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REVIEW

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Fungal phenalenones: chemistry, biology, biosynthesis and phylogeny Cite this: Nat. Prod. Rep., 2014, 31, 628

Mahmoud F. Elsebai,*abc Muhammad Saleem,*d Mysore V. Tejesvi,b Marena Kajula,c b Sampo Mattila,*c Mohamed Mehiri,*e Ari Turpeinenc and Anna Maria Pirttila ¨*

Covering up to the end of August 2013 Received 12th September 2013

Phenalenones are members of a unique class of natural polyketides exhibiting diverse biological potential. This is a comprehensive review of 72 phenalenones with diverse structural features originating from fungal

DOI: 10.1039/c3np70088g

sources. Their bioactive potential and structure elucidation are discussed along with a review of their

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biosynthetic pathways and the taxonomical relationship between the fungi producing these natural products.

1 2 3 4 5 6 7 8 9 10 10.1

Introduction Heptaketide phenalenones Hexaketide phenalenones Acetone adducts of phenalenones Homodimers of phenalenones Oxyphenalenones Heterodimers of phenalenones Metal complexed phenalenones Pyrrole- and oxazole-containing phenalenone compounds Biosynthesis of phenalenones Labeling studies and proposed biosynthesis of methyl phenalenones 10.2 Artifacts versus biosynthesis of phenalenones 11 The taxonomical relationship between the fungi producing phenalenone derivatives 12 Conclusion 13 References

1

Introduction

Phenalenones are a unique class of fused three-ring systems of hydroxyl-perinaphthenones. This group of natural a

Department of Pharmacognosy, Faculty of Pharmacy, Mansoura University, Egypt. E-mail: [email protected]

b

Department of Biology, University of Oulu, PO Box 3000, FIN-90014 Oulu, Finland. E-mail: am.pirttila@oulu.

c Department of Chemistry, University of Oulu, PO Box 3000, FIN-90014 Oulu, Finland. E-mail: sampo.mattila@oulu. d

Department of Chemistry, Baghdad-ul-Jadeed Campus, the Islamia University of Bahawalpur, 63100-Bahawalpur, Pakistan. E-mail: drsaleem_kr@yahoo. com

e

Nice Institute of Chemistry, UMR CNRS 7272, Marine Natural products team, UFR of Sciences, University Nice Sophia Antipolis, France. E-mail: Mohamed.MEHIRI@ unice.fr

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products showed diverse and signicant biological activities, including antimicrobial, anticancer and cytotoxic activities. Owing to the medical potential of this nucleus, a PCT patent describes the production and use of methyl phenalenones by fermentation of Penicillium herquei DSM 14142 and phenalenone derivatives. The invention also claimed uses of phenalenones to treat tumors, bacterial infections and/or mycoses and rheumatic diseases.1 Chemists have also synthesized many phenalenone derivatives bearing signicant biological activity.2–17 Phenalenone derivatives have been reported both from higher plants and microbial sources,18 and possess signicant biological and chemical importance. Despite their importance, this class of natural polyketides did not receive due attention, therefore, to explore these compounds further, we have focused on phenalenone derivatives, especially of fungal origin. Fungal phenalenones have been isolated as heptaketides, hexaketides (naphthalene derivatives), homodimers and heterodimers; reecting their chemical diversity. In this review article, we describe and summarize the occurrence, chemistry, biological activity and biosynthesis of fungal phenalenones and the phylogenetic relationship between the fungal producer strains. Phenalenone (1) and its derivatives have been identied as polluting substances resulting from combustion of fossil fuels. Phenalenone (1) itself was found to be mutagenic in Salmonella typhimurium TM677 and TA100 in the presence of rat liver postmitochondrial supernatant,19,20 toxic to a few species of microalgae,21 and carcinogenic in newborn mouse lung.19 In 1955 and 1956, the phenalene (2) nucleus was identied as a natural product from the fungi imperfecti and a monocotyledonous plant.18,22 Based on the number of primer units or number of carbon atoms in the precursor, and due to oxidative

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derivatization, phenalenones are classied into various subgroups.

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2 Heptaketide phenalenones The rst natural phenalenone derivatives: (+)-atrovenetin (3) and (+)-deoxyherqueinone (4) were isolated from the fungus Penicillium atrovenetum.23 Later, compound 3 was also isolated from P. herquei14,24 and P. paraherquei.25 Two tautomeric forms (between CO-5 and CO-7) of compound 3 were reported and their structures were substantiated by X-ray analysis,26,27 whereas, the absolute conguration at C-15 was determined as R through chemical derivatization.28 Atrovenetin (3) has

Mahmoud Elsebai graduated from the faculty of Pharmacy, University of Mansoura, Egypt, where he obtained his Master’s degree (Pharmacognosy Department). He obtained his PhD in 2011 from Bonn University, Germany, in the eld of chemistry and biology of marine natural products. In 2013, he received a grant to work in France collaborating with Dr Mohamed Mehiri. Currently he is a post-doc researcher at the departments of Biology and Chemistry, University of Oulu, Finland, under supervision of Dr Anna Maria Pirttil¨ a and Dr Sampo Mattila to work on eradication of hepatitis C virus using an Egyptian plant.

