Genus Kadsura, a good source with considerable characteristic chemical constituents and potential bioactivities

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Review

Genus Kadsura, a good source with considerable characteristic chemical constituents and potential bioactivities Jiushi Liu a , Yaodong Qi a , Hongwu Lai a , Jin Zhang a , Xiaoguang Jia b , Haitao Liu a,b,∗ , Bengang Zhang a,∗∗ , Peigen Xiao a a Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine (Peking Union Medical College), Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China b Xinjiang Institute of Chinese and Ethnic Medicine, Urumqi 830002, Xinjiang, China

a r t i c l e

i n f o

Article history: Received 5 September 2013 Received in revised form 11 November 2013 Accepted 31 January 2014 Keywords: Genus Kadsura Traditional efficacy Chemical constituents Bioactivities

a b s t r a c t In China, the plants of genus Kadsura had been used as the folk medicines for a long time and showed good effect of activating blood and dissolving stasis, promoting qi circulation to relieve pain, dispelling wind and eliminating dampness. The bioactivities of genus Kadsura were attributed to the existence of its characteristic chemical constituents. This review systematically summarized the traditional efficacy and medicinal application of genus Kadsura in China, chemical constituents and bioactivities of the plants of genus Kadsura. And, lignans and triterpenoids were the main bioactive constituents, which exhibited good anti-HIV, anti-tumor, anti-hepatitis, anti-oxidant, anti-platelet aggregation activities and neuroprotective effect etc. Moreover, some structure–activity relationships mining would greatly enrich the opportunity of finding new and promising lead compounds and promote the reasonable development and utilization of the plants of genus Kadsura. © 2014 Elsevier GmbH. All rights reserved.

Introduction The genus Kadsura, which belongs to the economically and medicinally important family Schisandraceae, consists of 16 species of scandent and twining woody vines. It is widely distributed in Asia, extending from Sri Lanka eastwards to the Philippines, and from Java and the Lesser Sunda Islands northwards to southern Korea and Japan, however its distribution center of diversity lies in China, and 8 species mainly distributed in the southwest and southeast in China (Wu et al., 2008; Saunders, 1998). In China, the stems and roots of genus Kadsura are commonly used as folk medicines and show good effect of activating blood and dissolving stasis, promoting qi circulation to relieve pain, dispelling wind and eliminating dampness (Liu et al., 2012). Among these

∗ Corresponding author at: Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine (Peking Union Medical College), Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China. Tel.: +86 10 57833196; fax: +86 10 57833196. ∗∗ Corresponding author. Tel.: +86 10 57833191; fax: +86 10 57833196. E-mail addresses: [email protected] (H. Liu), [email protected] (B. Zhang).

species, K. interior (called “Dian-ji-xue-teng” in Chinese) is recorded in the Chinese Pharmacopeia (2010 version, volume I) (Chinese Pharmacopeia Commission, 2010), K. coccinea (called “Hei-laohu” in Chinese), K. longipedunculata (called “Hong-mu-xiang” in Chinese), and K. heteroclita (called “Hai-feng-teng” in Chinese) are all recorded in Chinese Materia Medica standards of Guangdong Province, Fujian Province, Guangxi Zhuang Autonomous Region, and Hainan Province, respectively, which have good traditional efficacy and medicinal application with a long history (FuJian Food and Drug Administration, 2006; Guangdong Food and Drug Administration, 2004; Xiao, 2001; State Administration of Traditional Chinese Medicine, 1999; GuangXi Zhuang Autonomous Region Health Department, 1992). In recent years, lots of studies on the phytochemistry and bioactivity of genus Kadsura have been carried out. Many novel compounds with unprecedented structures were isolated, which further enriched the types of natural products. The results showed that this genus was a rich source of lignans and triterpenoids, which exhibit various beneficial bioactivities such as anti-HIV, anti-tumor, anti-hepatitis, anti-oxidant, anti-platelet aggregation activities and neuroprotective effect etc. In this review, the traditional efficacy and medicinal application of genus Kadsura in China was sorted out; the different types of chemical constituents

