Phytochemicals and Their Pharmacological Aspects of Acanthopanax koreanum

Botanical medicines have been applied for the treatment of various human diseases with thousands of years of history all over the world. In some Asian and African countries, 80 % of population depends on traditional medicine in primary health care. On the other hand, in many developed countries, 70 % to 80 % of the population has used some forms of alternative or complementary medicine. The long tradition of using plants for medicine, supplemented by pharmaceutical research, has resulted in many plant-based Western medicines. Traditional medicine has provided Western medicine with over 40 % of all pharmaceuticals (Samuelsson & Bohlin, 2004). In the past decades, therefore, research has been focused on scientific evaluation of traditional drugs of plant origin.


Introduction
Botanical medicines have been applied for the treatment of various human diseases with thousands of years of history all over the world.In some Asian and African countries, 80 % of population depends on traditional medicine in primary health care.On the other hand, in many developed countries, 70 % to 80 % of the population has used some forms of alternative or complementary medicine.The long tradition of using plants for medicine, supplemented by pharmaceutical research, has resulted in many plant-based Western medicines.Traditional medicine has provided Western medicine with over 40 % of all pharmaceuticals (Samuelsson & Bohlin, 2004).In the past decades, therefore, research has been focused on scientific evaluation of traditional drugs of plant origin.
Acanthopanax species (Araliaceae) are widely distributed in Asia, Malaysia, Polynesia, Europe, North Africa and the America.There are about 40 species of Acanthopanax to be found in over the world.Acanthopanax species have traditionally been used as a tonic and sedative as well as in the treatment of rheumatism, and diabetes.A. koreanum Nakai is an indigenous plant prevalently distributed throughout South Korea.It is deciduous shrub with upright to slightly arching stems, small, fresh green, trilobed to palmately divided leaves and several axillary as well as terminal round clusters of decorative, bluish black berries in late summer and autumn.Extensive investigation of chemical components in A. koreanum has been reported by many researchers in the worldwide.Several types of compounds have been isolated from this plant.Major active constituents are reported as lupanes and their glycosides, diterpenes, monoterpenes, lignans, phenylpropanoids, flavonoids from whole parts of A. koreanum.Of these, lupane triterpenes were reported as major components of leaves and ent-kauranes are main components of the roots of A. koreanum.They showed significant biological effects by several bioassay systems such as 1) anti-inflammatory activities: inhibit lipopolysaccharide (LPS)-stimulated TNF-, IL-6, and IL-12 p40 productions in bone marrow-derived dendritic cells, decrease the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) proteins, and reduce iNOS and COX-2 mRNA in a dose-dependent pattern, 2) anticancer, and 3) antiosteoporosis by effects on the differentiation of osteoblastic MC3T3-E1 cells.The desired target of this chapter is to introduce explanations of structures and pharmacological activities of novel compounds, which have been isolated and identified from A. koreanum since 1985.Those studies have reported and focused on bioactivities of unambiguous compounds from A. koreanum, therefore we discuss new pharmacological findings on these compounds.
The depth and breadth of research involving this plant has been organized into easily accessible and comparable information.Using Chemical Abstracts, Scifinder Scholar, and BIOSIS databases, relevant research papers were selected by based on pertinence and specificity to ethnopharmacology and phytochemistry, as well as readability.This collection was then carefully reviewed, extracted, and corroborated with available characterization data from other sources.

Lupane-triterpene glycosides
Up to date, eighteen lupane-type triterpene glycosides have been isolated from this plant and almost of them from the leaves of A. koreanum.They are main saponin components of the leaves of A. koreanum.The first lupane triterpene glycoside, acantrifoside A (1) was isolated from both A. koreanum and A. trifoliatus in a year of 1998 by (Yook et al., 1998).And then, two new saponins, acankoreoside A (10) and acankoreoside B (11) were isolated from the leaves of this plant (Chang et al., 1998)  significantly increased both IL-2 and IFN-.The structure-activity relationship of these compounds was also discussed.Moreover, lupane aglycones and lupane glycosides were assayed for LPS-stimulated pro-inflammatory cytokine production.These results suggested lupane aglycone inhibited pro-inflammatory cytokine production stronger than lupane glycosides (Kim et al., 2010).This was further confirmed by the study of (Cai et al., 2004b).