Mysore V. Tejesvi graduated in 2001 in Biotechnology from the University of Mysore, India, where he obtained his PhD in 2008. He focused on the molecular diversity of endophytic Pestalotiopsis species and their bioactivities. He then pursued his postdoctoral research with a CIMO fellowship, followed by a Marie Curie International Incoming fellowship to work on antimicrobial natural products of endophytes and unculturable microbes of Northern medicinal plants, under the guidance of Anna Maria Pirttil¨ a and Sampo Mattila, University of Oulu, Finland. He is currently focusing on the use of metagenomics to exploit unculturable endophytic fungal natural products and peptides.

Muhammad Saleem received his PhD in 2001 under supervision of Dr Muhammad Shaiq Ali (University of Karachi, Pakistan). He then joined the Pakistan Council of Scientic and Industrial Research Laboratories, Karachi, where he worked on applied pharmaceutical and cosmeceutical aspects of natural products. During 2003–2005 he worked as postdoctoral fellow and Visiting Scientist at KIST (with Prof. Yong Sup Lee, Seoul, South Korea). In 2006, he worked as Alexander von Humboldt Fellow at the University of G¨ottingen, Germany. He also worked with the late Prof. Karsten Krohn (University of Paderborn, Germany, 2010) and Prof. Harald Gross (University of Bonn, Germany, 2011). Currently, Dr Saleem is working as Associate Professor of Chemistry at the Islamia University of Bahawalpur, Pakistan, where he is leading a research group. His research interests are the discovery of new drug candidates from medicinal plants from the Cholistan Desert and the endophytes associated to them.

Sampo Mattila obtained his PhD at the University of Oulu in 2001. He was a post-doc at Purdue University, USA, during 2001–2004, and is now back at the University of Oulu as an Assistant Professor. His research is done in the Structural Elucidation Chemistry unit, which is part of the Bioeconomy Research Community Oulu (BRC-Oulu). His group's main tools are NMR spectroscopy and Mass spectrometry and he has found out on numerous occasions that it takes exactly the same time to solve a structure of a novel compound as one that is already published.

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been reported as an antioxidant,25 inhibiting the growth of Staphylococcus aureus, Bacillus subtilis, B. mycoides, Sarcina lutea, streptomycin-resistant gram-positive organism of the Subtilis group and Klebsiella pneumonia.29 (+)-Deoxyherqueinone (4) was also puried as antibacterial agent29 from the fungus P. herquei14,30 and from the Penicillium strain A-232.31 The absolute conguration was determined as R based on the specic optical rotation +121 .32 Erabulenol A (5) was identied as a product of the fungus Penicillium sp. FO-5637 as a positional isomer of 4 with S conguration at C-15. It acts as a prophylactic and therapeutic agent for atherosclerotic diseases through inhibition of cholesteryl ester transfer protein (CETP).33–35 Herqueinone (6), a red or copper-colored pigment, is also known as a product of Penicillium fungi and was isolated from P. herquei,36 P. atrovenetum23 and P. diversum var. aureum.37 Compound 6 was characterized by the means of chemical degradation and spectroscopic interpretation. The absolute conguration at C-15 was determined to be R due to chemical derivatization and the absolute conguration at C-1 was determined to be S on the basis of anisotropic effect of the carbonyl group (C-2) on the geminal dimethyl group in the 1HNMR spectrum. The latter was further substantiated by X-ray crystallography.38–40 P. herquei further produced isoherqueinone (7), the C-15 stereoisomer of 6, and ()-isonorherqueinone (8).28 Compound 7 exhibited very weak activity in autoxidation and synergism with tocopherol.41–43 Barton et al.23 puried (+)-norherqueinone (9) from the fungus P. atrovenetum. Although compounds 3 and 4 have a skeleton similar to the ones of antimicrobial compounds 6 and 9, they showed no antimicrobial activity,29 which indicates that the hydroxyl groups at C-2 and C-9 might have an important role in the activity. Erabulenol B (10), a C-10 benzyl derivative of 6, was isolated from the cultures of the fungus Penicillium sp. FO5637. It acts as a prophylactic and therapeutic agent for atherosclerotic diseases through inhibition of cholesteryl

ester transfer protein (CETP) and exhibited antibacterial activity.33–35 (+)-Atrovenetinone (11) is a dark-purple compound that was extracted from the cultures of Sirococcus 35B strain (UAMH 5401).44 Similarly, ()-atrovenetinone or ent-atrovenetinone (12), a dark burgundy compound which causes a green discoloration on contact with the skin and a blue-green discoloration of paper, was obtained from Gremmeniella abietina27,45 and from the marine-derived fungus Coniothyrium cereale.46 Nakanishi et al.47 have reported the isolation of 12 from P. verruculosum IAM-13756, but without a sign of optical rotation. Conioatrovenetinone (13) was produced by the fungus C. cereale.46 Rousselianone A (14) is a novel antibiotic that was found in the culture extracts of the fungus Phaeosphaeria rousseliana48 and from the marinederived fungus Nigrospora sphaerica.49 It was the rst phenalenone derivative containing a glycol moiety at C-6 and an isoprene unit as a noncyclised side chain, which is an uncommon feature among the phenalenone class of compounds. Compound 14 exhibited broad-spectrum antifungal activity in vivo against various plant pathogens48 and showed activity as antitumor agent or immunoadjuvant.49 Cillianone (MBA 176-19B; 15) is the structural isomer of 14 since the prenyl side chain is cyclized into a trimethyl-dihydro-furan ring with R conguration at C-15. This compound was also isolated from the culture of the fungus Phaeosphaeria rousseliana as antifungal agent against Botrytis cinerea in cucumber.50 Later 15 was also obtained from Penicillium sp. HAG 0259 and it showed antagonism of interleukin 4.51 Atrovenetinone methyl acetal MS-323 (16) was obtained as a mixture of diastereoisomers from Penicillium species.47,52 Compound 16 inhibited calmodulin-dependent activity of myosin light chain kinase with an IC50 value of 3.7 mM,47 inhibited HIV-1 integrase with an IC50 value of 19 mM and showed anti-HIV activity with an IC50 value of 6.7 mM.52

