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Volume 29 | Number 5 | May 2012 | Pages 505–608

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ISSN 0265-0568

COVER ARTICLE Suthananda N. Sunassee and Michael T. Davies-Coleman Cytotoxic and antioxidant marine prenylated quinones and hydroquinones

0265-0568(2012)29:5;1-0

C

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21.6 and 14.9 mM, respectively).97

This journal is ª The Royal Society of Chemistry 2012

The sponge Hippospongia metachromia has also yielded hippochromin A,137, which was reported as being unstable and was, hence, isolated as its diacetate derivative (138).99 Compound 138 was found to be strongly cytotoxic (IC50 0.47 mM) against the COLO-205 human colon cancer cell line.99 The structure of these metachromins is unprecedented and, according to Ishibashi et al.,96 they possess a biogenetically unusual carbon skeleton that is similar to that of the paniceins, 120 and 121, isolated from the marine sponge Halichondria panacea.91 The marine sponge Spongia sp. yielded the cytotoxic metachromins J and K (139 and 140),100 L and M (141 and 142),101 S and T (143 and 144),102 and isometachromin (145).104 Metachromins J and K exhibited in vitro cytotoxicity (IC50 2.8 and 31.3 mM respectively) against murine lymphoma L-1210 cells and human KB carcinoma cells (IC50 27.8 and > 49.7 mM

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respectively).100 The metachromins L, M, S and T all exhibited in vitro cytotoxicity against the L-1210 murine leukemia (IC50 10.0, 8.4, 12.2 and 8.1 mM respectively) and KB human epidermoid carcinoma cells (IC50 10.0, 13.0, > 23.4 and 15.0 mM respectively).101,102 Similarly, isometachromatin, 145, was found to be cytotoxic against the human lung cancer A-549 (IC50 7.3 mM) and the P-388 leukemia (IC50 > 27.9 mM) cancer cell lines.104 The Australian sponge Thorecta reticulata has recently afforded the metachromins U-W (146–148) that exhibited weak to strong cytotoxicity (IC50 ranging from 2.1–130 mM) against a panel of five human tumour cell lines.105

4.2 Ascidians Ascidians or tunicates belong to the phylum Chordata and are regarded as one of the most productive sources of bioactive and cytotoxic natural products in the marine environment.106,107 Out of the first six marine-derived antitumour compounds to reach clinical trials, three are derived from ascidians and one of these metabolites,107–109 trabectedin or ET-743 (149) isolated from the Carribean ascidian Ecteinascidia turbinate, has reached the market place as the first marine natural product to be prescribed as an anticancer drug (Yondelis) against soft tissue carcinoma.110–112 The metabolites isolated from ascidians can be divided in two groups; nitrogenous and non-nitrogenous.106 Prenylated quinones and hydroquinones (cyclic or linear) are the most common nonnitrogenous metabolites isolated from ascidians,106 and the majority of the cytotoxic members of this class of compounds are confined to the genus Aplidium (Family Polyclinidae), with the exception of the cyclized hydroquinone (150).113 These compounds generally adopt the structural class A (Fig. 2), with the exception of the non-cytotoxic verapliquinones A–D,114 and the cytotoxic longithorone/longithorol complex metabolites isolated from Aplidium longithorax,115 which are discussed at the end of this section. 526 | Nat. Prod. Rep., 2012, 29, 513–535

The cyclized diprenylated benzohydroquinone 150 was isolated from the Australian ascidian Synoicum castellatum and exhibited mild cytotoxicity (IC50 ¼ 40.9 mM) against P388 murine leukemia, A-549 human lung carcinoma and HT-29 human colon cancer cells.113 The first linear prenylated benzohydroquinone (151) from an ascidian was isolated by Fenical et al.116 in 1974 from an Aplidium sp. and exhibited cytotoxicity against leukemia cell lines, Rous sarcoma and mammary cincinoma in test animals. The discovery of this cytotoxicity along with the fact that, at the time, there was no record of neoplasms in ascidians, contributed to a renewed interest in the research on ascidians.117 Subsequently, ascidians have been the source of numerous metabolites with diverse biological activities.117 Benslimane and coworkers118 have reported the isolation of 151 from Aplidium antillense collected in Guadeloupe, together with the chromenol cordiachromene A (152). Both compounds 151 and 152 were found to be cytotoxic against P-388 leukemia (IC50 17.5 and 0.14 mM respectively) and against KB human epidermoid carcinoma cells (IC50 146 and 2.0 mM respectively).118 Interestingly, cordiachromene A was originally isolated from the marine ascidian This journal is ª The Royal Society of Chemistry 2012


