Peroxy natural products

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 compounds^{1, 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 antiinflammatory, 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. Previouslyreported 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 K–S (1–9)⁷ were isolated from the Australian sponge Plakinastrella clathrata. Detailed configurational investigation also revealed that the structure for previously reported plakortolide E⁶ should be 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 10–25.⁹ 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 Mosher's method to a derivative.¹⁴ The authors also detail the unreliability of specific rotation measurements in the determination of absolute 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 Kishi's 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 B–D 36–38, 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 values of approximately 0.05–0.1 μg/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 44–49 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 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 56–61 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 I–L 68–71, and two related compounds 72 and 73, respectively.^{37, 38} Plakortide I represents the first report of a polyketide-derived cyclic peroxide with an α, β-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 activity against pathogenic bacteria and fungi with IC₅₀ values of 0.9–5.0 μg/mL and 0.7–8.0 μg/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 B–D 76–78, which can lyse starfish oocytes without disruption of nuclear structure.⁴⁰ Interestingly, the absolute stereochemistries of 76–78, 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 7–15 μg/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

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

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 93–96 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 μg/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 B–D 102–104.⁵⁶ The same source, D. Erythraenus, afforded another three cytotoxic norsesterterpenoid peroxides, tasnemoxides A– C 105–107.⁵⁷

Bioassay-guided isolation of D. Levii collected from Papua New Guinea led to the isolation of four norsesterterpene peroxides, diacarnoxides A–D 108–111, 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 derivatives, diacarperoxides A–G 112–118, 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, ent-epimuqubilin 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 lipopolysaccharide (LPS)-activated murine macrophage RAW 264.7 cells, ⁶³ and suppressed cyclooxygenase-2 via IKK/IκB/NF-κB 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 A–D 130–133.⁶⁷ Three norsesterterpene cyclic peroxides named trunculins G–I 134–136 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

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 ω-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 153–155 were determined by the application of Mosher's 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 A–D 157–160 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 E–K 161–167 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 stereochemistries of known natural products chondrillin⁸⁵ and its C-3 epimer, plakorin^{86, 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 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 antiprotozoan 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-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 A–F 186–191, 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, 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 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}

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 200–203 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 hydroperoxysubstituted 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 ε-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 δ-lactone ring.¹¹⁹ Four γ-cembranolide-type diterpenes, uprolides H–J 213–214 and L 215 and M 216, were reported from Eunicea pinta collected from San Andrés 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 217–225, respectively.¹²² Another compound of the type 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 μg/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 upregulation 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 μg/mL, respectively.¹²⁸

2.5 Other Marine Metabolites

The Hainan Sponge Dysidea septosa contained a new sesquiterpene lingshuiperoxide 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 246–248, 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 250–254 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, 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

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 chaincontaining 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 282–285 with trypanocidal activity from Chenopodium ambrosioides. These hydroperoxides 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 286–291.¹⁶¹ The aerial part of Aster scaber afforded two monoterpene peroxide glycosides 291–293.¹⁶² 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 μM and potential inhibition against Plasmodium falciparum falcipain 2 (IC₅₀ = 4.06 μM). A plausible biogenetic pathway of catharoseumine was also proposed.¹⁶⁵

3.2 Sesquiterpenes

3.2.1 Guaianes

Three highly oxygenated guaianolides 297–299 were isolated from the aerial parts of Ajania fruticulosa. Compund 299 was inhibitory to the growth of Candida albicans with MICs being 20 μg/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 1α, 8α-epidioxy-4α-hydroxy-5αH-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 A–D 307–310 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 315–317 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, 7α-hydroperoxy-3, 11-eudesmadiene 319 and 7β-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 1β, 14-peroxy-4α-hydroxy-5αH, 7αH, 6βH-eudesm-11(13)-en-6, 12-olide 330 from the roots of Vladimiria souliei, ¹⁸⁸ 3α-dehydroxy-3α-hydroperoxyclypeotriol 331 from Achillea clypeolata, ¹⁸⁹ and 5α-hydroperoxy-eudesma-4(15), 11-diene 332 from Artemisia annua.¹⁹⁰

3.2.3 Bisabolanes and Germacranes

Four bisabolane-type sesquiterpenes, peroxylippidulcines A–C 333–335 and 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 C–F 350–353, 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 350–353.²⁰¹

3.2.5 Other Sesquiterpenes

The structures of cytosporolides A–C 355–357²⁰² 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 heteroDiels-Alder type cyclization.²⁰³

The novel norsesquiterpene peroxides steperoxides A–D 359–362 have been obtained from the mushroom Steccherinum ochraceum, ^{204, 205} while another nor-chamigrane merulin A, and the chamigranes merulins B–D 363–365, 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 A–D 366–369, 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 radiation^{204, 206, 208}

Five peroxy cuparene-type sesquiterpenoids 370–374 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.^223-225 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 393–395 were isolated from Illicium tsangii. These compounds appear to be derived from the ene-type addition of molecular oxygen to the known compound α-santalene.²³⁰ A bioassay-guided fractionation of extract from Scleria striatinux led to the isolation of okundoperoxide 396, a compound with antiplasmodial activity.²³¹

The aerial parts of Xanthium strumarium contained one xanthane-type sesquiterpenoid, 4β, 5β-epoxyxanthatin-1α, 4α-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.^237-240

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 2β-hydroperoxykolavelool 405 was reported from Aristolochia chamissonis.²⁴⁵ The plant Casearia arguta afforded further members of the series, argutins F–H 406–408.²⁴⁶

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 μg/mL.²⁴⁷ A different species of Aster, A. spathulifofius, provided further related 7α-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-3α-ol 414 from Croton stipuliformis, ²⁴⁸ and 8α-hydroxy-13-hydroperoxylabd-14, 17-dien-19, 16:23, 6α-diolide 415 from Salvia sahendica.²⁴⁹ The absolute stereochemistry of compound 414 was determined by application of Mosher's method.