Mohamed Mehiri, born in 1978 in Nice (France), is Assistant Professor at the Chemistry Institute of Nice, France. Aer a post-doc experience at Lehight University under the supervision of Dr Steven Regen, he was hired at the University of Nice Sophia Antipolis in 2008 in the Marine Natural Products group with Dr Philippe Amade. His research interests encompass the isolation and structural elucidation of bioactive secondary metabolites from marine invertebrates, mostly sponges, and the synthesis of interesting chemical structures initially produced by selected sponges.

Anna Maria Pirttil¨ a graduated in Biochemistry, University of Oulu, Finland, in 1996 and obtained her PhD in plant physiology in 2001 with the topic “Endophytes in the buds of Scots pine (Pinus sylvestris L.)”. She has gained post-doctoral experience during 2001–2004 at Purdue University, Indiana, USA, and obtained a Docentship (Adjunct Professor in Molecular Plant and Microbiology) in 2004, and Assistant Professorship in 2006 at the Department of Biology, University of Oulu. She leads a research group concentrating on plant-endophyte interactions in plant development and defence. The research is focused on northern plant species and forest trees.

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Review

()-Scleroderolide (17), a yellow pigment, has been reported from the fungi Godronia abietina,27 G. cassandrae53 and Penicillium sp. FO-5637.34 Recently the same compound was also isolated from the culture extract of the marinederived fungus C. cereale.54 The structure was proved by an Xray crystallographic study of the racemic 9-monoacetate derivative27 and extensive spectroscopic data.54 Scleroderolide (17) is the rst natural product to be reported that contains a

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phenylglyoxylate lactone functionality (a-keto-lactone). It exhibited antimicrobial activity against S. aureus, Micrococcus luteus, B. subtilis, Bacteroides fragilis, Pyricularia oryzae and Mycobacterium phlei. Moreover, preliminary tests have revealed that a 20-ppm solution of 17 inhibited 100% germination of lettuce seeds.53 (+)-Scleroderolide (18), a stereoisomer of 17, was also isolated from culture of the fungus G. abietina,55 whereas, conioscleroderolide (19) was

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isolated from C. cereale.54 Conioscleroderolide exhibited the antimicrobial activity similar to compound 17 and had an MIC of 24 mM towards S. aureus SG 511, which indicates that the presence of the a-keto-lactone ring in the tricyclic skeleton of both compounds might be responsible for antimicrobial activity.54

()-Sclerodin (20) and (+)-sclerodin (21) are pale yellow compounds exhibiting a strong blue uorescence. Both compounds were isolated from cultures of G. abietina.55 In other reports, the compounds 20 and 21 were isolated as a racemic mixture from the cultures of G. cassandrae53 and Sirococcus 35B strain (UAMH 5401),44 and exceptionally from the roots of the plant Peucedanum praeruptorum.56 Compound 20 has also been isolated from C. cereale,54 P. herquei,57 Roesleria pallida,58 Aspergillus silvaticus,59 R. hypogea,60 and Scytalidium sp.61; and 21 has been isolated from Fusicoccum putrefaciens.62 The absolute conguration at C-15 was determined by chemical derivatization and specic optical rotation.54,57 Preliminary tests have revealed that these compounds inhibit germination of lettuce seeds.53 The phenolic 8-OH()-sclerodin (22) and the alcoholic ()-sclerodinol (23), the derivatives of 20, have been reported as yellow substances from C. cereale.54 Coniosclerodin (24) and its oxidative products (Z)-coniosclerodinol (25) and (E)-coniosclerodinol (26) were also isolated from the fungus C. cereale.54 The same fungus yielded lamellicolic anhydride (27),54 which had earlier been reported from another fungus Verticillium lamellicola.63,64 Upon antimicrobial evaluation,54 compounds 23 and 25 exhibited clear inhibition zones against Mycobacterium phlei, whereas, no antibacterial activity was observed for 27, which indicates that the prenyl group plays an important role in inhibiting bacterial growth. Furthermore, compounds 19, 21 and 24 exhibited signicant activities against human leucocyte elastase enzyme (HLE) with IC50 values of 13.3, 10.9 and 7.2 mM, respectively.54

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()-Sclerodione (28) is a red acenaphthenequinone derivative isolated from G. abietina45 and from C. cereale,54 whereas, (+)-sclerodione (29) was reported from G. abietina.55 Both the compounds are considered the rst acenaphthenquinone derivatives isolated from natural sources. Coniothyrium cereale has yielded another compound, coniosclerodione (30), an analogue of 28.54

