Cembrane Diterpenes Chemistry and Biological

Current Organic Chemistry, 2012, 16, 0000-0000

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Cembrane Diterpenes Chemistry and Biological Properties Bin Yang, Xue-Feng Zhou, Xiu-Ping Lin, Juan Liu, Yan Peng, Xian-Wen Yang and Yonghong Liu* Key Laboratory of Marine Bio-resources Sustainable Utilization / Guangdong Key Laboratory of Marine Materia Medica / RNAM Center for Marine Microbiology, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou 510301, P. R. China Abstract: Cembrane-type diterpenoids are a large and structurally varied group of natural products isolated from both terrestrial and marine organisms. The present paper reviews all the metabolites of cembrane diterpenes, reported up to 2010. The natural products discussed in this review can be divided into several different structural families featuring a variety of ring sizes and oxidation patterns. The currently known biological activities will be presented as well.

Keywords: Diterpenoid, Cembrane, Natural product, Biological activity. 1. INTRODUCTION Cyclzation of a geranylgeraniol derived precursor between carbon 1 and 14 generate a 14 membered diterpenoid, named cembrane or thumbergane. Cembrane-type diterpenoids are a large and structurally varied group of natural products isolated from both terrestrial and marine organisms. In 1962, the first cembranoid diterpene, (+)-cembrene (1), was reported from pine oleoresin [1]. This was followed by the isolation of hundreds of cembranoids from plants and insects as well as of marine origin [2]. In the marine environment, coelenterates of the orders Alcyonacea and Gorgonacea are recognized as the most prominent source of cembranoids, which usually exhibit cyclic ether, lactone, or furane moieties around the cembrane framework [3-5]. Moreover, diterpenoids of the cembrane family have been shown to play an ecological role in the chemical defense against predator or competing reef organisms. From a biomedical perspective, cytotoxicity is the most remarkable property of this class of diterpenoids [6]. They also have been reported to possess multiple biological activities such as neuroprotective, anti-inflammatory, antiarthritic, calcium-antagonistic, and antimicrobial effects. This review covers the source, chemistry and bioactivites of 644 new cembrane diterpenes from both terrestrial and marine organisms. 2. CLASSIFICATION OF CEMBRANE-TYPE DITERPENOIDS 2.1. Simple Cembrene 2.1.1. Isopropyl Cembranes Soft corals have proven to be a rich source of a variety of diterpenes, of which cembranoids that exhibit a range of biological activities are the most commonly encountered ones [7]. Sarcophyton is among the most abundant soft coral genera on many coral reefs, and it tends to form large monospecific “carpets” of up to several square meters [8]. Sarcophyton is one of the more studied organisms. Three simple cembranoid diterpenes, namely (7R,8R,14S,1E,3E,11E)-7,8-epoxycembra-1,3,11-trien-(14)-ol (2), (7R,8R,14S,1E,3E,11E)-14- acetoxy-7,8-epoxycembra-1,3,11-triene *Address correspondence of this author at the South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou 510301, P. R. China; Tel: +86-2089023244; Fax: +86-20-84451672; E-mail: [email protected] 1385-2728/12 $58.00+.00

(3) and (7R,14S,1E,3E,8E,11E)-cembra-1,3,8,11- tetraene-7,14-diol (4), were isolated from the soft coral Sarcophyton trocheliophorum. Full NMR assignments for (11S,12S,14S,1E,3E,7E)-11,12epoxycembra-1,3,7-trien-14-ol (5) and (11S,12S,14S,l E,3E,7E)-14acetoxy-11,12-epoxycembra-l,3,7-triene (6) were given [9]. Eight new cembranoids, sarcophytol M (7), sarcophytol N (8), sarcophytol J (9), sarcophytol H (10) and its diacetate (11), sarcophytol O (12), sarcophytol I (13), and sarcophytol G (14) were reported by Kobayashi and his coworkers from the soft coral Sarcophyton glaucum [10]. From the soft coral Sarcophyton flexuosum collected near Reunion Island, Indian Ocean, three new cembranes, flexusines A (15) and B (16) and epimukulol (17), were identified [11]. Bishara have reported the investigation of Sarcophyton elegans collected near Kitangambwe, Kenya. Two unprecedented cembranoids, methyl tetrahydrosarcoate (18) and methyl tetrahydroisosarcoate (19), have been isolated [12]. Chemical investigation of the octocoral Sarcophyton ehrenbergi led to the isolation of three new simple cembranoids, ehrenberoxides A–C (20–22) [13]. Moreover, sarcophytol T (23), was isolated from the same species by Konig and his coworker [14]. From the soft coral Sarcophyton sp., studies have led to the identification of two new cembranes, epoxysartone B (24), and sartone E (25) [15]. Naturally occurring cembranes (26–29) have been isolated from Sarcophyton sp. These compounds have not previously been found to occur in nature but had been obtained as intermediates in a synthetic modification. Compounds 26 and 27 inhibited the binding of [3H]8-cyclopentyl-1,3dipropylxanthine to rat-brain adenosine A1 receptors [16]. Sarcrassins A–C (30–32) have been isolated from the soft coral Sarcophyton crassocaule collected from the Bay of Sanya, Hainan Island, China. Compounds 30, and 31 exhibited cytotoxic activities against KB cell lines with IC50 values of 19.0, 5.0 μg/mL respectively [17]. The lipid extract of the soft coral, Sarcophyton glaucum, was found to contain three cembrane-type diterpenes, sarcophytol A (33), sarcophytol acetate(34), and sarcophytol B(35) [18]. An investigation of the Caribbean octocoral Eunicea tourniforti collected along the southwest coast of Barbados afforded four new cembrane diterpenes (36–39) [19]. Alcyonols A–C (40–42) were reported by Zvia Kinamoni and his coworkers from Alcyonium utinumii [20], while gibberosenes B–G (43–48) were identified from the Formosan soft coral, Sinularia gibberosa [21]. Two new cembrane-type diterpenoids, 14-0-acetylsarcophytol B(49) and 14-0-acetylsarcophytol J (50), were isolated from the Okinawan soft coral Sinularia sp. [22]. © 2012 Bentham Science Publishers

2 Current Organic Chemistry, 2012, Vol. 16, No. 11

Yang et al.

OH O

HO OR

OH

2R=H 3 R = Ac

1

5R=H 6 R = Ac

4

R OH

OR

O

7

OH

OH

OH R

OH 8

10 R = OH 11 R = Ac

9 O

OH

OH 12

13 H

O OH

H

OH 14

OH

O

O

15

H

O

O COOMe

18

17

16

HO H

H H

O

O

H

O

H O

OMe HO

O O COOMe

H 21

20 OH

H

OH OH

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HO

COOMe

19

O

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22

23 OH

OH

OH

HO

HO

O

HO

OAc O

25

24

27

26 COOMe

OH

HO

O

O

O

COOMe

O

O H

O

H

28

COOMe MeO

H OH OR

O MeOOC 29

MeOOC

MeOOC

30 CH2OAc

33 R = H 34 R = Ac

32

31 O

O

O

HO OH

OAc 36

35

O

O 37

O 39

38

O

HO OH 40

O 41

44

OH

AcO

45

O 43

42

OH

O

HO

AcO

OH

HO

OAc

OAc

HO 46

H

AcO

AcO

HO OAc

OAc OH

47

48

49

Cembrane Diterpenes Chemistry and Biological Properties

Similar metabolites were also isolated from Lobophytum crassum (51) [23], Eunicea sp.(52) [24], Lobopytum sp. (53–55) [25], Sinularia ovispiculata (56) [26], Cladiella kashmani (57) [27], Alcyonium flaccidum (56) [28]. Five new cembradiene diterpenoids (58–63) have been isolated from an undescribed Caribbean gorgonian of the genus Eunicea [29]. Flabellatenes A (64), and B (65) have been isolated from the extract of the Antarctic sponge Lissodendoryx flabellata. Compound 64 was cytotoxic on mouse neuroblastoma cells (N18-T62) at low concentrations (0.16 μM), whereas significantly reduced cell proliferation of human tumoral cells (DU-145 and MCF-7) in a dose-depending manner [30]. Two new cembrane-type diterpenoids have been isolated from the 2propanol extract of the sea pen Gyrophyllum sibogae collected in South Africa: 7,8-dihydroflabellatene A (66) and 7,8dihydroflabellatene B (67). Compound 66 showed the activity against all of the lines tested. GI50 values (μM) for some of the lines evaluated are: DU-145 (82.0), IGROV (90.3), K-562 (62.7), and HT-29 (14.5) [31]. A new cembrane, echinoic acid (68), is the major secondary metabolite from Echinodorus grandiflorus [32]. The cuticlular wax of the leaf and flower of most tobacco varieties contains substantial amounts of diterpenoids of the cembrane class. Five new cembranoids have been isolated from Greek tobacco. They have been identified as (1S,2E,4S,7E,11S,12S)-11,12-epoxy-4-hydroxy-2,7cembradien-6-one (69), ( lS,2E,4S,7E,10E,12S)-4,12-dihydroxy2,7,10-cembratrien-6-one (70), (1S,2E,4S,8R,11S,12E)-8,11-epoxy4-hydroxy-2,12-cembradien-6-one (71), (1S,2E,4S,8R,11S)-8,11epoxy-4-hydroxy-2,12(20)-cembradien-6-one (72), and (lS,2E,4S,8R,11S,12R)-4,12-dihydroxy- 8,11-epoxy-2-cembren-6one (73). Moreover, the characteristic features in the spectroscopic data of 20 analogs (74–94) have been presented [33]. Further studies on the same species resulted in the discovery of eight new analogs, (1S,2E,4S,6R,7E,10R,11E)-2,7,11-cembratriene-4,6,10-triol (95), the corresponding (10S*)-; (4R*)- and (4R*,l0S*)diastereomers (96–98), (1S*,2E,4R*,6R*,7E,10S*,11Z)-2,7,11cembratriene-4,6,10-triol (99), (1S,2E, 4S,6R,7E,11E)-4,6dihydroxy-2,7,11-cembratrien-10-one (100), the corresponding (4R*)-epimer (101) and (1S*,2E,4S*,7E.l0S*,11E)-4,l0-dihydroxy2,7,11-cembratrien-6-one (102) [34]. Three new cembranoids, crotocembraneic acid (103) and neocrotocembraneic acid (104), neocrotocembranal (105), were isolated from the stem bark of Croton oblongifolius. Compound 105 inhibited platelet aggregation induced by thrombin, with an IC50 value of 47.21 μg/mL, and exhibited cytotoxicity against P-388 cells in vitro, with an IC50 value of 6.48 μg/mL [35, 36]. A new diterpene, setiformenol (106), has been isolated from the liverwort Tetralophuzia setifomis, which constitutes the first example of cembrane-type diterpene so far from the liverwort [37]. Cembrane-type diterpenoids, (8E)-4a-acetoxy12a,13a-epoxycembra-1(15),8-diene (107) and 13,18,20-epi-isochandonanthone (108) were isolated from the Tahitian liverwort Chandonanthus hirtellus (Web.) Mitt, while C. hirtellus produced three other analogs (109–111) [38-40]. Five new cembranoids, designated grandilobatins A-E (112– 116), were isolated from the soft coral Sinularia grandilobata. Grandilobatin C (114) was found to have a novel skeleton with the C-4 methyl group of the normal cembranoid rearranged to C-3, while the other metabolites were identified as new 10oxocembranoids. Metabolite 115 inhibited the accumulation of the pro-inflammatory iNOS protein of LPS-stimulated RAW264.7 macrophage cells at 50 μM [41]. Four new cembranoid diterpenes, 11,12-epoxy-1(E),3(E),7(E)-cembratrien-15-ol (117), 3,4:11,12-

