JIAN Shu-Xin TIAN Ying-Yuan WANG Jun-Zhi HU Wei-Min HUANG Nian-Yu

?

Research Progress on the Natural Anti-peptic Ulcer Chemical Structures①

JIAN Shu-Xin TIAN Ying-Yuan WANG Jun-Zhi HU Wei-Min HUANG Nian-Yu②

(443002)

Natural products provide an important original source of structural diversity for finding new compounds as anti-peptic ulcer drugs. The present review highlights some recent advances on gastro-protective flavonoids, terpenes, alkaloids, steroids, phenylpropanoids, glycosides and chromenes from natural herbs or traditional medicinal plants, and helps us analyze the structure-activity relationship (SAR) of natural products in healing of peptic ulcer for further drug development.

peptic ulcer, natural products, medicinal plants, chemical structures, structure-activity relationship;

1 INTRODUCTION

As a worldwide infectious disease, peptic ulcer usually includes two most common types called gastric ulcer and duodenal ulcer[1], which results from an imbalance between aggressive factors (such as acid, pepsin, Helicobacter pylori, nonsteroidal anti-inflammatory drugs) and defensive factors (i.e. bicarbonate, mucus, blood flow, prostaglandins)[2, 3]. Despite of extensive scientific advancements, this disease still remains an important clinical setback, largely because of the threat of increasing antimicrobial resistance worldwide and widespread use of complex anti-thrombotic therapy in the global population ageing[4, 5].

The medicinal plants mentioned in lots of ancient books worldwide have suggested their unique chemical and biological features for the treatment of diseases, which are gaining wide acceptance because they offer natural ways to promote healthcare[6, 7]. Natural products are also an important original source of chemical diversity for finding new structures as anti-gastric ulcer drugs[8]. In recent years, various natural products including flavonoids, terpenes, alkaloids, steroids, phenylpropanoids, glycosides and chromenes have been launched to possess gastro-protective activities from natural sources. The aim of the present review is to highlight the recent advances in current knowledge on natural products as anti-gastric ulcer agents and consider the future perspectives for the use of these compounds.

2 NATURAL ANTI-GASTRIC ULCER AGENTS

2. 1 Flavonoids

Mohod[9]isolated a 3,5,7,3?,4?-pentahydroxy flavone (Fig. 1, compound 1) from the leaves ofJ. F. Gmel. (Sapotaceae). Oral administration of the pentahydroxy flavones (5 and 10 mg/kg) showed significant and dose-dependent inhibition in the ulcerated area and ulcer index by using acetic acid induced ulcer in male Wistar rats (150～200 g). The SAR analysis indicated that its potent antiulcer activity is attributed to the presence of hydroxyl groups at C-5 of A-ring and C-4? of B-ring and carbonyl group at C-4 of the C-ring, which was responsible for its potent antioxidant potential to exert the ulcer healing property. Batista[10]investigated a flavonoid-rich ethanolic extract from scapes of. Five luteolin derivatives (2a～2e) were isolated and found to possess gastroprotective activity, with the mechanism of increasing endogenous SH com- pounds and helping to maintain antioxidative enzyme levels in the gastrointestinal mocusa. Shaker[11]found three anti-ulcer flavones (3a～3c) from the extract of a folklore medicine plant named(camelthorn), which showed the same protective effects on liver enzymes, oxidation status (malondialdehyde MDA and glutathione GSH), fucosidase tumor marker and risk lipid ratio as ranitidine. In the same year, Babu[12]also separa- ted a new flavonoid glycoside (4) with free phenyl ring (ring B) together with glucuronide linkage from the roots of the Indian traditional medicine plant(family: bignoniaceae), which exhibited potent gastroprotective effects against various gastric ulceritis inducing different models in rats.

Fig. 1. Chemical structures offlavonoids 1～4

Rocha’s group[13]reported seven unusual gly- cosylated dimeric flavonoids (Fig. 2, compounds 5a～5g) from the hydroethanolic root of Brazilian medicinal plant, which remarkably decreased the ulcer area after 7 and 14 days of treatment, similar to the commercial lanso- prazole in protecting and recovering gastric mucosa. Sidahmed[14]also obtained a pyranocycloartobi- loxanthone A (PA, see compound6), a xanthone derived from theJarret in the tropical forest of Malaysia, and the oral adminis- tration of PA could protect gastric mucosa from ethanol-induced gastric lesions, with the mechanism of over expression of HSP70 and suppression of Bax proteins. Besides that, PA also showed significant antibacterial action with interesting minimum inhibitory concentration (MIC) of 62.5 μg/mL and minimum bactericidal concentration (MBC) of 125 μg/mL againstJ99. Olaleye[15]isolated an isoflavonoid homopterocarpin (7) from, which offered gastroprotec- tion against indomethacin-induced ulcer in rats by antioxidative mechanism and the modulation of gastric homeostasis.

