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REVIEW Chemical Constituents of the Plants from the Genus Oplopanax by Wei-Hua Huang* a ), Qing-Wen Zhang b ), Chun-Su Yuan c ), Chong-Zhi Wang c ), Shao-Ping Li b ), and Hong-Hao Zhou a ) a
) Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, China (phone: þ 86-731-84805380; fax: þ 86-731-82354476; e-mail: [email protected]) b ) State Key Laboratory for Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China c ) Tang Center for Herbal Medicine Research, The Pritzker School of Medicine, University of Chicago, 5841 South Maryland Avenue, MC 4028, Chicago, IL 60637, USA
Contents 1. Introduction 2. Chemical Constituents 2.1. Triterpenoids 2.2. Sesquiterpenes 2.3. Monoterpenoids 2.4. Polyynes 2.5. Phenylpropanoids 2.6. Lignans 2.7. Anthraquinones 2.8. Flavonoids 2.9. Others 3. Biological Activities 3.1. Antibacterial Activity 3.2. Antidiabetes Activity 3.3. Anticancer Activity 3.3.1. Anti-Lung Cancer Activity 3.3.2. Anti-Breast Cancer Activity 3.3.3. Anti-Colorectal Cancer Activity 3.4. Antifungal Activity 3.5. Antipsoriasis Activity 3.6. Anti-Arthritis Activity 3.7. Anticonvulsant Activity 4. Conclusions 1. Introduction. – The genus of Oplopanax, which belongs to the family Araliaceae, comprises only three species, i.e., Oplopanax elatus (Nakai) native to temperate regions of the Northern China [1] [2], O. horridus (Smith) Miq. exclusively originated and distributed in North America [3] [4], and O. japonicus (Nakai) Nakai only 2014 Verlag Helvetica Chimica Acta AG, Zrich
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localized in Japan [5]. Among them, O. elatus has been used for treating neurasthenia, hypopiesis, schizophrenia, cardiovascular disorders, diabetes mellitus, and rheumatism by the local people in China [6] [7], while O. horridus, known as Devils Club, whose inner bark of aerial stems is probably the most important spiritual and medicinal herb for many indigenous tribes in North America [8 – 10]. In addition, these roots are also commonly used to treat arthritis, digestive tract ailments, fever, dandruff, respiratory ailments, headaches, and cancer by First Nations peoples and many cultural groups [11] [12]. It is nowadays being utilized and marketed as a ginseng-like herbal medicine [13]. O. japonicus was used for skin-care preparation for improving skin lineae atrophicae such as striae gravidarum [14]. Recently, increasing attention has been paid to the Oplopanax genus and its chemical constituents because of their diverse features, such as antioxidant, antimycobacterial, antifungal, antituberculosis, antibiotic, lineae atrophicae-relieving, antipsoriasis, and anticancer activities [9] [15 – 19]. In this review, we compile the phytochemical progress including all the compounds isolated from the genus Oplopanax over the past decades. The biological activities of these ingredients are also discussed. 2. Chemical Constituents. – The total number of isolated and identified secondary metabolites from the genus Oplopanax amounts to 123, which include triterpenoids, monoterpenoids, sesquiterpenes, polyynes, lignans, phenylpropanoids, flavonoids, anthraquinones, and some other components [20 – 61]. The structures of all the compounds are shown below, and their names and the corresponding plant sources are compiled in the Table, from which it as can be seen that most triterpenoids were found in O. elatus, while no polyynes had been reported from O. japonicus, from which only eight compounds were isolated and determined due to the limited investigation, and the main ingredients of O. horridus were polyynes and glycosides. 2.1. Triterpenoids. Triterpenoids are the most frequently occuring constituents of the genus Oplopanax. Forty one triterpenoids, 1 – 41, were isolated from the genus Oplopanax [20 – 32]. Oleanane-type triterpenoids, 1 – 22, were isolated only from O. elatus until now. Lupan-type triterpenoids, 23 – 41, were found in all the three species, but only three lupan-type triterpenoids have been isolated from O. horridus and O. japonicus, respectively [20] [29 – 32]. 2.2. Sesquiterpenes. Thirty-seven sesquiterpenes, 42 – 78, have been identified in the genus Oplopanax [33 – 41]. Two sesquiterpenes, named oplopanone and oplodiol (42 and 43, resp.) were isolated from O. japonicus [33 – 35], and three norsesquiterpenes, 44 – 46, were found in O. horridus [36] [38] [39]. The other sesquiterpene derivatives were identified from O. horridus and O. elatus by gas chromatography coupled with mass spectrometry (GC/MS) [37] [40] [41]. 2.3. Monoterpenoids. In the essential oil of O. elatus and O. horridus, monoterpenoids were not the major constituents. Five monoterpenoids, 79 – 83, were detected in O. horridus [37] [42] and O. elatus [43 – 47], which were identified by GC/MS. 2.4. Polyynes. Phytochemical studies of Oplopanax have afforded nine polyynes, 84 – 92, of which six, 84 – 89, obtained from the root bark of O. horridus, while the three remaining polyynes, 90 – 92, were isolated from the stems of O. elatus [38] [39] [48 – 50]. For their analytical evaluation, an HPLC fingerprint method was developed to analyze the stem and berry extracts of O. horridus. The results revealed that polyynes are not
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the major components in the stem and berries of O. horridus [9]. An online solid-phase extraction HPLC (SPE-HPLC) was developed to quantify polyynes in O. horridus and O. elatus. Six polyynes, 84 – 89, could be identified in the root bark of O. horridus, while only two polyynes, 84 – 85, could be detected both in the stem and root of O. elatus [38]. 2.5. Phenylpropanoids. Ten phenylpropanoids, 93 – 102, were isolated from O. elatus and O. horridus [51 – 54]. All the reported phenylpropanoids were phenolic glycosides. 2.6. Lignans. Five lignans, 103 – 107, were isolated and characterized from O. elatus [36] [51] [55]. Four of them were lignan glycosides, which were obtained from the chromatography of the hydrophilic extracts of the root bark of O. elatus. The hydrophilic constituents of the plant roots and stems of Oplopanax have been rarely investigated. 2.7. Anthraquinones. Five anthraquinones, 108 – 112, have been isolated and reported to date from O. elatus [52] [56]. Anthraquinones are rarely discovered in the Araliaceae family [62] [63]. 2.8. Flavonoids. Two flavone glycosides, 113 and 114, were obtained and characterized from the leaves of O. elatus [28] [57]. 2.9. Others. Some fatty acids, steroids, steroid glycosides, and sugars, 115 – 123, were identified in O. elatus [52] [58 – 61]. The composition of bioactive chemicals varies in different parts of the plants; further investigations on different parts of the plants may uncover additional compounds.
elatus, leaves elatus, leaves elatus, leaves elatus, leaves elatus, leaves elatus, leaves elatus, leaves elatus, leaves elatus, leaves elatus, leaves elatus, leaves elatus, leaves elatus, leaves elatus, leaves elatus, leaves elatus, leaves elatus, leaves elatus, leaves elatus, leaves elatus, leaves elatus, leaves elatus, leaves elatus, leaves; O. japonicus leaves elatus, leaves elatus, leaves; O. japonicus leaves elatus, leaves; O. japonicus leaves elatus, leaves; O. japonicus leaves elatus, leaves elatus, leaves elatus, leaves elatus, leaves elatus, leaves
O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O.
