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Review Nat. Prod. Bioprospect. 2013, 3, 161206 DOI 10.1007/s13659-013-0042-7

Peroxy natural products

Dong-Ze LIU,a,* and Ji-Kai LIUb,*

aTianjin Institute of Industrial Biotechnology, Chinese Academy of Science, Tianjin 300308, China

bState Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China

Received 16 June 2013; Accepted 5 August 2013

The Author(s) 2013. This article is published with open access at Springerlink.com

This review covers the structures and biological activities of peroxy natural products from a wide variety of terrestrial fungi, higher plants, and marine organisms. Syntheses that confirm or revise structures or stereochemistries have also been included, and 406 references are cited.

1 Introduction 2 Marine Metabolites 2.1 1,2-Dioxane Carboxylates 2.2 1,2-Dioxolane Carboxylates 2.3 Fatty Acid Derived Peroxy Ketals 2.4 Diterpenes 2.5 Other Marine Metabolites 3 Terrestrial Sources 3.1 Monoterpenes 3.2 Sesquiterpenes 3.2.1 Guaianes 3.2.2 Eudesmanes 3.2.3 Bisabolanes and Germacranes 3.2.4 Sesquiterpene Dimers 3.2.5 Other Sesquiterpenes 3.3 Diterpenes 3.4 Triterpenes 3.5 Others 4 Steroidal Peroxides 5 Fatty Acid Metabolites 6 Conclusions 7 Acknowledgements

1 Introduction

This review, which is of the literature from 1998 to 2013, follows the pattern of its predecessors and is devoted to the new occurrence of peroxy compounds1,2 and described 639

naturally occurring peroxides from 406 articles. In the past more than 10 years, peroxy compounds have been isolated from a wide variety of terrestrial fungi, higher plants, and marine organisms, especially sponge species, many of which exhibited diverse biological properties such as anti-inflammatory, antimalarial, antimicrobial, cytotoxic, antitumor activities, and so on.

As a result of the potential for new drug discovery, peroxy compounds have attracted the attention of biologists and chemists throughout the world. So far, some reviews have dealt with the class of natural peroxides: Peroxy natural products,1,2 Natural peroxy anticancer agents,3 Bioactive peroxides as potential therapeutic agents,4 and Naturally occurring peroxides with biological activities.5 Other general reviews are: Monoterpenoids, Sesquiterpenoids, Diterpenoids, Sesterterpenoids, Triterpenoids, and Marine natural products all published in the journal Natural Product Reports covering from 1998 to 2011. References to other reviews are appropriately placed in the following sections.

In this review, we showed the structures of new peroxides, and previously-reported ones where there has been a structural revision or a newly-established stereochemistry. Previously-reported peroxides for which first syntheses or new bioactivities are described are referenced, but separate structures are generally not shown. Relevant data published in MEDLINE, Google Scholar, and SciFinder since 1998 have been gathered to formulate the following review.

2 Marine Metabolites 2.1 1,2-Dioxane Carboxylates: Marine sponges, notably those from the genera Plakortis and Plakinastrella, continued to provide a source for six-membered ring cyclic peroxides that incorporate a lactone ring. Plakortolides KS (19)7 were isolated from the Australian sponge Plakinastrella clathrata. Detailed configurational investigation also revealed that the structure for previously reported plakortolide E6 should be

*To whom correspondence should be addressed. E-mail: [email protected] (D.Z. Liu); [email protected] (J.K. Liu)

162 D. Z. LIU and J. K. LIU Nat. Prod. Bioprospect. 2013, 3, 161206

revised to a non-peroxidic metabolite and the commonly assumed biosynthesis of the cyclic peroxide via Diels-Alder addition of singlet oxygen is incorrect.7 The first total synthesis of seco-plakortolide E also supported the structural revision of plakortolide E.8

Continuing investigation of the same sponge, P. clathrata, afforded an additional set of 16 plakortolide metabolites 1025.9 A Jamaican collection of Plakinastrella onkodes yielded two cyclic peroxides, plakortolide F 26 and plakortolide G 27. The absolute stereochemistry of plakortolide G was proposed from a combination of optical rotation and molecular modelling data. Plakortolide G exhibited potent inhibitory activity against the AIDS opportunistic parasitic infection Toxoplasma gondii.10 The trivial name plakortolide F was also given to a different peroxide 28, which was obtained from an unidentified species of Plakinastrella collected in the Seychelles.11 Two 1,2-dioxane peroxylactones, plakortolides H and I 29 and 30, have been isolated from a Madagascar specimen of Plakortis aff simplex, both of which were cytotoxic against a range of human tumour cell lines.12

Several years later, the relative and absolute configurations of plakortolide I were revised on the basis of synthetic studies and reassignment of the NMR data,8,13 thereby establishing that the metabolite isolated was ent-plakortolide I 31. Whilst the trivial name plakortolide I has been proposed for an unnamed plakortolide metabolite 32 from the Philippine Sponge Plakinastrella sp., whose absolute stereochemistry was determined by application of Moshers method to a derivative.14 The authors also detail the unreliability of specific rotation measurements in the determination of absolute

Dong-Ze Liu was born in Shandong province, China, in 1976. He received his B.Sc. (2001) and M.Sc. (2004) degrees from Qingdao Agricultural University and Shanghai Jiao Tong University, respectively. In 2007, he completed his Ph.D. degree in Phytochemistry from Kunming Institute of Botany, Chinese Academy of Sciences (CAS). From 2008 to 2010 he worked as a postdoctoral fellow at the South China Sea Institute of Oceanology, CAS, in Marine Natural Products. In 2011, he joined the Tianjin Institute of Industrial Biotechnology, CAS. His current research interests are focused on the isolation, structure determination, and structural modification of natural products.

Ji-Kai Liu is a professor of Kunming Institute of Botany since 1997. He acquired his Ph.D. degree at Lanzhou University in 1988. From 1993 to 1994 he worked as a research fellow of Alexander von Humboldt at the University of the Saarland in Germany. Then he worked as a research scientist at the Pharma Research Center of Bayer AG in Germany. His field of interest concerns natural bioactive compounds from higher fungi. He has published over 200 peer-reviewed articles in international journals including Chem. Rev., Angew. Chem. Int. Ed., Nat. Prod. Rep., and Org. Lett. etc. He is the author of the book Mycochemistry and also one of the inventers for ten patents. He is the main founder of BioBioPha Co. Ltd. and the open access journal Nat. Prod. & Bioprospect..

configuration within the plakortolide class of metabolites in the same paper.13 The first total synthesis of 32 has been achieved using a [2 + 4] photocycloaddition of a singlet oxygen to a diene and iodolactonization as key steps.15 A

different species of Plakortis, P. halichondrioides, yielded additional peroxide-lactone named plakortolide J 33, the absolute stereostructure of which was determined by degradation reactions followed by application of Kishis method for the assignment of absolute configuration of alcohols.16 Synthetic efforts in construction the 1,2-dioxane ring of plakortolides have been described.17,18

A further cyclic peroxide 34, with a terminal phenyl group but lacking the lactone, was isolated from P. Clathrata.9 The ester represents further structural variation within the growing family of cyclic peroxy sponge metabolites.

The stolonoxides and stolonic acids are a family of natural aliphatic endoperoxides obtained from the samples of marine ascidians belonging to the genus Stolonica. Stolonoxide A 35, the first member of the series, was isolated as its methyl ester from the marine tunicate Stolonica socialis.19 A further investigation conducted on the same species yielded stolonoxides BD 3638, with strong cytotoxic activity against a panel of five tumor cell lines.20 The methyl ester derivatives of stolonoxides A and C have been identified as potent inhibitors of the mitochondrial respiratory.21 In addition, two new members of this structural class possessing a longer aliphatic chain, stolonic acids A and B 39 and 40, were isolated from an Indian Ocean Ascidian Stolonica species. Both compounds exhibited antiproliferative activity against selected human melanoma and ovarian tumor cell lines, with IC50

D. Z. LIU and J. K. LIU Nat. Prod. Bioprospect. 2013, 3, 161206 163

O O

11 12

13 14

O O

HOO

O O

HOO

O O

values of approximately 0.050.1 g/mL.22 Two new members of the stolonoxide family, stolonoxides E and F 41 and 42, were obtained from samples of the marine ascidian S. socialis. Both compounds displayed low micromolar cytotoxicity against a panel of human tumor cell lines.23

The marine sponges of the genus Plakortis are also prolific producers of cyclic polyketide peroxides and structurally related compounds that exhibit a broad spectrum of biological properties. The bioactive cyclic peroxide plakortide Q 43 has been isolated from marine sponge P. zyggompha, together with six cyclic peroxide analogues 4449 in their methyl ester forms. The relative stereochemistry of the 1,2-dioxane ring was established after interpretation of the coupling constant

values and the NOESY data.24 Interestingly, a sample of the crude extract of the sponge left standing in methanol for one year yielded the methyl esters directly; this finding may go some way to accounting for the prevalence of methyl esters as reported metabolites of Plakortis species. The name plakortide Q was also proposed for a different peroxide 50, which was isolated from the Caribbean sponge P. Simplex.25 In the same paper, the complete spectroscopic and stereostructural assignments of known 3-epi-plakortin has been reported. Three further cyclic peroxides, dihydroplakortin 51, plakortides I 52 and J 53, were obtained from the same source, P. Simplex, by the same group, as well as providing the

164 D. Z. LIU and J. K. LIU Nat. Prod. Bioprospect. 2013, 3, 161206

O O

O O H

OMe

H H

HOOC

O O O

O O

HOOC

O O O

O O

HOOC

O O O

O O

HOOC

O O O

O O

absolute stereochemistries of known plakortin and plakortide H.26,27 The first synthesis of dihydroplakortin 51 has been achieved, featuring a one-pot three-step hydroperoxysilylation/ cyclization reaction for the construction of the endoperoxide ring system.28 An insight into the mechanism of the

antimalarial action of plakortin and dihydroplakortin, simple 1,2-dioxanes isolated from the sponge P. Simplex, has been reported.29