Fig. 2. Chemical structure of the dimeric flavonoids (5, 6) and isoflavonoid (7) derivatives

2.2 Terpenes

Viana[16]investigated the gastroprotective effect of monoterpenoid (-)-myrtenol (Fig. 3, compound 8), a natural fragrance in diverse plant essential oils in 2016. This compound significantly decreased the severity of ethanol-induced gastric lesions, affording gastroprotection at oral doses of 25～100 mg/kg through the mechanisms of a decrease in the activity of myeloperoxidase (MPO) and malondialdehyde (MDA), an increase in glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase activity in gastric tissues, and with well-maintained normal levels of nitrite/nitrate, gastric mucus and non- protein sulfhydryls (NP-SHs). Three sesquiterpene compounds (Fig. 3,-humulene (9a),-caryophyl- lene (9b) and caryophyllene oxide (9c)) from Brazil medicinal plantDesf., Fabaceae, were found by Lemos[17]in 2015 to possess a potent gastroprotective activity with reducing 70%～77% size of the gastric lesion in the ethanol/HCl-induced ulcer model, and their antiulcer effect might be associated with the ability to decrease gastric secretion and increase the produc- tion of mucus.

Fig. 3. Chemical structures ofmonoterpenoid (8) and sesquiterpenes (9a～9c)

In 2015, Deghrigue[18]isolated an eunicellin-type diterpenoid palmonine F (Fig. 4, compound 10) from Tunisian white gorgonian(Cnidaria: Octocorallia, Esper 1791), which also showed gastroprotective activity against HCl/EtOH induced gastric ulcers in rats. Oliveira[19]obtained gastroprotective diterpene marrubiin (11) from theleaves ofL. (Lamiaceae). Compared with commercial omeprazole (positive control), and the marrubiin at a dose of 25 mg/kg produced a significant reduction in lesion index, total injured area and the percentage injured area. The antiulcer mechanism of marrubiin was related to stimulating the synthesis of mucus (an important gastroprotective factor) and decreasing acid gastric secretion (aggressive factor).

Kazmi[20]recently evaluated the antiulcer activity of pentacyclic triterpenoid oleane-12-en-3-ol-28-oic acid 3--glucopyranoside (Fig. 4, compound 12) extracted fromL. (family: verbanaceae) leaves. It showed significant antiulcer activity by inhibiting gastric acid secretion, affor- ding protection against gastric mucosal damage through the mechanism of increased prostaglandin E2 level. Singh[21]isolated a tetracyclic triterpenoid named azadiradione (13) from the seeds of India medicinal plant(neem) in 2015, which exhibited anti-ulcerogenic activity in various models includingantiulcer activity in cold restraint induced gastric ulcer model, aspirin induced gastric ulcer model, alcohol induced gastric ulcers model and pyloric ligation induced ulcer model. The antiulcer activity of azadiradione was mainly exerted via the inhibition of H+/K+-ATPase (proton pump) activity with corresponding half maximal inhibitory concentration (IC50) of 87.75 μg/mL.

Fig. 4. Chemical structure of diterpenoid (10, 11) and triterpenoid (12, 13)

2.3 Alkaloids

Breviglieri[22]described the gastroprotective effect of an alkaloid called 2-phenylquinoline (Fig. 5, compound 14) from the bark of(Rutaceae) in 2017, and the bioactive ingredient could reduce the lesion area induced by ethanol/HCl with log half-maximal effective dose (50) of 1.507 through reducing oxidative damage and inhibiting acid secretion mediated by histaminergic and gastrinergic regulatory pathways. The imidazole alkaloid epiisopiloturine (15) from the leaves ofmedicinal plants in South America namedStapf (Rutaceae) was also reported by Nicolau[23], which could pretreatmently prevent naproxen (NAP)-induced macro and microscopic gastric damage with a maximal effect at 10 mg/kg, reduce MPO (3.4 ± 0.3 U/mg of gastric tissue) and inhibit changes in MDA (70.4 ± 8.3 mg/g of gastric tissue) and GSH (246.2 ± 26.4 mg/g of gastric tissue).