Kalopanax saponin G Cirensenoside B Cirensenoside O Cirensenoside C Cirensenoside D Cirensenoside Q Cirensenoside T Cirensenoside V Oleanolic acid 3-Epihederagenin Gypsogenin Hederagenin 3b,23-Dihydroxyolean-28-oic acid Cirensenoside J Cirensenoside I Cirensenoside M Cirensenoside U 3b-Hydroxyoleana-9(11),12-dien-28-oic acid (eucalyptanoic acid) 3b-Acetoxyoleana-9(11),12-diene Cirensenoside K Cirensenoside L Cirensenoside N 3a-Hydroxylup-20(29)-ene-23,28-dioic acid 28-O-a-l-rhamnopyranosyl(1 ! 4)-O-b-d-glucopyranosyl-(1 ! 6)-b-d-glucopyranoside 3-Epibetulinic acid 3-O-b-d-glucopyranoside Cirensenoside F Cirensenoside G Cirensenoside H Cirensenoside A Cirensenoside E Cirensenoside S Cirensenoside R Cirensenoside P
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
24 25 26 27 28 29 30 31 32
Source
Compound
No.
Table 1. Chemical Compounds from the Genus Oplopanax
[20] [20] [28] [29] [20] [28] [29] [20] [28] [29] [20] [20] [29] [20] [23] [24] [20] [22] [20] [21]
[20] [20] [20] [21] [20] [20] [20] [22] [20] [23] [24] [20] [23] [24] [13] [20] [20] [25] [20] [25] [20] [20] [20] [26] [20] [26] [20] [27] [20] [23] [24] [20] [20] [20] [26] [20] [26] [20] [27] [20] [28]
References
CHEMISTRY & BIODIVERSITY – Vol. 11 (2014) 187
O. elatus, root O. elatus, root O. elatus, root O. elatus, root O. elatus, root O. elatus, root O. elatus, root O. elatus, root O. elatus, root O. elatus, root O. elatus, root O. elatus, root O. elatus, root O. elatus, root O. elatus, root O. elatus, root
horridus, horridus, horridus, horridus, horridus, horridus, horridus, horridus, horridus, horridus, horridus, horridus, horridus, horridus, horridus, horridus, horridus, horridus,
O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O.
46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63
bark bark; bark; bark; bark; bark; bark; bark; bark; bark; bark; bark; bark; bark; bark; bark; bark; bark
japonicus, whole plant japonicus, whole plant horridus, inner stem bark horridus, inner stem bark
O. O. O. O.
root root root root root root root root root root root root root root root root root root
elatus, leaves elatus, leaves elatus, leaves; O. horridus leaves elatus, leaves elatus, leaves elatus, leaves horridus, leaves horridus, leaves horridus, leaves
O. O. O. O. O. O. O. O. O.
3b-Hydroxylup-20(29)-ene-23,28-dioic acid 3b,23-Dihydroxylup-20(29)-en-28-oic acid 3a-Hydroxylup-20(29)-ene-23,28-dioic acid 3b-Hydroxylup-20(29)-en-28-oic acid 3a-Hydroxylup-20(29)-ene-29-oic acid Betulinic acid 3-O-b-d-glucopyranoside 3a-Hydroxylup-20(29)-ene-23,28-dioic acid 3a-Hydroxylup-20(29)-ene-23,28-dioic acid 3-O-b-d-glucopyranoside 3-Oxo-24-nor-lup-20(29)-en-28-oic acid 28-O-a-l-rhamnopyranosyl(1 ! 4)-b-d-glucopyranosyl-(1 ! 6)-b-d-glucopyranoside Oplopanone Oplodiol 3,10-Epoxy-3,7,11-trimethyldodeca-1,6-dien-11-ol (neroplomacrol) rel-(3R,6S,7R,10S )-7,10-Epoxy-3,7,11-trimethyldodec1-ene-3,6,11-triol (neroplofurol) Nerolidol (1aH,6aH,7aH )-Copaene (ylangene; a-ylangene) (1bH,6bH,7aH )-Copaene (a-copaene; aglaiene) Elema-1,3,11-triene (b-elemene) b-Caryophyllene a-Bergamotene Aromadendr-10(14)-ene (b-diploalbicene) Humula-2,6,9-triene (a-humulene) Ishwarane (3Z,6E )-Farnesa-1,3,6,10-tetraene Cadina-4,9-diene Germacra-1(10),5-diene ( R )-Curcumene (a-Curcumene) Bicyclogermacrene a-Zingiberene (a-sesquiphellandrene) Cadina-3,9-diene (3E,6E )-Farnesa-1,3,6,10-tetraene endo-Bourbonan-1-ol
33 34 35 36 37 38 39 40 41
42 43 44 45
Source
Compound
No.
Table 1 (cont.)
[37 – 39] [37] [39] – [41] [37] [40] [41] [37] [40] [41] [37] [40] [41] [37] [40] [41] [37] [40] [41] [37] [40] [41] [37] [40] [41] [37] [40] [41] [37] [40] [41] [37] [40] [41] [37] [40] [41] [37] [40] [41] [37] [40] [41] [37] [40] [41] [37] [40] [41] [37]
[33 – 35] [35] [36] [36]
[20] [20] [20] [30] [20] [20] [20] [13] [31] [32] [13] [31] [32] [31] [32]
References
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64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93
horridus, root bark horridus, root bark horridus, root bark horridus, root bark horridus, root bark horridus, root bark horridus, root bark horridus, root bark horridus, root bark horridus, root bark horridus, root bark horridus, root bark horridus, root bark horridus, root bark horridus, root bark horridus, root bark; O. elatus, root horridus, root bark; O. elatus, root horridus, root bark; O. elatus, root horridus, root bark; O. elatus, root horridus, root bark; O. elatus, root horridus, root bark; O. elatus, root bark horridus, root bark; O. elatus, root bark horridus, root bark horridus, root bark horridus, root bark horridus, root bark horridus, inner bark elatus, stem elatus, stem elatus, stem and root bark
Source O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O.
Compound (1S,8aR )-Cadina-1(10),4-diene b-Sesquiphellandrene ((6R,7S )-sesquiphellandrene) Farnesa-1,6,10-trien-3-ol (þ)-Spathulenol (espatulenol) (1Z,5Z,8S )-1,5-Dimethyl-8-(1-methylethyl)cyclodeca-1,5-diene (1Z,4Z,7Z )-1,7-Dimethyl-4-(prop-1-en-2-yl)cyclodeca-1,4,7-triene (1Z,3R,6R,9R )-3,9-Dimethyl-6-(prop-1-en-2-yl)cyclodecene (1S,2S,3Z,6R,9R )-2,6-Dimethyl-9-(prop-1-en-2-yl)cyclodec-3-en-1-ol Spiroax-1-en-6-ol Guai-1(5)-en-11-ol Cadin-4-ene-1,11-diol (isocalamenediol) ent-t-Muurolol Cedrelanol (brown-algae cadinol; pilgerol) Bulnesol Eudesm-3-en-11-ol a-Pinene p-Mentha-1(7),2-diene (b-phellandrene) (3Z,5Z)-Deca-1,3,5-triene 3,7-Dimethylocta-1,6-dien-3-ol (3Z,5Z,7Z )-Deca-1,3,5,7-tetraene (3S,8S )-Falcarindiol Oplopandiol (9Z,11S,16S )-11,16-Dihydroxyoctadeca-9,17-diene-12,14-diyn-1-yl acetate Oplopandiol acetate Oplopantriol A Oplopantriol B Falcarinol Oploxyne A Oploxyne B 4-(3-Hydroxyprop-1-en-1-yl)-2,6-dimethoxyphenyl b-d-glucopyranoside (syringin)
No.