Current Organic Chemistry, 2012, Vol. 16, No. 11 3

diepoxy-15-methoxy-1(E),7(E)-cembradiene (118), 1(E),3(E),7(E),11(E)-cembratetraene-14,15-diol (119), and 3,14epoxy-1(E),7(E),11(E)-cembratriene-4,15-diol (120), have been isolated from the soft coral Sinularia gibberosa [42]. A series of analogs were isolated from the soft coral Sinularia flexibilis (121) [43], Sinularia gibberosa (122) [44], Sarcophyton decaryi (123, 124) [45, 46], Nephthea brassica (125) [47], Lobopbytum pauciflorum (126–127) [20, 48], Sarcophyton mililatensis (130) [49]. Three novel cembrane diterpenoids, decaryiols B–D (130–132), characterized by a bicyclic skeleton of the decaryiol-type, have been isolated from the Indonesian soft coral Lobophytum sp., meanwhile, a analogue, namely decaryiol (133), have been isolated from the soft coral Sarcophyton decaryi [50]. 2.1.2. Isopropenyl Cembranes Eight cembranoid diterpenes have been isolated from an unidentified soft coral. The compounds were identified as (lS*,3S*,4S*,7E,11Z)-3,4-epoxy-13-oxo-7,11,15-cembratriene (134), (1S*,3S*,4S*,7E,11E)-3,4-epoxy-13-oxo-7,11,15cembratriene (135), (3E,7E,11Z)-13-oxo-3,7,11,15-cembratetraene (136), (3E,7E,11E)-13-oxo-3,7,11,15-cembratetraene (137), (1S*,3S*,4S*,7E,11E)-3,4-epoxy-14-oxo-7,11,15-cembratriene (138), (1S* ,3S*,4S*,14R*,7E,11E)-3,4-epoxy-14-hydroxy7,11,15-cembratriene (139), (7E,11E)-3,4-epoxy-7,11,15cembratriene (140), and (-)-cembrene-A (141) [51]. A new norcembrene diterpenold (142) has been isolated from several species of the soft coral Sinularia collected in Palau, Western Caroline Islands [52]. Meanwhile, the genus Sinularia yielded a cluster of cembrane diterpenolds, namely the gyrosanin A (143) [53], sinulariols C (144), D (145), sinularial A (146), sinularones A (147), and B (148) [54], diepoxycembrene A (149) [3]. Compound 143 at concentration of 10 μM did not inhibit the COX-2 protein expression, but reduced the levels of the iNOS protein (66.9 ± 5.2%) by LPS stimulation [53]. The new cembrane diterpene, crassumolide E (150) [55], (3E,11E)-cembra-3,8(19),11,15-tetraene-7-ol (151) [56] have been isolated from the soft coral Lobophytum crassum, and Litophyton arboretum respectively. Two new cembranoid diterpenes, diepoxysarcophytonene (152) and sarconphytonol (153), were isolated from the Hainan soft coral Sarcophyton latum [57], while bisepoxide (154), from the soft coral Sarcophyton torturosum was reported by Leone and his coworkers [58]. The new cembrane diterpenes leptodienones A (155) and B (156) have been isolated from the gorgonian Leptogorgia laxa collected in the Gulf of California. Compound 155 showed growth inhibitory activity of MDA-MB-231 and HT-29 cells with GI50 values of 16.2 and 14.9 μM, respectively. Compound 156 was more potent and inhibited the growth of the three cell lines with GI50 values of 6.3, 5.6, and 10.9 μM against MDA-MB-231, A-549, and HT-29, respectively [59]. The chemical study of the gorgonian Lephogorgia peruana collected at the Gulf of California has led to the isolation of the new diterpene, lophodienone (157) [60]. Five cembrane diterpenes were separately isolated from the Caribbean gorgonian Eunicea succinea (158–160) [61], Eunicea mammosa (161, 162) [62], Eunicea knighti (163–165) [63]. Compounds 163, and 165 showed significant antimicrobial activity against bacterial isolates, and also showed excellent anti-QS inhibition activity measured by means of bioluminescence inhibition with biosensor model systems [63]. Cleome spinosa Jacq. (Capparaceae) is a tough-stemmed herb that is widely distributed throughout tropical climates and especially within the West Indies. Examination of the aerial portions of Cleome spinosa yielded five new cembranes,


Yang et al.

O

AcO OH

H

OCOMe

O OAc

54

53

52

51 HO

O O

OH

O

50

O

O

OH

HO

AcO

O

OAc

OAc O

O 55

O

57

56

58

59

O

RO

HO O

O HO

HO

OH

OH

60 R = H 61 R = Ac

62

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OH

OH O

OH O

65 OH

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OH O

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67 O

OH

68 OH

O

O

O

69 OH

O

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70

72

71

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73 OH

HO

OH

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O 76

75 O

OH

O

O

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OH

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O

O

O

O

OH

OH

O

O

O

OH

O O 87

OH

84 OH

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86

85

83

O OH

OH

OH

82 OH

OH

O

81 O

79 OH

O 80

OH

78

77 OH

O

OH

O

OH

O

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O

OH

COOH

O

66

O

O

O

O

O

64

63

O HO

O

O

OH

OH

OH

OH

88 OH

OH

89 OH

O

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O OH

OH 90

91

92

OH 93

OH

OH 94


OH

OH

OH


OH

OH

OH

OH

OH

OH

OH

HO OH

OH

95

OH

OH 97

96 OH

OH

O

O

OH

98

101

99

OH

COOH

OH 102

O 100

OH

COOH 104

103 OCOMe

O

H

H O

O

O O

O

H

O

O

OH 105

O

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106

OH

H

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107

O H

109 R1 = H, R2 = CH3, R3= -H 110 R1 = CH3, R2 = H, R3= -H 111 R1 = CH3, R2 = H, R3= -H

108

O

O OMe OH

O

O

O 114

113

115

116

OH

O OH

OH

OH

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O 112

OH

OH

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OMe OH

O

OH

O

117

118

120

119

O

OH

OH

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OH

121

O OH

OH

OH

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OH

O 122

124

123

125

126

OH OH OH

OH

OH

O

O

R 1O

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R2O

OH

127

128

129

130 R1 = H, R2 = H 131 R = OH, R2 = H 132 R1 = H, R2 = Ac

133


Yang et al. O

O

O O

O

O

O O

136

135

134 O

137

138

O

O

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O

O

O

OH COOMe

O 139

141

140

OH COOMe

HO

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142

OH

O O

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OH

O 145

144

147

146 O

OH OH

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HOO

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148

150

149

151 O

O

OH

O

CH2OAc O

O

H

O

O

HO

O

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156

155

154

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H

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153

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OH 152

O

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O O

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H

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O 158

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159 OR

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160

161

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O H OH

OH OH 163 R = H 164 R = Ac

162

165

166

OH 167

HO H OH

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OH

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OH

168

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OH 169

named cleospinols A–D (166–169), and the 3-hydroxy-iso-pentan10-oate ester of cleospinol A (170) [64]. 2.1.3. Isopropyl/ Isopropenyl Acid Cembranes A systematic examination of the Chinese soft coral Dendronephthya sp. resulted in the isolation and characterization of 15

O

170

new cembranoid diterpenes, namely, dendronpholides C–F, I–P, R (171–183), sinulaflexiolides E, and F(184, 185). Dendronpholides C (171), and J (176) showed a selective and significant inhibition against BGC-823 (IC50 = 0.05, 0.20 μg/mL, respectively) [65, 66]. The soft coral Sinularia flexibilis produced an abundance of cembranoids, including flexibilisin A (186), and flexibilisin B (187)