The Australian marine sponge Plakortis sp. yielded two plakortide Q derivatives 54 and 55. Both were potent (nM) inhibitors of Trypanosoma brucei.30 Six cyclic peroxides 5661 were isolated from an Okinawan Plakortis sp. and one of these, the peroxide 61, was shown to be cytotoxic.31,32 The

antileishmanial peroxides 62 and 63 were reported from P. aff. angulospiculatus collected from Palau together with peroxide 64, which were inactive.33 Peroxides 56 and 64 have the same gross structure but the difference in optical rotations suggests that they have different stereochemistries. Fractionation of the sponge Plakortis sp. collected around the Amirantes Islands provided peroxides 63, 65 and 66.34 The relative and absolute stereochemistry of the cyclic peroxide 67, originally isolated from P. angulospiculatus,35 has been proposed by comparison to the optical rotation and NMR spectral data of synthesized diastereomers.36

Two independent collections of an undescribed sponge Plakortis sp. from Discovery Bay, Jamaica, yielded four cyclic peroxides plakortides IL 6871, and two related compounds 72 and 73, respectively.37,38 Plakortide I represents the first report of a polyketide-derived cyclic peroxide with an ,-unsaturated ketone moiety in the side chain and exhibits significant antimalarial activity against the W2 Clone of Plasmodium falciparum with an IC50 value of 570 ng/mL, whilst both 72 and 73 exhibited significant antimicrobial

D. Z. LIU and J. K. LIU Nat. Prod. Bioprospect. 2013, 3, 161206 165

O O COOH O O COOH

O O COOH O O COOH O O COOH

O O COOH

43 44 45

46 47 48

O O COOCH3

O O COOH

52 53

O O OH

activity against pathogenic bacteria and fungi with IC50 values of 0.95.0 g/mL and 0.78.0 g/mL, respectively. The plakortides named I and J have been renamed plakortides M and N as the trivial names had been used previously for related metabolites isolated from P. Simplex.27 Unfortunately, the trivial names plakortides M and N were also proposed for another two compounds 74 and 75 from the Caribbean marine sponge P. Halichondrioides, which exhibited potent cytotoxicity to an array of human tumour cell lines.39 A

Japanese specimen of Monotria japonica yielded the monotriajaponides BD 7678, which can lyse starfish oocytes without disruption of nuclear structure.40 Interestingly, the absolute stereochemistries of 7678, as determined by reduction and a modified Mosher method, were opposite to those determined for the plakortides 74 and 75. Investigation of the bioactive crude extract from the sponge P. angulospiculatus from Brazil led to the isolation of the cyclic

peroxide plakortenone 79.41 A sample of the Norwegian sponge P. simplex was found to contain two cyclic peroxides 80 and 81, of which 81 exhibited moderate in vitro activity against several solid human tumor cell lines with IC50 values in the range 715 g/mL.42 An Indonesian sponge P. nigra was the source of two isomeric cytotoxic trans epoxides, plakorstatins 1 (82) and 2 (83).43

Three cytotoxic cyclic peroxides, ethyl plakortide Z 84, ethyl didehydroplakortide Z 85, which demonstrated selective activity in vitro against solid tumors but lacked activity in vivo, and methyl didehydroplakortide Z 86 were isolated from P. lita collected from Papua New Guinea.44 An Okinawan specimen of the same species provided two futher cytotoxic endoperoxides, haterumadioxins A and B 87 and 88 with moderate cytotoxicity.45 Plakortide F, originally isolated from P. Halichondrioides,46 interfered with Ca2+ homeostasis to mediate the antifungal activity.47

166 D. Z. LIU and J. K. LIU Nat. Prod. Bioprospect. 2013, 3, 161206

HOOC

O O

O O COOR

62 R = H63 R = CH365 R = C2H5

COOH

O O COOH

O O COOH 64

O O CO2H O O CO2CH3

O O CO2CH3

68 69 70

O O CO2CH3

O COOH

O O COOH

76 R1 = CH3, R2 = H77 R1 = CH3 R2 = CH378 R1 = Et, R2 = CH3

74 75

R O O COOH

O O

COOMe

O O

COOCH3

O O

COOCH3

O O COOR

85 R = CH2CH386 R = CH3

O O

O O COOEt

82 9S, 10S or 9R, 10R 83 9R, 10R or 9S, 10S

OMe

O O COOH

A Jamaican collection of P. Halichondrioides afforded a peroxide acid 89 with moderate antifungal activity.48 A two-sponge complex comprising P. halichondrioides and Xestospongia deweerdtae (Bahamas) yielded one -phenyl

polyketide peroxide named plakinic acid K 90. The absolute configurations of the isolated chiral centres were determined using liposomal circular dichroism and comparison with synthetic standards.49

D. Z. LIU and J. K. LIU Nat. Prod. Bioprospect. 2013, 3, 161206 167

O O COOH 90

O O

OMe

91 R = H92 R = Me

O O COOH

COOH 93

O O OCH3

OOH

O O

COOH

OCH3

100

O O OCH3

Fractionation of the P. onkodes extract led to the isolation of the cytotoxic cyclic peroxide methyl capucinoate A 91 and the previously reported, but incompletely characterized, aromatic peroxide 92.50 Since P. onkodes was extracted in MeOH, the methyl esters 91 and 92 may be isolation artifacts.51 Four aromatic peroxides 9396 were isolated from Plakortis sp. (Orote Peninsula, Guam), of which compounds 93 and 96 showed weak activity against Staphylococcus aureus, with MIC values of 128 and 64 g/mL, respectively.52 Plakinic acid I 97 was obtained from P. Halichondrioides, and the absolute configuration determined from CD curves by degradation and liposomal ordering of naphthamide derivatives.53 Methylation of the crude extract of a Sigmosceptrella sp. from Southern Australia with diazomethane produced a mixture of products, from which nuapapuin methyl ester 98 and sigmosceptrellin D and E methyl esters 99 and 100 were isolated and identified. Their relative stereochemistries were assigned by established empirical rules and absolute stereochemistries by the advanced Mosher procedure. A plausible biosynthetic pathway has also been proposed that rationalizes key transformations in the

biosynthesis of known norterpene cyclic peroxides and related norterpene ketones, dienes and sigmosceptrins.54

Sponges of the genus Diacarnus are known to produce terpene peroxides and related metabolites. A norsesterterpene acid, named muqubilone 101, was isolated from the Red Sea sponge D. Erythraeanus. It showed in vitro antiviral activity against herpes simplex type 1 (HSV-1).55 The same compound 101, named aikupikoxide A, was also isolated almost at the same time by the Scheuer group from the lipophilic extract of the Red Sea sponge D. Erythraenus along with three other cytotoxic cyclic norterpene peroxides, aikupikoxides BD 102104.56 The same source, D. Erythraenus, afforded another three cytotoxic norsesterterpenoid peroxides, tasnemoxides A C 105107.57

Bioassay-guided isolation of D. Levii collected from Papua New Guinea led to the isolation of four norsesterterpene peroxides, diacarnoxides AD 108111, with diacarnoxides A and B displaying cytotoxic properties and increased activity under hypoxic conditions.58 Chemical investigation of the sponge D. megaspinorhabdosa provided a series of norterpene

168 D. Z. LIU and J. K. LIU Nat. Prod. Bioprospect. 2013, 3, 161206

COOCH3

108

109

110

111

COOCH3

COOH

COOMe

O O

derivatives, diacarperoxides AG 112118, of which, diacarperoxide D was cytotoxic.59 Re-investigation of D. megaspinorhabdosa afforded one further norsesterpene cyclic peroxide, diacarperoxide S 119, which exhibited strong cytotoxic and antimicrobial activities.60

Examination of D. bismarckensis (Sanaroa, Papua New Guinea) led to the isolation of two peroxiterpenes ent-()-muqubilone 120 and (+)-muqubilone B 121, active against Trypanosoma brucei (African sleeping sickness).61 Specimens of D. cf. spinopoculum from the Solomon Islands and Papua New Guinea yielded a series of norterpenes including four norsesterterpene peroxides, ent-muqubilin A 122, entepimuqubilin A 123, muqubilin B 124, and epimuqubilin B

125, and two norditerpene peroxides, nuapapuin B 126 and epinuapapuin B 127, all of which were evaluated for cytotoxicity using a soft agar assay system and the NCI's 60 cell-line screening. Overall, the norsesterterpene peroxides were less selective as cytotoxins than norditerpene peroxide analogs.62 The norsesterterpenoid peroxide, epi-muqubilin A 122, inhibited nitric oxide (NO) production in lipopolysaccha-ride (LPS)-activated murine macrophage RAW 264.7 cells,63

and suppressed cyclooxygenase-2 via IKK/IB/NF-B pathways.64,65 Esterification of carboxylic acid mixtures from the New Caledonian sponge D. levii resulted in the isolation of the benzyl esters of ent-muqubilin A 122 and deoxydiacarnoate B 128 and the methyl ester of diacarnoate B 129, all of which were screened for antimalarial activity.66

Examination of the Taiwanese sponge Negombata cortica revealed a series of related peroxide terpenoids negombatoperoxides AD 130133.67 Three norsesterterpene cyclic peroxides named trunculins GI 134136 were isolated as their methyl esters from an Australian Latrunculia sp., whose absolute stereochemistry about the cyclic peroxide terminus was established by application of the Horeau and Mosher procedures.68

112

113

O O O

COOCH3

O O

COOMe

114

D. Z. LIU and J. K. LIU Nat. Prod. Bioprospect. 2013, 3, 161206 169

Investigation of a southern Australian sponge of the genus Mycale resulted in the isolation of one norsesterterpene mycaperoxide G methyl ester 137, which was obtained after treatment of the crude extract with diazomethane.69 The absolute stereochemistry previously assigned to mycaperoxide F methyl ester by application of the Horeau procedure has been revised by application of the Mosher procedure in the same paper. Bioassay-guided isolation of a Thai marine sponge Mycale sp. afforded a cytotoxic norsesterterpene peroxide mycaperoxide H 138. Its relative and absolute stereochemistries were established by standard methodology, including chemical interconversions.70 Synthetic efforts towards mycaperoxide B, originally isolated from a Mycale sp. from Thailand71, have been reported using a biomimetic approach.72,73

2.2 1,2-Dioxolane Carboxylates: Although the majority of cyclic peroxides contain 1,2-dioxanes, while a growing number possess the more rare 1,2-dioxolane ring system. Bioassay-guided purification of a Plakinastrella species collected in the Seychelles led to the isolation of two moderately antifungal plakinic acid F 139 and epiplakinic acid F 140, containing a conjugated triene on the side chain.11

Examination of a Puerto Rican collection of Plakortis halichondrioides resulted in the isolation of two polyketide endoperoxides, epiplakinic acid F methyl ester 141 and epiplakinidioic acid 142 as well as providing the absolute configuration of known epiplakinic acid F.16 The antifungal plakortisinic acid 143 was isolated from a species of Jamaican Plakortis. The absolute configuration was determined by comparison of calculated and experimental optical rotations.74