Table 1 (cont.) References [37] [37] [37] [37] [37] [37] [37] [37] [37] [37] [37] [37] [37] [37] [37] [37] [42 – 47] [37] [42] [44] [47] [37] [42 – 47] [37] [42] [45] [47] [37] [42] [46] [47] [38] [39] [48] [49] [38] [39] [48] [49] [38] [39] [48] [49] [38] [39] [48] [49] [38] [48] [38] [48] [49] [50] [50] [51] [52]
CHEMISTRY & BIODIVERSITY – Vol. 11 (2014) 189
[51] [51] [52] [52] [54] [54] [54] [51]
elatus, stem and root bark elatus, stem and root bark elatus, stem elatus, stem horridus, root bark horridus, root bark horridus, root bark elatus, stem and root bark elatus, stem and root bark elatus, stem and root bark elatus, stem and root bark horridus, inner stem bark; O. elatus, stem elatus, stem and root elatus, stem and root elatus, stem and root elatus, stem and root elatus, stem and root elatus, leaves; O. japonicus leaves elatus, leaves; O. japonicus leaves elatus, root elatus, root elatus, stem elatus, stem elatus, stem elatus, root elatus, root elatus, stem and root elatus, stem and root
O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O.
104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123
96 97 98 99 100 101 102 103
[51] [51] [51] [36] [55] [56] [56] [56] [56] [52] [28] [57] [28] [57] [52] [58] [58] [59] [59] [59] [58] [60] [58] [60] [61] [61]
[53]
O. elatus, stem and root
95
[53]
O. elatus, stem and root
(1R,2S )-3’-Methoxy-1-(3,4-dihydroxyphenyl)propane-1,2,3-triol 4’-O-b-d-glucopyranoside (1S,2R )-3’-Methoxy-1-(3,4-dihydroxyphenyl)propane-1,2,3-triol 5’-O-b-d-glucopyranoside 4-(3-Hydroxyprop-1-en-1-yl)-2-methoxyphenyl b-d-glucopyranoside (coniferin) 4-(3-Hydroxypropyl)-2-methoxyphenyl b-d-glucopyranoside 3-O-Caffeoylquinic acid 1-O-Caffeoylquinic acid Oplopanpheside A Oplopanpheside B Oplopanpheside C 4’,7-Epoxy-4,9,9’-trihydroxy-3,3’-dimethoxy-5’,8-lignan 4,9-bis[ O-b-d-glucopyranoside] 5-Methoxylariciresinol 4-O-b-d-glucopyranoside (þ)-Isolariciresinol 3-O-b-d-glucopyranoside (þ)-5’-Methoxyisolariciresinol 3-O-b-d-glucopyranoside Sesamin Chrysophanol Aloe-emodin Physcion Emodin Rhein Kaempferol 3-O-b-d-galatopyranosyl-(1 ! 2)-b-d-glucopyranoside Quercetin 3-O-b-d-galatopyranosyl-(1 ! 2)-b-d-glucopyranoside Sucrose l-Rhamnose Heptacosanoic acid Tetracosanoic acid Docosanoic acid b-Sitosterol Daucosterol Stigmasterol Stigmasterol b-d-glucopyranoside
94
References
Source
Compound
No.
Table 1 (cont.)
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& 3. Biological Activities. – Some investigations have been conducted on the pharmacological properties of the medicinal plants classified as Oplopanax, and more research was focused mainly on O. horridus and O. elatus [64 – 75]. However, there is almost no report on the bioactivity of O. japonicus. 3.1. Antibacterial Activity. In agreement with the traditional usage of O. horridus, the extracts from O. horridus showed antibacterial properties mycobacteria, the genus of bacteria that causes leprosy and tuberculosis in humans. The results displayed by the extracts of O. horridus revealed a definitive efficacy against mycobacteria [16] [49] [64] [65]. To identify the bioactive compounds, five polyynes, 84 – 87 and 90, including oplopandiol, falcarindiol, falcarinol, oplopandiol acetate, and (9Z,11S,16S)11,16-dihydroxyoctadeca-9,17-diene-12,14-diyn-1-yl acetate, were isolated and identified; specifically, oplopandiol and falcarindiol are the main effective antimycobacterial compounds of the extract [49]. Additionally, all the identified polyynes were shown to have the ability to kill M. tuberculosis and M. avium at 10 mg/disk in a disk diffusion assay, and were effective against two Gram-positive bacteria, Staphylococcus aureus and Bacillus subtilis, and two Gram-negative bacteria, Escherichia coli DC2 and Pseudomonas aeruginosa Z61. Among them, falcarindiol exhibited the strongest antibacterial activities [49]. 3.2. Antidiabetes Activity. There are early reports mentioning that the extracts from O. horridus have an obvious effect as antidiabetics. However, few investigations were reported on this pharmacological effect except the traditional use by indigenous people against diabetes [64] [65]. Two decades ago, the O. horridus tea was regarded as having no significant hypoglycemic effects based on a primary study at a very small dosage [66]. Recently, three phenolic glycosides, 100 – 102, which were inactive for aglucosidase inhibition (IC50 > 50 mm, resp.), were obtained from hydrophilic extracts of O. horridus roots bark [54]. The unique evidence on the hypoglycemic effects of O. horridus extract was reported in 1938, in which a substance was mentioned to lower blood sugar [67]. 3.3. Anticancer Activity. Although no record was found that any herb from the title genus was used to treat cancer in the long history, the extracts and compounds from O. horridus exhibited anticancer activities in recent pharmacological investigations [19] [39] [68 – 71]. Using the male F344 rats as the experimental animal material, nerolidol (46), a sesquiterpene from O. horridus, was shown to inhibit azoxymethaneinduced neoplasia of the large bowel [68]. The extracts mainly containing polyynes from O. horridus root bark were effective in inhibiting the proliferation of several ovarian, breast, lung, and colorectal cancer cell lines [69 – 71]. The mechanisms of anticancer activities are still not well-known [71]. In accordance with the results of these studies, the polyynes obtained from O. horridus were regarded to possess anticancer activities [9] [19] [70] [71]. Of the tested polyynes, falcarindiol (84) showed the strongest inhibition of the growth of all examined cancer cell lines. 3.3.1. Anti-Lung Cancer Activity. The extract of O. horridus root bark and its fractions eluted from Dianion HP20 resin column using H2O, and 30, 50, 70, and 100% EtOH were investigated for their antiproliferative effects on the non-small cell lung cancer (NSCLC) cells. The IC50 values of the extract, and 50, 70, and 100% EtOH fractions for antiproliferation on NSCLC cells were 125.3, 271.1, 17.6, and 23.2 mg/ml, respectively, while the H2O and 30% EtOH fractions displayed no significant effects.