Herqueichrysin (31) was puried from the culture extract of P. herquei as a potential antibacterial agent. Compound 31 inhibited growth of B. subtilis and S. aureus in a serial tube dilution analysis at the concentration of 1 mg mL1.14,65 It was fully characterized by spectroscopic methods, derivatization and using feeding experiments.14,66,67 Herqueichrysin (31) is the only phenalenone compound containing the isoprenoid

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unit between C-1 and C-2. ()-Cereolactone (32) and coniolactone (33) have been reported from the marine-derived fungus C. cereale54 and considered as the rst natural products containing a lactone moiety condensed to naphthoquinone. ()-Cereolactone (32) is also reported from G. abietina.45

3 Hexaketide phenalenones

Sculezonones A (34) and B (35) are known as new representatives of inhibitors of DNA polymerases, because both the compounds inhibited bovine DNA polymerases a and g with IC50 values of 17 and 90 mM, respectively.68 Therefore, they can be potential candidates for new anticancer drugs. These compounds were isolated from Penicillium sp. of the Okinawan marine bivalve Mytilus coruscus.69 Their structures were determined through spectroscopic data, whereas the absolute stereochemistry at C-6 was established to be S by measuring the CD spectra. Sculezonone A (34) was also obtained from the culture of Nigrospora sphaerica and is used in medical preparations as an antitumor agent or an immunoadjuvant.49 Aurantionone (36) is a yellow crystalline compound with a phenalenedione nucleus that was isolated from the fungus P. aurantiovirens as a potent antioxidant and found to exhibit a synergic effect with tocopherol.41,42 Funalenone (37) was isolated from the mycelium of Aspergillus niger FO-590470 and from Aspergillus tubingensis, a fungal strain from the rhizosphere of a Sonoran Desert plant.71 Funalenone (37) inhibited type I collagenase (MMP-1),70 showed antibacterial activity72 and inhibited HIV-1 integrase with an IC50 value of 10 mM.52 Myeloconone A2 (38) has been reported as a constituent of the lichen Myeloconis erumpens.73 The compounds 37 and 38 represent a complete heptaketide phenalenone skeleton without prenylation.

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The aforementioned methyl phenalenones are derived biosynthetically from a heptaketide, or a heptaketide minus one carbon with or without prenylation. The current section describes methyl phenalenones that are derived from a hexaketide and a hexaketide minus one carbon. Among them are the four antibiotics, (+)-trypethelone (39), trypethelone methyl ether (40), methoxytrypethelone methyl ether (41), and 40 -hydroxy-8-methoxytrypethelone methyl ether (42), which were isolated from cultures of a mycosymbiont of the tropical cortical lichen Trypethelium eluteriae Sprengel. The structures were determined by spectroscopic analysis, whereas the absolute conguration R was determined by CD spectra and optical rotation measurements.74 Compounds 39, 40 and 42 were also isolated from the cultured mycobiont of Astrothelium sp.75

Coniothyrium cereale was also found to produce structurally the most unusual polyketide-type alkaloids: ()-trypethelone

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(43), cereoanhydride (44), ()-cereolactam (45), conioimide (46) and ()-cereoaldomine (47), incorporating a lactam; an unprecedented isoindole unit; and imine functionality in 45, 46, and 47, respectively. Their structures were established from extensive NMR spectroscopic investigations and X-ray crystallography. The absolute conguration was determined based on CD spectra and optical rotation values.76,77 Compounds 45–47 exhibited selective inhibition of human leukocyte elastase (HLE) with IC50 values of 9.28, 0.69 and 3.01 mM, respectively. Compound 43 is antibacterial against M. phlei, S. aureus and E. coli and exhibited cytotoxicity against mouse broblast cells (IC50 ¼ 7.5 mM).76,77

was not evaluated for such activities. FR-901235 (49) is a new type of immunoactive substance produced by an imperfect fungus Paecilomyces carneus F-4882.78 This compound has immunomodulatory effect, because the mitogen-induced lymphocyte proliferation suppressed by immunosuppressive factor was restored to normal levels by addition of 49. Administration of 49 also partially restored an impaired delayed-type hypersensitivity DTH reaction to sheep red blood cells SRBC in tumor-bearing mice by an ED50 of 16 mg mL1. However, this compound was inactive against E. coli, P. aeruginosa, B. subtilis, S. aureus, C. albicans, Aureobasidium pullulans and A. niger. 49Derived demethyl FR-901235 (50) was isolated from Penicillium sp. JP-1, an endophytic fungus originating from the inner bark of the mangrove tree Aegiceras corniculatum,79 whereas the acetone adduct 51 has been reported from many fungal strains.45,46,61,80

4 Acetone adducts of phenalenones Rousselianone A0 (48) is an acetone adduct that has been isolated from the culture of Phaeosphaeria rousseliana.48 In contrast to antimicrobial rousselianone A (16), compound 48

Fig. 1

Acetonation of juglone derivatives to check the artefact.

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The above-discussed compounds 48–51 can be declared as acetone adducts depending on biosynthetic considerations. Otomo et al.81 separated two juglone derivatives (Fig. 1), which were dissolved in acetone containing KHCO3 and stirred at room temperature. No expected acetone-derived naphthalenone derivatives were obtained, which indicated that the acetonederived naphthalenones are naturally occurring compounds and not artefacts. However, the above conclusion might not be authentic, because the absence of optical activity in acetone adducts revealed that two enantiomers are present, which could be the result of unselective addition of acetone to the natural

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molecule. Therefore further studies using labelled acetone or feeding experiments should be done to give a nal and correct answer to this issue.