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isolated from genus Kadsura over the past 20 years were classified; and the bioactivities as well as some structure–activity relationships were also summarized. Traditional efficacy and medicinal application of genus Kadsura in China Most Kadsura plants showed good traditional efficacy and medicinal application in southwest and south China with a long history. The fruits, leaves, stems and roots of the plants of genus Kadsura could be used as folk medicines with different traditional efficacy and medicinal application respectively. But the same used part of different species had the similar preparations, functions and treatments, and the stems and roots were their main medicinal parts. The fruits of the plants of genus Kadsura were used for the treatment of chronic cough and dyspnea in deficiency condition, nocturnal emission and spermatorrhea, chronic diarrhea, palpitation and insomnia and so on, and they were similar to the fruits of Schisandra chinensis. The leaves were usually used for the treatment of traumatic bleeding, alleviate the swelling and ease pain. The stems and roots were the main used part as folk medicines in most districts, which were used for the treatment of traumatic injury, arthralgia with wind-dampness, fracture, irregular menstruation, and wound bleeding. For example, the stems of K. japonica named “Zuan-gu-feng” were used to treat arthralgia with wind-dampness, duodenal ulcer, acute gastroenteritis, dysmenorrhea and postpartum abdominal pain in Fujian Province (Xiao, 2001). K. oblongifolia mainly distributed in Hainan Province, and its stems named “Xifeng-teng”, were used as folk medicine for the treatment of cough, arthralgia with wind-dampness, dysmenorrhea, traumatic injury (State Administration of Traditional Chinese Medicine, 1999; Song, 1988). The stems of K. ananosma named “Xiao-xue-teng” were used to traumatic injury, fracture and irregular menstruation in Yunnan Province (Yunnan Food and Drug Administration, 2006). Moreover, different functions and treatments were accompanied with different preparations. The fruits were generally decocted and took orally or powdered and took orally with warm water for the treatment of lumbago due to deficiency of the kidney, neurasthenia, bronchitis, and the leaves were usually powdered and sprinkled on the wound for the treatment of traumatic bleeding. The stems and roots were usually decocted and took orally for the treatment of stomachache, gastrelcoma, duodenal ulcer, chronic gastritis, dysmenorrhea, irregular menstruation, postpartum abdominal pain, or they were soaked in the wine and drank for the treatment of traumatic injury, arthralgia with wind-dampness. Or the fresh stems and roots were ground and plastered with wine for the treatment of traumatic injury, arthralgia with winddampness, pyogenic infection and ulcerous disease of skin and poisonous snake bite (State Administration of Traditional Chinese Medicine, 1999). In China, many plants of genus Kadsura were usually used together with other medicinal materials to compose folk recipes. For example, the stems and roots K. coccinea (15 g), the roots K. longipedunculata (15 g), Calathodes oxycarpa (30 g), Lindera aggregata (3 g) were decocted together and took orally for treatment of dysmenorrheal (Xie et al., 1975). K. interior (60 g), Clematis chinensis Osbeck (30 g), Homalomena occulta (40 g), Achyranthes bidentata (15 g) were decocted together and took orally or pound with topical application for treatment of arthralgia with wind-dampness (State Administration of Traditional Chinese Medicine, 1999). Chemical constituents Many chemical constituents have been identified in genus Kadsura such as lignans, triterpenoids, flavonoids, monoterpenoids,