Cembrane Diterpenes Chemistry and Biological Properties OH

R

Current Organic Chemistry, 2012, Vol. 16, No. 11 7 OH

OH

O COOMe

OH COOR

COOEt

COOH O

O OH

OH

171 R = OH 172 R = OAc OH

AcO

OH COOR2

OR1 OR2 175 R1 = R2 = H, R3 = Ac 176 R2 = R3 = H, R1 = Ac 177 R1 = H, R2 = Me, R3 = Ac OH R

174 R = H 184 R = Me 185 R = Et OH AcO

173

O

R3O

O

2

COOR

COOH

COOMe R1

O OR1 OH

AcO

AcO

O

OH

OH O

178 R1 = H, R2 = Et 179 R1 = H, R2 = Me 180 R1 = Me, R2 = Et

181 R = Et 182 R = Me

OH

O

186 R1 = H, R2= OAc 187 R1 = OH, R2= H

183

OH

O

COOR

OH

OH

COOEt

OH

COOMe

COOMe

O OH

O

AcO

188 R = Me 189 R = Et

190

O

O

O

COOMe

COOH

O 195

196

OH COOMe

H

COOMe H

H

194 OH

AcO

H

HOO

O

193

192 O

H

OH

OH

191

COOMe

HO

R1

O

O O

COOMe OAc

R2

COOMe

O

O H

O

O

197 R1 = CH3, R2 = OH 198 R1 = OH, R2 = CH3

199

O

200

O

201

O

O

H

H

HO COOMe

202

H

203

[67], sinulaflexiolides E–H (188–191) [43], sinuflexibilin (192) [68], sinuladiterpene I (193) [69], flexilarins B, and C (194, 195) [70]. Sinulaflexiolide E showed selective inhibitory activity against the gastric gland carcinoma cell line BGC-823 at 0.12 μM [43]. Meanwhile, the genus Sinularia yielded a cluster of cembranoids, including sinularic acid A (196) [54], granosolides C (197) and D (198) [71], querciformolide E (199) [71]. A series of analogs were isolated from Sarcophyton glaucum (200) [72], Lobophytum crassum (201) [23], Eunicea succinea (202) [61], Eunicea mammosa (203) [62]. Two new cembranoid-based diterpenes, (1E,3E,7E,11R*12R*)15-(acetoxymethyl)cembra-11,12-epoxy1,3,7-triene (204), [1E,3R*,4R*,7E,11R*,12R* or (11S*,12S*)]-15(acetoxymethyl)cembra-3,4:11,12-diepoxy-1,7-diene (205) were isolated from the dichloromethane extract of the soft coral Sarcophyton ehrenbergi [14].

COOMe

H O

AcO 204

AcO

205

2.2. Cembranolides Cembranolides are a class of diterpenes containing a 14membered carbocyclic nucleus, commonly fused to a five-, six-, or seven-membered lactone ring. There is a wide range of structural complexity within the series [43]. 2.2.1. 5-membered Lactone A large number of highly functionalized cembranoid diterpenes, containing an -methylidene--lactone moiety, have been isolated and identified from marine soft corals, especially from the genera Lobophytum, Sarcophyton, and Sinularia. All of which belong to the family Alcyoniidae within the order of Alcyonacea. Three new diterpenoids have been isolated from three soft corals Lobophytum crassum. The compounds were shown to be: deacetyldeepoxy lobolide (207), deepoxy lobolide (208), deacetyl-13-hydroxy lobolide


(211), all three closely related to the previously reported lobolide (206) and the epiimeric 13-hydroxy lobolide pair (209, 210, 212) [20, 73]. Four new cembranoids, presinularolide B (213), 3dehydroxylpresinularolide B (214), 3-dehydroxyl-20acetylpresinularolide B (215), and 20-acetylsinularolide B (216), together with five analogs, sinularolides B–E (218–221) and 20acetyl sinularolide C (210) were isolated from a South China Sea soft coral Lobophytum crassum. Sinularolides A–E (217–221) were firstly isolated from the soft coral Sinularia gibberosa. 3Dehydroxylpresinularolide B (214) showed significant cytotoxicity against both A-549 and P-388 cell lines with 95.7% and 100% inhibition at 10-5 mol/L, Moderate antitumor activities were observed for presinularolide B (166) against A-549 cells and for sinularolide C (218) against P-388 cells with 64.0% and 63.8% inhibition at a concentration of 10-5 mol/L, respectively [28, 74, 75]. Meanwhile, the genus Lobophytum yielded twelve analogs, durumolides A–L (222–233). Anti-inflammatory activity of metabolites 227 and 232 (10 μM) significantly reduced the levels of the iNOS protein to 0.8 ± 0.6% and 5.7 ± 2.2%, respectively, and COX-2 protein to 47.8 ± 9.0% and 71.6 ± 5.8%, respectively [76, 77]. The soft coral Lobophytum crassum continues to provide novel cembranoids with lactone, including crassumolides A–D, F (234–238) [55], 2hydroperoxysarcophine (239) [78], lobocrassolide (240) [79], and two unnamed diterpenes (241, 242) [23]. Crassumolide C (236) was isolated for the first time from a natural source. Compounds 234, and 236 were cytotoxic toward Ca9-22 cancer cells, moreover, they were found to inhibit the accumulation of the pro-inflammatory proteins iNOS and COX-2 at 10 μM [55]. Compounds 241, and 242, showed significant inhibitory effect of NO production, and their IC50 values were 3.8 ± 0.97%, 4.0 ± 0.91%, respectively [23]. Eleven new cytotoxic cembranolides, michaolides A–K (243–253) were isolated from the CH2Cl2 extract of the Formosan soft coral Lobophytum michaelae [80]. Bioactivity-guided fractionation of a CHCl3 extract of the soft coral Lobophytum micbaeh afforded a new cytotoxic cembranolide, lobomichaolide (254) [81]. Oenticulatolide (255), an ichthyotoxic cembranoid diterpene, has been isolated from the soft coral Lobophytum denticulatum [82]. From the samples of Lobophytum sp., studies have let to the identification of lobophytolides A–F (256–261) [83], and crassumolide E (262) [84]. The soft coral of genus Sarcophyton are rich sources of cembranoid diterpenes, possessing an -methylidene--lactone moiety, including (+)-12-methoxycarbonyl-11Z-sarcophine (263) [13], trocheliophorol (264) [85], (7R,8S)-dihydroxydeepoxy-entsarcophine (265) [72], sarcocrassocolides A–E (266–270) [86], crassocolides A–F (271–276) [87], (–)-7-hydroxy-8methoxydeepoxysarcophine (277) [88], 13-dehydroxysarcoglaucol16-one, sarcoglaucol-16-one (278, 279) [89], 16- oxosarcoglaucol acetate (280) [8]. Among these compounds, compounds 266–269 were shown to exert significant in vitro anti-inflammatory activity in LPS-stimulated RAW264.7 macrophage cells [86]. Crassocolide A (271) was cytotoxic against the four cancer cell lines, being significant (IC50 3.1 μg/mL) to moderate (IC50 8.6–11.9 μg/ mL) against Hep G2, and MCF-7, MDA-MB-231, and A549, respectively [87]. Seven new marine diterpenoids (281–287) having a cembrane skeleton were isolated from the Okinawan soft coral Clavularia koellikeri. Compound 281 showed cytotoxic activity against human colorectal adenocarcinoma cells (DLD-1, IC50 4.2 μg/mL) and strong growth inhibition against human T lymphocytic leukemia cells (MOLT-4, IC50 0.9 μg/mL) [90]. Moreover, two new cembrane diterpenoids (288, 289) was obtained again by Iwashima and

Yang et al.