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This study revealed that the 70 and 100% EtOH fractions were active antiproliferative fractions [71]. Besides the extract from O. horridus root bark, the stem and berry extracts were also evaluated for the ireffectiveness on NSCLC cells. The results suggested that the stem extract had potent antiproliferative effect at a low concentration, i.e., 0.1 mg/ml for the stem extract vs. 1 mg/ml for the berry extract, and indicated that the stem extract might comprise anti-lung cancer active natural products [9]. 3.3.2. Anti-Breast Cancer Effect. The extract of O. horridus root bark and its fractions as mentioned in Sect. 3.3.1. have been studied on human breast cancer MCF-7 cells. The data revealed that the 70 and 100% EtOH fractions exhibited more potent antiproliferative effects than the total extract, while the H2O and 30% EtOH fractions significantly promoted cell proliferation on MCF-7 cells at concentrations 100 mg/ml, implying that the hydrophilic fractions should be removed when the samples are to be used for cancer chemoprevention to obtain desirable activities. The IC50 values of the extract, and 50, 70, and 100% EtOH fractions for antiproliferation on MCF-7 cells were 248.4, 123.1, 44.0, and 31.5 mg/ml, respectively. The 100% EtOH fraction, which possessed the most potent antiproliferative activity, showed the strongest apoptotic induction activity [71]. Additionally, stem and berry extracts were also assayed and compared for their antiproliferation effects on MCF-7 cells. The stem extract exhibited potent antiproliferation activity [9]. 3.3.3. Anti-Colorectal Cancer Activity. The extracts from O. horridus root, stem, berry, and root bark, and the fractions referred to in Sect. 3.3.1 were assayed on different colorectal cancer cell lines for their potential antiproliferative effects [9] [19] [39] [71]. The results showed that the stem, root, and root bark extracts, and hydrophobic fractions of root bark displayed potent antiproliferative effects. The hydrophilic fractions were evaluated resulting in a percentage of apoptotic cells, including early and late apoptosis, which was much lower than found for the hydrophobic fractions. The cell cycle distribution suggested that G2/M phase was arrested by O. horridus extract in these cancer cells, evidencing that G2/M arrest was checkpoint of the target cell cycle [19]. Furthermore, five polyynes were isolated and evaluated as the bioactive compounds from hydrophobic fractions of O. horridus [39]. Among these polyynes, falcarindiol (84) indicated the most potent effects, and the primary structureactivity analysis showed that these anticancer activities were related to the ethylenic bonds and acylations in the structures [19] [39] [71]. 3.4. Antifungal Activity. The essential oil from O. elatus was evaluated for its antimycotic activity in vitro by serial dilutions on solid nutrient medium. The fungistatic effects were visible on five species, Microsporum gypseum, M. lanosun, Tricophyton gypseum, T. purpureatum, and Epidermophyton floccosum. The MIC value was 0.0625% for each species [43]. The steam-distilled extract of O. elatus showed a significant antifungal activity aganist Trichophyton rubrum, T. verrucosum, T. tonsurans, T. violaceum, Microsporum canis, and M. nanum (MIC values 0.063 – 0.125%) [41]. Most of the constituents were aldehydes and cyclic sesquiterpenes in the volatile oil analyzed by GC/MS [41] [43] [72] [73]. 3.5. Antipsoriasis Activity. The 60% EtOH/H2O extract of O. elatus root bark was found to possess antipsoriasis activity. Only the activity was reported without any supporting data, so the bioactivities of O. elatus extract need further investigations and
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explicit descriptions. In this anecdotal report about the antipsoriasis effect, several lignan and phenolic glycosides were mentioned to be isolated and identified from the hydrophobic parts of O. elatus root bark extract, which were, however, not evaluated for their antipsoriasis activities [51]. 3.6. Anti-Arthritis Activity. Since the stem of O. elatus has been traditionally used as an analgesic folk medicine to treat arthritis, 40% EtOH extract was evaluated for its anti-arthritis effect. The results showed that the rats swelling of the hind paw was inhibited significantly, and subsided more rapidly when they were treated with the extract at a dosage of 10 g/kg in average. Additionally, the extract exerted inhibiting effect on the cotton-pellet granuloma induced in rats [74]. However, the extract from O. elatus had no effect on the bilateral adrenalectomized rats with the inflammation induced by dextran [74]. The volatile oil from O. elatus as intravenous emulsion, as 0.09 ml volatile oil/ml praeparatum, was injected to paw edema rats treated with carrageenan at the dosage of 1.1 and 2.2 ml/kg, and fed at a usage of 11 and 22 ml/kg [75]. The observation suggested that the volatile oil led to significant recovery of the rats edema paw, by intraperitoneal injection at a dosage of 2.2 ml/kg [75]. Although the compositions of the 40% EtOH extract and volatile oil varies differently, they exhibited anti-inflammation activities to different rat models. However, the compounds in the 40% EtOH extract from O. elatus root bark have not been still well-studied, and the essential oil constituents were identified by GC/MS 20 years ago. 3.7. Anticonvulsant Activity. The essential oil from O. elatus, 0.1 ml volatile oil/ml emulsion, was given to rats using intraperitoneal injection at a dosage of 0.67 ml/kg, keeping the animal quiet, tame, and lacking locomotor activity. When the dose was increased to 2.76 ml/kg, the rats were prostrate with drooping eyelids, but they could still respond to the outside stimuli. The O. elatus essential oil emulsion had good synergistic effect on antagonism with pentobarbital, chloral hydrate and chlorpromazine to pentylenetetrazol-induced and electroconvulsive convulsions [76 – 79]. 4. Conclusions. – The genus Oplopanax contains three species, in which O. horridus and O. elatus have been used as traditional herbal medicines, while O. japonicus was rarely reported for medically utilization. In this review, phytochemical studies conducted on O. elatus and O. horridus, together with few chemical constituents of O. japonicus were compiled. Some components identified from this genus exhibit significant bioactivities. Chemical studies revealed that secondary metabolites of the plants of Oplopanax comprise triterpenoids, sesquiterpenes, diterpenoids, polyynes, lignans, phenylpropanoids, flavonoids, and anthraquinones. Of these natural products, terpenoids and polyynes are common, so they seem to be systematically important within the genus Oplopanax. To date, ca. 40 triterpenoids were isolated from the leaves of O. elatus and O. horridus, most of them being novel compounds from these plants, though the aglycones of these glycosides are of known oleanane and lupan type. However, these compounds are not found both in the stems and roots of these plants in the genus. As mentioned above, nine polyynes have been reported in plants of O. horridus and O. elatus. Polyynes are not abundant in the nature, but they occur in several species of Araliaceae, Asteraceae, and Apiaceae [80 – 83]. Nevertheless, polyynes are unstable and so, no further polyynes have been obtained from the genus so far [84 – 86]. More
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phytochemical and biological studies should focus now on different parts of these plants to obtain additional potentially bioactive components. This work was supported in part by the NIH/NCCAM (AT004418 and AT005362 to C.-S. Y.), the University of Macau (UL015/09-Y1 to S.-P. L.) grants.