Cavidine (Fig. 5, compound 16), a major alkaloid compound isolated from, was found to exhibit gastroprotective effects on ethanol-induced experimental gastric ulcer in mice by Niu’s group[24]. At the safe dose of 10 mg/kg, the cavidine could effectively decrease the size of mucosal lesions, and its anti-ulcer effect was pri- marily attributed to the modulation of oxi- dant/anti-oxidant balance, the inhibitory effect on neutrophil infiltration, inhibition of nuclear factor-kappa B (NF-B) signal transduction pathway, subsequent tumor necrosis factor-alpha (TNF-), interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2), and mediation of the endogenous prostaglandin E2 (PGE2) production.

Fig. 5. Chemical structures of alkaloid 2-phenylquinoline (14), epiisopiloturine (15) and cavidine (16)

Zhang[25]reported four alkaloids of columbamine (Fig. 6, compound 17), jatrorrhizine (18), palmatine (19) and berberine (20) from the stems of Chinese medicinal plant(Fort), which significantly decreased the gastric ulcer areas (11.28 mm2) with corresponding ulcer inhibition ratio of 57.2%. It also showed a significant effect in inhibiting the release of H+/K+-ATPase, reducing the content of gastrin and decreasing the gastric acidity on experimental animals.

Fig. 6. Chemical structures of four alkaloids (17～20)

2.4 Other natural products

Xu’s group[26]reported the separation and structure elucidation of five phenylpropanoid deri- vatives, named as xanthiumnolics A～E from the fruits of, and xanthiumnolic E (Fig. 7, compound 21) showed strong inhibitory activities with IC50value of 8.73 μM against the production of nitric oxide (NO) with IC50value of 8.73 μM. The corresponding structure-activity ana- lysis indicated that the anti-inflammatory activities and direct free-radical scavenging capacities might be enhanced by the presence of more phenolic hydroxyl groups. Ahmad[27]reported a new steroid named albosteroid (22) from Asian herbsstem bark ofL. in 2013, and this compound ex- hibits significant antiulcer activity in pylorus- ligation- and ethanol-induced ulcer models. Besides that, this compound showed significant dose-depen- dent reversal of ethanol-diminished activity in anti- oxidant enzymes, such as SOD, catalase (CAT), GPx and GSH, and reduced the ethanol-elevated levels of glutathione reductase (GR) and lipid peroxidation (LPO).

Fig. 7. Chemical structures of xanthiumnolic E (21) and albosteroid(22)

Singh[28]isolated and evaluated a polyphenolic glycoside called verbascoside (Fig. 8, compound 23) from Indian teak, and it could significantly decrease the gastrin secretion in ethanol induced ulcer model with the inhibition of H+/K+- ATPase activity (50value: 60.98 μg/mL) and suppression of gastrin hormone release. Therefore, verbascoside might act as a potent therapeutic agent against gastric ulcer disease. Sánchez-Mendoza[29]found an anti-ulcer chromene named encecanescin (24) from the leaves ofusing the experimental model of an ethanol induced gastric ulcer in rats. This bioactive com- pound showed a dose-dependent gastroproprotective effect of 68.62 ± 7.8% at 100 mg×kg-1and ulcer index of 87.68 ± 11.66 mm2, whose gastroprotective mechanism was related to endogenous NO, prostaglandins and sulfydryl groups.

Fig. 8. Chemical structure of verbascoside (23) and encecanescin (24)

3 CONCLUSION

Peptic ulcer disease, also known as a stomach ulcer, is the most commonly encountered diseases in gastroenterology clinics affecting millions of people worldwide[30, 31]. Signs and symptoms of peptic ulcer disease usually include abdominal pain, upper abdo- minal discomfort, bloatedness, poor appetite, weight loss, nausea or vomiting[1]. Due to the wide struc- tural diversity and specific biological activities, natural products have been proved as an important role for the development and discovery of new drugs[32, 33]. Peptic ulcer, which is mainly caused by bacterial attack or excess of acid secretion, can be cured effectively by these isolated plant com- pounds[34, 35], such as alkaloids, flavonoids and terpenoids. For example, the alkaloids consist of one or more basic nitrogen atoms in heterocyclic ring or chain, which might be essential for the activity antiulcer activity in previous studies[36, 37].