and sesquiterpenoids. Lignans and triterpenoids are the main responsible for its pharmacological activity. The recent surge of interest in the phytochemical study of genus Kadsura has led to the isolation and identification of 439 compounds, which most of them could be assigned as lignans and triterpenoids. More than 110 papers were published about the phytochemical study on fourteen species of Kadsura. The number of different styles of compounds isolated from genus Kadsura was shown in Table 1. Lignans Lignans were the main bioactive constituents of genus Kadsura, which showed various structures and complex stereochemical configurations. So far, the phytochemical studies have led to isolation and identification of 282 lignans. Some of them were common and similar with compounds isolated from Schisandra genus, such as schisandrins, gomisins and their derivatives. But some characteristic chemical constituents were isolated and identified from genus Kadsura, which was spirobenzofuranoid dibenzocyclooctadienes. According to the skeleton types, lignans could be divided into five categories: dibenzocyclooctadienes(A), spirobenzofuranoid dibenzocyclooctadienes (B), aryltetralins (C), diarylbutanes (D) and tetrahydrofurans (E). Abundant dibenzocyclooctadienes (A) have been isolated from genus Kadsura: out of the total 282 lignans from this genus, 198 belonged to this category. Dibenzocyclooctadienes showed various skeletons in the chemical structure. According to the configuration and conformation, it could be divided into three types: S-TBC (twist boat chair), R-TBC, S-TB. And the S-TBC accounted for more than half of the total. Dibenzocyclooctadienes had different substituted groups in most position, including methoxy, methylenedioxy, hydroxyl and ester group, etc. And they featured a methylenedioxy group at C-12 (13) or C-2 (3) and hydroxyl group at C-6, 7. The substituted of octatomic ring was primarily ester in C-6, 9 positions, including angeloyl, benzoyl, acetyl, butanoyl, caproyl and so on. The octatomic ring containing an oxygen-bridged was a special type of dibenzocyclooctadienes, which of them had been only isolated from genus Kadsura. Dibenzocyclooctadienes were deemed as the characteristic constituents of Schisandraceae family. There were about 53 spirobenzofuranoid dibenzocyclooctadienes (B) isolated from genus Kadsura, and most of them had been only found in this genus, which could be considered as the characteristic chemical constituents of genus Kasura and demonstrate important taxonomic significance. This category featured a furan ring at C-14, 15, 16 positions and a ketonic group at C-1 or C-3 position. There were also eight arylteralins (C), seventeen diarylbutanetype lignans (D) and six terahydrofuran-type lignans (E) isolated from genus Kadsura. Triterpenoids Triterpenoids were another kind of important bioactive constituents in genus Kadsura. A series of highly oxygenated triterpenoids with different skeletons had been isolated from this genus. Those unusual ring system and highly oxygenated structural features made it distinctive from other naturally occurring triterpenoids. So far, phytochemical studies had led to isolation and identification of 157 triterpenoids. Triterpenoids isolated from genus Kadsura could be classified into three categories on the base of their different structural skeletons: lanostane-type, cycloartanetype, nortriterpenoids and others triterpenoids. According to the different oxygenated patterns and structure characteristic, they could be divided into several sub-types, which include intact lanostanes (F), 3,4-seco-lanostanes (G), 18(13→12)-abeolanostanes (H), 14(13→12)-abeo-lanostanes (I), norlanostanes (J),

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Table 1 Number of different types of compounds isolated from genus Kadsura. Lignans

K. interior K. heteroclita K. longipedunculata K. coccinea K. matsudai K. philippinensis K. polysperma K. oblongifolia K. japonica K. angustifolia K. ananosma K. induta K. lancilimba K. renchangiana

Triterpenoids

A

B

15 23 15 36 12 30 19 17 10 27 34 5

9 16 4 8 7 10

4

C

D

5 2

3 8 3

Total

E

F

G

H

I

5

6 3 2

1 1 10

8

2 2 2

2

5

11

1

J

K

L

M

2

3 1 2

20 5 3

N

4 9 7

O

6 8

1

P

Q

10 1

3

7 2 6 1

2 1 1

5

4 2

3

4 2

2

1 13

8

1 1

24 78 64 103 19 42 41 24 12 41 67 7 4 8

A: Dibenzocyclooctadienes; B: Spirobenzofuranoid dibenzocyclooctadienes; C: Aryltetralins; D: Diarylbutanes; E: Tetrahydrofurans; F: Intact lanostanes; G: 3,4-seco-Lanostanes; H: 18(13→12)-abeo-Lanostanes; I: 14(13→12)-abeo-Lanostanes; J: Norlanostanes; K: Intact cycloartanes; L: 3,4-seco-Cycloartanes; M: 14(13→12)abeo-Cycloartanes; N: Norcycloartanes; O: Kadlongilactone-type triterpenoids; P:Nortriterpenoids; Q: Others triterpenoids.