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REVIEW Chemical Constituents of the Plants from the Genus Oplopanax by Wei-Hua Huang* a ), Qing-Wen Zhang b ), Chun-Su Yuan c ), Chong-Zhi Wang c ), Shao-Ping Li b ), and Hong-Hao Zhou a ) a
) Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha 410078, China (phone: þ 86-731-84805380; fax: þ 86-731-82354476; e-mail: [email protected]) b ) State Key Laboratory for Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China c ) Tang Center for Herbal Medicine Research, The Pritzker School of Medicine, University of Chicago, 5841 South Maryland Avenue, MC 4028, Chicago, IL 60637, USA
Contents 1. Introduction 2. Chemical Constituents 2.1. Triterpenoids 2.2. Sesquiterpenes 2.3. Monoterpenoids 2.4. Polyynes 2.5. Phenylpropanoids 2.6. Lignans 2.7. Anthraquinones 2.8. Flavonoids 2.9. Others 3. Biological Activities 3.1. Antibacterial Activity 3.2. Antidiabetes Activity 3.3. Anticancer Activity 3.3.1. Anti-Lung Cancer Activity 3.3.2. Anti-Breast Cancer Activity 3.3.3. Anti-Colorectal Cancer Activity 3.4. Antifungal Activity 3.5. Antipsoriasis Activity 3.6. Anti-Arthritis Activity 3.7. Anticonvulsant Activity 4. Conclusions 1. Introduction. – The genus of Oplopanax, which belongs to the family Araliaceae, comprises only three species, i.e., Oplopanax elatus (Nakai) native to temperate regions of the Northern China [1] [2], O. horridus (Smith) Miq. exclusively originated and distributed in North America [3] [4], and O. japonicus (Nakai) Nakai only 2014 Verlag Helvetica Chimica Acta AG, Zrich
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localized in Japan [5]. Among them, O. elatus has been used for treating neurasthenia, hypopiesis, schizophrenia, cardiovascular disorders, diabetes mellitus, and rheumatism by the local people in China [6] [7], while O. horridus, known as Devils Club, whose inner bark of aerial stems is probably the most important spiritual and medicinal herb for many indigenous tribes in North America [8 – 10]. In addition, these roots are also commonly used to treat arthritis, digestive tract ailments, fever, dandruff, respiratory ailments, headaches, and cancer by First Nations peoples and many cultural groups [11] [12]. It is nowadays being utilized and marketed as a ginseng-like herbal medicine [13]. O. japonicus was used for skin-care preparation for improving skin lineae atrophicae such as striae gravidarum [14]. Recently, increasing attention has been paid to the Oplopanax genus and its chemical constituents because of their diverse features, such as antioxidant, antimycobacterial, antifungal, antituberculosis, antibiotic, lineae atrophicae-relieving, antipsoriasis, and anticancer activities [9] [15 – 19]. In this review, we compile the phytochemical progress including all the compounds isolated from the genus Oplopanax over the past decades. The biological activities of these ingredients are also discussed. 2. Chemical Constituents. – The total number of isolated and identified secondary metabolites from the genus Oplopanax amounts to 123, which include triterpenoids, monoterpenoids, sesquiterpenes, polyynes, lignans, phenylpropanoids, flavonoids, anthraquinones, and some other components [20 – 61]. The structures of all the compounds are shown below, and their names and the corresponding plant sources are compiled in the Table, from which it as can be seen that most triterpenoids were found in O. elatus, while no polyynes had been reported from O. japonicus, from which only eight compounds were isolated and determined due to the limited investigation, and the main ingredients of O. horridus were polyynes and glycosides. 2.1. Triterpenoids. Triterpenoids are the most frequently occuring constituents of the genus Oplopanax. Forty one triterpenoids, 1 – 41, were isolated from the genus Oplopanax [20 – 32]. Oleanane-type triterpenoids, 1 – 22, were isolated only from O. elatus until now. Lupan-type triterpenoids, 23 – 41, were found in all the three species, but only three lupan-type triterpenoids have been isolated from O. horridus and O. japonicus, respectively [20] [29 – 32]. 2.2. Sesquiterpenes. Thirty-seven sesquiterpenes, 42 – 78, have been identified in the genus Oplopanax [33 – 41]. Two sesquiterpenes, named oplopanone and oplodiol (42 and 43, resp.) were isolated from O. japonicus [33 – 35], and three norsesquiterpenes, 44 – 46, were found in O. horridus [36] [38] [39]. The other sesquiterpene derivatives were identified from O. horridus and O. elatus by gas chromatography coupled with mass spectrometry (GC/MS) [37] [40] [41]. 2.3. Monoterpenoids. In the essential oil of O. elatus and O. horridus, monoterpenoids were not the major constituents. Five monoterpenoids, 79 – 83, were detected in O. horridus [37] [42] and O. elatus [43 – 47], which were identified by GC/MS. 2.4. Polyynes. Phytochemical studies of Oplopanax have afforded nine polyynes, 84 – 92, of which six, 84 – 89, obtained from the root bark of O. horridus, while the three remaining polyynes, 90 – 92, were isolated from the stems of O. elatus [38] [39] [48 – 50]. For their analytical evaluation, an HPLC fingerprint method was developed to analyze the stem and berry extracts of O. horridus. The results revealed that polyynes are not
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the major components in the stem and berries of O. horridus [9]. An online solid-phase extraction HPLC (SPE-HPLC) was developed to quantify polyynes in O. horridus and O. elatus. Six polyynes, 84 – 89, could be identified in the root bark of O. horridus, while only two polyynes, 84 – 85, could be detected both in the stem and root of O. elatus [38]. 2.5. Phenylpropanoids. Ten phenylpropanoids, 93 – 102, were isolated from O. elatus and O. horridus [51 – 54]. All the reported phenylpropanoids were phenolic glycosides. 2.6. Lignans. Five lignans, 103 – 107, were isolated and characterized from O. elatus [36] [51] [55]. Four of them were lignan glycosides, which were obtained from the chromatography of the hydrophilic extracts of the root bark of O. elatus. The hydrophilic constituents of the plant roots and stems of Oplopanax have been rarely investigated. 2.7. Anthraquinones. Five anthraquinones, 108 – 112, have been isolated and reported to date from O. elatus [52] [56]. Anthraquinones are rarely discovered in the Araliaceae family [62] [63]. 2.8. Flavonoids. Two flavone glycosides, 113 and 114, were obtained and characterized from the leaves of O. elatus [28] [57]. 2.9. Others. Some fatty acids, steroids, steroid glycosides, and sugars, 115 – 123, were identified in O. elatus [52] [58 – 61]. The composition of bioactive chemicals varies in different parts of the plants; further investigations on different parts of the plants may uncover additional compounds.
elatus, leaves elatus, leaves elatus, leaves elatus, leaves elatus, leaves elatus, leaves elatus, leaves elatus, leaves elatus, leaves elatus, leaves elatus, leaves elatus, leaves elatus, leaves elatus, leaves elatus, leaves elatus, leaves elatus, leaves elatus, leaves elatus, leaves elatus, leaves elatus, leaves elatus, leaves elatus, leaves; O. japonicus leaves elatus, leaves elatus, leaves; O. japonicus leaves elatus, leaves; O. japonicus leaves elatus, leaves; O. japonicus leaves elatus, leaves elatus, leaves elatus, leaves elatus, leaves elatus, leaves
O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O.