his coworkers from the same species [91]. Some other analogs were isolated from Sinularia polydactyla (290, 291) [88], Sinularia mayi (292–294) [92], Briareum violacea (295) [93], Clavularia violacea (296) [94]. Pachyclavulariolides E–R (297–310), have been isolated from specimens of Pachyclavularia violacea collected in Papua New Guinea [95-97]. Among these compounds, pachyclavulariolide F (298) showed in vitro cytotoxicity against murine leukemia P388 with an IC50 1.0 μg/mL [95]. Compound 303 exhibited significant cytotoxicity against P-388 and HT-29 tumor cells with ED50’s of 2.8 and 3.3 μg/ml, and moderate cytotoxicity against KB and A-549 tumor cell with ED50’s of 7.6 and 6.7 μg/ml, respectively. Metabolites 301, and 302 also were found to exhibit significant cytotoxicity against P-388 cells with ED50’s of 1.3, and 2.5 μg/ml, respectively [96]. Compound 306 has been shown to exhibit significant cytotoxicity toward P-388 cancer cells (ED50 3.2 μg/mL) [97]. A large number of cembranoids have been isolated from the gorgonian coral. A new chemical study of the Caribbean gorgonian Eunicea succinea collected in Puerto Rico afforded seven new cembranolides (311–317) [98]. Three new cembranolide diterpenes, named 12,13-bisepieupalmerin acetate (318), 12-epi-eupalmerin acetate (319), and succinolide (320), were isolated from the same species [99]. Five new cytotoxic cembranolides (321–325) possessing a rare 4,7-oxa-bridged functionality were isolated from the gorgonian Eunicea mammosa [100]. Other seven cembranolides including eupalmerin (326) [101], eupalmerone (327), chlorohydrin (328) [62], euniolide (329) [102], 12-epieunicin (330), 4epijeunicin (331), 13-epieupalmerin (332) [103], were also isolated from Eunicea mammosa. The first chemical investigation of the gorgonian octocoral Eunicea pinta, lead to the isolation and structure determination of eight new cembranolides, including 12epieupalmerone (333) and uprolides H–M (334–340). Compound 333 showed strong growth inhibition against non-small cell lung cancer cells (NCI-H322M, IC50 0.90 μg/ mL) and renal cancer cells (TK-10, IC50 0.13 μg/mL), whereas compound 334 displayed strong growth inhibition against human T lymphocytic leukemia cells (MOLT-4, IC50 0.01 μg/mL; SR, IC50 0.07 μg/mL) [104]. A novel cembrane, diterpene styelolide (341), was isolated from the tunicate Styela plicata [105]. Bioassay-directed fractionation led to the isolation of five new cembrane-type diterpenoids (342–346), along with two known compounds, ovatodiolide (347) and 4,5epoxovatodiolide (348) from a methanol extract of Anisomeles indica [106-108]. Compound 347 exhibited moderate cytotoxicity against all of the lung (A-549), breast (MDA-MB-231 and MCF-7), and liver (Hep G2 and Hep 3B) cancer cell lines. Compounds 345 and 347 exhibited selective activities toward collagen with IC50 values of 41.9 ± 7.1 and 19.7 ± 6.7 μM, respectively. In contrast to 342 and 347, compounds 345, 346, and 348 showed selective activities toward thrombin with IC50 values of 20.0 ± 6.2, 11.9 ± 5.3, and 4.8 ± 0.4 μM, respectively. Sarcophine (349), isolated in good yield from the Red Sea soft coral Sarcophyton glaucum, was found to serve as an effective inhibitor of JB6 cell transformation. This compound was subjected to preparative-scale fermentation with Absidia glauca ATCC 22752, Rhizopus arrhizus ATCC 11145, and Rhizopus stolonifer ATCC 24795, resulting in the production of ten new metabolites (350–359) [109]. A new cembranoid, 17dimethylaminolobohedleolide (360), containing a dimethylamino functional group, has been isolated from the soft coral Lobophytum sp. It exhibited moderate HIV-inhibitory activity (EC50 = 3.3 μg/mL, IC50 = 10.2 μg/mL) in a cell-based in vitro anti-HIV assay [110].


OAc


OR3

OR

O

O

R1

R2 O

O

O

O

OAc HO H O

HO

HO

O O

O

OAc

R1

OH

O

O

R3 O

O

R2 H O

O

227 R1 = OH, R2 = H 228 R1 = OAc, R2 = OH 229 R1 = OAc, R2 = OAc

O

H

OH

O O

H O

O

233

O

O

234

HOO O

O

O

O

O

HO

O

O

O

232

O

226

O

O

R

OH O

O

225

O

O

O

H

H

O

230 R1 = OAc, R2 = OAc, R3 = OH 231 R1 = H, R2 = OH, R3 = H

O

O

223 R = OAc 224 R = OH OH

R1 R2

O

H

222

217

OAc

OAc HO

OH O

OH

HO

213 R1 = R2 = OH 214 R1 = H, R2 = OH 215 R1 = H, R2 = OAc

R

H H

O O 216 R1 = -OH, R2 = OAc 218 R1 = -OH, R2 = OH 219 R1 = -OH, R2 = OH 220 R1 = H, R2 = OH 221 R1 = -OH, R2 = H

O

O

HO

O

O

O

209 R1 = H, R2 = OH, R3 = Ac 210 R1 = OH, R2 = H, R3 = Ac 211 R1 = OH, R2 = H, R3 = H 212 R1 = OAc, R2 = H, R3 = Ac

O

R2

R2

O

207 R = H 208 R = Ac

206

R1

R1

CH2OAc

HO 235 R = CH2OH 236 R = COOMe

237 O

H O

238 O

H O

R1

OAc

R3

R2

OAc

O

O

H

H

H

O

240

239 243 R1 = R3 = OAc, R2 = OH 244 R1 = R2 = OAc, R3 = OH 245 R1 = OH, R2 = R3 = OAc 246 R1 = R3 = OAc, R2 = O 247 R1 = R3 = OAc, R2 = H 248 R1 = OAc, R2 = H, R3 = OH

AcO

O H

H

OAc AcO

O

242

241 AcO

O

O

O

249 R2

AcO

O

R1 O

O

AcO

OAc

AcO

OAc

O

COOMe

O

AcO

O

O O

OAc

O

OAc

251 R1 = R2 = OH, R3 = OAc 252 R1 = R3= OAc, R2 = OH 253 R1 = R2 = OH, R3 = H

250

O O

O

CH2OMe

H

O

O

256

255

254

H

R1 O R2

HO O

O

O 258

257 H

H

O

O

O

O

O

259 O

HO O H

O

O

H O

H

O

262 H OH

O

HO

264

265

OH O

R

COOMe 263

O

COOH

260 R1 = H, R2 = OH 261 R1 = R2 = OAc O H O

HO

O

O

266 R = OAc 267 R = H

O

R O

268 R = OAc 269 R = H

O


Yang et al.

HO

O EtOCO

HO R OAc

O

R O

O

O

271 R = OH 272 R = OAc

270 H O

O

O

OR1

O

O

O

OAc

O

O

OR2 OAc 281 R1 =R2 = Ac 282 R1 = Ac, R2 = H 283 R1 = H, R2 = Ac OAc O H O

280

OR1

O

O 277

OAc

279

O

O

COOMe OH

OH

OMe O

275 R = H 276 R = OAc O

COOMe

278

O

273 R = OH 274 R = OAc

H O

COOMe

R O

O

H O

HO

O

O

O

H O

OAc

H OAc

284

OH

OH

H

OAc

O

O

HO

OH

OR2 286 R1 = Ac, R2 = H 287 R1= H, R2 = Ac

285 O

H O

HO

288

290

289

O OH

O

O

O

R

294

OAc

OH

R1

R2

R1

300 R1 = OAc, R2 = OAc 301 R1 = OH, R2 = OH

O

R2

OAc OAc

O

O

O

RO

O

O

O

312 R = H 313 R = Ac

HO OAc

O O

O

O

O

O

H

O

OH

H

O 317

AcO O

O 318

319

O

O O

O

O

316

HO AcO

OH O

315

O

O

311 OH

314

O

309 R = H 310 R = OH

H O

O

HO O

O

O

O

HO

H

O

308

O

306

R

O

OH

O

OH

305

H

O

O

O

OAc

HO O

307

O

O

O

HO O O

OH

OH

OAc

303

302 R1 = OAc, R2 = OCOPr 304 R1 = OH, R2 = OH

O

O

O

O

O O

OAc OAc 399

H OH

O

O

O

OMe

298

O

O

O

O

OH

HO

OH

O

O

O

O

297

296

295

O

O

O O

OH OH

O

292 R = H2 293 R = OAc OAc O OAc

291 OAc

O

HO

HO

O

MeO O

O

O

O

O

H O 320

O

O

H R H O

321 R = OAc 322 R = OH

O



H

H

O

OH

OH H

O AcO

RO

H O

H

O AcO

HO

OH

O O

O

329

O

O O

O O

OH

O

O

O

O

R H O

O

340

339

H

H

O

O

O O

O 342 R = OH 343 R = OOH

341 O

O

O

O

HO O

O O

O

O

O

O HO

O

O

O

337 R = H 338 R = Ac

O

O

OAc

O O

O

O

336 OH

O

O

O

HOO

HO

O RO

335 OH

O

O

O

334

HOO

333

332

O O

O

O

HOO

HOO

O

O

O

O

HOO

O

O

331

330

O

HO

O

O

328

O

O

O

O

O

327

326

OH

O

O

O

O

324 R = Ac 325 R = CH3

323

OH

O O

H O

O

Cl

O

O

O

R 344

R1 O

345 R = OH 346 R = OOH

O

O

348

347 O

HO

R2

R1

O

O H

R2

O

R3

NMe2

COOH H O

356

R4

O 349 R1 = H, R2 = CH3, R3 = -OH, R4 = H 350 R1 = H, R2 = CH2OH, R3 = H, R4 = H 351 R1 = H, R2 = CH3, R3 = -OH, R4 = H 352 R1 = -OH, R2 = CH3, R3 = H, R4 = H 353 R1 = H, R2 = CH3, R3 = H, R4 = -H 354 R1 = H, R2 = CH3, R3 = H, R4 = -OH

355

O

O

358 R1 = CH3, R2 = OH 359 R1 = OH, R2 = CH3

O

360

O

357

Ten new cembranoid diterpenes, sarcophytonolides C–L (361– 370), in that all contain an , -unsaturated butenolactone moiety, were isolated from the Hainan soft coral Sarcophyton latum [57, 111, 112]. A cluster of analogs, namely isosarcophytonolide D (371) [113], sarcostolides A–G (372–378) [114], brassicolide (379) and brassicolide acetate (380) [115], have been isolated from the soft coral. Two new special cembrane diterpenes (381, 382) have been isolated from an unidentified species of soft coral of the genus Sarcophyton, collected along the South coast of Madagascar [116].

2.2.2. 6-membered Lactone A large number of cembrane-type diterpenoids possessing a lactone ring were isolated from the soft coral. Manaarenolides A–I (383–391) have been isolated from the ethyl acetate extract of the Taiwanese soft coral Sinularia manaarensis. Among these metabolites, diterpenes (383, 384, 387, and 388) were discovered for the first time as the hydroperoxycembranolides, and compounds 389 and 390 exhibited moderate cytotoxicities against the tested cell lines (ED50’s 7.2, 8.7, 10.9, and 13.4 μg/mL for 389, and 7.4, 7.6,


O

O O

Yang et al.