In this review, some recent progresses on gastro- protective flavonoids,terpenes, alkaloids,steroids,phenylpropanoids, glycosides and chromenes from natural plants have been highlighted. Most of them were separated from ancient traditional medicinal plants used in rural or distant areas for the treatment of peptic ulcer, including Brazilian medicinal plant[9, 38]and[18, 39], Egyptian medicinal plant[14, 40], Asian traditional medicine(L.) Kurz[15, 41], India medicinal plant(neem)[20, 42], traditional Chinese medicinal plant(Fort)[25, 43]andL.[27, 44], and so on. For the SAR analysis of these natural products, Badu[12]reported the substituent effects for the gastroprotective flavones. The glucuronization of hydroxyl group at the 7th position in dihydro oroxylin A significantly im- proved the gastroprotective properties in all the ulcer induced models as evident in the case of the new flavonoid glycoside (Fig. 1, compound 4). Besides, the presence of free phenyl ring (ring B), hydroxyl group at the 7th position, methoxy group at the 7th position, glycosidation at the 2?-position and the absence of methoxyl group at the 6th position could improve gastroprotection. Elevated oxidative stress is a hall mark of gastric ulceration[45]. Mohod[9]found that 3,5,7,3?,4?-pentahydroxy flavone (Fig. 1, compound 1) shows the highest antioxidant activity due to the presence of additional 3-OH to structure, suggesting an important role of the number of OH groups and/or 3-OH of ring B in the antioxidant activity of flavonoid. The presence of -OH group at C-5 of ring A, and C-4′ of ring B exert much better antioxidant effect rather than-H in its flavonoid structure, and additional presence of 5,7-OH groups on ring A in the structure of that flavonoids has a potent inhibitory action against tyrosine kinase and protein kinase C activity. In addition, Singh[21]inve- stigated the major mechanism of gastroprotection of triterpenoids (Fig. 4, compound 13), and found the gastroprotective effect was attributed to the presence of a free hydroxyl group or derivative at position C-3 of triterpenoids through the activation of mucous membrane secretion and inhibition of gastric acid secretion.

Nowadays, natural products have been a rich source of drug discovery for decades, and lots of new leads isolated from plants, microbes or animals are under certain phase of clinicial trials, or successfully passed clinical trials and have been commercialized[46, 47]. For example, genistein[48]is under phase 2 of drug development in the treatment of neuroblastoma, germ cell tumor, and prostate cancer. POL6326 (Polyphor Ag)[49]becomes a candidate for seriousinfections, which has recently successfully com- pleted phase 1 trials. Although there are no com- mercial natural products for the medical treatment of peptic ulcer and related disorders, we can explore the structure-activity relationships of these mole- cules in this review. The provided data may be useful for the discovery of new therapeutic alter- natives in healing of peptic ulcer in further research, and also help us understand the SARs and mode of action for natural products.

(1) Chung, K. T.; Shelat, V. G. Perforated peptic ulcer - an update.2017, 27, 1–12.

(2) Chaudhari, A. B.; Nehal, G.; Komal, K.; Lambole, V.; Shah, D. P. A review: peptic ulcer disease.2017, 8, 210-218.

(3) Martin, G. R.; Wallace, J. L. Gastrointestinal inflammation: a central component of mucosal defence and repair.2006, 231, 130-137.

(4) Lanas, A.; Chan, F. K. L. Peptic ulcer disease.2017, 390, 613-624.

(5) Thung, I.; Aramin, H.; Vavinskaya, V.; Gupta, S.; Park, J. Y.; Crowe, S. E.; Valasek, M. A. Review article: the global emergence of Helicobacter pylori antibiotic resistance.2016, 43, 514-533.

(6) Mukherjee, P. K.; Bahadur, S.; Harwansh, R. K.; Biswas, S.; Banerjee, S. Paradigm shift in natural product research: traditional medicine inspired approaches.2017, 16, 803-826.

(7) Gadekar, R.; Singour, P. K.; Chaurasiya, P. K.; Pawar, R. S.; Patil, U. K. A potential of some medicinal plants as an antiulcer agents.2010, 4, 136-146.

(8) Wang, Y. C. Medicinal plant activity on Helicobacter pylori related diseases.2014, 20, 10368-10382.