Kalopanax saponin G Cirensenoside B Cirensenoside O Cirensenoside C Cirensenoside D Cirensenoside Q Cirensenoside T Cirensenoside V Oleanolic acid 3-Epihederagenin Gypsogenin Hederagenin 3b,23-Dihydroxyolean-28-oic acid Cirensenoside J Cirensenoside I Cirensenoside M Cirensenoside U 3b-Hydroxyoleana-9(11),12-dien-28-oic acid (eucalyptanoic acid) 3b-Acetoxyoleana-9(11),12-diene Cirensenoside K Cirensenoside L Cirensenoside N 3a-Hydroxylup-20(29)-ene-23,28-dioic acid 28-O-a-l-rhamnopyranosyl(1 ! 4)-O-b-d-glucopyranosyl-(1 ! 6)-b-d-glucopyranoside 3-Epibetulinic acid 3-O-b-d-glucopyranoside Cirensenoside F Cirensenoside G Cirensenoside H Cirensenoside A Cirensenoside E Cirensenoside S Cirensenoside R Cirensenoside P
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
24 25 26 27 28 29 30 31 32
Source
Compound
No.
Table 1. Chemical Compounds from the Genus Oplopanax
[20] [20] [28] [29] [20] [28] [29] [20] [28] [29] [20] [20] [29] [20] [23] [24] [20] [22] [20] [21]
[20] [20] [20] [21] [20] [20] [20] [22] [20] [23] [24] [20] [23] [24] [13] [20] [20] [25] [20] [25] [20] [20] [20] [26] [20] [26] [20] [27] [20] [23] [24] [20] [20] [20] [26] [20] [26] [20] [27] [20] [28]
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O. elatus, root O. elatus, root O. elatus, root O. elatus, root O. elatus, root O. elatus, root O. elatus, root O. elatus, root O. elatus, root O. elatus, root O. elatus, root O. elatus, root O. elatus, root O. elatus, root O. elatus, root O. elatus, root
horridus, horridus, horridus, horridus, horridus, horridus, horridus, horridus, horridus, horridus, horridus, horridus, horridus, horridus, horridus, horridus, horridus, horridus,
O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O.
46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63
bark bark; bark; bark; bark; bark; bark; bark; bark; bark; bark; bark; bark; bark; bark; bark; bark; bark
japonicus, whole plant japonicus, whole plant horridus, inner stem bark horridus, inner stem bark
O. O. O. O.
root root root root root root root root root root root root root root root root root root
elatus, leaves elatus, leaves elatus, leaves; O. horridus leaves elatus, leaves elatus, leaves elatus, leaves horridus, leaves horridus, leaves horridus, leaves
O. O. O. O. O. O. O. O. O.
3b-Hydroxylup-20(29)-ene-23,28-dioic acid 3b,23-Dihydroxylup-20(29)-en-28-oic acid 3a-Hydroxylup-20(29)-ene-23,28-dioic acid 3b-Hydroxylup-20(29)-en-28-oic acid 3a-Hydroxylup-20(29)-ene-29-oic acid Betulinic acid 3-O-b-d-glucopyranoside 3a-Hydroxylup-20(29)-ene-23,28-dioic acid 3a-Hydroxylup-20(29)-ene-23,28-dioic acid 3-O-b-d-glucopyranoside 3-Oxo-24-nor-lup-20(29)-en-28-oic acid 28-O-a-l-rhamnopyranosyl(1 ! 4)-b-d-glucopyranosyl-(1 ! 6)-b-d-glucopyranoside Oplopanone Oplodiol 3,10-Epoxy-3,7,11-trimethyldodeca-1,6-dien-11-ol (neroplomacrol) rel-(3R,6S,7R,10S )-7,10-Epoxy-3,7,11-trimethyldodec1-ene-3,6,11-triol (neroplofurol) Nerolidol (1aH,6aH,7aH )-Copaene (ylangene; a-ylangene) (1bH,6bH,7aH )-Copaene (a-copaene; aglaiene) Elema-1,3,11-triene (b-elemene) b-Caryophyllene a-Bergamotene Aromadendr-10(14)-ene (b-diploalbicene) Humula-2,6,9-triene (a-humulene) Ishwarane (3Z,6E )-Farnesa-1,3,6,10-tetraene Cadina-4,9-diene Germacra-1(10),5-diene ( R )-Curcumene (a-Curcumene) Bicyclogermacrene a-Zingiberene (a-sesquiphellandrene) Cadina-3,9-diene (3E,6E )-Farnesa-1,3,6,10-tetraene endo-Bourbonan-1-ol
33 34 35 36 37 38 39 40 41
42 43 44 45
Source
Compound
No.
Table 1 (cont.)
[37 – 39] [37] [39] – [41] [37] [40] [41] [37] [40] [41] [37] [40] [41] [37] [40] [41] [37] [40] [41] [37] [40] [41] [37] [40] [41] [37] [40] [41] [37] [40] [41] [37] [40] [41] [37] [40] [41] [37] [40] [41] [37] [40] [41] [37] [40] [41] [37] [40] [41] [37]
[33 – 35] [35] [36] [36]
[20] [20] [20] [30] [20] [20] [20] [13] [31] [32] [13] [31] [32] [31] [32]
References
188 CHEMISTRY & BIODIVERSITY – Vol. 11 (2014)
64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93
horridus, root bark horridus, root bark horridus, root bark horridus, root bark horridus, root bark horridus, root bark horridus, root bark horridus, root bark horridus, root bark horridus, root bark horridus, root bark horridus, root bark horridus, root bark horridus, root bark horridus, root bark horridus, root bark; O. elatus, root horridus, root bark; O. elatus, root horridus, root bark; O. elatus, root horridus, root bark; O. elatus, root horridus, root bark; O. elatus, root horridus, root bark; O. elatus, root bark horridus, root bark; O. elatus, root bark horridus, root bark horridus, root bark horridus, root bark horridus, root bark horridus, inner bark elatus, stem elatus, stem elatus, stem and root bark
Source O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O.
Compound (1S,8aR )-Cadina-1(10),4-diene b-Sesquiphellandrene ((6R,7S )-sesquiphellandrene) Farnesa-1,6,10-trien-3-ol (þ)-Spathulenol (espatulenol) (1Z,5Z,8S )-1,5-Dimethyl-8-(1-methylethyl)cyclodeca-1,5-diene (1Z,4Z,7Z )-1,7-Dimethyl-4-(prop-1-en-2-yl)cyclodeca-1,4,7-triene (1Z,3R,6R,9R )-3,9-Dimethyl-6-(prop-1-en-2-yl)cyclodecene (1S,2S,3Z,6R,9R )-2,6-Dimethyl-9-(prop-1-en-2-yl)cyclodec-3-en-1-ol Spiroax-1-en-6-ol Guai-1(5)-en-11-ol Cadin-4-ene-1,11-diol (isocalamenediol) ent-t-Muurolol Cedrelanol (brown-algae cadinol; pilgerol) Bulnesol Eudesm-3-en-11-ol a-Pinene p-Mentha-1(7),2-diene (b-phellandrene) (3Z,5Z)-Deca-1,3,5-triene 3,7-Dimethylocta-1,6-dien-3-ol (3Z,5Z,7Z )-Deca-1,3,5,7-tetraene (3S,8S )-Falcarindiol Oplopandiol (9Z,11S,16S )-11,16-Dihydroxyoctadeca-9,17-diene-12,14-diyn-1-yl acetate Oplopandiol acetate Oplopantriol A Oplopantriol B Falcarinol Oploxyne A Oploxyne B 4-(3-Hydroxyprop-1-en-1-yl)-2,6-dimethoxyphenyl b-d-glucopyranoside (syringin)
No.