intact cycloartanes (K), 3,4-seco-cycloartanes (L), 14(13→12)abeo-cycloartanes (M), norcycloartane (N), kadlongilactone-type triterpenoids (O), nortriterpenoids (P), and others triterpenoids (Q). Since kadlongilactone-type triterpenoids featured an unprecedented rearranged hexacyclic system, which were assigned to a new group, named kadlongilactone-type triterpenoids, and they could be considered as the characteristic chemical constituents of genus Kadsura. Moreover, nortriterpenoids (P) represented a series of recently discovered novel structures from genus Kadsura. In earlier years, more than 60 highly oxygenated, polycyclic nortriterpenoids had been isolated from the plants of the Schisandra genus, and some scholars assigned this series of unique nortriterpenoids as Schisandra nortriterpenoids (Xiao et al., 2008). But the recent phytochemical studies showed nineteen compounds of this type were also isolated from genus Kadsura. Others There were also some other kinds of constituents isolated from genus Kadsura, including flavonoids, monoterpenoids, sesquiterpenoids. Seven flavonoids were isolated and identified from K. oblongifolia, included kaempferol-3-O-˛-l-arabofuranoside, quercetin-3-O-˛kaempferol-3-O-˛-d-arabinopyranoside, l-arabofuranoside, quercetin-3-O-˛-d-arabinopyranoside, quercetin-3-O-ˇ-d-gluco-pyranoside, quercetin, and kaempferol (Liu et al., 2009a). Some monoterpenoids were isolated from genus Kadsura, included myrceane, terpinene, limonene, carene, pinene, tricyclene and so on (Zhao, 2008). And some sesquiterpenoids were also isolated from genus Kadsura, included farnesane, bisabolane, germacrane, elemane, humulane, cadinene, copaene, cubebene, muurolene and so on (Li and Luo, 2002). In addition, two guaianolide-type sesquiterpenoids (4␤,9␤-dihydroxy-1␣,5␣-H-guaia-6,10(14)-dien and 4␤,9␤,10␣trihydroxy-1␣,5␣-H-guaia-6-en) were isolated and identified from K. interior (Dong et al., 2013).

Bioactivities Compounds isolated from genus Kadsura exhibited various beneficial bioactivities such as anti-HIV, anti-tumor, anti-hepatitis, anti-oxidant, anti-platelet aggregation activities, and neuroprotective effect etc. The chemical structures of some promising compounds are shown in Fig. 1.

