (130aand 131a) are shown in Figure 7. The CD spectra of 130and 131were found to be similar to 130aand 131aindicating the absolute configuration at C-11 as Rand S, respectively.

Figure 7.

Experimental CD and calculated ECD spectra of130and131(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 of77; experimental ECD spectra of (+)-77/(−)-77and calculated ECD spectra of (8′R, 9′R)/(8′S, 9′S) of77.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 Zanthoxylumspecies.

5. Conclusions

Alkaloids are the main constituents of Zanthoxylumspecies, 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 Zanthoxylumspecies 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 Zanthoxylumalkaloids 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.

© 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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Nguyen Xuan Nhiem, Pham Minh Quan and Nguyen Thi Hong Van (March 12th 2020). Alkaloids and Their Pharmacology Effects from <em>Zanthoxylum</em> Genus, Bioactive Compounds in Nutraceutical and Functional Food for Good Human Health, Kavita Sharma, Kanchan Mishra, Kula Kamal Senapati and Corina Danciu, IntechOpen, DOI: 10.5772/intechopen.91685. Available from:

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