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5 Homodimers of phenalenones Scleroderris blue (52) is a blue-green pigment of bis(phenalenyl) imine which was puried from G. abietina,55 new Brunswick strain of G. abietina,82 R. hypogea,60 G. cassandrae,53 Sirococcus 35B strain (UAMH 5401),44 P. herquei57 and Polytolypa hystricis.80 In an antifungal assay, 52 exhibited no activity against Ascobolus furfuraceus,45,46,61,80 but preliminary tests have revealed that it inhibits germination of lettuce seeds.53 A green pigment; scleroderris green (53) has also been reported from the culture of G. abietina.53,82 This compound has a secondary amine function between two phenalenone moieties. Another compound; scleroderris yellow (54) was isolated from cultures of G. cassandrae,53 having a methylene moiety between two monomers.

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isolated rat liver mitochondria,92 having a marked uncoupling effect on oxidative phosphorylation by rat liver mitochondria at a dose of 25 nM mg1 protein.93 Growth inhibition of murine leukemia L-1210 culture cells by 55 and related compounds is in the order duclauxin z desacetylduclauxin > the semisynthetic N-methylduclauxamide > duclauxamide, meaning that 55 exhibited the strongest effect on mitochondrial respiration.94 Other analogues; cryptoclauxin (57) and xenoclauxin (58) have also been reported as the constituents of the fungus P. duclauxi.95 Compounds 56 and 58 were examined for their effects on the growth of L-1210 murine leukemia cells, on the induction of DNA repair in the rat and mouse hepatocyte primary culture (HPC/DNA repair test), and on oxidative phosphorylation in mitochondria from rat livers in comparison to 55. Both the compounds 56 and 58 inhibited the growth of L-1210 culture cells with a similar potential to 55. Xenoclauxin (58) exhibited a potent uncoupling effect accompanying a marked depression of state 3 respiration of mitochondria in a similar fashion to that of 55, whereas, 56 signicantly inhibited the state 3 respiration without causing uncoupling of oxidative phosphorylation in mitochondria. Evidently, 56 and 58 from P. duclauxii are not genotoxic but are cytotoxic mainly due to their potent inhibition of ATP synthesis in mitochondria.87

Oxyphenalenones

The oligophenalenone dimer duclauxin (55), a lipophilic phenol compound with a lactone ring, has been reported as the metabolite of P. duclauxi,83 P. herquei (ATCC 34665)84 and P. stipitatum.85 The full structure and absolute stereochemistry were determined by X-ray determination of monobromoduclauxin.86 Acetyl derivative of 55, desacetylduclauxin (56), was also reported from the fungus P. duclauxi.83,87 Compound 55 exhibited antitumor activity as demonstrated by its effects on protein and nucleic acid formation in various in vitro test systems.88–91 Duclauxin (55) is not effective against Grampositive and Gram-negative bacteria, fungi, or viruses, but a concentration-dependent inhibition of wheat coleoptile growth has been reported.84 Duclauxin (55) has also been reported as an inhibitor of respiration in tumor cells and

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Bacillosporins A–C (59–61) were discovered from the fungus Talaromyces bacillosporus.96 Compound 59 has antibacterial activity against B. subtilis and Sarcina lutea, whereas the three metabolites have no mutagenic activity in mutation tests with Salmonella typhimurium. Bacillosporin C (61) along with bacillosporin D (62) was further isolated from the mangrove endophytic fungus SBE-14 from the South China Sea.97 Bacillosporin C (61) was also found among the metabolites of the fungus ZZF13 isolated from the leaves of the mangrove sample Kandelia candel in Zhanjiang.98 T. bacillisporus also produced bacillosporin E (63) together with 55 and 59–61.99 All of these compounds (55, 59–63) were evaluated for cytotoxicity against three human cancer cell lines, and bacillisporin A (59) was highly active against MCF-7 and NClH460 and moderately active against SF-268. Three compounds (55, 60 and 61) were moderately active against all the three cell lines.99 An important point to note is that the chemical structure of bacillosporin D (62) in ref. 99 is not the same as that found in the SciFinder data base, and in turn bacillosporin E (63) is missing from SciFinder. We assume that the structure of compound 63 is the acetyl derived form of 62. This issue needs to be addressed for revision and conrmation. Gilmaniellin (64) and dechlorogilmaniellin (65), constituents of Gilmaniella humicola BARRON were fully identied by spectroscopic and X-ray analysis.100 Their absolute conguration was determined from their chiroptical data by applying the coupled-oscillator theory to the CD couplet around 272 nm and from the sign of its n / p* Cotton effect.101 More recently, the oxaphenalenones corymbiferan lactone E (66) and neonectrolide A (67) were isolated from cultures of the fungus Neonectria sp. The absolute conguration of 67 was assigned by electronic CD (ECD) calculations.102

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fungus P. herquei also produced a blue pigment whose structure was determined as 72, which is a zinc complex of the elemental formula C76H64O20N2Zn, in which two anions of the dimeric phenalenone scleroderris blue (52) act as the tridentate ligands.57

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9 Pyrrole- and oxazole-containing phenalenone compounds Most recently, herqueiazole (73) and herqueioxazole (74) polyaromatic metabolites, with a novel phenlenone-derived skeletal class, were isolated from the marine derived fungus Penicillium sp.103 Their structures were determined to be the rst examples of pyrrole- and oxazole-containing phenalenone compounds, respectively.