Anti-HIV activity Several studies showed that many compounds isolated from Kadsura had anti-HIV activity. Chen et al. reported the EtOH extract of K. interior showed significant inhibitory activity in vitro against HIV replication in H9 lymphocytes, and schisantherin D, interiotherin B and angeloylgomisin R demonstrated potent anti-HIV activity. Further investigation discovered, seven compounds isolated from K. interior were active as anti-HIV agents, and gomisin G (1) exhibited the strong inhibitory activity against HIV-1 replication in acutely infected H9 cells with EC50 and therapeutic index (TI) values of 0.006 ␮g/mL and 300, respectively, and other six compounds were also active, but not so potent as gomisin G (Chen et al., 1996, 1997). Structure–activity relationship indicated that benzoyl and hydroxyl groups at C-6 and C-7, respectively, were important for enhanced anti-HIV activity. And 2, 3-methylenedioxy and 12, 13-dimethoxy substitutions on the aromatic rings also were important to enhanced anti-HIV activity. Pu et al. reported seven of compounds isolated from K. heteroclita showed activity in an HIV growth inhibition assay with TI values >5. In particular, interiorin and interiorin B exhibited moderate anti-HIV activity with EC50 values of 1.6 ␮g/mL, and 1.4 ␮g/mL, TI values of 52.9, and 65.9, respectively (Pu et al., 2008b). Binankadsurin A isolated from K. angustifolia showed potent anti-HIV activity with an EC50 of 3.86 ␮M, CC50 of 227.16 ␮M, and SI (EC50 /CC50 ) of 58.92, respectively (Gao et al., 2008b). Kadsulignan N (2) isolated from K. coccinea exhibited a significant activity against HIV in vitro with IC50 of 0.0119 ␮M and EC50 of 6.03 ␮M (Liu and Li, 1995a). Schizarin E (3) isolated from K. matsudai also demonstrated strong toxicity against HIV replication in H9 lymphocyteds (IC50 = 2.08 ␮g/mL). Structure–activity relationship indicated that the C-6 substituent in C18 lignans as well as the corresponding C-5 substituent (same relative position but different carbon numbering) in C19 homolignans could be significant for bioactivity (Kuo et al., 2001). Anti-tumor activity Many compounds isolated from genus Kadsura were evaluated for their antitumor activity and cytotoxicity. Ananosic acids A-C (4–6) isolated from K. anaosma showed significant cytotoxic activity in vitro against CCRF-CLM leukemia cells and HeLa cells (Chen et al., 2004b). Yang et al. reported compounds isolated from K. ananosma were assayed for their cytotoxicity against a small panel of human cancer cell lines (HL-60, SMMC-7721, A-549, PANC-1, and SK-BR-3) by the MTT method, and longipedlactones A (7), F

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Fig. 1. Chemical structures of some promising compounds isolated from genus Kadsura.

(8), M (9), and J (10) exhibited most potent cytotoxicity against HL-60 acute leukemia cell (Yang et al., 2009). Kadlongilactones A (11) and B (12) isolated from K. longipedunculata showed significant inhibitory effects against human tumor K562 cells with IC50 of

1.40 and 1.71 ␮g/ml, respectively (Pu et al., 2005). And longipedlactones A, B (13), C (14), F, and H (15) showed significant cytotoxicity against A549, with HT-29 and K562 cell lines. Structure–activity relationship indicated that the formation of a double bond between

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C-10 and C-19 conjugated with an ˛, ˇ-unsaturated lactone had a significant IC50 values. In contrast, the epoxy ring was displaced by the double bond, which destroyed the conjugated system, resulting in no cytotoxicity. So the big conjugated system (˛, ˇ, , ı-unsaturated lactone) was probably of crucial importance in its antitumor activity (Pu et al., 2006). Moreover, Kadlongilactones A-B, C-D (16–17) showed significant cytotoxicity against A549, HT29, and K562 cell lines with IC50 of 0.49 to 3.61 ␮M (Pu et al., 2007a). Kadlongilactones A and B isolated from K. coccinea exhibited potent cytotoxicity against K562, Bel-7402, and A549 cell lines with IC50 values less than 0.1, 0.1, and 1.0 ␮M, respectively (Gao et al., 2008c). Seco-coccinic acids F, G, and K isolated from K. coccinea showed antiproliferative effects against human leukemia HL-60 cells with GI50 values of 16.6, 28.4, and 15.2 ␮M, respectively. Structure–activity relationship indicated that it may be assumed that the side chain at the C-17 position led to an increased effect on cell growth inhibition (Wang et al., 2012c). Heteroclitalactone D (18) showed the strongest cytotoxic activity against the HL-60 cells with an IC50 of 6.67 ␮M (Wang et al., 2006a). Kadsufolin D (19) isolated from K. oblongifolia was the most active compound, exhibiting strong cytotoxic activities against A549 and HCT-8 with GI50 values of 5.1 and 5.7 ␮g/mL, respectively (Huang et al., 2011).