A Madagascar specimen of P. aff. simplex yielded one cyclic peroxide, andavadoic acid 144, which was cytotoxic against a range of human tumour cell lines.13 Two peroxide acids 145 and 146, isolated from P. onkodes collected in Florida, possessed moderate antifungal activity.48 The Palauan Sponge P. nigra provided two cyclic peroxides designated epiplakinic acids G and H 147 and 148. Isolated metabolites were found to inhibit the growth of HCT-116 cells.75 The first asymmetric synthesis of 1,2-dioxolane-3-acetic acids has been reported, and a further optimized strategy was applied to the synthesis of four stereoisomers of plakinic acid A,76 allowing a complete configurational assignment of plakinic acid A.77

One -phenyl polyketide peroxide, plakinic acid L 149, was isolated from a two-sponge association of P. halichondroides and X. deweerdtae.49 Synthesis of four possible diastereomers of plakortide E78 established the absolute configuration of plakortide E as shown.79 Plakinic acid J 150 was obtained from P. Halichondrioides, and the absolute configuration determined from CD curves by degradation and liposomal ordering of naphthamide derivatives.53 The Philippine sponge Plakinastrella sp. yielded two further cyclic peroxides 151 and 152.12

2.3 Fatty Acid Derived Peroxy Ketals: Two acetylenic cycloperoxides named peroxyacarnoic acids C and D (153 and 154) have been isolated as their methyl esters from the Indian sponge Acarnus bicladotylota,80 and the structurally related methyl peroxyacarnoates A and B 155 and 156, have been found from the Red Sea marine sponge A. cf. bergquistae.81

The absolute stereochemistries of 153155 were determined

by the application of Moshers method. The syntheses of methyl peroxyacarnoates A and D have been accomplished on the basis of chemoselective ozonolysis within a polyunsaturated framework and Pd-mediated cross-couplings of a functionalized 1,2-dioxane.82 The endoperoxyketal polyketides manadoperoxides AD 157160 with moderate antimalarial activity were isolated from the Indonesian sponge Plakortis cfr. simplex and their stereostructures were established by means of spectroscopic data and semisynthetic transformations.83

Chemical investigation of the marine sponge P. cfr. lita afforded a library of endoperoxyketal polyketides named manadoperoxides EK 161167 and peroxyplakoric ester C 168, of which manadoperoxides F 162, H 164, I 165, and K 167 exhibited remarkable antitrypanosomal activity without cytotoxicity. The report have also demonstrated unambiguously that the endoperoxy group does not confer per se activity against Trypanosoma.84 The structures and absolute stereo-chemistries of known natural products chondrillin85 and its C-3 epimer, plakorin86,87 have been confirmed by syntheses of (+)-and ()-chondrillin and (+)-and ()-plakorin.88

2.4 Diterpenes: One eunicellin-type diterpenoid astrogorgin G 169 has been repored from a Chinese gorgonian Astrogorgia sp.,89 and the structurally related oxylitophynol 170 and klysimplexin D 171 have been obtained from the soft coral Cladiella krempfi and Klyxum simplex, respectively.90,91 From

a biogenetical standpoint, oxylitophynol might derive from the formal photo-oxygenation of the corresponding 6,7 olefin. Another two substances of this type, briarellin K hydroperoxide 172 and briarellin D hydroperoxide 173, have been isolated

COOH O O

COOH

O O

115 116

O O

COOH

O O

117 118

O O

H3COOC

119

170 D. Z. LIU and J. K. LIU Nat. Prod. Bioprospect. 2013, 3, 161206

O O

120

121

COOH COOMe

COOMe

COOH

H H

124 125

122 123

COOH

COOMe

COOH

H H

O O

126 127 H

R 128 R = H2 129 R = O

130 131

COOH

O O

132 133

O O OH

134

135

O O CO2CH3

O O

COOH

O O O OH

136

137

138

from a Puerto Rican collection of Briareum polyanthes,92 and this study has also led to a revision of the structure of previously reported briarellin A93 to 174. The structure originally assigned to 11-acetoxy-4-deacetoxyasbestinin F94

has been revised to 175.95 Spectroscopic discrepancies observed for the enantioselectively synthesised structure originally proposed for alcyonin96 have led to the proposal that the correct structure of the natural product is the allylic

peroxide 176.97

Two dolabellane diterpenoids 177 and 178 with anti-protozoan activity have been obtained from a Colombian gorgonian coral of the genus Eunicea.98 New diterpenoid, 179 having a dolabellane skeleton, was isolated from the Okinawan soft coral of the genus Clavularia. This diterpenoid showed cytotoxic activity against several tumor cell lines.99 Other compounds of this type included calyculatine 180 from E. calyculata, and (1R*,7R*)-7-hydroperoxydolabella-

D. Z. LIU and J. K. LIU Nat. Prod. Bioprospect. 2013, 3, 161206 171

HOOC

O O

HOOC

O O

HOOC

O O

139

140

146

COOH

O O

COOCH3

O O

COOH

O O

147

141

142

O O

COOH

O O

148

COOH

149

O O OH

COOH

143

O O

150

COOH

144

O O

COOR

O O

HOOC

O O

151 R = CH3152 R = H

145

4(16),8(17),11(12)-triene-3,13-dione 181 from C. inflata.100,101

Compound 181 showed strong cytotoxic activity against several cancer cell lines.

One unusual pyran-ring containing cladiellane diterpene designated tritoniopsin B 182 was isolated from both the nudibranch Tritoniopsis elegans and its soft coral prey Cladiella kremp.102 Bioassay-guided fractionation of extracts from a Fijian red alga in the genus Callophycus provided one new compound of the diterpene-benzoate class, bromophycoic acid C 183, which exhibited modest activities against methicillin-resistant Staphylococcus aureus and the human

malaria parasite Plasmodium falciparum.103 Two xeniaphyllane peroxides gibberosins B and C 184 and 185 were isolated from a Taiwanese soft coral Sinularia gibberosa.104

Six further members of this family containing the unusual cyclic peroxyhemiketal moiety, sinugibberosides AF 186191, have been reported from the same species, S. Gibberosa.105 It is conceivable that the biogenesis of these compounds derives from intramolecular cyclisation of a hydroperoxide structurally related to gibberosin B. The Formosan soft coral Xenia umbellata collected in Taiwan,

172 D. Z. LIU and J. K. LIU Nat. Prod. Bioprospect. 2013, 3, 161206

China, contained a cytotoxic xenicane diterpenoid xeniolide G 192.106 One meroditerpenoid, stypohydroperoxide 193, was obtained from Stypopodium flabelliforme (Long Island, Papua New Guinea).107

One cytotoxic bromoditerpene 194 and the related antibacterial bromoditerpene 2S-hydroperoxy-12R-hydroxyisobromosphaerol 195 were successively isolated from the

OCH3

O O COOCH3

161

162

163

164

165

166

167

168

OCH3

O O COOCH3

OCH3

O H

O O COOCH3

OCH3

CHO

O O COOCH3

O OH

OCH3

O O COOCH3

O OH

OCH3

O O COOCH3

H3CO

OCH3

O O COOCH3

OCH3

same collection of Sphaerococcus coronopifolius by the same group. The structure of the previously reported 12S-hydroxybromosphaerodiol108 and 2S,12S-dihydroxyisobromosphaerol109 were revised to 196 and 197, respectively. The absolute stereochemistry of 194 was established by X-ray crystallographic analyses.110,111

O O COOCH3

D. Z. LIU and J. K. LIU Nat. Prod. Bioprospect. 2013, 3, 161206 173

OOH

HOO

OCOC3H7

HOOC

182

185

191

OOH

183

OOH

186 R = OAc 187 R = OH 188 R = H

192

193

HOO

O O

HOO

O OMe

189 R = OAc 190 R = H

184

OH OH

Br H

OH OH

Br H

HOO H

HOO

194 195 196 197

OAc

OOH

HOO

O O

HOO

198

199 200

OOH

202

OOH

201

203

Chemical investigation on the gorgonian coral Briareum sp. yielded a hydroperoxybriarane diterpene named briarenolide B 198 with a rare 9-ketobriarane moiety.112 The same group

afforded a further related briarenolide D 199 from a cultured specimen of the same organism.113 Four diterpene compounds

174 D. Z. LIU and J. K. LIU Nat. Prod. Bioprospect. 2013, 3, 161206

HOO O

HOO

COOMe

OOH

204

205

206

O O

207 11R 208 11S

COOH OH

209 R1 = H, R2 = OOH 210 R1 = OOH, R2 = H

211 R1 = OOH, R2 = CH3 212 R1 = CH3, R2 = OOH

HOO

O O

213 214 215

216

217

HOO

AcO

218

HOO

O O

200203 representing a new skeletal type, the dactylomelanes, have been found from specimens of Laurencia sp.114

A large number of highly functionalized cembranoid diterpenes and related metabolites have been isolated and identified from marine soft corals, especially from the genera Lobophytum, Sarcophyton, and Sinularia. A hydroperoxy-substituted cembranoid diterpene, 2-hydroperoxysarcophine 204, was isolated from South-China-Sea soft coral L. crassum. It remains unclear whether 204 is a true natural product or an artifact.115 One further cembranoid, crassumolide E 205, was found from the same species.116 A Kenting (Taiwan) collection of Sinularia flexibilis contained the cembranoid hydroperoxide flexilarin C 206.117 The same group provided two further structurally-related -lactones sinuladiterpenes A 207 and B 208 from the same species.118 The Taiwanese soft coral S. manaarensis contained four cembrane-type diterpenoids, manaarenolides A 209 and B 210 and manaarenolides E 211 and F 212, which were discovered for the first time as the hydroperoxycembranolides possessing a -lactone ring.119