Aplidium constellatum collected from the Canadian east coast119 and from the heartwood of a tropical American tree, Cordia alliodora.120 The Mediterranean Aplidium sp. also yielded geranylhydroquinone 151, along with the benzohydroquinone (153).121 The hydroquinones 151 and 153 were both found to have very good cytotoxicity against P-388 (IC50 0.81 and 4.5 mM) and against various other cancer cell lines which, according to Rueda et al.,121 indicates that the hydroxylation of the prenyl chain may result in a marginal decrease in the cytotoxicity. The hydroxylated prenylated hydroquinones (154–158) have been reported to have either cytotoxic or antioxidant properties.122–124 Rossinones A and B, 154 and 155, were isolated from an Antarctic Aplidium species and exhibited potent antiproliferative activity (IC50 0.39 and 0.084 mM, respectively) against the P-388 murine leukemia cell line.123 The novel molecular structure of the highly bioactive 155, coupled to its potentially interesting biosynthetic pathway have prompted Zhang and co-workers125 to complete the first highly efficient biomimetic total synthesis of rossinone B. Their proposed biosynthesis of 155, seemingly from 154, through a series of three cyclizations involves the generation of a novel vinyl quinone followed by a Diels–Alder reaction.125,126 The tunicate Aplidium savignyi collected in the Indian Ocean, near the Comoros Islands, yielded the hydroquinone 156 and the two known hydroquinones 151 and 157, all of which were found to have antioxidant properties.122 The benzohydroquinone 157 was first isolated from the tunicate Amaroucium multiplicatum, along with the novel metabolites 158 and (159), all of which were shown to have potent antioxidant properties.124 The Californian tunicate Aplidium californicum afforded two novel cytotoxic metabolites (160 and 161).127 The prenylhydroquinone 161 exhibited in vivo activity against P-388 This journal is ª The Royal Society of Chemistry 2012

lymphocytic leukemia,127 and has, more recently, been shown to be slightly cytotoxic (IC50 ¼ 41 mM) against the P-388 murine leukemia cell line.123 Both prenylhydroquinone 160 and the chromenol 161 were found to have significant antimutagenic and antioxidant properties.127,128 However, Pettit et al.129 have suggested that the cytotoxic properties of the extracts of the marine ascidian Aplidium californicum can possibly be attributed to the bioactive bryostatin metabolites isolated from the symbiotic bryozoan Bugula neritina. The meroterpene methoxyconidiol (162) was isolated from the Aplidium aff. densum collected in Oman by Simon-Levert et al.,130 and was subsequently found to have antimitotic activity against sea urchin eggs, making 162 a potential antiproliferative agent

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for cancer cells.131 The ascidian A. glabrum yielded the bioactive metabolite glabruquinone (163) which exhibited moderate cytotoxicity against various cancer cell lines,132 and has recently been patented as a potential antitumour compound.133 A five step synthesis of glabruquinone confirmed the structure of this marine natural product.134,135 The Mediterranean Aplidium conicum collected at Capo Caccia in Italy yielded the unusual sulfone heterocycles aplidinones A–C (164–166) and the thiaplidiaquinones A and B (167 and 168).136,137 Of these prenylated benzoquinones, only 167 and 168 have been reported to be cytotoxic against the human leukemia T Jurkat cells.137 Aiello and co-workers138 have recently synthesized and confirmed the structural assignment of aplidinone A and reported the cytotoxicity of a series of synthetic analogues of 164 against several tumour cell lines.

of this class of compounds is characterized by a farnesyl unit that bridges the C-2, C-5 positions of the benzoquinone moiety to form a macrocycle with two such units fusing to yield the final carbocyclic structure.106,115 The Australian Aplidium longithorax has yielded the moderately cytotoxic (IC50 63.6 mM) longithorone J (170) and the absolute configuration at C-1 was determined using the advanced Mosher’s method.141,142 The structural similarity of the longithorones to the yanuthones isolated from the symbiotic Aspergillus niger fungus in the Aplidium sp. sample, has prompted Bugni et al.15 to propose that the quinone moiety of the longithorones may, in fact, originate from the shikimate biosynthetic pathway in marine fungi.