Anti-hepatitis activity In the folk medicine, the plants of genus Kadsura were used for the treatment of hepatopathy as TCM (traditional Chinese medicine). Research results have shown that compounds isolated from genus Kadsura have good anti-hepatitis activities. Kadsuphilactone B isolated from K. philippinensis exhibited in vitro anti-HBV activity with IC50 values of 6 ␮g/mL by HBsAg enzyme immunoassay (Shen et al., 2005a). Kadsumarin A isolated from K. matsudai had antiviral activity in vitro against hepatitis B virus (HBV) at a concentration of 40 ␮g/ml (Kuo et al., 1999). Moreover, the EtOH extract of K. matsudai exhibited anti-HBsAg and anti-HBeAg acitivities, and bioassay-directed fractionation of this active extract found schizarin B (20) showed moderate to strong activity for antihepatitis in both anti-HBsAg and anti-HBeAg assays (54.9% and 42.1% for anti-HBsAg and anti-HBeAg, respectively), schizarin D and E also exhibited the inhibitory activity (Kuo et al., 2001). Structure–activity relationship indicated that the C-6 substituent in C18 lignans as well as the corresponding C-5 substituent (same relative position but different carbon numbering) in C19 homolignans could be significant for bioactivity. Gomisin B (21), G (4), and (+)-gomisin K3 (22) isolated from K. matsudai displayed strong inhibition at concentrations of 100, 100 and 50 ␮g/ml in anti-HBsAg assay respectively (Wu et al., 2003). Structure–activity relationship indicated that the substituted moiety at C-9 in the C18 dibenzocyclooctadiene lignans would decrease the inhibitory effects, whereas C-6 substituent seemed not significant for the bioactivity.

Anti-oxidant activity The antioxidant activity has been found in the compounds isolated from genus Kadsura. Kadsuphilol C from K. philippinensis exhibited more potent activity than vitamins C and E at several concentrations (6.25, 12.5, 25, 50, and 100 ␮M) (Shen et al., 2007a). Chen et al. reported that kadsurin (23), heteroclitin D (24), interiorin and heteroclitin G (25) isolated from K. heteroclita showed significant anti-lipid peroxidative effect, and heteroclitins A-C, E have more or less antioxidant properties (Chen et al., 1992). And kadsurin seems to be the major constituent responsible for the antilipid peroxidative action of the K. heteroclita extract, due to its high content in the extract (Toda et al., 1988).