Four -cembranolide-type diterpenes, uprolides HJ 213214

and L 215 and M 216, were reported from Eunicea pinta collected from San Andrs Island, Colombia. This study also led to the revision of the structures for nine previously reported uprolide B, uprolide B acetate, 8-epi-uprolide B, uprolide C acetate, 8-epi-uprolide B acetate,120 12,13-bis-epiuprolide B, 12,13-bisepiuprolide B acetate, uproeunicin, and uprolide C121

to 217225, respectively.122 Another compound of the type

D. Z. LIU and J. K. LIU Nat. Prod. Bioprospect. 2013, 3, 161206 175

226 was isolated from the soft coral Sarcophyton crassocaule collected from the Xisha Islands in South China Sea. It exhibited strong cytotoxicity against the P388 cell line with an IC50 value of 0.1 g/mL.123 The same source, S. crassocaule, provided three further cembranoid sarcocrassocolides F 227, G 228, and J 229, all of which inhibited LPS-induced up-regulation of the pro-inammatory protein iNOS.124 A chemical investigation of another species of the same genus, S. Glaucum, has led to the isolation of two peroxide diterpenes 230 and 231, the absolute configuration of which were confirmed by X-ray diffraction and circular dichroism (CD) analyses. Compound 231 was found to be promising inhibitors of cytochrome P450

1A activity as well as inducers of GST and QR activity in vitro assays.125

A decalin-type bicyclic diterpenoid, lemnaloside C 232, has been obtained from an extract of the marine soft coral Lemnalia sp.126 The Japanese marine sponge Epipolasis sp. afforded a novel diterpene peroxypolasol 233.127 The Formosan soft coral Nephthea pacifica contained four prenylbicyclogermacrane diterpenoids, pacificins C 234, E 235, G 236, and H 237, of which 234 and 237 exhibited cytotoxicity against P388 cells with ED50 of 1.44 and 2.01 g/mL, respectively.128

2.5 Other Marine Metabolites: The Hainan Sponge Dysidea septosa contained a new sesquiterpene lingshui-peroxide 238.129 Three isothiocyanate sesquiterpenes axinisothiocyanates H 239 and I 240, axinisothiocyanate N 241, and aristolane derivative axinysone C 242 have been obtained from a sponge of the genus Axinyssa collected in the

Gulf of California by the same authors. Axinisothiocyanate N were mildly cytotoxic.130,131

Hydroperoxides have rarely been found in algae: two examples, dictyohydroperoxide 243 and hydroperoxyacetoxycrenulide 244, were isolated from Dictyota dichotoma (Troitsa Bay, Sea of Japan, Russia).132 A aromandendrane sesquiterpenoid 245 was isolated from the Formosan soft coral ClaVularia inflata.133 Chemical investigations of the soft coral Nephthea erecta have afforded three new sesquiterpenoids 246248, of which, 247 and 248 exhibited significant cytotoxicty against P388 and HT-29.134 The Formosan soft coral Nephthea erecta provided the sesquiterpenoid 249.135 Five sesquiterpene peroxides sinularioperoxides 250254 have been isolated from a Formosan soft coral of the genus Sinularia by the same group.136,137

An unusual 1,2-dioxolane-3-ol-containing sesquiterpene,

HOO

O O

223 224

HOO

AcO

O O

225

176 D. Z. LIU and J. K. LIU Nat. Prod. Bioprospect. 2013, 3, 161206

OOH

H NCS

R1 R2

239 R1 = i-Pr, R2 = OOH 240 R2 = OOH, R1 = i-Pr

SCN H

OOH

OH 238

241 242

OH H

O OOH

OAc

309

HOO H

O O

243 244

250

HOO

HH H

H H OOH

O O OMe

245 248 249

246 R = OH 247 R = OOH

O O

HO O O

O O

251 252 253

O O

OCH3

OOH

254

255 256

dioxosarcoguaiacol 255, was reported from an Egyptian (Red Sea) collection of Sarcophyton glaucum.138 A Dysidea sp. from the Great Barrier Reef contained a cytotoxic sesquiterpene 256, the structure of which was determined by single crystal X-ray analysis.139 Bioassay-guided fractionation of the Okinawan marine sponge Dysidea chlorea afforded two tricyclic spiro-sesquiterpenes, haterumadysins C and D 257 and 258, both of which may be isolation artifacts.140 One cuparene-derived sesquiterpene, laureperoxide 259, has been reported from the red alga Laurencia okamurai.141 The guaiane derivative peroxygibberol 260 has been obtained from the Formosan soft coral, Sinularia gibberosa, which was found to exhibit moderate cytotoxicity toward a human liver carcinoma

cell line.142

The sipholane-type triterpenoids, sipholenol M 261, siphonellinol E 262, and siphonellinol hydroperoxide 263, were isolated from the red sea sponge Callyspongia (Siphonochalina) siphonella.143 Although there are several documented natural plant-derived triterpene hydroperoxides in the literature, it is also plausible that these three compounds are artifactual oxidation by products generated during the extraction and isolation process. Bruguiera gymnorrhiza yielded a dammarane-skeletoned triterpene bruguierin C 264 that activated antioxidant response element with micromolar potency.144

D. Z. LIU and J. K. LIU Nat. Prod. Bioprospect. 2013, 3, 161206 177

HOO

AcO

HOO

257 258 259 260

O H

HOO

OOH

H OH

OOH

261 262 263

264

O OOH

OOH

MeO

OOH

265 266

A Mediterranean collection of Placida dendritica afforded an unprecedented hydroperoxide 265. Whether the hydroperoxide is an artifact of isolation, or a true natural product is unclear.145 One halogenated nonterpenoid C15-acetogenin, laurendecumenyne A 266, has been reported from the Marine Red Alga Laurencia decumbens.146

Dihalenaquinolides A 267 and B 268, from the Taiwanese marine sponge Petrosia elastica, have an unusual peroxide linkage between two meroterpenoid units.147 Bioassay-guided fractionation of the marine cyanobacterium Lyngbya sp. led to the isolation of biselyngbyasides C 269 and D 270, whose stereochemistries were established based on NOESY spectra and CD data.148

Two prenylated indole diketopiperazine alkaloids, spirotryprostatin E 271 and 13-oxoverruculogen 272, have been obtained from the fermentation of Aspergillus fumigatus from a holothurian, Stichopus japonicus (Lingshan Is., Qingdao, China).149 The antimalarial gracilioether A 273, from the sponge Agelas gracilis (Oshima-Shinsone, Japan), are of mixed acetate/butanoate origin.150 The sponge Plakinastrella mamillaris was a new source for gracilioether A 273.151 The same source, P. Mamillaris, afforded additional antimalarial gracilioether H 274 structurally related to gracilioether A. The existence of endoperoxide ring is important for the antimalarial activity.152

A collection of the sacoglossan Placobranchus ocellatus from the Philippines provided three propionate-derived metabolites, tridachiapyrone J 275, and tridachiahydropyrones B 276 and C 277, all of which are probably artifacts from oxidation during storage or workup.153 Several years later, tridachiahydropyrones B and C were proved to be the same compound characterized as 278.154 The same species, P. ocellatus, provided the possibly artefactual peroxy derivative 279,155 whose relative configuration was confirmed at the same year.156 A Panamanian collection of the sacoglossan mollusc Elysia diomedea yielded the endoperoxide 280, structurally closely related to 279.157 The observation of rearrangement of 280 with triethylamine to yield the known vicinal diexpoxide elysiapyrone A158 prompted speculation of the biosynthetic intermediate of 280, likely to be in turn derived from a putative polypropionate alkenyl chain-containing precursor reacting with singlet oxygen.

3 Terrestrial Sources 3.1 Monoterpenoids: One p-menthane hydroperoxide, (1R,4S)-1-hydroperoxide-p-menth-2-en-8-ol-acetate 281 with strong trypanocidal avtivity, was isolated from the leaves of Laurus nobilis.159 The same group afforded four further monoterpene hydroperoxides 282285 with trypanocidal activity from Chenopodium ambrosioides. These hydroperox-

178 D. Z. LIU and J. K. LIU Nat. Prod. Bioprospect. 2013, 3, 161206

O O

HOO

O O

OMe

MeO OH

OMe

MeO OH

269 270

267 R = CH3 268 R = CH2CH3

HOO

OH OH

MeO

H H

O O

H H

N N

O O

MeO

271 272

273

274

OMe

O O

OMe OO O

OMe

HOO

275 276 277

OMe

O O

OMe

278

279

280

ides are likely formed through the singlet-oxygen oxidation of limonene, and the hydroperoxy group is essential for their trypanocidal activities.160 The liverwort Riella helicophylla yielded six new monoterpenes 286291.161 The aerial part of Aster scaber afforded two monoterpene peroxide glycosides 291293.162 A cyclic monoterpene peroxide 294 with the irregular santolinyl framework was found from aerial parts of Artemisia fragrans.163 The complete stereostructure of 295 has been established by application of the modified Mosher method.164

Catharoseumine 296, a monoterpenoid indole alkaloid

possessing a unique peroxy bridge moiety, was isolated from the whole plants of Catharanthus roseus. Its absolute configuration was determined by ECD and chemical methods. Catharoseumine exhibited cytotoxicity against HL-60 cell line with IC50 value of 6.28 M and potential inhibition against Plasmodium falciparum falcipain 2 (IC50 = 4.06 M). A plausible biogenetic pathway of catharoseumine was also proposed.165

3.2 Sesquiterpenes 3.2.1 Guaianes: Three highly oxygenated guaianolides 297299 were isolated from the aerial parts of Ajania

D. Z. LIU and J. K. LIU Nat. Prod. Bioprospect. 2013, 3, 161206 179

fruticulosa. Compund 299 was inhibitory to the growth of Candida albicans with MICs being 20 g/mL.166,167 The aerial

parts of Achillea setacea afforded a guaianolide 300 containing an endoperoxide ring.168 Two guaianolides, anthemolide B 301 and 8-O-angeloyl-9-O-acetylanthemolide B 302, were identified from the aerial parts of the flowering plant Anthemis cretica.169 A cytotoxic sesquiterpene lactone, lactucin-8-O-p-methoxyphenyl acetate 303, has been obtained from Mulgedium tataricum.170 The structure of 1,8-epidioxy-4-hydroxy-5H-guai-7(11),9-dien-12,8-olide 304, isolated from Curcuma wenyujin with anti-influenza viral activity, has been confirmed by single-crystal X-ray diffraction experiment.171 The complete relative configuration of the known sesquiterpene (+)-dioxo-sarcoguaiacol has been established. This compound has now been isolated from Acorus calamus.172

Chemical examinations of the roots of Nardostachys chinensis afforded two antimalarial guaiane endoperoxides, nardoperoxide 305 and isonardoperoxide 306, whose absolute stereochemistries were determined by CD spectra. The endoperoxide moiety of the molecules was assumed to relate to the antimalarial activity.173 A subsequent report described another four related endoperoxides nardoguaianones AD 307310 from the same plant.174 Three hydroperoxides 311 313 with trypanocidal activity have been isolated from Pogostemon cablin,175 whilst the sesquiterpene peroxide 314 has been found from the aerial parts of Croton arboreous.176