The Indonesian Aplidium sp. specimen collected from Flores Island yielded three novel bioactive metabolites (171–173) known as floresolides A–C, respectively.143 These compounds are similar to the longithorone/longithorol family and were found to be moderately cytotoxic (IC50 2.9–30.8 mM) against KB cells.143 The interesting unusual structural architecture of the cytotoxic floresolide B, 172, has prompted its total synthesis by Nicolaou and co-workers144 and more recently by Chen and Harmata.145

4.3 Cnidarians The unprecedented and unusual macrocyclic metabolite longithorone A (169) was first isolated from the tunicate Aplidium longithorax collected in Palau, and was found to be moderately cytotoxic (ED50 15.8 mM) against P-388 murine leukemia cells.115 The complex and elaborate structure of 169 was determined by X-ray analysis,115 and the absolute configuration confirmed several years later via an enantioselective synthesis of 169 using a series of Diels–Alder reactions.139,140 The structure 528 | Nat. Prod. Rep., 2012, 29, 513–535

4.3.1 Gorgonians. The cytotoxic prenylated toluhydroquinone moritoside (174), was isolated from the gorgonian Euplexaura sp. collected from the Gulf of Sagami (Japan) in 1985.146 Compound 174 is a farnesylated hydroquinone bearing a glycoside moiety and is, possibly, the first example of the occurrence of a b-D-altrose sugar in a natural product.146 Moritoside was found to inhibit cell division at 0.16 mM in the fertilized starfish egg assay.146 This journal is ª The Royal Society of Chemistry 2012


Subsequently, a series of similar farnesylhydroquinone glycosides (175–181), with cytotoxic properties, were isolated from the Korean gorgonian Euplexaura anastomosans.147,148 Compounds 175–179, also known as euplexides A–E, are structurally similar to 174 except that a b-D-galactose sugar moiety replaces the b-D-altrose moiety of the latter compound.147 Additionally, Shin et al.147 have assigned the absolute configuration of the oxygenated chiral centre on the farnesyl side chain of 175 and 176, using the modified Mosher’s method. The euplexides A–E, 175–179, exhibited moderate cytotoxicity (IC50 4.1, 4.6, 8.4, 12.8 and 14.54 mM, respectively) against the K-462 human leukemia cell line and, additionally, all the compounds, with the exception of 178, showed antioxidant properties.147

The isolation of the cytotoxic euplexides F and G (180 and 181) from Euplexaura anastomosans was reported in 2001 by Seo et al.148 and these two novel euplexides were found to be modestly cytotoxic (LC50 15.17 and 19.7 mM respectively) against the K-562 human leukemia cell line.148 This journal is ª The Royal Society of Chemistry 2012

4.3.2 Soft corals. Cytotoxic prenylated toluquinones and hydroquinones have been isolated from the soft coral genera Nephthea,149–151 Sinularia150,152 and Alcyonium.153 Su et al.149 have reported the isolation of the novel naphthoquinone (182) and toluhydroquinone (183) metabolites from the Formosan soft coral Nephthea chabrolii. Both compounds were shown to be weakly cytotoxic against the Hep-G2 (IC50 26.6 and 37.8 mM, respectively) and the MDA-MB-231 breast (IC50 10.1 and 37.0 mM, respectively) cancer cell lines. The naphthoquinone (184), subsequently isolated from the same soft coral, was also found to be moderately cytotoxic against various cancer cell lines.151

The South African soft coral Nephthea sp. collected in Sodwana Bay yielded the bioactive nephthoside (185), while the soft coral Sinularia dura from the same collection afforded the bioactive metabolite sindurol (186).150 Both nephthoside and sindurol were found to be cytotoxic (IC50 3.8 and 2.1 mM, respectively) to P-388 mouse leukemia cells.150 The soft coral Sinularia capillosa collected off the Dongsha Atoll, Taiwan has recently yielded the new metabolite capilloquinol (187), with an unusual cyclic farnesyl moiety, that was found to be cytotoxic (ED50 11.2 nM) against the P-388 leukemia cells.152 Another South African soft coral, Alcyonium fauri, collected over 1000 kms south of Sodwana bay, yielded the cytotoxic sesquiterpene hydroquinone rietone (188).153 Compound 188 exhibited activity (IC50 9.3 mM) in the NCI’s Nat. Prod. Rep., 2012, 29, 513–535 | 529

toluhydroquinones 189–194 from its diet of octocorals (gorgonians and soft corals).