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 μg/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 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(9→10)-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 E–L 430–437, have been isolated from the wood spurge, Euphorbia amygdaloides.²⁶⁰ A methanol extract of Anisomeles indica afforded two cembrane hydroperoxides 4-methylene-5β-hydroperoxyovatodiolide 438 and 4α-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 B–D 442–444 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 447–449 were isolated as their methyl ester derivatives from the leaves of Juniperus thurifera and 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, 3β-acetoxy-19α-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 1α, 5α-dioxy-11α-hydroxyurs-12-en-3-one 462.²⁷⁴ Other ursene triterpenoids were including 3β, 28-dihydroxy-11α-hydroperoxy-12-ursene 463 from Tolpis proustii, ²⁷⁵ speciosaperoxide 464 from Chaenomeles speciosa, ²⁷⁶ and (2β, 3β)-3, 25-epidioxy-2, 24-dihydroxyursa-12, 20(30)-dien-28-oic acid 465 and (2β, 3β)-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 μM.^{279, 280} The same species contained six dammarane-type triterpene diglycosides, floralginsenosides A–F 470–475, five dammarane triterpene triglycosides, floralginsenosides G–K 476–480, and a dammarane triterpene obligoglycoside, ginsenoside SF 481.^281-283

Six dammarane triterpenes, named probosciderols D–I 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 5α, 8α-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 antitrypanosomal activity.²⁹⁴ Combretum quadrangulare contained a novel cycloartane-type triterpene named methyl quadrangularate B 506 that exhibited potent cytotoxicity with a ED₅₀ value of 9.54 μM.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, 4α-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 I–O 517–523, 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 afforded further euphane/tirucallane derivatives 526–530.³⁰⁸

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 Q–S 534–536. The stereochemical structures of these compounds were confirmed by singlecrystal 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 μM.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 Gräfe 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 multidrugresistant (MDR) strain of Staphylococcus aureus SA-1199B.³²⁰

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 hydroperoxyquinolone alkaloid, glycopentaphyllone 550, was reported from the fruits of Glycosmis pentaphylla, whose absolute configuration was established by applying Mosher's 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 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 A–C 570–572, which possess an unprecedented skeleton comprising the adduct of a butenolide moiety and apigenin glycoside linked via a 1, 2-dioxane moiety. Apigenosylides B–C possess moderate inhibitory activity against α-glucosidase.³³⁹ Highthroughput 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-κB 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 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 biosynthetic pathways for them has been proposed.³⁴⁵ Bioassayguided fractionation of the extract from Kielmeyera coriacea afforded a novel δ-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 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 peroxygenated 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 μg/mL.³⁵⁸ Ergosterol peroxide from 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 μM (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 μM.³⁶⁶ Anti-inflammatory activity has been found for ergosterol peroxide isolated from several species.^367-369 Ergosterol peroxide also displayed strong anticomplement activity on the classical pathway with IC₅₀ values of 126.8 μM.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 5α, 8α-epidioxysterols with variations in the side chains. A 5α, 8α-epidioxysterol sulfate 592 was isolated from the cultured diatom Odontella aurita.³⁷⁵ Four steroidal saponins, pariposides A–D 593–596, 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 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 5α, 8α-epidioxysterol 599 was isolated from a soft coral Sinularia sp.³⁷⁸ Sinularia flexibilis (Hainan Is., China) afforded two new members of the 5α, 8α-epidioxygorgostane family of metabolites 600 and 601, as well as the 22α, 28-epidioxycholestane C-22 epimers 602 and 603.³⁷⁹ A group of 5α, 8α-epidioxysterols, topsentisterols A1–A3 604–606, were isolated from a marine sponge Topsentia sp.³⁸⁰ The marine sponge Luffariella cf. variabilis was the source for a series of 5α, 8α-epidioxy sterols 607–609.³⁸¹ Eunicella cavolini (Lichadonissia Is., Greece) provided another group of 5α, 8α-epidioxysterols 610–612.³⁸² 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 5α, 9α-epidioxy steroids have also been characterized. The mushroom Pleurotus eryngii afforded the first example of a naturally occurring 5α, 9α-epidioxy-8α, 14α-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 627–629 were obtained from the marine brown alga Turbinaria conoides.³⁹² A Formosan soft coral sinularia sp. was the source for 7β-hydroperoxy-24-methylenecholesterol 630, which exhibited significant cytotoxicity against P-388 tumor cell with a ED₅₀ of 2.6 μg/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 pregnanetype 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 crystallographic diffraction analysis. The compound showed dosedependent 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 A–E 635–639³⁹⁷ and previously reported periplocosides A–K^{398, 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 production of important signal and defensive metabolites in mammals, higher plants, and algae.^401-404 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.^401-403

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 from the moss Physcomitrella patens. The moss produces metabolites typical for animals, plants, algae, and mushrooms by new transformations of arachidonic acid, combining in a unique way metabolic themes from all these organisms.⁴⁰⁵ Recent genome sequences leading to an increasing number of enzyme-mechanistic and structural analysis of LOXs and new members of the oxylipin pathway, as well as oxylipin profiling shed new light on the biosynthesis and occurrence of oxylipins in non-mammalian organisms. A review of these new aspects has been published.⁴⁰⁶

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).