Table 1 (cont.) References [37] [37] [37] [37] [37] [37] [37] [37] [37] [37] [37] [37] [37] [37] [37] [37] [42 – 47] [37] [42] [44] [47] [37] [42 – 47] [37] [42] [45] [47] [37] [42] [46] [47] [38] [39] [48] [49] [38] [39] [48] [49] [38] [39] [48] [49] [38] [39] [48] [49] [38] [48] [38] [48] [49] [50] [50] [51] [52]
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[51] [51] [52] [52] [54] [54] [54] [51]
elatus, stem and root bark elatus, stem and root bark elatus, stem elatus, stem horridus, root bark horridus, root bark horridus, root bark elatus, stem and root bark elatus, stem and root bark elatus, stem and root bark elatus, stem and root bark horridus, inner stem bark; O. elatus, stem elatus, stem and root elatus, stem and root elatus, stem and root elatus, stem and root elatus, stem and root elatus, leaves; O. japonicus leaves elatus, leaves; O. japonicus leaves elatus, root elatus, root elatus, stem elatus, stem elatus, stem elatus, root elatus, root elatus, stem and root elatus, stem and root
O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O. O.
104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123
96 97 98 99 100 101 102 103
[51] [51] [51] [36] [55] [56] [56] [56] [56] [52] [28] [57] [28] [57] [52] [58] [58] [59] [59] [59] [58] [60] [58] [60] [61] [61]
[53]
O. elatus, stem and root
95
[53]
O. elatus, stem and root
(1R,2S )-3’-Methoxy-1-(3,4-dihydroxyphenyl)propane-1,2,3-triol 4’-O-b-d-glucopyranoside (1S,2R )-3’-Methoxy-1-(3,4-dihydroxyphenyl)propane-1,2,3-triol 5’-O-b-d-glucopyranoside 4-(3-Hydroxyprop-1-en-1-yl)-2-methoxyphenyl b-d-glucopyranoside (coniferin) 4-(3-Hydroxypropyl)-2-methoxyphenyl b-d-glucopyranoside 3-O-Caffeoylquinic acid 1-O-Caffeoylquinic acid Oplopanpheside A Oplopanpheside B Oplopanpheside C 4’,7-Epoxy-4,9,9’-trihydroxy-3,3’-dimethoxy-5’,8-lignan 4,9-bis[ O-b-d-glucopyranoside] 5-Methoxylariciresinol 4-O-b-d-glucopyranoside (þ)-Isolariciresinol 3-O-b-d-glucopyranoside (þ)-5’-Methoxyisolariciresinol 3-O-b-d-glucopyranoside Sesamin Chrysophanol Aloe-emodin Physcion Emodin Rhein Kaempferol 3-O-b-d-galatopyranosyl-(1 ! 2)-b-d-glucopyranoside Quercetin 3-O-b-d-galatopyranosyl-(1 ! 2)-b-d-glucopyranoside Sucrose l-Rhamnose Heptacosanoic acid Tetracosanoic acid Docosanoic acid b-Sitosterol Daucosterol Stigmasterol Stigmasterol b-d-glucopyranoside
94
References
Source
Compound
No.
Table 1 (cont.)
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& 3. Biological Activities. – Some investigations have been conducted on the pharmacological properties of the medicinal plants classified as Oplopanax, and more research was focused mainly on O. horridus and O. elatus [64 – 75]. However, there is almost no report on the bioactivity of O. japonicus. 3.1. Antibacterial Activity. In agreement with the traditional usage of O. horridus, the extracts from O. horridus showed antibacterial properties mycobacteria, the genus of bacteria that causes leprosy and tuberculosis in humans. The results displayed by the extracts of O. horridus revealed a definitive efficacy against mycobacteria [16] [49] [64] [65]. To identify the bioactive compounds, five polyynes, 84 – 87 and 90, including oplopandiol, falcarindiol, falcarinol, oplopandiol acetate, and (9Z,11S,16S)11,16-dihydroxyoctadeca-9,17-diene-12,14-diyn-1-yl acetate, were isolated and identified; specifically, oplopandiol and falcarindiol are the main effective antimycobacterial compounds of the extract [49]. Additionally, all the identified polyynes were shown to have the ability to kill M. tuberculosis and M. avium at 10 mg/disk in a disk diffusion assay, and were effective against two Gram-positive bacteria, Staphylococcus aureus and Bacillus subtilis, and two Gram-negative bacteria, Escherichia coli DC2 and Pseudomonas aeruginosa Z61. Among them, falcarindiol exhibited the strongest antibacterial activities [49]. 3.2. Antidiabetes Activity. There are early reports mentioning that the extracts from O. horridus have an obvious effect as antidiabetics. However, few investigations were reported on this pharmacological effect except the traditional use by indigenous people against diabetes [64] [65]. Two decades ago, the O. horridus tea was regarded as having no significant hypoglycemic effects based on a primary study at a very small dosage [66]. Recently, three phenolic glycosides, 100 – 102, which were inactive for aglucosidase inhibition (IC50 > 50 mm, resp.), were obtained from hydrophilic extracts of O. horridus roots bark [54]. The unique evidence on the hypoglycemic effects of O. horridus extract was reported in 1938, in which a substance was mentioned to lower blood sugar [67]. 3.3. Anticancer Activity. Although no record was found that any herb from the title genus was used to treat cancer in the long history, the extracts and compounds from O. horridus exhibited anticancer activities in recent pharmacological investigations [19] [39] [68 – 71]. Using the male F344 rats as the experimental animal material, nerolidol (46), a sesquiterpene from O. horridus, was shown to inhibit azoxymethaneinduced neoplasia of the large bowel [68]. The extracts mainly containing polyynes from O. horridus root bark were effective in inhibiting the proliferation of several ovarian, breast, lung, and colorectal cancer cell lines [69 – 71]. The mechanisms of anticancer activities are still not well-known [71]. In accordance with the results of these studies, the polyynes obtained from O. horridus were regarded to possess anticancer activities [9] [19] [70] [71]. Of the tested polyynes, falcarindiol (84) showed the strongest inhibition of the growth of all examined cancer cell lines. 3.3.1. Anti-Lung Cancer Activity. The extract of O. horridus root bark and its fractions eluted from Dianion HP20 resin column using H2O, and 30, 50, 70, and 100% EtOH were investigated for their antiproliferative effects on the non-small cell lung cancer (NSCLC) cells. The IC50 values of the extract, and 50, 70, and 100% EtOH fractions for antiproliferation on NSCLC cells were 125.3, 271.1, 17.6, and 23.2 mg/ml, respectively, while the H2O and 30% EtOH fractions displayed no significant effects.