Pimarane-type diterpenes
A number of pimarane-type diterpenes have been isolated and associated with significant biological activity.There are seven pimarane-type diterpenes from A. koreanum.All of them were isolated from the roots.Acanthoic acid was presented in roots and leaves of this plant, and was one of compounds having potent anti-inflammatory activity.Acanthoic acid, a pimarane diterpene ((-)-pimara-9(11),15-dien-19-oic acid), was isolated for the first time from A. koreanum in a year of 1988 by (Kim et al., 1988b) and was proved with high content of this plant.Acanthoic acid has widely exhibited of biological activities.In study of (Kang et al., 1996), acanthoic acid has potent anti-inflammatory effects by reducing the production of proinflammatory cytokines such as IL-1 and TNF-.It was also effective in supressing experimental silicosis and cirrhosis.Furthermore, acanthoic acid was found to suppress TNF-gene expression (Kang et al., 1998) and TNF--induced IL-8 production in a dosedependent manner.Acanthoic acid also inhibited TNF--induced MAPKs activation, IκB degradation, NF-κB nuclear translocation, and NF-κB/DNA binding activity (Kim et al., 2004).Furthermore, acanthoic acid significantly inhibited production of both TNF-and tryptase in trypsin-stimulated human leukemic mast cell-1 at concentrations of 10 and 100 μg/mL with a dose-dependent manner.Acanthoic acid inhibited ERK phosphorylation and NF-κB activation induced by trypsin treatment without blocking of trypsin activity even though 100 μg/mL.These results suggested that acanthoic acid may inhibit the production of inflammatory mediators through inhibition of ERK phosphorylation and NF-κB activation pathway in human mast cells (Kang et al., 2006).The hepatoprotective effects of acanthoic acid were evaluated in a D-galactosamine/ lipopolysaccharide-induced fulminant hepatic failure mouse model.The effects were likely associated with a significant decrease in serum TNF-levels, which are correlated not only with those of alanine aminotransferase and aspartate aminotransferase but also with the reduced number of apoptotic hepatocytes in the liver as confirmed using the terminal deoxynucleotidyl transferase-mediated (dUTP) nick end-labeling method and DNA fragmentation assay (Nan et al., 2008).The protective effect of acanthoic acid was investigated in acetaminophen-induced hepatic toxicity.These results indicated that acanthoic acid protected liver tissue from oxidative stress elicites by acetaminopheninduced liver damage (Wu et al., 2010).Acanthoic acid markedly suppressed the protein expression of TNF-, COX-2, NF-κB and chymase as well as the mRNA expression of TNFand COX-2 (Kang et al., 2010).In study of (Cai et al., 2003a), a new compound, acanthokoreoside acid A (30) as well as acanthoic acid ( 27), (-)-pimara-9(11),15-dien-19-ol ( 26), and sumogaside (32) were isolated from CH 2 Cl 2 fraction of A. koreanum roots.They were evaluated for inhibitory activity on IL-8 secretion in TNF--stimulated HT-29 and TNF-secretion in trypsin-stimulated HMC-1.

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phenylpropanoid, syrinoside (44) were isolated from the roots of A. koreanum by (Hahn et al., 1985) and then was ariensin (43) (Kim et al., 1988a).In study antioxidant activity of chemical components from the leaves of this plant, (Nhiem et al., 2011) isolated one new phenylpropanoid named acanthopanic acid and one known 1,2-O-dicaffeoylcyclopenta-3ol.These compounds showed significantly antioxidant activity by the intracellular ROS radical scavenging DCF-DA assay with IC 50 values of 3.8 and 2.9 μM, respectively.Until now, only rutin (45), a quercetin glycoside was isolated from this plant with large amount.Rutin is used in many countries as medication for blood vessel protection and are ingredients of numerous multivitamin preparations and herbal remedies.Rutin has various biological activities that are beneficial to human health such as antioxidant effect (Nhiem et al., 2011), protective effect against hepatotoxicity, and anti-inflammatory effect.

NMR data of lupane aglycones
Lupane triterpenes are a class of the most compounds isolated from the leaves and roots of A. koreanum, which were determined that this type of compounds are main chemical components of this plant.
Observed the isolated compounds from A. koreanum, we found that there are four main classes including lupane triterpenoids, pimarane diterpenoids, ent-kaurane diterpenoids, and lignans.Among of them, lupane triterpenes were isolated as numerous of compounds with high yield.These lupanes often contain hydroxyl group at C-3, carboxyl at C-28.In some compounds, hydroxyl, aldehydic, carboxylic groups were at C-11, C-23, and C-30, glycoside was at C-28 and rarely at C-3.
From Table 1, we summarized all 13 C-NMR characteristics of lupane aglycones as follows: 1.When hydroxyl group at C-3, chemical shift of C-3 was about 73.0 ppm and configuration of hydroxyl group at C-3 is orientation.When glycosidation is at C-3, chemical shift of C-3 moved to down field with C of 81.0 ppm. 2. Free carboxylic group at C-28 were confirmed by chemical shift about 178.0~180.0ppm.
3. When 23-methyl group was replaced with aldehydic group, chemical shifts of C-23 and C-4 moved to down field from 28.0-28.8 to 209.0-210.0,37.5-39.5 to 54.9-56.3ppm, respectively.When 23-methy group was replaced with carboxylic group, chemical shifts of C-23 and C-4 changed from 28.5 to 178.0, 37.8 to 53.0 respectively, and when 23methyl group was replaced with CH 2 OH, chemical shift of C-23 had a large change from 28.0 to 71.5 ppm; chemical shift of C-4 had small change about 2.0ppm.4. When 30-methyl group was replaced with CH 2 OH, the chemical shifts of C-20 and C-30 downshifted from 151.0 to 156.5, from 19.5 to 64.5 ppm, respectively; chemical shifts of C-19 and C-29 upshifted from 47.5 to 43.0, from 110.0 to 106.0 ppm, respectively.5.When hydroxyl group was at C-11, chemical shift of C-11 downshifted from 21.1 to 71.0 ppm.Furthermore, configuration of hydroxyl group at this position is .

Conclusion
This chapter is intended to serve as a reference tool for people in all fields of ethnopharmacology and natural products chemistry.The pharmacological studies on A. koreanum indicated the immense potential possibility of this plant in the treatment of conditions such as inflammation, rheumatism, diabetes, cardiovascular, and virus.However, the diverse pharmacological activities of solvent extracts and phytochemicals of A. koreanum have only been tested in in vitro assay using laboratory animals, and obtained too unclearly and ambiguously for the case of human beings to be conducted on enough.However, these gaps in the studies demand to be bridged in order to exploit medicinal potential of the entire plant of A. koreanum.It is still clear that A. koreanum is massively and widespreadly consumed, and also contiuously studied expecting clinical treatment of various diseases for the future in Korea as well as in the world.From these viewpoints, impressic acid and acanthoic acid, major components of A. koreanum are good candidates for further studies in clinical trials, and the development of products derived from A. koreanum can be an important part of our biodiversity to respect and sustain for coming generation.

Table 1 .
13C-NMR data of lupane aglycone moieties (continued)www.intechopen.comPhytochemicals-A Global Perspective of Their Role in Nutrition and Health