O

O

O HO

O

O

R

O

HO

O

O

OAc

OAc 361

362 O

O

O

O

O

O

O

OAc

OH

368 O

O

O

O

O

OAc

367

O

364 R = -OH 365 R = -OH O

363

O

OAc 370 O

371 O

O

O

O

O

O

O

O

OAc

O

O

O O

O

369

O

366

O

O

O

O

374

373

372 O

O

O

O

377

O O

O

O

O

378

376

375

O

COOMe

O

O

O

H

COOMe

H O

OR

379 R = H 380 R = Ac

9.3, and 5.8 μg/mL for 390, against the growth of Hepa59T/VGH, KB, Hela, and Med cells, respectively) [117]. Two new cytotoxic cembranoid diterpenes, sinuflexolide (392), dihydrosinuflexolide (393), have been isolated from the soft coral Sinularia flexibilis. Compound 392 exhibited cytotoxicity toward the growth of A549, HT-29, KB, and P-388 cells, and compound 393 exhibited cytotoxicity toward the growth of P-388 cells [68]. Two cembranolides, sinularin (394), and dihydrosinularin (395) were isolated from the soft coral Sinularia flexibilis from Hayman island on the Great Barrier Reef of Australia [118]. Flexilarins A (396), was isolated from the same species, collected from the southern coast of Taiwan [70]. Chemical investigations of the soft coral Lobophytum durum have led to the isolation of three unprecedented hemiketal cembranolides, durumhemiketalolides A–C (397–399). Both metabolites 397 and 399 reduced the levels of iNOS to 11.0 ± 1.3% and 0.0 ± 0.0%, respectively, and of COX-2 to 66.7 ± 6.4% and 34.7 ± 4.2%, respectively, in comparison with those of the control groups. Metabolite 398 reduced iNOS protein expression (6.4 ± 0.2%), but did not inhibit COX-2 protein expression [119]. Six new cembranoids, laevigatlactones A–F (400–405) were isolated from leaves of Croton laevigatus. Among these compounds, the hydroxy of C-1 and the carboxy of C-12 are connected to form a 6-membered lactone. Compound 401 exhibited modest cytotoxicity against HeLa cells, with an IC50 value of 38.4 μM [120]. 2.2.3. 7-membered Lactone An abundance cembrane diterpenes of containing a -lactones ring were identified from the soft coral especially from the genus

COOMe

COOMe 381

382

Sinularia. Chromatographic investigation of the octocoral Sinularia flexibilis afforded eight new diterpenes, sinuladiterpenes A–H (406–413), Compound 407 exhibited in vitro cytotoxic activity against human colon adenocarcinoma (WiDr) cell line with ED50 8.37 μg/ml [69, 121]. Moreover, a series of analogs were also isolated from Sinularia flexibilis, including sinulaflexiolides B–D, J, and K (414–418) [43], flexilarins D–J (419–425) [70], sinulariolone (426) [122], sandensolide monoacetate (427) and flexibolide (428) [123], and sinulariolide (429) [124]. Sinulaflexiolides D (416) showed selective inhibitory activity against the gastric gland carcinoma cell line BGC-823 at 8.5 μM. Sinulaparvalides A and B (430, 431) were isolated from the Hainan soft coral Sinularia parva [125]. Four new cembranoids, querciformolides A–D (432–435) have been isolated from the soft coral Sinularia querciformis. Furthermore, chemical investigation of Sinularia granosa has afforded three cembranoids, querciformolide B, granosolides A (436), and B (437). At a concentration of 10 μM, compound 434 was found to significantly reduce the levels of iNOS to 23.7 ± 2.3% relative to the control cells stimulated with LPS [126]. A systematic examination of the Chinese soft coral Dendronephthya sp. resulted in the isolation and characterization of a new cembranoid diterpene, dendronpholide Q (438) [65, 66]. Four new cembrane diterpenes (439– 443), which contain an intriguing seven-membered lactone moiety were isolated from the genus Sarcophyton. Sarcrassins D (440), and E (441) exhibited cytotoxic activities against KB cell lines with IC50 values of 13.0, and 4.0 μg/mL, respectively [17, 127, 128].


O

OH

R1


OH

O

O O

OH

OH

O

O

R1

383 R1 = H, R2 = OOH 384 R1 = OOH, R2 = H 385 R1 = H, R2 = OH 386 R1 = OH, R2 = H

R2

OH

O

O

OH

O

OH

O O

OH

R2 O

387 R1 = OOH, R2 = CH3 388 R1 = CH3, R2 = OOH

O

O

OH

O

389 O

OH

O

390 O

OH

O

O

OH OH

OH

O

AcO

O

O

398 OH

O

O 401

400 OH

HO

HOO

O

O

O

399 OH

OH

OH

OH O

397

396

O

OH

OH

O

OH

O

O

O

O

395

OAc

O

O

O

H

O 394

OAc

OH

O

OH

O

393

392

391

OH

OH

402

O

O

O

O

403

404

O

O 405

O O HO

OOH O

R

O

O

406 R = -OH 407 R = -OH

HO O

HO

O

OAc

HO O

OAc

O

O

413

OH

AcO

414 O

O

R

417 R = -OH 418 R = -OH

416

O

O

HO OH

O

O HO

O

420 R = -OAc 421 R = -OAc 422 R = -OH

423

O HO

O

O

HO O OAc

O

AcO

R

HO

O

419

O

O

AcO

OH

HO

415

OH O

O

O

HO

HO

HOO

O

412

O

O

O

O

AcO

O

O OH

O

O

411

409 R = -OH 410 R = -OH

O

O

HO

HO

HO

AcO

O

408

O O

R

424

OH 425

2.2.3. 8-membered Lactone

2.3. Furanocembranoids

Two new cembrane diterpenoids with an eight-membered lactone ring, echinodolides A (444) and B (445), were isolated from the leaves of the Brazilian medicinal plant Echinodorus macrophyllus (Chapéu-decouro) [129].

Furanocembranoids feature a canonical cembrane skeleton and a 14-membered carbocyclic ring as well as a furan heterocycle. In addition, these natural products typically feature a butenolide moiety encompassing C10–C12, as well as C20, which is why they


O

O

O

O

O

O

OAc H

H

HO

Yang et al.

O OH

428

427

O

O

O

R 1O

O O

O O OH

H

HO

O

431

430

HO

HO

O

OR

OAc

436 R = H 437 R = Ac

438

O

O

R1 R 2

AcO

AcO

H

O

O

O

O

R2

O

O

440

H

O

R1

O

O 439

O

O

AcO

O

433 R1 = Ac, R2 = H 434 R1 = Ac, R2 = Ac 435 R1 = H, R2 = H COOMe

COOMe

O

O

OR2

432 COOMe

O

O

O

OH

AcO

OH

429

O

O

O

O

HO

H

O HO

OH

426

O

O

HO

OH

O

H

O

444 R1 = H, R2 = OH 445 R1 = OH, R2 = H

442 R1 = H, R2 = OH 443 R1 = R2 = O

441

COOMe OAc O O

O

OAc

OAc O R

O O

O

OAc O

O

O

O 446 R = COOMe 447 R = CHO

OAc O

O

OAc

O

OAc O

R

HO

H

454

O

O

O 455

H

O

O

O

456

O O

COOMe

COOMe

O 457

HO HO

O

O

O O

OH

O O

O

OAc

CHO O

459

458

O

OH

O OAc

OH OAc O

OAc

OH OAc

O

H

O

H

O

O

H HO

O

H O MeO HO

O

O

O

O 451

OAc

452 R = Me 453 R = COOMe

H

O

O

OH

O

O

OAc

450

O O

O O

O

CHO

OAc

O

OAc

O

O O

CHO

449

448

H

O

OAc

O

H

O 460

O

O 461

O

OAc O

O

462

CHO

have been sometimes referred to as “furanocembranolides” in the older literature [130]. Wright et al. reported the isolation and structure elucidation of four cytotoxic furanocembranolides, denoted as bipinnatins A–D (446–449), from a specimen of Pseudopterogorgia bipinnata. Furthermore nine analogs, bipinnatins E–M (450–458), were isolated from the same gorgonian specimen [131-134]. A new similar diterpene, rubifolide (459), has been isolated from the soft

coral Gersemia rubiformis [135]. Coralloidolide A (460) and B (461)was isolated from the Mediterranean alcyonacean Alcyonium coralloides [136]. The chemical study of the gorgonian Lophogorgia peruana collected at the Gulf of California has led to the isolation of the five new diterpenes, lophodiol A, lophodiol B, 17acetoxylophotoxin, 15,16-epoxylophotoxin, and 17-acetoxy-15, 16epoxylophotoxin (462–466) [60], along with the known com-