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Heterodimers of phenalenones

Chemical analysis of the culture extract of the fungus C. cereale46 has revealed that this fungus has a spectacular ability to combine sterols with phenalenones to give a unique combination of two different classes of natural products. In contrast to the heterodimers produced by Sirococcus 35B, the fungus C. cereale produces the heterodimers as pure epimers, such as compounds 68 and 69. Another fungus, which has such ability, is Sirococcus 35B strain (UAMH 5401).44 This fungus produced compounds 68 and its epimer 70 as a mixture of epimers regarding the stereogenic centre of the phenalenone moieties.

8 Metal complexed phenalenones Metal complexes with secondary metabolites are not a common feature of natural products. Very few organisms have been observed to produce such chemicals. For example the nickel complex (71) with two molecules of scleroderris blue has been isolated from two different fungi: R. hypogea60 and P. herquei.57 The structure of this complex was elucidated by microanalysis and nickel estimation with X-ray uorescence and dithizone. The

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10 Biosynthesis of phenalenones 10.1 Labeling studies and proposed biosynthesis of methyl phenalenones Thomas22 stated that the fungal phenalenones are polyketides, unlike the plant phenalenones which are derived from shikimates.18 This statement was conrmed by the feeding experiment with labelled acetate on deoxyherqeinone (4), which is a typical phenalenone compound.66,67 In this experiment it was demonstrated that the fungal phenalenone nucleus originates from a heptaketide, which cyclises to a tricyclic aromatic ring system, or as a prenyl side chain, as depicted in Fig. 2. Ayer et al.104 studied the biosynthetic origin of carbon atoms of the oxygenated ring (ring C) of phenalenones, i.e. C-5 to C-7 of compounds scleroderolide (17), sclerodin (20) and sclerodione (28) in the fungus G. abietina. The fungus was grown in liquid still culture supplemented with sodium [l-13C]acetate and of sodium [2-13C]-acetate, separately. Examination of the 13C NMR spectrum of sclerodione (28), isolated from the culture containing [1-13C]-acetate, revealed that carbons 2, 4, 5, 7, 9, 11, 14, 16 and 17 were enriched in relation to the natural abundance spectrum. When sclerodione (28) was isolated from the culture containing [2-l3C]-acetate, carbons 1, 3, 8, 10, 12, 13, 15, 18 and 19 were enriched. The authors stated that these results are fully consistent with the hypothesis of formation of sclerodione (28) by loss of CH3 from an acetate unit. The 13C NMR spectrum of sclerodin (20) showed the same labeling pattern as that for sclerodione (28), i.e. C-5 and C-7 were enriched. Ayer et al.104 speculated that the triketone entatrovenetinone (12) could be a

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Fig. 2 Results of feeding experiments on deoxyherqueinone (4), sclerodin (20) and scleroderolide (17) and proposed biosynthetic pathways of the other derivatives (12, 19, 28, 68, 69).

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Fig. 3

Labelling studies of trypethelone (43) and proposed biosyntheses for other hexaketides (32–33, 44–47).

precursor of sclerodione (28) by loss of C-6 through oxidative decarboxylation (Fig. 2), and that sclerodione (28) may be a biosynthetic precursor to sclerodin (20) but not to

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scleroderolide (17) (Fig. 2). Therefore, the phenalenone derivatives with a heterocyclic or retracted ring C are formed by oxidative loss of carbon, and thus, the metabolites 17, 20 and 28