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Anti-platelet aggregation activity Some compounds isolate from genus Kadsura showed the antiplatelet aggregation activity. Han et al. reported using platelet activating factor (PAF) binding to human platelet membrane assay, tigloylgomisin P, angeloylgomisin P and R (+)-gomisin M1 isolated from K. heteroclica showed PAF receptor antagonistic activities (Han et al., 1992). Kadsuphilin C (26) isolated from K. philippinensis exhibited significant in vitro antiplatelet aggregation activity with IC50 at 14 ␮M by PAF assay (Shen et al., 2007b). Heteroclitin D and gomisin J isolated from K. heteroclita could inhibit L-type calcium channel (Zhang et al., 2000). Furthermore, heteroclitin D and gomisin J also showed the effects of expansion of blood vessels (Li et al., 1999). Neuroprotective effect Polysperlignans A-B (27–28), polysperlignans D-E (29–30), kadsurin (23) and tiegusanin I (31) showed statistically significant neuroprotective effects in vitro assays for their neuroprotective effects against PC12 neuroblastoma cells (Dong et al., 2012b). Ananolignans F (32) and L (33) isolated from K. ananosma showed significant neuroprotective effects in an in vitro assay (Yang et al., 2011b). Ananonin M (34) isolated from K. ananosma showed moderate neuroprotective effects (Yang et al., 2011a). NO production inhibitory activity Kadsuralignan C (35) and H (36) isolated from K. coccinea showed somewhat stronger effective than quercetin (IC50 = 24.8 ␮M) inhibiting NO production in a LPS and IFN-␥ activated murine macrophage like cell line RAW 264.7 (Li et al., 2006, 2007). Hu et al. reported that in vitro anti-allergic screening of the EtOAc extract of K. coccinea inhibited NO production, and further fractionation of the EtOAc extract found kadsuralignans G and L showed moderate NO production inhibitory activities weaker than quercetin (Hu et al., 2012). Other activities Furthermore, the compounds isolated from genus Kadsura also exhibited other activities. Li et al. reported that arrest of the cell cycle of Xenopus laevis embryos by kadsuracoccinic acid A isolated from K. coccinea may be related to the preservation of the progression of the M phase (Li et al., 2008). Goh et al. reported that kadsuralignan F isolated from K. coccinea significantly reduced melanin synthesis in a dose-dependent manner in a murine melanocyte cell line and human skin equivalents (Goh et al., 2013). Conclusions Plants of genus Kadsura are economically and medicinally important plants with various applications. Most Kadsura plants show good traditional efficacy and medicinal application in southwest and south China with a long history. The traditional medicinal use of Kadsura plant, in addition to bioactivities as referenced in scientific publications and official pharmacopeias contribute to substantiate the well-established medicinal use. From this genus, 282 lignans and 157 triterpenoids with different structural skeletons have been isolated and identified, some of which have exhibited potential developmental prospects. These structurally complex compounds have brought great interests and challenges for phytochemists and pharmacologists. The extensive studies on pharmacology of the compounds isolated form genus Kadsura have exhibited some promising bioactivities and compounds, such as