(9) Mohod, S. M.; Kandhare, A. D.; Bodhankar, S. L. Gastroprotective potential of pentahydroxy flavoneisolatedfrom Madhuca indica J. F. Gmel. leaves against acetic acid-induced ulcer in rats: the role of oxido-inflammatory and prostaglandins markers.2016, 182, 150-159.

(10) Batista, L. M.; Almeida, A. B. A.; Lima, G. R. M.; Falc?o, H. S.; Magri, L. P.; Luiz-Ferreira, A.; Santos, L. C.; Hiruma-Lima, C. A.; Vilegas, W.; Brito, A. R. M. S. Gastroprotective effects (in rodents) of a flavonoid rich fraction obtained from Syngonanthus macrolepsis.2013, 66, 445–452.

(11) Shaker, E.; Mahmoud, H.; Mnaa, S. Anti-inflammatory and anti-ulcer activity of the extract from Alhagi maurorum (camelthorn).2010, 48, 2785–2790.

(12) Babu, T. H.; Manjulatha, K.; Kumar, G. S.; Hymavathi, A.; Tiwari, A. K.; Purohit, M.; Rao, J. M.; Babu, K. S. Gastroprotective flavonoid constituents from Oroxylum indicum Vent.2010, 20, 117–120.

(13) Rocha, C. Q.; Faria, F. M.; Marcourt, L.; Ebrahimi, S. N.; Kitano, B. T.; Ghilardi, A. F.; Ferreira, A. L.; Almeida, A. C. A.; Dunder, R. J.; Souza-Brito, A. R. M.; Hamburger, M.; Vilegas, W.; Queiroz, E. F.; Wolfender, J. L. Gastroprotective effects of hydroethanolic root extract of Arrabidaea brachypoda: evidences of cytoprotection and isolation of unusual glycosylated polyphenols.2017, 135, 93-105.

(14) Sidahmed, H. M. A.; Hashim, N. M.; Amir, J.; Abdulla, M. A.; Hadi, A. H. A.; Abdelwahab, S. I.; Taha, M. M. E.; Hassandarvish, P.; The, X.; Loke, M. F.; Vadivelu, J.; Rahmani, M.; Mohan, S. Pyranocycloartobiloxanthone A, a novel gastroprotective compound from Artocarpus obtusus Jarret, against ethanol-induced acute gastric ulcer.2013, 20, 834–843.

(15) Olaleye, M. T.; Akinmoladun, A. C.; Crown, O. O.; Ahonsi, K. E.; Adetuyi, A. O. Homopterocarpin contributes to the restoration of gastric homeostasis by Pterocarpus erinaceus following indomethacin intoxication in rats.2013, 6, 200–204.

(16) Viana, A. F. S. C.; Silva, F. V.; Fernandes, H. B.; Oliveira, I. S.; Braga, M. A.; Nunes, P. I. G.; Viana, D. A.; Sousa, D. P.; Rao, V. S.; Oliveira, R. C. M.; Santos, F. A. Gastroprotective effect of (-)-myrtenol against ethanol-induced acute gastric lesions: possible mechanisms.2016, 68, 1085–1092.

(17) Lemos, M.; Santin, J. R.; Mizuno, C. S.; Boeing, T.; Sousa, J. P. B. de; Nanayakkara, D.; Bastos, J. K.; Andrade, S. F. Copaifera langsdorffii: evaluation of potential gastroprotective of extract and isolated compounds obtained from leaves.2015, 25, 238–245.

(18) Deghrigue, M.; Festa, C.; Ghribi, L.; D'Auria, M. V.; Marino, S. D.; Jannet, H. B.; Bouraoui, A. Anti-inflammatory and analgesic activities with gastroprotective effect of semi-purified fractions and isolation of pure compounds from Mediterranean gorgonian Eunicella singularis.2015, 8, 606–611.

(19) Oliveira, A. P.; Santin, J. R.; Lemos, M.; Júnior, L. C. K.; Couto, A. G.; Bittencourt, C. M. S.; Filho, V. C.; Andrade, S. F. Gastroprotective activity of methanol extract and marrubiin obtained from leaves of Marrubium vulgare L. (Lamiaceae).2011, 63, 1230–1237.

(20) Kazmi, I.; Saleem, S.; Ahmad, T.; Afzal, M.; Al-Abbasi, F. A.; Kumar, V.; Anwar, F. Protective effect of oleane-12-en-3-ol-28-oic acid 3-D-glucopyranoside in ethanol induced gastric ulcer by enhancing the prostaglandin E2 level.2018, 211, 394–399.