3.2.2 Eudesmanes: The aerial parts of Montanoa hibiscifolia afforded three eudesmanolides 315317 with a

rare endoperoxide structural element.177 The novel eudesmanolide 318 has been isolated from Atractylodes macrocephala.178 The aerial parts of Aster spathulifolius was the source for two cytotoxic sesquiterpene hydroperoxides, 7-hydroperoxy-3,11-eudesmadiene 319 and 7-hydroperoxyeudesma-11-en-4-ol 320.179,180 The sesquiterpene schisansphene A 321 was identified from the species Schisandra sphenanthera.181 A eudesmane derivative hydroperoxygynuradiene 322 has been obtained from the root of Gynura bicolor.182 Another two compounds of this type 323 and 324 were discovered from Xylopia emarginata and Ecdysanthera rosea, respectively.183,184

Two novel eudesmene-type sesquiterpene peroxides, kandenols C 325 and D 326, have been reported from Streptomyces sp. derived from the mangrove plant Kandelia candel.185 The aerial parts of Inula japonica contained two eudesmane sesquiterpenoids 327 and 328. Compound 328 was confirmed by means of single-crystal X-ray diffraction analysis.186 One eudesmane derivative 329 has been isolated from the liverworts Chiloscyphus polyanthus.187 Other eudesmane peroxides included 1,14-peroxy-4-hydroxy-5H,7H,6H-eudesm-11(13)-en-6,12-olide 330 from the roots of Vladimiria souliei,188 3-dehydroxy-3-hydroperoxyclypeotriol 331 from Achillea clypeolata,189 and 5-hydroperoxy-eudesma-4(15),11-diene 332 from Artemisia annua.190

3.2.3 Bisabolanes and Germacranes: Four bisabolane-type sesquiterpenes, peroxylippidulcines AC 333335 and

180 D. Z. LIU and J. K. LIU Nat. Prod. Bioprospect. 2013, 3, 161206

peroxyepilippidulcine B 336, have been obtained from the aerial parts of Lippia dulcis. The relative configurations of 334 and 336 were confirmed by X-ray crystallographic analysis data.191 The aerial parts of Carthamus lanatus afforded two oxygenated bisabolane fucosides 337 and 338.192 Another species of the genus, C. glaucus, contained two bisabolane fucopyranosides 339 and 340.193 Another bisabolene derivative 341 was found from the aerial parts of Achillea clavennae.194

A germacranolide peroxide 342 was identified as a component of mulgedium tataricum.170 Chemical investigation of Santolina insularis afforded two germacrane sesquiterpene peroxides 343 and 344, which might derive from the formal photo-oxygenation of the corresponding 4,5 olefin, a reaction well precedented in medium-sized olefins.195

3.2.4 Sesquiterpene Dimers: A dimeric sesquiterpene lactone japonicone E 345 bearing a rare hydroperoxide group was obtained from the aerial parts of Inula japonica, which displayed strong inhibitory activity against LPS-induced

NO production in RAW264.7 macrophages.196 Further investigations of the same species afforded additional related dimeric sesquiterpene, japonicone T 346.197 The leaves of Xylopia vielana contained a dimeric guaiane peroxide named vielanin C 347 with a central cyclobutane ring that are generated from two equal guaiane moieties by [2 + 2] cycloaddition.198 Two further related vielanins D 348 and E 349 were isolated from the same plant as epimeric mixtures. Both compounds consist of bridged ring systems formally representing the Diels-Alder products from the hypothetical guaiane-type monomers.199 Spicachlorantins CF 350353, new lindenane sesquiterpene dimers possessing a hydroperoxy group, were isolated from the roots of Chloranthus spicatus, whose absolute stereostructures were established by CD spectroscopic analyses. These compounds were considered to be biogenetic precursors of the corresponding hydroxyl derivatives of dimeric lindenane sesquiterpenoids distributed in Chloranthus plants.200 Another species of the genus, C. Japonicus, contained one more dimeric sesquiterpene peroxide 354, structurally related to 350353.201

D. Z. LIU and J. K. LIU Nat. Prod. Bioprospect. 2013, 3, 161206 181

3.2.5 Other Sesquiterpenes: The structures of cytosporolides AC 355357202 have been revised on the basis of synthetic studies and reinterpretation of the NMR data.

Cytosporolide A, which was originally assigned the strained nine-membered peroxylactone structure, has been revised to 358, which is probably biogenetically formed by a hetero-Diels-Alder type cyclization.203

182 D. Z. LIU and J. K. LIU Nat. Prod. Bioprospect. 2013, 3, 161206

The novel norsesquiterpene peroxides steperoxides AD 359362 have been obtained from the mushroom Steccherinum ochraceum,204,205 while another nor-chamigrane merulin A , and the chamigranes merulins BD 363365, have been found in an extract of the culture broth of a Thai mangrove-derived fungus.206,207 We have observed that

steperoxide B and merulin A have the same structure 360. Among these isolated metabolites, merulin C exhibited potent antiangiogenic activity. Another four compounds of this type, talaperoxides AD 366369, have been obtained from Talaromyces flavus. Talaperoxides B and D were moderately cytotoxic to several human tumour cell lines.208 The structures of 359, 360, 366 and 367 were further confirmed by X-ray crystallographic analysis, and the absolute configurations of the latter three compounds were also determined using copper radiation204,206,208

Five peroxy cuparene-type sesquiterpenoids 370374 were identified from the Japanese liverwort Jungermannia infusca. The stereostructure of 370 was confirmed by X-ray crystallographic analysis.209,210 An inseparable diastereomeric mixture acetylmajapolene A 375 in the part of the peroxide with antibacterial activity have been found in an extract of an undescribed Malaysian species of the Laurencia genus, whose absolute configurations have been unambiguously determined as (1R,4R,7S,10S) and (1S,4S,7S,10S), respectively, by vibrational circular dichroism (VCD).211,212

Two novel muurolane sesquiterpene peroxides, 1,4-peroxymuurol-5-ene 376 and 1,4-peroxy-5-hydroxy-muurol-6-ene 377 have been obtained from Illicium tsangii. The absolute stereochemistry of 376 was confirmed by X-ray crystallography.213 A peroxy muurolane-type sesquiterpenoid 378 was isolated from the Belgium liverwort Scapania undulata.214 The essential oil of the liverwort Plagiochila asplenioides contained one oxygenated sesquiterpene (+)-muurolan-4,7-peroxide 379.215 The NMR data of the sesquiterpene peroxide 380216 are also reported for the first time in the same paper. The aerial parts of the invasive plant Eupatorium adenophorum contain the new sesquiterpene 381.217 Dihydroartemisinic acid hydroperoxide 382 was isolated for the first time as a natural product from the plant Artemisia annua. The compound is a probable precursor of artemisinin under nonenzymatic conditions.218 The same plant, A. annua, afforded a rare seven-membered endoperoxide lactone arteannuin H 383, a biomimetic synthesis of which has confirmed biogenetic speculations regarding its formation from a secondary allylic hydroperoxide.219,220 The structure of 384, isolated from the leaves of Eupatorium adenophorum, was determined by single-crystal X-ray crystallography.221

A phytochemical study of Robinsonecio gerberifolius afforded a eremophilane derivative 385, whose absolute configuration was established from CD analysis.222 Three species of the Ligularia genus, L. subspicata, L. Kanaitzensis, and L. Veitchiana, provided the eremophilane peroxides 386, 387, and 388, respectively.223225 Another compound of this type 389 was isolated from Cacalia tangutica.226

The aerial parts of Anthemis arvensis contained two irregular linear sesquiterpene lactones 390 and 391, both of which were re-isolated from the same plant by another group of researchers.227,228 A different species of Anthemis, A. cotula, afforded additional related peroxide, 5-hydroperoxy-6,13-dehydro-5,6-dihydroanthecotuloide 392.229

Three isomeric sesquiterpene hydroperoxides 393395 were isolated from Illicium tsangii. These compounds appear to be derived from the ene-type addition of molecular oxygen to the known compound -santalene.230 A bioassay-guided fractionation of extract from Scleria striatinux led to the

D. Z. LIU and J. K. LIU Nat. Prod. Bioprospect. 2013, 3, 161206 183

362

359

360 361

O R O

CH2OH

OAc

363 364 365

366 R = CH3 367 R = CH3

O R O

O H

370 371 372

368 R = CH3 369 R = CH3

O H O

373 374 OAc O

375

isolation of okundoperoxide 396, a compound with antiplasmodial activity.231

The aerial parts of Xanthium strumarium contained one xanthane-type sesquiterpenoid, 4,5-epoxyxanthatin-1,4-endoperoxide 397.232 One allohimachalane peroxide 398 has been obtained from Illicium tsangii.233 The extract of the aerial parts of Artemisia diffusa contains tehranolide 399, a new type of sesquiterpene lactones with an endoperoxide group.234

Successful biomimetic syntheses of the litseaverticillol family of sesquiterpenes have been achieved, using singlet oxygen chemistry.235 In this work, the structure of the previously reported litseaverticillol E236 has been revised to 400.

Artemisinin, the well-known antimalarial agent, has been the focus of continuing study. Its antimalarial activity, structural modification, structure-activity relationships, mode of actions, and use in therapy have been well reviewed.237240

3.3 Diterpenes: A dolabellane diterpene derivative 401 with the naturally rare peroxy function was identified as a component of the aerial parts of Cleome droserifolia,241 and

additional related peroxide 402 was found from Aglaia odorata.242 Jatropha integerrima provided a rhamnofolane

endoperoxide 2-epicaniojane 403, whose structure was confirmed by X-ray diffraction analysis.243

A clerodane peroxide, 15(16)-peroxy-3,13-clerodadien-18-oic acid 404, was isolated from the Taiwanese liverwort Schistochila acuminata,244 and the structurally related 2-hydroperoxykolavelool 405 was reported from Aristolochia chamissonis.245 The plant Casearia arguta afforded further members of the series, argutins FH 406408.246

The aerial parts of Aster oharai contained two labdane peroxides 409 and 410, of which compound 409 showed moderate cytotoxicity against several human tumor cell lines with ED50 values ranging from 1.1 to 7.7 g/mL.247 A different species of Aster, A. spathulifofius, provided further related 7-hydroperoxymanool 411 that showed moderate cytotoxicity against human cancer cells.179 Other compounds of this type included (8S)-hydroperoxy-(13S)-hydroxy-9(11),14-labdadiene 412 from Jungermannia infuscua,210 ent-12,15-dioxo-3,4-seco-4,8,13-labdatrien-3-oic acid 413 and ent-12,15-dioxo-8,13-labdadien-3-ol 414 from Croton stipuliformis,248 and 8-hydroxy-13-hydroperoxylabd-14,17-dien-19,16:23,6-diolide 415 from Salvia sahendica.249 The absolute stereochemistry of compound 414 was determined by application of Moshers method.

