*Bioactive Compounds in Nutraceutical and Functional Food for Good Human Health*


#### **Table 3.**

*Quinolines, quinolones, and quinazolines from* Zanthoxylum *species.*

**Figure 5.** *The structures of alkaloids 98–107.*


*Alkaloids and Their Pharmacology Effects from* Zanthoxylum *Genus DOI: http://dx.doi.org/10.5772/intechopen.91685*

**Table 4.**

*Indolopyridoquinazolines, acridones, and canthinones from* Zanthoxylum *species.*

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*,

#### **Figure 6.**

*The structures of alkaloids 108–131.*


*Alkaloids and Their Pharmacology Effects from* Zanthoxylum *Genus DOI: http://dx.doi.org/10.5772/intechopen.91685*


#### **Table 5.**

*Other alkaloids from* Zanthoxylum *species.*

*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 TNFα/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].