Cembrane Diterpenes Chemistry and Biological Properties CHO

CHO

R HO

Current Organic Chemistry, 2012, Vol. 16, No. 11 15 CHO O

O O

O

O O

O

O O

OAc

OAc O

466 R = OAc 467 R = H

465

O O OAc

OAc

O

O

O

O

O

O 468

CHO

CHO

O

O O

OAc

O

O 463 R = OH 464 R = OAc

O R

OAc

O

CHO

CHO

469

COOMe

COOMe

CHO

OMe HO

O

O O

O OAc O 470

O

471

473

O

474 COOMe

O

O OAc

O

O

COOMe

COOMe

O

H

O

O 472

COOMe

O

O OAc

H

O

O

O O

O

O

OAc

OAc O

O

O

O

COOMe

O OAc

O

HO O

H

H

O

H

O

O

O

O

O

476

475

OH

477 COOMe

COOMe AcO O OAc

O OAc

HO

COOMe

O

OCOMe

O O

483

COOMe

COOMe

O O

HO

OCOMe

O

482

COOMe

H

MeOOC

O O

HO

COOMe

481

480

H

HO

O OH

O

O

O

COOMe

H HO

O

479

COOMe

COOMe

O

O

O

478

O

HO

COOMe

O

484

COOMe

COOMe

MeO

O

O O

O

O

O

O

O

O

OCOMe

O O 485

O

O

O 486

O O

O

O

487

pounds, lophotoxin (467) [137, 138], lopholide (468) [138, 139], deoxylophotoxin (469) [140], and the lophotoxin analogs 470 and 471[140]. Pukalide (472), isolated from the soft coral Sinularia abrupt, is a diterpenoid with a cembrane skeleton, bearing butenolide, epoxide, isopropenyl, and an unprecedented ,disubstituted furan--carboxylate function [141]. Thirteen highly oxygenated cembranolides, which are structurally similar to pukalide, were isolated including 13-acetoxypukalide (473), pukalide aldehyde (474) [138], 11b,12b-epoxypukalide (475), and unnamed furanocembranoid (476) [142], acerosolide (477) [143], sethukarailin (478), sethukarailide (479) [144], danielid (480), 3ethoxyfuranocembranoid (481) [145], unnamed furanocembranoid (482) [146], leptodiol(483), acetate of leptodiol(484), 8-epiLopholide (485) [147]. Three furanocembranolides, (Z)deoxypukalide (486), (E)-deoxypukalide (487), and isopukalide (488) were isolated from Leptogorgia spp. [148]. Two unusual cembranoids, sarcofuranocembrenolides A (489) and B (490), were

488

O O

O

O

489

OH

O 490

isolated from a soft coral Sarcophyton sp.. Compound 490 was a furanocembrenolide, but a C1 unit (C-20) was attached to C-10 instead of C-12 of the ordinary cembrenolide [149]. The oxidative cleavage of the furan ring is often observed in furanocembranoids. New norcembrane-based diterpenoids, leptocladolides A (391), B (492), and C (493) have been isolated from the Taiwanese soft coral Sinularia leptoclados. Also, Sinularia parva Tixier-Durivault which is investigated for the first time afforded leptocladolide A, and its related isomers 1-epi-leptocladolide A (494) and 7E-leptocladolide A (495). The new metabolite 493 was found to contain a novel 2,7-dioxa-bicyclo[2,2,1]heptane structural unit, which has not been found previously in diterpenoids [150]. Three novel cembranoids, sinulochmodin B (496), sinulochmodins D (497), and E (498) were isolated by Tseng and his coworkers from the soft coral Sinularia lochmodes [151, 152]. A new norcembrane, designated sinularectin (499), was isolated from the Kenyan soft coral Sinularia erecta. Sinularectin is a chlorinated

16 Current Organic Chemistry, 2012, Vol. 16, No. 11 O

O

O

O

OH

O

O OH

O

O

O

R OH

H

O OR

O

O 496

O

O

O 487 R = CH2CH3 498 R = H

HO

O O

O

O

COOMe Cl

O

O

H

O

OH OH

O

O

O 500

501 O

O

O

O

O

O

O

O

O

O

O

O 495

H

O

H

O

O

OH O

494

499

OH

O

O

O

O HO

H

OEt

EtO OH O

493

H

O

O

O O H

O

O 492

491

O

H

O OH

O

O

O

O

O

H

O

EtO OH O

Yang et al.

O H OMe

OH O

O

O 502 R = S-OH 503 R = R-OMe H

O H

O

O OH O

O O

O

H O

O

O

506

505

H

O

O

O

504 O

O

O

O

O

H

507 O

H

O H

O

O

R3

O R1

R2 O

OH O

H

O

H

H

O

O

O

O O

O

O

O

O

O 515

O

COOMe

O

H O 516

O

highly oxygenated norcembrane with an unprecedented functionalisation of the cembrane isopropyl group [152]. Moreover, epinorcembrene (500) was isolated from the same soft coral Sinularia erecta collected from the lagoon of Mayotte, Comoros Islands, northwest of Madagascar [151]. Gyrosanolides A–F (501–506) have been reported from the soft coral Sinularia gyrosaisolated. Compounds 501–503 at concentration of 10 μM did not inhibit the COX-2 protein expression, but reduced the levels of the iNOS protein (55.2 ± 14.6%, 18.6 ± 6.7%, 10.6 ± 4.6%, respectively) by LPS stimulation [53]. Investigation of the chemical constituents of a Taiwanese soft coral Sinularia scabra has afforded five new norditerpenoids, scabrolides C–G (507–510), which were found to be analogs with those of sinuleptolide (511) and 5-epi-sinuleptolide (512) also isolated previously from the same species and other Sinularia. Metabolite 508 was found to exhibit significant cytotoxicity against the growth of Hepa59T/VGH and KB cell lines (ED50’s 0.5 and 0.7 μg/mL, respectively) [153-155]. Four new norcembrene diterpenolds (513–515) have been isolated from several species of the soft coral Sinularia collected in Palau, Western Caroline Islands [52]. Chemical investigation of the hybrid soft

H O 517

O

H

O

O

O H

O

COOMe

O

H

O 512 R1 = OH, R2 = H R3 = -H 513 R1 = OH, R2 = H R3 = -H 514 R1 = H, R2 = OH R3 = -H

O 511

O 510

509

508

O

H

O 518

COOMe

O

O

COOMe

O O

O

O

OCOMe

O 519

O

coral Sinularia maxima Sinularia polydactyla yielded three new cembranolide diterpenes (516–518). Compound 518 shows strong cytotoxicity on the breast cancer SK-BR3 cell line and cervical cancer HeLa and HeLa-Apl cell lines with GI50 values of 0.039, 0.48, and 0.56 μM, respectively [156]. Leptogorgolide (519), a 1,4diketo-cembranoid with an oxidized C-18 as a methyl ester has been discovered in Leptogorgia sp. for the first time [147]. A novel cembranoid (520) was isolated from the stem bark of Croton oblongifolius and it showed broad cytotoxic activity against five further cell lines (BT474, CHAGO, Hep-G2, KATO-3, and SW-620) [157]. A chemical study of the sea feather Pseudopterogorgia bipinnata from Colombia has produced bipinnatolides F–J (521–525), which are highly oxygenated cembranolide diterpenes [131]. A group of the highly oxygenated cembranolides, namely isoepoxylophodione (526) [60], bipinnatins N–Q (527–530) [134], bipinnatolide K (531) [158], gorgiacerolide (532) [159], coralloidolides C–F (533–536) [160, 161], and epilophodione (537) [135], were reported. Two new cembrane-type diterpenoids, lobophynins B (538), and C (539), were isolated from the soft coral Lobophytum schoe-



OH

HO

OH OH

OH OH O

O O O

HO H

O

H

O

O

H

O

O O

O

O

O

O

O 523

O

OH

O

O

522

OH O

O

O

521

520

O

OH OH

H

O

O

OCOMe

H O

O

OO OCOMe

H

H

O

O

O

526 O

O

COOMe O

O

HO

O

O OCOMe

H

OEt

O

OH OH

H

O

O

O

O

OCOMe H

H

O

O

529

O

O O

O

O O

530

OO

O

COOMe

CHO

O 528

HO H

O

O 527

O

H

H

O

O

525

524

H

O

O

COOMe

O

O

531

532

O HO

HO

O

O O H

O

H O

OH

O

H

O

O

O

O

O

O

O 537

536

O OAc MeOOC

O

H

535

O

H

O

H O

OH

H

O

COOMe

539 H O

HO

540

O O

HO

MeO

OH

544

545

546

dei. Lobophynin C displayed ichthyotoxicity with an LC100 value of 30 ppm and exhibited toxicity with an LC50 value of 22.5 ppm in the brine shrimp lethality bioassay [24]. Furthermore, other similar diterpenes were discovered in the soft corals, including sarcophytonin E (540) [161], 13-dehydroxysarcoglaucol (541) [89], (+)-12carboxy-11Z-sarcophytoxide (542), lobophynin C (543) [13], (–)-7 -hydroxy-8-methoxydeepoxysarcophytoxide (544), (–)-7,8 – dihydroxydeepoxysarcophytoxide (545), and (–)-17-hydroxysarcophytonin A (546) [49], 11,12-epoxy-sarcophytoxide (547) [160]. Sarcophytoxide (548), (2S, 11R, 12R)-isosarcophytoxide (549) [48]. Biocatalytic transformation of 2-epi-16-deoxysarcophine using Rhizopus stolonifer ATCC 6227a and Absidia spinosa ATCC 6648 afforded five new metabolites (550–553) [162].

R 542 R = COOH 543 R = COOMe

541 H O

H O

HO

H O

H

O 538

O

O

O

534

533

O

O O O

O

547

H O O

548

Three novel furanocembranoids (554–556) were isolated from the stem bark of Croton oblongifolius. Compounds 554, and 556 showed broad cytotoxic activity against five further cell lines (BT474, CHAGO, Hep-G2, KATO-3, and SW-620) [157]. A new bicyclic oxa-bridged 2,5-dihydrofuran-containing cembranoid diterpene, (+)-marasol (557), was isolated from the gorgonian Plexaura flexuosa [163]. A analogue, gibberosenes A (558) was isolated from the Formosan soft coral, Sinularia gibberosa [21]. Two new furanocembranoid diterpenes, crematofuran (559) and isocrematofuran (560), have been isolated from the Dufour gland secretion of the Brazilian ant Crematogaster brevispinosa rochai. The toxicity of 559 towards other ants is on the same level as that of nicotine [164]. Moreover five new analogous(561–565) were obtained again


H O

Yang et al.