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This study revealed that the 70 and 100% EtOH fractions were active antiproliferative fractions [71]. Besides the extract from O. horridus root bark, the stem and berry extracts were also evaluated for the ireffectiveness on NSCLC cells. The results suggested that the stem extract had potent antiproliferative effect at a low concentration, i.e., 0.1 mg/ml for the stem extract vs. 1 mg/ml for the berry extract, and indicated that the stem extract might comprise anti-lung cancer active natural products [9]. 3.3.2. Anti-Breast Cancer Effect. The extract of O. horridus root bark and its fractions as mentioned in Sect. 3.3.1. have been studied on human breast cancer MCF-7 cells. The data revealed that the 70 and 100% EtOH fractions exhibited more potent antiproliferative effects than the total extract, while the H2O and 30% EtOH fractions significantly promoted cell proliferation on MCF-7 cells at concentrations 100 mg/ml, implying that the hydrophilic fractions should be removed when the samples are to be used for cancer chemoprevention to obtain desirable activities. The IC50 values of the extract, and 50, 70, and 100% EtOH fractions for antiproliferation on MCF-7 cells were 248.4, 123.1, 44.0, and 31.5 mg/ml, respectively. The 100% EtOH fraction, which possessed the most potent antiproliferative activity, showed the strongest apoptotic induction activity [71]. Additionally, stem and berry extracts were also assayed and compared for their antiproliferation effects on MCF-7 cells. The stem extract exhibited potent antiproliferation activity [9]. 3.3.3. Anti-Colorectal Cancer Activity. The extracts from O. horridus root, stem, berry, and root bark, and the fractions referred to in Sect. 3.3.1 were assayed on different colorectal cancer cell lines for their potential antiproliferative effects [9] [19] [39] [71]. The results showed that the stem, root, and root bark extracts, and hydrophobic fractions of root bark displayed potent antiproliferative effects. The hydrophilic fractions were evaluated resulting in a percentage of apoptotic cells, including early and late apoptosis, which was much lower than found for the hydrophobic fractions. The cell cycle distribution suggested that G2/M phase was arrested by O. horridus extract in these cancer cells, evidencing that G2/M arrest was checkpoint of the target cell cycle [19]. Furthermore, five polyynes were isolated and evaluated as the bioactive compounds from hydrophobic fractions of O. horridus [39]. Among these polyynes, falcarindiol (84) indicated the most potent effects, and the primary structureactivity analysis showed that these anticancer activities were related to the ethylenic bonds and acylations in the structures [19] [39] [71]. 3.4. Antifungal Activity. The essential oil from O. elatus was evaluated for its antimycotic activity in vitro by serial dilutions on solid nutrient medium. The fungistatic effects were visible on five species, Microsporum gypseum, M. lanosun, Tricophyton gypseum, T. purpureatum, and Epidermophyton floccosum. The MIC value was 0.0625% for each species [43]. The steam-distilled extract of O. elatus showed a significant antifungal activity aganist Trichophyton rubrum, T. verrucosum, T. tonsurans, T. violaceum, Microsporum canis, and M. nanum (MIC values 0.063 – 0.125%) [41]. Most of the constituents were aldehydes and cyclic sesquiterpenes in the volatile oil analyzed by GC/MS [41] [43] [72] [73]. 3.5. Antipsoriasis Activity. The 60% EtOH/H2O extract of O. elatus root bark was found to possess antipsoriasis activity. Only the activity was reported without any supporting data, so the bioactivities of O. elatus extract need further investigations and
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explicit descriptions. In this anecdotal report about the antipsoriasis effect, several lignan and phenolic glycosides were mentioned to be isolated and identified from the hydrophobic parts of O. elatus root bark extract, which were, however, not evaluated for their antipsoriasis activities [51]. 3.6. Anti-Arthritis Activity. Since the stem of O. elatus has been traditionally used as an analgesic folk medicine to treat arthritis, 40% EtOH extract was evaluated for its anti-arthritis effect. The results showed that the rats swelling of the hind paw was inhibited significantly, and subsided more rapidly when they were treated with the extract at a dosage of 10 g/kg in average. Additionally, the extract exerted inhibiting effect on the cotton-pellet granuloma induced in rats [74]. However, the extract from O. elatus had no effect on the bilateral adrenalectomized rats with the inflammation induced by dextran [74]. The volatile oil from O. elatus as intravenous emulsion, as 0.09 ml volatile oil/ml praeparatum, was injected to paw edema rats treated with carrageenan at the dosage of 1.1 and 2.2 ml/kg, and fed at a usage of 11 and 22 ml/kg [75]. The observation suggested that the volatile oil led to significant recovery of the rats edema paw, by intraperitoneal injection at a dosage of 2.2 ml/kg [75]. Although the compositions of the 40% EtOH extract and volatile oil varies differently, they exhibited anti-inflammation activities to different rat models. However, the compounds in the 40% EtOH extract from O. elatus root bark have not been still well-studied, and the essential oil constituents were identified by GC/MS 20 years ago. 3.7. Anticonvulsant Activity. The essential oil from O. elatus, 0.1 ml volatile oil/ml emulsion, was given to rats using intraperitoneal injection at a dosage of 0.67 ml/kg, keeping the animal quiet, tame, and lacking locomotor activity. When the dose was increased to 2.76 ml/kg, the rats were prostrate with drooping eyelids, but they could still respond to the outside stimuli. The O. elatus essential oil emulsion had good synergistic effect on antagonism with pentobarbital, chloral hydrate and chlorpromazine to pentylenetetrazol-induced and electroconvulsive convulsions [76 – 79]. 4. Conclusions. – The genus Oplopanax contains three species, in which O. horridus and O. elatus have been used as traditional herbal medicines, while O. japonicus was rarely reported for medically utilization. In this review, phytochemical studies conducted on O. elatus and O. horridus, together with few chemical constituents of O. japonicus were compiled. Some components identified from this genus exhibit significant bioactivities. Chemical studies revealed that secondary metabolites of the plants of Oplopanax comprise triterpenoids, sesquiterpenes, diterpenoids, polyynes, lignans, phenylpropanoids, flavonoids, and anthraquinones. Of these natural products, terpenoids and polyynes are common, so they seem to be systematically important within the genus Oplopanax. To date, ca. 40 triterpenoids were isolated from the leaves of O. elatus and O. horridus, most of them being novel compounds from these plants, though the aglycones of these glycosides are of known oleanane and lupan type. However, these compounds are not found both in the stems and roots of these plants in the genus. As mentioned above, nine polyynes have been reported in plants of O. horridus and O. elatus. Polyynes are not abundant in the nature, but they occur in several species of Araliaceae, Asteraceae, and Apiaceae [80 – 83]. Nevertheless, polyynes are unstable and so, no further polyynes have been obtained from the genus so far [84 – 86]. More
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phytochemical and biological studies should focus now on different parts of these plants to obtain additional potentially bioactive components. This work was supported in part by the NIH/NCCAM (AT004418 and AT005362 to C.-S. Y.), the University of Macau (UL015/09-Y1 to S.-P. L.) grants.
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