184 D. Z. LIU and J. K. LIU Nat. Prod. Bioprospect. 2013, 3, 161206

O O

376 377

O O

378

379 380

H O

H H

O H

O O

OOH

HOOC

381

382 383

384

H OH

O O

AngO

HOO

385

386 387 388

OOH O

HOO

OOH

389

390 391 392

OOH OOH

OOH

393 394 395 396

O O

OH O O

397

398 399 400

The leaves of Viburnum awabuki afforded two vibsane hydroperoxides vibsanin K 416 and 18-O-methylvibsanin K 417 as well as their corresponding C-5 epimers 418 and 419,250,251 of which vibsanin K exhibited significant cytotoxicity against human gastric (NUGC) and oral

epidermoid (HONE-1) tumor cells at a concentration of 50 g/mL.252 An unusual macrocyclic endoperoxide structure was assigned to neovibsanin C 420 that was obtained from Viburnum aurabuki.253 Two cytotoxic diterpenes, dysokusones B 421 and C 422, were isolated from the stem of Dysoxylum kuskusense.254 A rare open chain peroxide designated

D. Z. LIU and J. K. LIU Nat. Prod. Bioprospect. 2013, 3, 161206 185

OAc

O O O

H H

HOO

COOH

OOH

O O

OAc

COOCH3

401 402 403 404

OH H

HOO

405

HOO

O OH

OOH H

OAc

O OH

OOH H

OAc

O O X =

406 R1 = X, R2 = OH, R3 = H 407 R1 = X, R2 = OH, R3 = OH 408 R1 = OH, R2 =X, R3 = OH

OOH

OAc

AcO

409 410

OOH

415

H OOH

411 412 413 414

OH OCH3

OOH R1

OR2

OOH

416 417

418 R1 = OOH, R2 = H 419 R1 = OOH, R2 = CH3

O O

OOH

420

421 422

423

leucoperoxyterpene 423 with good antibacterial activity has been isolated from aerial parts of the medicinal plant Leucosceptrum canum.255

Jungermatrobrunin A 424, which was obtained from the liverwort Jungermannia atrobrunnea, has an unusual rearrangedent-kaurene skeleton with a peroxide bridge. Its relative configuration was further supported by a single-crystal X-ray crystallographic analysis.256 A phytochemical investigation on the stems of Annona squamosa led to the isolation of additional two ent-Kaurane hydroperoxides, annosquamosins F 425 and G 426.257

The leaves of Croton steenkampianus provided a novel diterpenoid steenkrotin B 427, which possess a new carbon skeleton that may be derived from the daphnanetype by an 8(910)-abeo rearrangement.258 A rare 3,4-seco-cleistanthane hydroperoxide designated as trigonochinene C 428 with antimicrobial activity was isolated from the aerial parts of Trigonostemon chinensis.259

Nine jatrophane hydroperoxides, amygdaloidins C 429 and EL 430437, have been isolated from the wood spurge, Euphorbia amygdaloides.260 A methanol extract of Anisomeles indica afforded two cembrane hydroperoxides 4-methylene-5-hydroperoxyovatodiolide 438 and 4-Hydroperoxy-5-enovatodiolide 439, of which 439 showed inhibitory effects on antiplatelet aggregation induced by thrombin.261

Two abietane endoperoxides 440 and 441 were isolated as the corresponding acetate derivatives from the cones of Cedrus atlantica.262 The aerial parts of Illicium angustisepalum contained four more abietane diterpenes, angustanoic acids BD 442444 and I 445.263 Investigation of the leaves and twigs of Callicarpa longissima resulted in the isolation of a 3,4-seco-abietane peroxide named callilongisins A 446 with significant anti-inflammatory effect, whose structure was further confirmed by X-ray crystallographic analysis.264 Three diterpenic acids 447449 were isolated as their methyl ester derivatives from the leaves of Juniperus thurifera and

186 D. Z. LIU and J. K. LIU Nat. Prod. Bioprospect. 2013, 3, 161206

H OH

OAc

H OAc

MeOOC

OOH

HOO H

425 R = CH2OCOCH3 426 R = CH2OH

424 427 428

OR5

OR4

OR1

OR5

OR4

OR1

OR3

H OR2

O 429 R1 = Hydrp, R2 = H, R3 = Ang, R4= Ac, R5 = Nic 430 R1 = Ang, R2 = H, R3 = Hydrp, R4= Ac, R5 = Ac 431 R1 = Ang, R2 = Ac, R3 = H, R4 = Hydrp, R5 = Ac 432 R1 = Hydrp, R2 = Ac, R3 = H, R4 = Ang, R5 = Ac 433 R1 = Ac, R2 = Hydrp, R3 = H, R4 = Ang, R5 = Ac 434 R1 = Hydrp, R2 = Ac, R3 = Ang, R4 = H, R5 = Ac 435 R1 = Ac, R2 = Hydrp, R3 = Ang, R4 = H, R5 = Ac 436 R1 = Ang, R2 = Ac, R3 = Hydrp, R4 = H, R5 = Ac

OR3

H OR2

437

Nic =

Ang =

Hydrp =

OOH

Juniperus phoenicea.265 Further members of the type included triptotins A 450 and B 451 from Tripterygium wilfordii,266 6-oxo-12-peroxyabieta-8,11,13-triene 452 from Salvia multicaulis,267 and glutinosin C 453 from Isodon glutinosa.268 The structures of triptotin A and glutinosin C were confirmed by single crystal X-ray analysis. Phytochemical investigation of the above-ground parts of Siegesbeckia pubescens yielded one ent-pimarane diterpenoid 454.269

3.4 Triterpenes: A taraxastane-type triterpene, 3-acetoxy-19-hydroperoxy-20-taraxastene 455, has been isolated from the aerial roots of Ficus microcarpa.270 Reinvestigation of the aerial root extract afforded five ursene derivatives 456 460.271,272 The structure of 460 was confirmed by X-ray crystallography. Another compound of this type 461 were obtained from Arnica montana.273 The rhizome of Vladimiria muliensis provided one antimicrobial ursane triterpenoid 1,5-dioxy-11-hydroxyurs-12-en-3-one 462.274 Other ursene triterpenoids were including 3,28-dihydroxy-11-hydroperoxy-12-ursene 463 from Tolpis proustii,275 speciosaperoxide 464 from Chaenomeles speciosa,276 and (2,3)-3,25-epidioxy-2,24-dihydroxyursa-12,20(30)-dien-28-oic acid 465 and (2,3)-3,25-epidioxy-2,24-dihydroxyurs-12-en-28-oic acid 466 from Gentiana aristata.277

Ginsenoside SG2 467 has been reported from black ginseng.278 A pair of allylic hydroperoxides, ginsneoside-Rh6 468 and floralginsenoside ka 469, were obtained from the leaves and flower buds of Panax ginseng, respectively. Floralginsenoside ka displayed potent scavenging activity with the inhibition value of 64% at 10 M.279,280 The same species contained six dammarane-type triterpene diglycosides,

floralginsenosides AF 470475, five dammarane triterpene triglycosides, floralginsenosides GK 476480, and a dammarane triterpene obligoglycoside, ginsenoside SF 481.281283

Six dammarane triterpenes, named probosciderols DI 482 487, have been found in Proboscidea louisiana.284 The stem bark of Rhus javanica contained a dammarane triterpene designated as isofouquierone peroxide 488.285 Ginsenosides I and II from Panax ginseng have new genins 489 and 490.286 The fruits of Ceriops tagal was the source for a dammarane triterpene cereotagaloperoxide 491.287 Aglaiabbreviatin F 492 was identified as a component of the stems of Aglaia abbreviata.288 Another two compounds of this type 493 and 494 were isolated from the fruits of Ligustrum lucidum.289

One lanostane peroxide 5,8-peroxydehydrotumulosic acid 495 was isolated from the epidermis of the sclerotia of Poria coco.290 Additional two compounds of this type, inoterpenes C 496 and E 497, were discovered from the sclerotia of Inonotus obliquus.291 The leaves of Melaleuca ericifolia was the source for two antiproliferative norlupane triterpenes 498 and 499.292 The aerial roots of Ficus microcarpa afforded another norlupane triterpene 500.272

One novel 29-nor-3,4-seco-cycloartane triterpene methyl ester 501 was isolated from the aerial parts of Antirhea acutata, which showed moderate inhibitory activities in cyclooxygenase-1 and -2 assays.293 Phytochemical investigation of the leaves of Markhamia lutea resulted in the isolation of two cycloartane triterpenoids, musambins A 502 and B 503, as well as corresponding xylosides, musambiosides A 504 and B 505. These compounds showed anti-plasmodial and anti-trypanosomal activity.294 Combretum quadrangulare contained a novel cycloartane-type triterpene named methyl quadrangularate B 506 that exhibited potent cytotoxicity with

D. Z. LIU and J. K. LIU Nat. Prod. Bioprospect. 2013, 3, 161206 187

a ED50 value of 9.54 M.295 The same source afforded additional related quadrangularic acid F 507 by the same group.296

The aerial roots of Ficus microcarpa afforded two oleanane triterpenoids 508 and 509. The structures of 508 was further confirmed by X-ray crystallography.271,272 Another

compound of this class, sarmentolin 510, was identified as a hepatoprotective agent from Sedum sarmentosum.297 A

glutinane triterpene 511 was identified as a component of the aerial parts of Maytenus apurimacensis.298 Aceranol acetate 512 was a 5,6-cleaved glutinane derivative from Acer mandshuricum.299

A peroxy-multiflorane triterpene ester 513 has been isolated from the processed seeds of Trichosanthes kirilowii.300 The

plant Azadirachta indica contained a tetranortriterpenoid,

4-hydroperoxy-6-O-acetylnimbandiol 514.301 The absolute configuration of known longilene peroxide302, isolated from the wood of Eurycoma longifolia, has been established by total synthesis.303

Two euphane hydroperoxides, meliasenins A 515 and C 516, were isolated from the stem bark of Melia toosendan.304