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anti-HIV activity (gomisin G, kadsulignan N et al.), anti-tumor activity (ananosic acids A-C et al.), antioxidant activity (kadsuphilol C, kadsurin et al.), anti-hepatitis activity (acetylepigomisin R et al.), anti-platelet aggregation activity (heteroclitin D et al.), neuroprotective effect (ananolignan F, ananonin M et al.), and NO production inhibitory activity (kadsuralignans C, G et al.). Genus Kadsura is a good source of pharmacologically active compounds, as demonstrated in this review. Continuing study on the plants of genus Kadsura might lead to the discovery of more relevant compounds with interesting biological activities, and we anticipate further progress in the search for medicinal applications with the development of pharmacological models. Moreover, these unprecedented compounds could be used as models to attain more potent and effective synthetic derivatives. To fully exploit the therapeutic value and utilize the plant resources of the species in this genus, their pharmacophylogenetics and structure–activity relationship should be further studied, more relevant compounds with interesting biological activities might be found. Acknowledgements The authors are grateful for the financial support provided by the National Natural Science Foundation of China (No. 81373913 and No. 81001609) and the Fundamental Research Funds for the Central Scientific Research Institutes for Public Welfare. References Chen, D.F., Xu, G.J., Yang, X.W., Hattori, M., Tezuka, Y., Kikuchi, T., Namba, T., 1992. Dibenzocyclooctadiene lignans from Kadsura heteroclita. Phytochemistry 31, 629–632. Chen, D.F., Zhang, S.X., Chen, K., Zhou, B.N., Wang, P., Cosentino, L.M., Lee, K.H., 1996. Two new lignans, interiotherins A and B, as anti-HIV principles from Kadsura interior. J. Nat. Prod. 59, 1066–1068. Chen, D.F., Zhang, S.X., Lan, X., Xie, J.X., Ke, C., Kashiwada, Y., Zhou, B.N., Pei, W., Cosentino, L., Lee, K.H., 1997. Anti-AIDS agents–XXVI. Structure–activity correlations of gomisin-G-related anti-HIV lignans from Kadsura interior and of related synthetic analogues. Bioorg. Med. Chem. 5, 1715–1723. Chen, Y.G., Hai, L.N., Liao, X.R., Qin, G.W., Xie, Y.Y., Halaweish, F., 2004b. Ananosic acids B and C, two new 18 (13→12)-abeo-lanostane triterpenoids from Kadsura a nanosma. J. Nat. Prod. 67, 875–877. Chinese Pharmacopeia Commission, 2010. Pharmacopoeia of the People’s Republic of China Version (2010). Chinese Medical Science Press, Beijing, pp. 339. GuangXi Zhuang Autonomous Region Health Department, 1992. Chinese Materia Medica Standards of GuangXi Province. Guangxi Science and Technology Press, Nanning. Dong, K., Pu, J.X., Du, X., Li, X.N., Sun, H.D., 2013. Two new guaianolide-type sesquiterpenoids from Kadsura interior. Chin. Chem. Lett. 2, 111–113. Dong, K., Pu, J.X., Zhang, H.Y., Du, X., Li, X.N., Zou, J., Yang, J.H., Zhao, W., Tang, X.C., Sun, H.D., 2012b. Dibenzocyclooctadiene lignans from Kadsura polysperma and their antineurodegenerative activities. J. Nat. Prod. 75, 249–256. FuJian Food and Drug Administration, 2006. Chinese Materia Medica Standards of FuJian Province. HaiFeng Press, Fujian. Gao, X.M., Pu, J.X., Huang, S.X., Yang, L.M., Huang, H., Xiao, W.L., Zheng, Y.T., Sun, H.D., 2008b. Lignans from Kadsura angustifolia. J. Nat. Prod. 71, 558–563. Gao, X.M., Pu, J.X., Xiao, W.L., Huang, S.X., Lou, L.G., Sun, H.D., 2008c. Kadcoccilactones K–R, Triterpenoids from Kadsura coccinea. Tetrahedron 64, 11673–11679. Goh, M.J., Lee, H.K., Cheng, L., Kong, D.Y., Yeon, J.H., He, Q.Q., Cho, J.C., Na, Y.J., 2013. Depigmentation effect of kadsuralignan F on melan-A murine melanocytes and human skin equivalents. Int. J. Mol. Sci. 14, 1655–1666. Guangdong Food and Drug Administration, 2004. Chinese Materia Medica Standards of GuangDong Province. Guangdong Science and Technology Press, Guangzhou. Han, G.Q., Xue, P.D.R., Arison, B.H., Lankin, D.C., Hwang, S.B., 1992. Dibenzocyclooctadiene lignans with platelet-activating factor (PAF) antagonist activity from Kadsura heteroclita. J. Chin. Pharm. Sci. 1, 20–27. Hu, W., Li, L., Wang, Q., Ye, Y., Fan, J., Li, H., Kitanaka, S., Li, H., 2012. Dibenzocyclooctadiene lignans from Kadsura coccinea. J. Asian Nat. Prod. Res. 14, 364–369. Huang, Z.H., Lu, Y., Liu, Y.N., Bastow, K.F., Lee, K.H., Chen, D.F., 2011. Kadsufolins A–D and related cytotoxic lignans from Kadsura oblongifolia. Helv. Chim. Acta 94, 519–527. Kuo, Y.H., Li, S.Y., Huang, R.L., Wu, M.D., Huang, H.C., Lee, K.H., 2001. Schizarin B, C, D, and E, four new lignans from Kadsura matsudai and their antihepatitis activities. J. Nat. Prod. 64, 487–490. Kuo, Y.H., Li, S.Y., Wu, M.D., Huang, R.L., Yang, K.L., Chen, C.F., 1999. A new anti-HBeAg lignan, kadsumarin A, from Kadsura matsudai and Schizandra arisanensis. Chem. Pharm. Bull. 47, 1047–1048.

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Please cite this article in press as: Liu, J., et al., Genus Kadsura, a good source with considerable characteristic chemical constituents and potential bioactivities. Phytomedicine (2014), http://dx.doi.org/10.1016/j.phymed.2014.01.015