(21) Singh, R.; Mishra, V.; Pandeti, S.; Palit, G.; Barthwal, M. K.; Pandey, H. P.; Narender, T. Cytoprotective and anti-secretory effects of azadiradione isolated from the seeds of Azadirachta indica (neem) on gastric ulcers in rat models.2015, 29, 910–916.

(22) Breviglieri, E.; Silva, L. M.; Boeing, T.; Somensi, L. B.; Cury, B. J.; Gimenez, A.; Filho, V. C.; Andrade, S. F. Gastroprotective and anti-secretory mechanisms of 2-phenylquinoline, an alkaloid isolated from Galipea longiflora.2017, 25, 61–70.

(23) Nicolau, L. A. D.; Carvalho, N. S.; Pacífico, D. M.; Lucetti, L. T.; Arag?o, K. S.; Véras, L. M. C.; Souza, M. H. L. P.; Leite, J. R. S. A.; Medeiros, J. V. R. Epiisopiloturine hydrochloride, an imidazole alkaloid isolated from Pilocarpus microphyllus leaves, protects against naproxen-induced gastrointestinal damage in rats.2017, 87, 188–195.

(24) Li, W.; Wang, X.; Zhang, H.; He, Z.; Zhi, W.; Liu, F.; Wang, Y.; Niu, X. Anti-ulcerogenic effect of cavidine against ethanol-induced acute gastric ulcer in mice and possible underlying mechanism.2016, 38, 450–459.

(25) Zhang, S. L.; Li, H.; He, X.; Zhang, R. Q.; Sun, Y. H.; Zhang, C. F.; Wang, C. Z.; Yuan, C. S. Alkaloids from Mahonia bealei posses anti-H+/K+-ATPase andanti-gastrin effects on pyloric ligation-induced gastric ulcer in rats.2014, 21, 1356–1363.

(26) Jiang, H.; Yang, L.; Ma, G. X.; Xing, X. D.; Yan, M. L.; Zhang, Y. Y.; Wang, Q. H.; Yang, B. Y.; Kuang, H. X.; Xu, X. D. New phenylpropanoid derivatives from the fruits of Xanthium sibiricum and their anti-inflammatory activity.2017, 117, 11–15.

(27) Ahmad, A.; Gupta, G.; Afzal, M.; Kazmi, I.; Anwar, F. Antiulcer and antioxidant activities of a new steroid from Morus alba.2013, 92, 202–210.

(28) Singh, N.; Shukla, N.; Singh, P.; Sharma, R.; Rajendran, S. M.; Maurya, R.; Palit, G. Verbascoside isolated from Tectona grandis mediates gastric protection in rats via inhibiting proton pump activity.2010, 81, 755–776.

(29) Sánchez-Mendoza, M. E.; Reyes-Trejo, B.; Sánchez-Gómez, P.; Rodríguez-Silverio, J.; Castillo-Henkel, C.; Cervantes-Cuevas, H.; Arrieta, J. Bioassay-guided isolation of an anti-ulcer chromene from Eupatorium aschenbornianum: role of nitric oxide, prostaglandins and sulfydryls.2010, 81, 66–71.

(30) Kim, B. W. Diagnosis and treatment of peptic ulcer disease: present and future perspective.2016, 67, 318–320.

(31) Di Mario, F.; Goni, E. Gastric acid secretion: changes during a century.2014, 28, 953–965.

(32) Li, J.; Yu, H.; Wang, S.; Wang, W.; Chen, Q.; Ma, Y.; Zhang, Y.; Wang, T. Natural products, an important resource for discovery of multitarget drugs and functional food for regulation of hepatic glucose metabolism.2018, 12, 121–135.

(33) Zhang, H.; Bai, L.; He, J.; Zhong, L.; Duan, X.; Ouyang, L.; Zhu, Y.; Wang, T.; Zhang, Y.; Shi, J. Recent advances in discovery and development of natural products as source for anti-Parkinson's disease lead compounds.2017, 141, 257–272.

(34) Jain, P. Secondary metabolites for antiulcer activity.2016, 30, 640–656.

(35) Nascimento, R. F.; Sales, I. R. P.; Oliveira Formiga, R.; Barbosa-Filho, J. M.; Sobral, M. V.; Tavares, J. F.; Diniz Mde, F.; Batista, L. M. Activity of alkaloids on peptic ulcer: what's new?2015, 20, 929–950.