O

O

O

O

O

OH

HO

O

OH 549

551

550 OH

OH

H

O

O

HO

555

O

O

O

O

H

OR2

H

H O

OR1

OAc 558

557

556 O

561 R1 = R2 = CO-n-C3H7 562 R1 = CO-n-C3H7, R2 = COCH3 563 R1 = COCH3, R2 = CO-n-C3H7 564 R1 = CO-n-C3H7, R2 = H 565 R1 = H, R2 = COCH3

560

559

O

O

O

H

H

O

O

H

O

H

O

HO

H

H

OH

O

AcO

R

OH

MeOOC

H OH

O O HO

HO 568 R = OH 569 R = Cl

567

566

H

O

HO

HO

HO

O

O

MeOOC

MeOOC

MeOOC

570

O

O

O COOMe

O COOMe

O O

O

O

O

O O

O

O

O

554

553

552 OH

OH

HO

O

H

H O

H O

H O

H O

H

O H

O O

MeOOC

H

H O

MeOOC

O H

O H

HO 571

O

H

by Leclercq group from another closely related Brazilian Crematogaster taxon, Crematogaster brevispinosa ampla Forel [165]. 2.4. Biscembranoids Biscembranoids are a family of marine natural products with unusual structure pattern mainly found from marine soft corals, featured by a 14-6-14 membered tricyclic backbone of tetraterpenoids. Their structures varied mainly in ring C where high oxygenation and tri-, penta-, and hexa-epoxy cyclic moieties are frequently observed. The plausible biogenetic pathway of biscembrane analogs was assumed to be derived by a Diels–Alder cycloaddition of two “mono” cembranoids, representing cembranoid-diene and cembranoid- dienophile. This depiction was late on supported by the natu-

O

HO

HO 572

H

H

HO 573

O

H

H

H O

HO

H 574

HO

H

ral occurring monomeric cembranoids, such as dienophiles methyl sarcoate and methyl tetrahydrosarcoate (methyl tortuosoate), which were regarded to be the precursors to form left part of biscembranoids [166]. Biscembranoid diterpenoids were discovered in two species of the genus Lobophytum pauciflorum yielded lobophytones A–S (566–584) [166-168], while Sarcophyton producted other analogs, ximaolides A–G (585–591) [169, 170], methyl neosartortuate acetate (592) [58], methyl tortuoate A (593), methyl tortuoate B (594) [7], nyalolide (595) [8], bisglaucumlides A–K (596–606) [171, 172]. Compound 576 showed significant inhibition toward LPSinduced nitric oxide (NO) in mouse peritoneal macrophage with IC50 values of 4.70 μM [167]. Compounds 593, and 594 exhibited


O


O

O

O

O

O COOMe

O COOMe

O COOMe

O COOMe

H

O

H

H

H

O AcO HO

H

576 R = OH, R1 = Me 577 R = Me, R1 = OH 578 R = R1 = H 579 R = EtO, R1 = Me

575

O

H

R1 R

580 R = OH 581 R = OAc 582 R = Cl

OH

H

HO

583

O

O

O

O COOMe

O COOMe

O COOMe

O COOMe

O

H

H

H

O

O

H

H

O

H

OH

H

O

H

OH O

OH

585

586

O

O

O

O COOMe

O COOMe

O COOMe

Cl 587 O

H

H

OH

H

O

H

H

HO

HO

588

H

H O

593

H

O H

HO

H

O

H

O H

O H 594

O

HO

in vitro cytotoxicity against the human nasophyringeal carcinoma CNE-2 cell line, with IC50 values of 22.7 and 24.7 μg/mL, and the murine P-388 tumor cell line, with IC50 values of 3.5 and 5.0 μg/mL, respectively [7]. Two biscembranes with an unprecedented fused carbon skeleton, bislatumlides A (607) and B (608), were isolated from the Hainan soft coral Sarcophyton latum, and they exhibited mild cytotoxicity toward several cell lines. IC50 values of 7 μg/mL were determined in assays against A-549 lung carcinoma and HT-29 colon adenocarcinoma human tumor cell lines, and 5.8

H H AcO

O

O

O

O COOMe

O COOMe H

H H O

AcO 595

OAc

H

592

H

H

O

O

H

HO

590 R = OH 591 R = OAc

O COOMe

H H O

R

O COOMe

H

O

O COOMe

HO

O

H

589

O

O

OH

O

OH

H

OH Cl

O

O 584

OH

O

O

HO

O

H

H

O

HO

H

H

R

H

O

HO

OH

O

O

OH

H

HO

H

O

H

H

H O

OH R 596 R = OH HO 597 R = OAc

OH

H

μg/mL against the P388 murine lymphocytic leukemia cell line [113]. Two bis-pukalide diterpenes, mayotolides A and B (609, 610) were isolated from the soft coral Sinularia erecta, collected from the lagoon of Mayotte, northwest of Madagascar [151]. A bioassayguided fractionation and chemical examination of the soft coral Sinularia flexibilis resulted in the isolation and characterization of sinulaflexiolide A (611) [43]. Sinuflexlin (612), was isolated from the same soft coral species by Duh and his coworkers [173]. An


O

Yang et al.

O

O

O COOMe

O COOMe

H

O

H

H O AcO

H

H

H O

OH AcO

H

HO

O

O COOMe

O COOMe O

H

H O

OH HO

H

O

OH AcO 601

O

O O O COOMe

O COOMe O OH H

H

HO

H

H

H

H

H

O

AcO OH

H

H

H O

OH

O

O HO

AcO

O

O

O

H

H

HO

600

OH

O

O

O

H

H

H

HO

699

598

O

H

H

HO

O

HO

H

HO

OH

H

O

O O

OH H

R

H O

AcO

O

COOMe

H H

OH

COOH

O

O

O O

H

O

H

608

OH H

H H

OH

607

603

602

H

O R1

R2

O

O

COOMe

H

OH

H

O

O

O

O 604 R = OH 605 R = OAc

OH

O

O O

609 R1 = OH, R2 = Me 610 R1 = Me, R2 = OH

606

O

OH

O O O

611

HO

O

HO O

HO

O

O

O O

O

O O

OH

612

O

O OH

unprecedented C,C-linked dimeric norcembranoid, sinulochmodin A (613), was isolated from the soft coral Sinularia lochmodes [174]. Study of Sinularia gardineri (Pratt) (Alcyoniidae), collected in the Red Sea, revealed a new heptacyclic norcembranoid dimer singardin (614). Compound 614 show cytotoxicity to murine leukemia (P-388), human lung carcinoma (A-549), human colon carcinoma (HT-29), and human melanoma cells (MEL-28) [175].

O

O O

O OH

O

O

O

O

O

O

O

O

O

O

613

O

O 614

secta (618) [176], Pseudopterogorgia bipinnata (619) [158], Eunicea succinea (620) [61] respectively. 2.5.2. 13-membered Carbocyclic Cembranoids Six novel 13-membered carbocyclic cembranoids, named sartol acetate B (621) [15], sarcotol (622), sarcotol acetate (623), sarcotal acetate (624) [177], and two isomers (625, 626) from an unidentified Sarcophyton species [178].

2.5. Special Cembrenes

2.5.3. Cembrane Glycosides

2.5.1. Secocembranes

Five novel cembrane glycosides calyculaglycosides A–E(627– 631) isolated from the Caribbean Gorgonian Octocoral Eunicea sp. [179].

Six unprecedented secocembranoids were isolated from Sinularia mayi (615) [92], Nephthea sp. (616, 617) [89], Sinularia dis-



COOMe O HO

O

HO

HO HO

H

O

H

O

O H

616

O O COOMe

O

617 OH

O

O

O

615

OH

H

O

O

O

H

O

OMe

OH

618

H

O

O 619

OH

HO OH CH2OAc

O

OH

R2

R1

621

620 H O HO

H H

CH2OAc R3

O

H OR1R2

627 R1 = Ac, R2 = OH, R3 = H 628 R1 = H, R2 = H, R3 = OAc 639 R1 = H, R2 = OAc, R3 = H 630 R1 = H, R2 = OH, R3 = H 631 R1 = H, R2 = H, R3 = OH

H

H H

H

H

O O

O

H

O

O

H

633 R1 = COOMe, R2 = OCOMe

O

O

O

638

H

639

H

OAc 643

2.5.4. cembrane-africanane Chemical investigation of the hybrid soft coral Sinularia maxima S. polydactyla resulted in the isolation of six new terpenoids, polymaxenolide(632), 7E-polymaxenolide (633), 7E-5epipolymaxenolide (634), and polymaxenolides A–C (635–637), possessing a cembrane-africanane skeleton [180, 181]. 2.5.5. Other Cembrenes The stem bark of Croton gratissimus (Euphorbiaceae) yielded a new cembranolides (+)-[1R*,2S*,7S*,8S*,12R*]-7,8-epoxy-2,12cyclocembra-3E,10Z-dien-20,10-olide (638) [182]. A novel cytotoxic cembranoid, planaxool (639), was isolated from the marine mollusk Planair sulratru. Planaxool showed cytotoxicity against L1210 (mouse murine leukemia) cell line at a level of 2.4 μg/ml (IC100) [183]. Five new representatives of the cembrane class of marine natural products (640–644) have been isolated from an un-

H

H O

O

COOMe H

O

O O

O 636

OH

OR

O

O

COOMe

637

Cl

HO

O

OOH

O

O 634 R1 = COOMe, R2 = OCOMe 635 R1 = COOMe, R2 = OH

O

H H

H

H

O

H

641 R = Ac 642 R = H

H

O

H

O

H

O

O

O

O

640

H

O

H

O

632 R1 = COOMe, R2 = OCOMe

H

R2 R1

O

O

625 R = H 626 R = Ac

OR

H

H

R2 R1

R2 R1

O

H

H

H

O

622 R1 = O, R2 = CH2OH 623 R1 = O, R2 = CH2OAc 624 R1 = -OAc, R2 = CHO

HO

O

OAc 644

described species of Eunicea, a sea whip collected near the Colombian Southwestern Caribbean Sea. Compounds 640, 641, and 643 were active against Plasmodium falciparum W2 (chloroquineresistant) strain with IC50 values of 23, 15, and 16 μg/mL, respectively [184]. CONCLUSION In 1962, the first cembranoid diterpene was reported from oleoresin of Pinus albicaulis. This was followed by the isolation of hundreds of cembranoids from other pine trees, tobacco leaves or flowers, Croton oblongifolius Roxb (Euphorbiaceae), insects, and marine organisms. Marine invertebrates expecially gorgonians and soft corals account for the largest number of cembrane diterpenoids (Table 1). Gorgonians and soft corals, two groups of coelenterates that belong to the orders Gorgonacea and Alcyonacea respectively, are


Yang et al.