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have one carbon atom less than the parent phenalenone heptaketide. Consequently, in the nal skeleton of sclerodin (20) and sclerodione (28), two acetate C1 carbons are neighbouring and the C2 of an acetate precursor unit (C-6) is missing (Fig. 2). In the case of scleroderolide (17), C-5 is derived from C1 of the acetate unit, C-6 is derived from C2 of the acetate unit, and C-7 is missing, indicating decarboxylation of C2 of the last acetate unit. Ayer et al.27,104 suggested that the triketone 12 was the precursor of the dione 28 and the naphthalic anhydride derivative 20 (Fig. 2). Recently, Elsebai et al.76 studied the biosynthetic origin of ()-trypethelone (43) using labelling experiments with 1-13C enriched acetate. The feeding experiment showed enrichment of 13C at positions C-2, C-4, C-9, C-11, C-14, C-16 and C-17. From these results it is clear that compound 43 is a hexaketide with the nal C2-building block being truncated, leaving only one carbon, i.e., C-3 of 43, in the molecule. The higher fungi, mainly Ascomycetes and Basidiomycetes, produce many ergosterol analogues.105 Biogenetically, D5-, D6- and D7-ergosteroids originate from D5,7-ergosterol which is widely distributed in both fungi and marine organisms.106 The co-occurrence of compounds 68, 69 and the ergosterol derivative suggested that the sterol portion of compounds 68 and 69 could also derive from ergosterol.46 The exact mechanism of condensation between the two nuclei is not yet studied, but the co-occurrence of compounds 13, 68 and 69 within the extract of C. cereale may illustrate a possible biogenetic pathway uniting ergosterol and phenalenone derivatives through a free radical pathway (Fig. 2), or a cyloaddition condensation.46 Scleroderolide (17) was also found in this study, together with conioscleroderolide (19), cereolactone (32), and coniolactone (33).46 Their possible biosynthesis pathway is shown in Fig. 2 and 3. Based on the aforementioned biosynthetic studies, C-8 is derived from C2 of acetate, and therefore a post-PKS reaction oxidation on C-8 is possible. For the ketolactone compounds scleroderolide (17) and conioscleroderolide (19), a decarboxylation of the last carbon of the heptaketide chain may occur, followed by lactonization between the newly created carboxylic group (C1 of the terminal acetate unit) and OH-8. This explains why C2 of the terminal acetate unit is missing in the feeding experiments for scleroderolide (17) biosynthesis (Fig. 2).46 Compounds 32–33 and 43–45 are related to metabolites with a phenalenone skeleton (Fig. 3). A hexaketide instead of a heptaketide origin could be proposed for 32–33 and 43–45 to produce a naphthalene skeleton with a biosynthetic origin related to methyl phenalenones. For the formation of the basic skeleton of the compound cereolactam (45), the hexaketide undergoes methylation on C-8 using S-adenosyl methionine, followed by cyclization, aromatization and oxidation of CH3-7 to form a carboxylic group. A transamination at the carbonyl substituted position C-3 and closure of the lactam ring can be proposed (Fig. 3). The skeleton of trypethelone (43) would result from loss of C-5 through aoxidation of the cyclized hexaketide to produce a naphthoquinone derivative. Compound 47 may arise from compound trypethelone (43) through oxidation of CH3-12 into

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Fig. 4 The conversion of side chain isoprene unit into a trimethyldihydrofuran ring through Claisen rearrangement.

an aldehyde group, hydroxylation on C-8, and transamination at the carbonyl-substituted position C-3 (Fig. 3).76,77 According to the proposed biosynthetic pathways of the naphthalene derivatives 32–33 and 43–45 and the reported feeding experiments of the related phenalenone derivatives, the folding of these compounds is unique and not typical F- or S-mode107 because there are two intact and half acetate units in the initial folded ring. Compound 44 may have resulted from trypethelone (43) by enzymatic oxidation between the two carbonyl groups and a second oxidation of the double bond between C-1 and C-14 to produce a dioxa-anhydride derivative (Fig. 3). The presence of a methylene group CH2-1 in compound 46 seems abnormal. According to the architecture of the reported phenalenones54,76,77 produced by C. cereale, they lack reducing moieties in their acetogenic structures, thus their PKSs system either lacks the ketoreductase domain, or is cryptic, which is the normal case with most of PKSs enzymes producing aromatic polyketides. Therefore, the proposed biosynthetic pathway shown in Fig. 3 is reliable since it explains the origin of the methylene group (CH2-1), which does not proceed through the ketoreductase domain, but through dioxygenation, followed by decarboxylation. Also this proposed biosynthetic pathway explains the origin of the nitrogen group and both diones of the pyrrole ring. The skeleton of the spiroketal compound 67 can be derived from the co-isolated putative precursors, corymbiferan lactone E (66) and 3-dehydroxy-4-O-acetylcephalosporolide C.102 The cooccurrence of lamellicolic anhydride (27) with the other sclerodin and coniosclerodin derivatives (20, 22–26) within the culture extract of C. cereale indicates that the backbone skeleton of the phenalenone nucleus is rst formed and then prenylation occurs. The prenylation takes place through C-O14 either to produce a side chain, as in compounds 19, 24–26, 30, 33 and 69, or is further processed through a Claisen rearrangement to produce a furanoid ring, as in compounds 3–12, 15–18, 20–23, 28–29, 32, 39–45, 47, 51–54 and 68. Therefore, the phenalenone derivatives containing an

Fig. 5

Alternative polyketide derivations of the phenalenone ring

system.

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Fig. 6 Incorporation pattern of acetate and malonate into deoxyherqueinone and herqueichrysin.

Fig. 7 Oxa- and azaphenalene derivatives from the plant Lachnanthes tinctoria (pm ¼ plant metabolite).

isoprene unit as a side chain can be represented as a precursor for the one containing a furanoid ring through a Claisen rearrangement (Fig. 4). Also the prenylation occurs as a side chain through C-6 in compounds 34 and 35 and through C-1 in compound 36; and as a furanoid ring in between C-1 and C2 as in compound 31. Many phenalenones and related compounds have been isolated from fungi and from higher plants. The fungal phenalenones contain a methyl moiety at C-11 and are derived from the acetate pathway, whereas the plant phenalenones contain a phenyl moiety at C-11 and are derived from shikimate pathway.18,22 14C-tracer studies have indicated the polyketide origin of the fungal phenalenone nucleus and the mevalonate origin of the C5 side chain.108 The phenolic polyketides can be folded through one of three folding modes, namely foldings a, b and c (Fig. 5).22 Biosynthetic studies by Simpson66,67 on deoxyherqueinone (4) using 13C NMR techniques revealed that the phenalenone skeleton is derived through the alternate folding (b). For deoxyherqueinone (4) and herqueichrysin (31), preliminary experiments with [14C]-acetate indicated that acetate was efficiently incorporated into the phenalenone metabolites. Thus on feeding [1-13C]- and [2-13C]-acetate, the phenalenone ring system is formed by condensation of a heptaketide chain folded as shown in Fig. 6.66,67