(36) Takeuchi, K.; Kato, S.; Amagase, K. Gastric ulcerogenic and healing impairment actions of alendronate, a nitrogen-containing bisphosphonate - prophylactic effects of rebamipide.2011, 17, 1602–1611.

(37) Sousa, F. H.; Leite, J. A.; Barbosa-Filho, J. M.; Athayde-Filho, P. F.; Oliveira Chaves, M. C.; Moura, M. D.; Ferreira, A. L.; Almeida, A. B.; Souza-Brito, A. R.; Fátima Formiga Melo Diniz, M.; Batista, L. M. Gastric and duodenal antiulcer activity of alkaloids: a review.2008, 13, 3198–3223.

(38) Bieski, I. G. C.; Leonti, M.; Arnason, J. T.; Ferrier, J.; Rapinski, M.; Violante, I. M.; Balogun, S. O.; Pereira, J. F.; Figueiredo Rde, C.; Lopes, C. R.; Silva, D. R.; Pacini, A.; Albuquerque, U. P.; Martins, D. T. Ethnobotanical study of medicinal plants by population of Valley of Juruena Region, Legal Amazon, Mato Grosso, Brazil.2015, 173, 383–423.

(39) Ribeiro, R. V.; Bieski, I. G. C.; Balogun, S. O.; Martins, D. T. O. Ethnobotanical study of medicinal plants used by Ribeirinhos in the North Araguaia microregion, Mato Grosso, Brazil.2017, 205, 69–102.

(40) Muhammad, G.; Hussain, M. A.; Anwar, F.; Ashraf, M.; Gilani, A. H. Alhagi: a plant genus rich in bioactives for pharmaceuticals.2015, 29, 1–13.

(41) Dinda, B.; SilSarma, I.; Dinda, M.; Rudrapaul, P. Oroxylum indicum (L.) Kurz, an important Asian traditional medicine: from traditional uses to scientific data for its commercial exploitation.2015, 161, 255–278.

(42) Gupta, S. C.; Prasad, S.; Tyagi, A. K.; Kunnumakkara, A. B.; Aggarwal, B. B. Neem (azadirachta indica): an indian traditional panacea with modern molecular basis.2017, 34, 14–20.

(43) Kaufmann, D.; Kaur Dogra, A.; Tahrani, A.; Herrmann, F.; Wink, M. Extracts from traditional Chinese medicinal plants inhibit acetylcholinesterase, a known Alzheimer's disease target.2016, 21, E1161.

(44) Chan, E. W.; Lye, P. Y.; Wong, S. K. Phytochemistry, pharmacology, and clinical trials of.2016, 14, 17–30.

(45) Brzozowska, I.; Strzalka, M.; Drozdowicz, D.; Konturek, S. J.; Brzozowski, T. Mechanisms of esophageal protection, gastroprotection and ulcer healing by melatonin implications for the therapeutic use of melatonin in gastroesophageal reflux disease (GERD) and peptic ulcer disease.2014, 20, 4807–4815.

(46) Brown, D. G.; Lister, T.; May-Dracka, T. L. New natural products as new leads for antibacterial drug discovery.2014, 24, 413–418.

(47) Zhang, M. G.; Lee, J. Y.; Gallo, R. A.; Tao, W.; Tse, D.; Doddapaneni, R.; Pelaez, D. Therapeutic targeting of oncogenic transcription factors by natural products in eye cancer.2018, 129, 365–374.

(48) Sureda, A.; Sanches, S. A.; Sánchez-Machado, D. I.; López-Cervantes, J.; Daglia, M.; Nabavi, S. F.; Nabavi, S. M.Hypotensive effects of genistein: From chemistry to medicine.2017, 268, 37–46.

(49) Nigris, F.; Schiano, C.; Infante, T.; Napoli, C. CXCR4 inhibitors: tumor vasculature and therapeutic challenges.2012, 7, 251–264.

23 February 2018;

8 May 2018

① This project was supported by the National Natural Science Foundation of China (No. 21272136) and Youth Talent Development Foundation of China Three Gorges University

. Prof. Huang Nian-Yu (1979-), majoring in synthetic medicinal chemistry. E-mail: hny115@126.com

10.14102/j.cnki.0254-5861.2011-1990