4.4 Molluscs

5

The only example of cytotoxic prenylated quinones or hydroquinones occurring within the phylum Mollusca is the series of ortho-prenylated toluquinones and toluhydroquinones (189–194) isolated by McPhail et al.155 from the South African endemic nudibranch Leminda millecra collected from Algoa Bay, Port Elizabeth. The ortho-prenylated toluquinones and toluhydroquinones 189–194 have shown variable cytotoxic activity against the oesophageal cancer cell line WHCO1, with the metabolite 191 emerging as the most active (IC50 9.5 mM).4,155 Compounds 189–194 have also been reported to induce apoptosis in the WHCO1 cells by triggering the JNK/c-Jun signalling pathway, through the generation of reactive oxygen species.4 Similar to other nudibranchs, it is probable that L. millecra sequesters the prenylated toluquinones and

The biogenesis of antioxidant and cytotoxic prenylated naphthoquinones, e.g. 23, 27 and 32–37 have exclusively dominated biosynthetic studies of marine prenylated quinones. Seto and coworkers’ early study of the biosynthesis of 23 using [1-13C] and [1,2-13C2] labelled acetate identified pentaketide-derived THN (1,3,6,8 tetrahydroxynaphthalene, 195) as the prerequisite polyketide precursor for the biogenesis of this compound.32 THN is a biosynthetic product of a type-III polyketide synthase THN synthase, a common actinomycete enzyme.35 Further 13C NMR evidence was presented for the alkylation of a naphthoquinone nucleus originating from 195, with a mevalonate-derived geranyl residue. A proposed cyclization of the side-chain initiated by epoxidation of the terminal D16 exocyclic olefin and migration of the D12 to a D11 double bond would provide the fused bicyclic


CEM-SS cell line screen, used to identify metabolites with anti-HIV properties,153 and has recently been shown to be mildly cytotoxic against several oesophageal cancer cell lines.154

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Biosynthesis



Scheme 1 Seto and co-workers’ proposed biosynthesis of naphterpin, 23.32 (Bold lines represent doubly enriched [1,2-13C2]acetate labelling patterns).

ether moiety in 23 (Scheme 1). Although methylation of the naphthoquinone nucleus at C-5, via S-adenosyl methionine, was unequivocally established with deuterium labelled methionine, the timing of this methylation in the biosynthetic sequence remained ambiguous.32 Moore and co-workers further confirmed the mixed polyketide–terpenoid origin of prenylated naphthoquinones from their labelling studies of the biosynthesis of debromomarinone, 27, and neomarinone, 32.35 Superficially, 27 differs from 23 in the configuration at C-11 and C-16 and the addition of a farnesyl, as opposed to a geranyl, residue to the same THN-derived naphthoquinone precursor initiating the biosynthesis of 23. Although Moore and co-workers were able to observe significant acetate incorporation of acetate into the naphthoquinone nucleus of 27, neither [1-13C] nor [1,2-13C2] acetate was incorporated into the sesquiterpene side-chain. However, feeding experiments with [1-13C]-glucose, [U13C]-glucose and [13C]-alanine (which is converted in vivo to [3-13C]-pyruvate that can further decarboxylate to [1-13C]-acetate) afforded equally labelled polyketide and terpenoid moieties in 27, thus suggesting that the sesquiterpene-derived


side-chain in 27 is the product of the non-mevalonate pathway,35 and not the mevalonate pathway, as previously suggested for the biosynthesis of 23.32 Interestingly, close inspection of the 13C NMR data acquired for [U13C]-glucose labelled neomarinone (196) revealed a coupling pattern which was clearly inconsistent with the original structure 31 proposed for neomarinone and led to a revision of the structure of this compound to 32.35 Turning their attention to the cohort of chlorinated meroterpenoid napyradiomycin antibiotics 33–37 from the marine sediment-derived Streptomyces strain CNQ-525, the research group at the University of California in San Diego proposed that a chloronium ion initiated side-chain cyclization of the diprenylated intermediate SF2415B1 (197, Scheme 2).42 In a series of elegant experiments, they were able to sequence, clone and heterologously express the CNQ-525 napyradiomycin (nap) gene cluster into S. alba, from which they harvested one new and several known napyradiomycin antibiotics, including 33–37.42,156 Through a bioinformatics analysis of the nap gene cluster, Winter et al.42 were able to provide the first in vivo corroboration of vanadium-dependent haloperoxidase genes (napH1–H4). The recent biochemical characterization of the heterologously expressed NapH1 protein confirmed the role of this enzyme in stereoselective chlorination reactions in the biosynthesis of napyradiomycin antibiotics (Scheme 2).43 Although, seemingly structurally different to 33–37, the pyridazine azamerone (198), isolated from a marine-derived actinomycetales bacterium,157 shares a common biosynthetic pathway with the napyradiomycins156 in which nitrogen is first introduced into intermediate 197 following oxidation of the Nat. Prod. Rep., 2012, 29, 513–535 | 531