Further members of this type, meliasenins IO 517523, were obtained from the fruits of the same plant. The relative configuration of 517 was further confirmed by single-crystal X-ray diffraction analysis.305 Another two species of this genus, M. dubia and M. azedarach, contained meliastatin 524 and 25-hydroperoxytirucalla-7,23(24)-diene-3,6-dion-21,16-olide 525, respectively. Meliastatin exhibited significant inhibition of the P388 cancer cell line.306,307 The roots of Euphorbia micractina

188 D. Z. LIU and J. K. LIU Nat. Prod. Bioprospect. 2013, 3, 161206

HOO

HOO O

HOO

AcO

R1O

AcO

455

456 R1 = Ac 457 R1 = H

AcO

458 459

OOH

HOO

O O

AcO

O O

460

461

462 463

HOO

COOH

HO COOH

HO 465

HO COOH

AcO

464 466

afforded further euphane/tirucallane derivatives 526530.308

Three 3(4),9(10)-disecocycloartane peroxy triterpene lactones, pseudolarolides Q2 531, T1 532, and T2 533, were discovered from the seeds of Pseudolarix kaempferi.309 The

leaves of the same species contained three more triterpene peroxides, pseudolarolides QS 534536. The stereochemical structures of these compounds were confirmed by single-crystal X-ray analyses.310 One triterpene dilactones with a rare rearranged pentacyclic skeleton, longipedlactone K 537, was found from the stems of Kadsura ananosma.311 A cytotoxic triterpenoid schinalactone A 538, an endoperoxide with an unusual contracted ring A, has been isolated from the roots and stems of Schisandra sphenanthera, which showed significant cytotoxicity against PANC-1 cell lines with a IC50

value of 5.9 M.312 The structure of a non-peroxidic metabolite, named podocarpaside E,313 has been revised to 539 on the basis of an X-ray analysis.314

3.5 Others: The structurally novel antiproliferative metabolite designated hexacyclinol 540 was first described by Grfe and co-workers from basidiospores collected from Panus rudis growing on dead betula woods in Siberia.315 The

structure of hexacyclinol was subsequently revised, and an alternative structure 541 was confirmed via total synthesis. In addition, an X-ray crystal structure was obtained, providing unequivocal structural confirmation.316,317 The first peroxide among the prenylated benzophenones, plukenetione C 542, was reported from the fruits of Clusia plukenetii.318 Continuing

investigations of the plant yielded two further related prenylated benzophenone derivatives, 33-hydroperoxyisoplukenetione C 543 and 15,16-dihydro-16-hydroperoxyplukenetione F 544.319 Another two compounds of this type, peroxysampsones A 545 and B 546, were isolated from the roots of the Chinese medicinal plant Hypericum sampsonii, of which peroxysampsone A showed comparable activity with norfloxacin against a NorA over-expressing multidrug-resistant (MDR) strain of Staphylococcus aureus SA-1199B.320

D. Z. LIU and J. K. LIU Nat. Prod. Bioprospect. 2013, 3, 161206 189

OH HOHO

O O

OOH

HOHO

OH HOHO

HOHO

O O

OOH

472

473

OH HOHO

O OH

OO H

OOH

OH HOHO

O O

474

OH HOHO

475

AcO

HOHO

476

OH HOHO

OOH

OH HOHO

OOH

OH HOHO

O O

478

479

AcO

477

OH HOHO

O O

HOHO

OH HOHO

OOH

OH HOHO

O O

AcO

HOHO

OH HOHO

480

481

A neurofibromatosis type 1 (NF1)-based bioassay-guided phytochemical investigation on Zanthoxylum armatum collected in Nepal led to the isolation of two isomeric timuramides A 547 and B 548, both of which can inhibite growth of Nf1-defective tumor cell line at noncytotoxic concentrations.321 One antibacterial acylphloroglucinol, olympicin D 549, was isolated and characterized from the aerial parts of Hypericum olympicum.322 A hydroperoxyquino-lone alkaloid, glycopentaphyllone 550, was reported from the fruits of Glycosmis pentaphylla, whose absolute configuration was established by applying Moshers method.323

Walsuronoid A 551 was the first limonoid with a peroxide linkage from Walsura robusta. The structure of walsuronoid A was also confirmed by X-ray analysis.324 The stems of Khaya anthotheca afforded one further limonoid 552,325 and the related xylocarpin G 553 was obtained from the Chinese

mangrove plant, Xylocarpus granatum.326 Additional member of the group, munronoid F 554, was discovered from Munronia unifoliolata.327

Two unprecedented spiroketal peroxides, chloropupukeanolides A 555 and B 556, were isolated from an endophytic fungus Pestalotiopsis fici, with chloropupukeanolide A showing significant anti-HIV-1 and cytotoxic effects. A possible biosynthetic pathway to chloropupukeanolides A and B has been proposed.328 A cytotoxic prenylated flavone, named artoindonesianin B 557, was obtained from the root of Artocarpus champeden.329 The root of Zanthoxylum zanthoxyloides provided an aromatic peroxide 558.330

A peroxy acid urticic acid 559 was discovered from the whole plant of Leucas urticifolia.331 A spiranoid withanolide 560 was obtained from the leaves of Jaborosa odonelliana.332

190 D. Z. LIU and J. K. LIU Nat. Prod. Bioprospect. 2013, 3, 161206

The stems of Millettia taiwaniana contained one isoflavonoid peroxide millewanin E 561.333 Brasixanthone C 562 was identified as a constituent of the stem bark of Calophyllum brasilienses collected in Brazil.334 One lignan tiegusanin M 563 was a constituent of the aerial parts of Schisandra propinqua.335 The unique neolignan mansoxetane 564, isolated from the heartwood of Mansonia gagei, is the first example of a biphenylneolignan with a dioxetane ring discovered in nature.336

Two prenylated polyketides, harrisotones C 565 and D 566 representing a rare spirocyclic skeleton, along with a cytotoxic hydroperoxypolyketide harrisonol A 567, were isolated from Harrisonia perforata.337 Two butanolides, litseadioxanins A 568 and B 569 bearing a 1,2-dioxane moiety, were obtained from the stem bark of Litsea akoensis.338

Chemical investigation of the leaves of Machilus japonica resulted in the isolation of apigenosylides AC 570572, which possess an unprecedented skeleton comprising the

D. Z. LIU and J. K. LIU Nat. Prod. Bioprospect. 2013, 3, 161206 191

OOH

AcO

500

501

COOH

H 502

OOH

XylO

COOH

503 504

XylO

COOH

505

OHC

HOOC

OOH

HOO

OOH

HO MeOOC

AcO

506 507

510

COOMe

508

HOO

AcO

509

511

H3CO

O O

514

O O

513

AcO O

HOO OAc

512

adduct of a butenolide moiety and apigenin glycoside linked via a 1,2-dioxane moiety. Apigenosylides BC possess moderate inhibitory activity against -glucosidase.339 High-

throughput natural products chemistry methods have facilitated the isolation of a beilschmiedic acid peroxide beilschmiedic acid N 573 from the leaves of a Gabonese species of Beilschmiedia, which may be an artifact of isolation formed through Diels-Alder addition of singlet oxygen.340 A cyclic

peroxide named kramecyne 574 with good anti-inflammatory activity has been isolated from Krameria cytisoides.341

Xanthoangelol E, originally obtained from the root of Angelica keiskei,342 showed the effects of xanthoangelol, on NF-B activation and ET-1 gene expression in cultured porcine aortic endothelial cells.343 Two furanocoumarins, melicotriphyllins B 575 and D 576 bearing a hydroperoxy group on the geranyloxy side chain, were isolated from the

192 D. Z. LIU and J. K. LIU Nat. Prod. Bioprospect. 2013, 3, 161206

OOH

H O

OOH

H O

OOH

R1 517 R1 = H, R2 = OH, R3 = CH3 518 R1 = O, R2 = O, R3 = CH3

515

516

OOH

HOO

H O

O H

519 R1 = H, R2 = OH, R3 = OOH 520 R1 = O, R2 = O, R3 = OOH

521

522 24S 523 24R

OOH

CH2O2CH3

HO 526 R1 = -Me, R2 = -OOH

527 R1 = -Me, R2 = -OOH 528 R1 = -Me, R2 = -OOH

O 524 525

OOH

529

530

fruits of Melicope triphylla.344

Two rare four-membered peroxide-containing pheophytin, bidenphytins A 577 and B 578, were identified from Biden pilosa, a popular Taiwanese folk medicine. Possible biosyn-

thetic pathways for them has been proposed.345 Bioassay-guided fractionation of the extract from Kielmeyera coriacea afforded a novel -tocotrienol peroxy-dimer 579.346 Two dimeric anthrone peroxides, adxanthromycins A 580 and B 581, were new inhibitors of ICAM-1/LFA-1 mediated cell adhesion molecule isolated from the fermentation broth of an

D. Z. LIU and J. K. LIU Nat. Prod. Bioprospect. 2013, 3, 161206 193

undescribed Streptomyces species.347 The aerial parts of the medicinal plant Clerodendrum bungei afforded additional peroxide dimer named bungein A 582.348

Clausamine G 583 containing a hydroperoxy moiety in the molecule, is the first example of the isolation of a peroxygen-

194 D. Z. LIU and J. K. LIU Nat. Prod. Bioprospect. 2013, 3, 161206

OOH

O O

N H

OH O

547

548

549

O OH

OMe

OAc OAc

OOH

OOAc

552

OMe

OAc

550

OAc

551

OTig

OOH

O O O

OCH3

OOAc

OAc

553

554

OCH3

555 R = CH3 556 R = H

H3CO

OOH

557

558

ated carbazole alkaloid in nature.349 The leaves of Piper aduncum afforded an prenylated benzoic acid derivative 584 with antifungal activity whilst the related 585 was obtained from the aerial parts of Aster spathulifolius. The presence of a hydroperoxide group at the side chain could be directly associated to its fungitoxicity.179,350 Bioactivity-guided fractionation of the extract from Piper crassinervium afforded one prenylated hydroquinone 586.351