Table 1. Cembrane-type Diterpenoids Isolated from both Terrestrial and Marine Organisms Source

Species

Compounds

Ref.

Alcyoniidae

Alcyonium flaccidum

56

[28]

Alcyonium utinumii

40-42

[20]

Alcyonium coralloides

460, 533-536

[136, 187, 188]

Briareum violacea

295

[93]

Cladiella kashmani

281- 289

[90, 91]

Clavularia violacea

296

[94]

Clavularia koellikeri

57

[27]

Dendronephthya sp.

171-185, 438

[65, 66]

Gersemia rubiformis

459, 537

[135]

Pachyclavularia violacea

297-310

[95-97]

Lobophytum sp.

53-55, 130-132, 222-233, 256-262, 360, 549

[25, 50, 76, 77, 83, 84, 110, 160]

Lobophytum michaelae

243-253

[80]

Lobophytum durum

397-399

[119]

Lobophytum denticulatum

255

[82]

Lobophytum pauciflorum

126-128, 548, 549, 566-584

[20, 48, 166-168]

Lobophytum schoedei

538, 539

[24]

Lobophytum micbaeh

254

[81]

Lobophytum crassum

51, 150, 201, 207-221, 234-242

[20, 23, 28, 55, 73-75, 78, 79]

Litophyton arboretum

151

[56]

Nephthea sp.

616, 617

[89]

Nephthea brassica

125, 379, 380

[47, 115]

2-6, 24-29, 381, 382, 439, 442, 443, 489, 490, 540,

[9, 15-17, 116, 127, 128, 149, 161, 177,

621-626

178]

Sarcophyton trocheliophorum

264, 277

[85, 88]

Sarcophyton crassocaule

30-32, 91-96, 266-270

[17, 86, 87]

Sarcophyton glaucum

7-14, 33-35, 200, 265, 280, 349, 595-606

[8, 10, 18, 72, 109, 171, 172]

Sarcophyton decaryi

123, 124, 133

[45, 46, 50]

Sarcophyton flexuosum

15-17,

[11]

Sarcophyton stolidotum

372-378

[114]

Sarcophyton elegans

18, 19

[12]

Sarcophyton cherbonnieri

277, 279, 541

[89]

Sarcophyton ehrenbergi

20-23, 204, 205, 263, 542, 543

[13, 14]

Sarcophyton tortrrosurn

154, 592-594

[58]

Sarcophyton tortuosum

585-591

[169, 170]

Sarcophyton latum

152, 153, 361-371, 607, 608

[57, 111-113]

Sarcophyton mililatensis

129, 544-546

[49],

Sinularia sp

49, 50, 142-149, 196-199, 513-515

[3, 22, 52-54, 71]

Sinularia abrupt

472

[141]

Sinularia asterolobata

480, 481

[145]

Sarcophyton sp.



Table 1. contd…

Source

Species

Compounds

Ref.

Sinularia dissecta

482, 618

[146, 176]

Sinularia maxima Sinularia polydactyla

516-518, 635-637

[156, 180, 181]

Sinularia maxima

478, 479

[144]

Sinularia scabra

507-512

[153-155]

Sarcophyton crassocaule

440, 441

[17, 127, 128]

Sinularia manaarensis

383-391

[117]

Sinularia erecta

498, 500, 609, 610

[151, 152]

Sinularia leptoclados

491-493

[150]

Sinularia lochmodes

496-498, 461

[174, 189]

Sinularia querciformis

432-435

[126]

Sinularia polydactyla

290, 291

[88]

Sinularia grandilobata

112-116

[41]

Sinularia flexibilis

121, 186-195, 392-396, 406-429, 611, 612

[43, 67-70, 118, 121-124, 173]

Sinularia gardineri

614

[175]

Sinularia granosa

436, 437

[126]

Sinularia gibberosa

43-48, 117-120, 122, 217-221, 558

[21, 28, 42, 44, 74, 75]

Sinularia parva

430, 431, 494, 495

[125, 150]

Sinularia mayi

292-294, 615

[92]

Sinularia gyrosaisolated

500-505

[53]

Sinularia ovispiculata

56

[26]

unidentified soft coral

134-141

[51]

Euniceu sp.

52, 58-63, 627-631, 640-644

[24, 29, 179, 184]

Eunicea pinta

333-340

[104]

Eunicea knighti

163-165

[63]

Eunicea mammosa

161, 162, 203, 321-332

[62, 100-103]

Eunicea succinea

158-160, 202, 311-320, 620

[61, 98, 99]

Eunicea tourniforti

36-39

[19]

Leptogorgia sp.

482-487, 519

[147, 148]

Leptogorgia alba

473, 474

[138]

Leptogorgia laxa

155, 156

[59]

Leptogorgia setacea

475, 476

[142]

Lophogorgia peruana

157, 462-471, 526

[60, 137-140, 143]

Pseudopterogorgia sp.

532

[159]

Pseudopterogorgia bipinnata

531, 619

[158]

Pseudopterogorgia kallos

527-530

[134]

Plexaura flexuvsa

557

[163]

Sea pen

Gyrophyllum sibogae

66, 67

[31]

Sea feather

Pseudopterogorgia acerosa

477

[143]

Pseudopterogorgia bipinnata

446-458, 521-525

[131-134]

Gorgonacea


Yang et al. Table 1. contd…

Source

Species

Compounds

Ref.

Sponge

Lissodendoryx flabellata

64, 65

[30]

Marine mollusk

Planair sulratru

639

[183]

Tunicate

Styela plicata

341

[105]

Liverwort

Tetralophuzia setifomis

106

[37]

Chandonanthus hirtellus

107-111

[38-40]

Echinodorus macrophyllus

444, 445

[129]

Anisomeles indica

342-348

[106-108]

Cleome spinosa

166-170

[64]

Echinodorus grandiflorus

68

[32]

Croton gratissimus

638

[182]

Croton laevigatus

400-405

[120]

Croton oblongifolius

103-105, 520, 554-556

[35, 36, 157]

Greek tobacco

69-102

[33, 34]

Pinus albicaulis

1

[1]

Crematogaster brevispinosa rochai

559-560

Crematogaster brevispinosa ampla

561-565

[165]

350-359

[109]

550-553

[162]_ENREF_162

Plant

Brazilian ant

Microorganisms

Absidia glauca ATCC 22752, Rhizopus arrhizus ATCC 11145, and Rhizopus stolonifer ATCC 24795 Rhizopus stolonifer ATCC 6227a and Absidia spinosa ATCC 6648

very abundant in tropical reef environments. The abundance and ease of collection of these invertebrates has facilitated an extensive investigation of their secondary metabolism. Diterpenoids, having a wide variety of both well-known and rare carbon skeletons, are the most common soft coral and gorgonian metabolites [135]. In general, marine natural product chemists believe that the cembrane skeleton originates from the cyclization of geranylgeranyl pyrophosphate, a hypothesis supported in part by the observation that in almost all derivatives the geometry of the double bonds is E, as in geranylgeraniol [62]. Cembrane diterpenoids are a large family of natural products having many structural variations, including further cyclizations and a multitude of functional groups, e.g., lactone, epoxide, furan, ester, ether, hydroxyl, aldehyde, and carboxylic moieties [185]. Cembranoids exhibit a wide range of biological activities including anti-inflammatory, Ca-antagonistic, antiparasitic, and, more frequently, cytotoxic properties. Some cembranoid diterpenes from soft corals are known to be toxic and have been cast in the role of deterrents to predation by reef fishes [186]. CONFLICT OF INTEREST

2011CB915503), Knowledge Innovation Program of Chinese Academy of Science (KSCX2-YW-G-073 and KSCX2-EW-G12B), and National Natural Science Foundation of China (Nos. 30973679, 21172230, and 21002110), Guangdong Province-CAS Joint Research Program (2011B090300023 National High Technology Research and Development Program of China (863 Program, 2012AA092104), Guangdong Province Marine and Fishery Special Project for Science and Technology Popularization (A201101F03). REFERENCES [1] [2] [3] [4] [5] [6] [7]

None declared. [8]

ACKNOWLEDGMENT This study was supported by the National Basic Research Program of China (973 Program, Nos. 2010CB833800 and

[9]

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Accepted: March 18, 2012