Scheme 2 Proposed biosynthesis of napyradiomycin antibiotics 34 and 37 catalyzed by enzymes identified from analysis of the CNQ-525 nap gene cluster (adapted from Winter et al.42,156 and Bernhardt et al.43) Bold lines and dots represent doubly and singly enriched [1,2-13C2]acetate labelling patterns, respectively. Enrichment from L-[methyl-13C]methionine is represented by a dotted line.

naphthyl ring at C-5. Winter et al.156 further proposed that diazotization of the C-5 amino group with nitrous acid followed by a subsequent Baeyer–Villiger-type oxidation of the diazonaphthoquinone (199) would yield the intermediate (200). Hydrolysis of the lactone ring in 200, Wagner–Meerwein-type

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rearrangement of the monoterpene moiety and assembly of the pyradazine ring through nucleophilic addition of the diazo functionality to the keto-tautomer at C-8, finally followed by both decarboxylation and dehydration, would ultimately afford 198.156 Hypothetical biosynthetic sequences have been proposed for the cyclization of the farnesyl side chain in several of the prenylated quinone metabolites isolated from marine organisms.19,72,89,90,95 Recently Garson and co-workers158 drew attention to the co-ocurrence of the sesquiterpene quinones, (+)-hyatellaquinone (201) and ()-illimaquinone (202) and a series of closely related analogues in a Dysidea sponge. The presence of both 201 and 202 in a single sponge specimen is unusual as their biogenesis requires a series of rearrangement reactions around the putative antipodal carbocation intermediates (203) and (204), respectively. Garson and co-workers158 suggest that the occurrence of antipodal terpene precursors in sponges may reflect either precursor binding preferences of a single cyclase enzyme or the presence of multiple terpene synthase enzymes in these organisms. They use this example to stress the importance of the careful assignment of absolute configuration in related prenylated quinones isolated from marine organisms by natural products chemists.158 This journal is ª The Royal Society of Chemistry 2012

the terpenoid moiety has little significant influence on the biological activity of sesquiterpene quinones and hydroquinones from marine sponges,3 may possibly be extrapolated to the other prenylated metabolites discussed in this review.


7

Acknowledgements

Financial support from Rhodes University, DAAD, South African Medical Research Council, National Research Foundation and the Department of Environmental Affairs through the SeaChange Programme is gratefully acknowledged.

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References 1 2 3 4 5 6 7

6 Conclusion

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With the inclusion of the sesquiterpene quinones and hydroquinones (e.g. 108 and 109) from marine sponges, which have been recently reviewed elsewhere3 and are not included in this review, approximately 260 cytotoxic/antioxidant prenylated quinones, hydroquinones and naphthoquinones have been isolated from at least ten marine phyla over the last four decades. There appears to be a reasonably consistent correlation between phyletic distribution and substitution patterns around either the quinone, hydroquinone or naphthoquinone nuclei of these compounds. Exceptions to this general trend may suggest a microbial origin for metabolites, which may previously have been erroneously reported as products of a macro-invertebrate or marine algal secondary metabolism. The isolation of three, structurally simple, prenylated hydroquinones (e.g. 1 and 151) and naphthoquinone (e.g. 103) from both marine and terrestrial sources is of interest and is suggestive of either convergent biosynthesis or a common microbial origin for these compounds. The polyketide and terpene mixed biosynthetic origin of several prenylated naphthoquinones from marine-derived bacteria has been unequivocally established. These biosynthetic studies have not only provided evidence that the prenylated side-chains may arise from either mevalonate or non-mevalonate pathways but have also afforded the first in vivo verification of vanadiumdependent haloperoxidases and, subsequent to this, the important discovery of the first biochemical characterization of a bacterial vanadium-dependent chloroperoxidase (NapH1). The pharmacophore, seemingly responsible for the cytotoxicity of these naturally occurring secondary metabolites, appears to be the quinone, hydroquinone or naphthoquinone nucleus.57 The general IC50 cytotoxicity values for the group of compounds presented here averages in the low micromolar range. A notable exception is the IC50 cytotoxicities of the microbial chlorinated naphthoquinones 34–37, which are reported at low nanomolar levels. Therefore, Gordaliza’s observation that the structure of

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