The buds of Lonicera japonica contained a novel cyclic peroxide named shuangkangsu 587 with significant antiviral activities, whose absolute stereochemistry was determined by CD analysis.352 Echinobithiophene A 588, a peroxide bithiophene with significant antimicrobial activity, was isolated from Echinops ritro, and its structure was identified by spectral analysis including 2D NMR, and comparison of optical rotation values and chemical shifts of 13C NMR between the predicted and experimental data.353 A pyrrolidone peroxide cucubalactam 589 has been reported from Cucubalus

baccifer.354 A mutualist actinomycete of the southern pine beetle, Dendroctonus frontalis, produced a polyene peroxide, mycangimycin 590, with pronounced antifungal activity. Its absolute configuration was determined by chemical modification followed by the modified Mosher method.355 The

stem bark of the African tree Antiaris africana afforded a cardiac glycoside africanoside 591, which effected a concentration-dependent inhibition of tumor cell growth with a mean IC50 value of 5.3 nM.356

4 Steroidal Peroxides

The ubiquitous ergosterol peroxide357 continued to be isolated from any number of sources, marine as well as terrestrial, particularly mushrooms. The diverse biological activities have been attributed to ergosterol peroxide. Ergosterol peroxide was found to be a inhibitor to the proliferation of K562, Jurkat, WM-1341, HL-60, and RPM1-8226 tumor cell lines by 10 to 40% at 10 g/mL.358 Ergosterol peroxide from

D. Z. LIU and J. K. LIU Nat. Prod. Bioprospect. 2013, 3, 161206 195

O OH

O O

559

560

O O

OOH

563

O O

OH OH

MeO

OOH

O O

MeO

OOH

MeO

561

562

OMe

OOH

HO OMe

MeO

OHC

564

565

566

O O

HOO

568 569

567

the marine sponge Spirastrella abata showed cytotoxicity against several human solid tumor cell lines,359 and also against human gastric tumor cell line (SNU-1), human hepatoma cell line (SNU-354), human colorectal tumor cell line (SNU-C4), and murine sarcoma-180 were 18.7, 158.2, 84.6 and 74.1 M (IC50), respectively.360 Ergosterol peroxide from two species of the Pleurotus genus, P. eryngii and P. ostreatus, exhibited osteoclastogenesis inhibitory and trypanocidal activity, respectively.361,362 Ergosterol peroxide was obtained for the first time from Oryza sativa in 2006. This is the first report of potential allelopathic activity of steroids on weeds based on their phytotoxicity on barnyardgrass (Echinochloa crus-galli) as target species.363 Ergosterol peroxide was found to be a DNA topoisomerase I inhibitor,364

and exhibit potent of rat lens aldose reductase inhibition.365

Among the lipophilic extracts of seven traditional edible mushrooms, the acetone extract of Sarcodon aspratus markedly inhibited the growth of HL60 human leukemia cells and induced apoptosis after 24 h incubation. The major active

component was identified as ergosterol peroxide. It is completely inhibited growth and induced apoptosis of HL60 cells at a concentration of 25 M.366 Anti-inflammatory activity has been found for ergosterol peroxide isolated from several species.367369 Ergosterol peroxide also displayed strong anticomplement activity on the classical pathway with IC50 values of 126.8 M.370 In addition, the antimicrobial,371,372 antituberculosis,373 and melanogenesis inhibitory effects374 of ergosterol peroxide have also been reported.

In addition to ergosterol peroxide, a number of other steroidal endoperoxides have been reported, which are most commonly 5,8-epidioxysterols with variations in the side chains. A 5,8-epidioxysterol sulfate 592 was isolated from the cultured diatom Odontella aurita.375 Four steroidal saponins, pariposides AD 593596, were isolated from the roots of Paris polyphyllava. These compounds are the first spirostanol saponins with a peroxy group located between C-5 and C-8 of the aglycon.376 Bioassay-guided fractionation of an

196 D. Z. LIU and J. K. LIU Nat. Prod. Bioprospect. 2013, 3, 161206

extract of a marine sponge, Lendenfeldia chondrodes, has led to the isolation and identification of new epidioxy sterols 597 and 598 as an inseparable mixture, which might be formed in the sponge during sample storage and extraction.377 A

cytotoxic 5,8-epidioxysterol 599 was isolated from a soft coral Sinularia sp.378 Sinularia flexibilis (Hainan Is., China) afforded two new members of the 5,8-epidioxygorgostane family of metabolites 600 and 601, as well as the 22,28-epidioxycholestane C-22 epimers 602 and 603.379 A group of 5,8-epidioxysterols, topsentisterols A1A3 604606, were isolated from a marine sponge Topsentia sp.380 The marine sponge Luffariella cf. variabilis was the source for a series of 5,8-epidioxy sterols 607609.381 Eunicella cavolini (Lichadonissia Is., Greece) provided another group of 5,8-epidioxysterols 610612.382 Three epoxysteroids 613, 614383 and 615384 were obtained from Helianthus tuberosus and Lentinus edodes, respectively. An undescribed endophytic Phomopsis species from Maytenus hookeri provided a new sterol 616.385 A peroxy steroid, 9(11)-dehydroxyaxinysterol 617, from an Okinawan species of the genus Axinyssa, was found to inhibit the growth of several human cancer cell lines.386 Fermentation of a Rhizopus sp. from the bryozoan Bugula sp. (Jiaozhou Bay, China) yielded a cytotoxic

ergosterol 618.387

In addition, several rare 5,9-epidioxy steroids have also been characterized. The mushroom Pleurotus eryngii afforded the first example of a naturally occurring 5,9-epidioxy-8,14-epoxy-6-ene sterol 619.388 One osteoclast-forming suppressing sterol, gargalol B 620, was obtained from the mushroom Grifola gargal.389 The mushroom Lepista nuda was the source for two new sterols, 621 and its C-6 epimer 622.390 Another two compounds of this class, 623 and 624, were isolated from the mushroom Hypsizigus marmoreus.384

Besides endoperoxides, steroids containing hydroperoxy groups have also been identified. Two isomeric hydroperoxides, 625 and 626, previously reported as synthetic products, were isolated as mildly cytotoxic metabolites of a Taiwanese collection of Eudistoma sp.391 Three cytotoxic oxygenated fucosterols 627629 were obtained from the marine brown alga Turbinaria conoides.392 A Formosan soft coral sinularia sp. was the source for 7-hydroperoxy-24-methylenecholesterol 630, which exhibited significant cytotoxicity against P-388 tumor cell with a ED50 of 2.6 g/mL.393 A pair of allylic regioisomers, 631 and 632, were found from the bark of Melia azedarach, which showed significant cytotoxic effects against several human cancer cell lines.394 A pregnane-

D. Z. LIU and J. K. LIU Nat. Prod. Bioprospect. 2013, 3, 161206 197

type steroid sclerosteroid E 633 was a constituent of the soft coral Scleronephthya gracillimum.395 A chemical investigation of the roots of Cynanchum stauntonii has resulted in the characterization of a new hydroperoxide with a 13,14:14,15-disecopregnane-type skeleton, named stauntonine 634, whose relative stereochemistry was determined by X-ray crystallo-graphic diffraction analysis. The compound showed dose-dependent relaxation on aortic rings with endothelium contracted by phenylepherine or KCI.396

The structures of a series of peroxy function containing pregnane glycosides including periperoxides AE 635639397 and previously reported periplocosides AK398,399 have been

revised to be orthoester group bearing ones using 2D NMR techniques as well as chemical transformations and X-ray crystallographic diffraction analysis.400

5 Fatty Acid Metabolites

Lipoxygenase (LOX) pathways are involved in the

198 D. Z. LIU and J. K. LIU Nat. Prod. Bioprospect. 2013, 3, 161206

606 O

607 R = 608 R =

609 R = 610 R =

611 R = 612 R =

613 R =

614 R =

HCOO OO

HO OO

617

615 R =

616

HO O

HO O O 618

619

620

623

621 R = -OH, -H 622 R = -OH, -H

624

HOO

625 R = -OOH 626 R = -OOH

627 628

production of important signal and defensive metabolites in mammals, higher plants, and algae.401404 In these pathways molecular oxygen is introduced into a polyunsaturated fatty acid to form an intermediate hydroperoxide, which may then be cleaved to give shorter chain-length oxygenated products, collectively known as oxylipins. Interestingly, different principles of transformations have been identified. While plants use almost exclusively C18 fatty acids for the production of oxylipins,401 algae and animals rely predominantly on the transformation of C20 fatty acids.403 In animals cleavage of the intermediate hydroperoxy fatty acids is achieved by a dual

function of LOXes, while plants and algae rely often on hydroperoxide lyases (HPLs) to produce shorter chain oxylipins.401403

The mechanism of fatty acid transformation in the Diatom Thalassiosira rotula does not, however, follow established lipoxygenase/hydroperoxide lyase pathways known from higher plants or mammals but rather relies on a unique transformation of polyunsaturated hydroperoxy fatty acids. These intermediates are then transformed to polyunsaturated short chain aldehydes and short chain hydroxylated fatty acids, which are novel oxylipins.404 The similar transformation mechanism of fatty acid hydroperoxides has also been reported

D. Z. LIU and J. K. LIU Nat. Prod. Bioprospect. 2013, 3, 161206 199

OOH

HOO

OOH

629

630

631

HOO H

OOH

HOO H

AcO H

H H

633

H H

HO H

632

634

6 Conclusions

This article reviewed several hundreds of new peroxy natural products produced by terrestrial fungi, higher plants, and marine organisms not only their structures and chemistry, but also their diverse biological activities. However, only a limited number of them have been further evaluated since a limited supply of the active ingredients from the natural sources. It needs more research attention on total synthesis of important compounds and further biological evaluation. Further studies on their previously untapped resources with further unprecedented bioactive metabolites needs to be conducted. This review also emphasizes the role of peroxides from terrestrial fungi, higher plants, and marine organisms as an important source of leads for drug discovery.

7 Acknowledgements

This study was supported by the National Natural Science

Foundation of China (NSFC 31100012, U1132607) and the National Basic Research Program of China (973 Program, 2009CB522300).

Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.

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The Author(s) 2013

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This review covers the structures and biological activities of Peroxy natural products from a wide variety of terrestrial fungi, higher plants, and marine organisms. Syntheses that confirm or revise structures or stereochemistries have also been included, and 406 references are cited. [Figure not available: see fulltext.]

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Title

Peroxy natural products

Author

Liu, Dong-ze; Liu, Ji-kai

Pages

161-206

Publication year

2013

Publication date

Sep 2013

Publisher

Springer Nature B.V.

ISSN

21922195

e-ISSN

21922209

Source type

Scholarly Journal

Language of publication

English

DOI

https://doi.org/10.1007/s13659-013-0042-7

ProQuest document ID

1652837106

The Author(s) 2013

Peroxy natural products

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