10.2

Artifacts versus biosynthesis of phenalenones

The phenalenone nucleus is comparatively stable, although oxidative cleavage probably leads to the formation of naphthalic

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anhydrides. Thus, atrovenetin (3) and deoxyherqueinone (4) are readily converted to the naphthalic anhydride via photochemical oxidation.109 The latter was supported by the fact that the concentration of the anhydride is initially very low and increases with time (within a week) of storage of the crude fungal extracts containing 3 and 4. Therefore, it is possible that the reported anhydride may be the result, at least partially, of the isolation procedure.22 However, the discovery of oxa- and aza-phenalene derivatives; (N-(2-hydroxyethyl)lachnanthopyridone (pm1), and L. tinctoria naphthalide (pm2) in Lachnanthes tinctoria,110 together with the phenyl naphthalic anhydride (pm3) (Fig. 7), is indicative of an enzymatic oxidation of the phenalenone ring in this plant.22 Conrmation of the enzymatic origin of the naphthalic anhydrides is conrmed by the experiments with the fungus C. cereale.46 The fresh fungal biomass was extracted under two different conditions: normal aerobic conditions, and N2 gas. The extracts were analyzed by LC/MS immediately aer extraction and aer one week of extraction. In all four LC/MS measurements, the m/z of signals for ()-sclerodin (20) and coniosclerodin (24) were observed at the same retention time as of the pure compounds. In addition, they were produced in high yield (10 mg L1), which was not signicantly affected by extraction and fractionation procedures designed to minimize photochemical oxidative process. The same phenomenon happened with the fungus Fusicoccum putrefaciens, where (+)-sclerodin (21) was obtained in high yields (from 18 to 24 mg L1)62 when the extraction was done in the dark using solvents pre-treated with sodium metabisulphite. To avoid the formation of acetone adducts 48 and 51, the isolation was done under nitrogen and without using acetone. Hence, these acetonyl derivatives were not observed; rather their genuine triketone compounds were seen.46 Based on the same LC/MS analysis, the signal at m/z 312 Da for the diketone sclerodione was obtained, indicating that the oxidation of triketones 12 and 13 to the diketone sclerodiones 28 and 30 is enzymatically processed. Another point, which indicates the enzymatic origin of the oxidized phenalenones by the fungus C. cereale, is the discovery of compound 44, as the naphthalic anhydride moiety of compound 44 demonstrates the enzymatic oxidation of the naphthlaic anhydrides 20–27. The LC/MS measurements also showed a signal for a compound with the mass of the dione derivatives 28 and 30 at m/z 312 Da, and the masses for naphthalic anhydrides 20 and 24 were found at m/z 328 Da. This was additional conrmation of the enzymatic origin of the dione derivatives (28 and 30) and the naphthalic anhydrides (20–27).46

11 The taxonomical relationship between the fungi producing phenalenone derivatives To study the phylogenetic relationship of the phenalenoneproducing fungal strains, we constructed a phylogenetic tree (Fig. 8) based on sequencing of the Internal Transcribed Spacer region (full length, ITS1-5.8S-ITS2), which were retrieved from

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Fig. 8 Neighbour-joining analysis of Internal Transcribed Spacer 2(ITS2) fungal sequences. The tree was derived from 32 fungal sequences retrieved from GenBank. Branch lengths are scaled in terms of expected numbers of nucleotide substitutions per site, number of branches are bootstrap values (1000 replicates, values below 50% are not shown). The robustness of the phylogeny was tested by bootstrap analysis using 1000 iterations. Branches corresponding to partitions reproduced in less than 50% bootstrap replicates were collapsed. All positions containing gaps and missing data were eliminated from the dataset (Complete Deletion option). The metabolites produced by the fungi are indicated next to the species names.

the GenBank. The ITS2 region was extracted using ITS extractor111 from each sequence and used for the alignment and the phylogenetic study. All sequences were aligned using ClustalX with default settings.112 The phylogenetic analysis was performed by the Neighbour-joining method using Molecular Evolutionary Genetics Analysis (MEGA5).113 The resulting phylogenetic tree of the fungal ITS2 sequences is shown in Fig. 8. Based on the phylogenetic analysis of 32 fungal sequences, the majority of the fungi were distributed to two main clusters. In the rst cluster, there were 28 fungi including Penicillium herquei, Polytolypa hystricis, P. aurantiovirens, P. atrovenntum, Aspergillus niger, Aspergillus tubingensis, Talaromyces bacillisporus, Paecilomyces carneus, Neonectria sp. Sirococcus tsugae, Godronia cassandrae and G. abietina. Other cluster constitutes of Coniothyrium cereale, Phaesphaeria rousseliana and Scytalidium sp. The fungal genera producing unique compounds were clustered together. Even though compounds 3, 4, 6 & 9 are produced by different species such as P. herquei and P. atrovenetum, they were grouped in the same cluster. Compounds 17 and 20 are produced by G. abietina, G. cassandrae and C. cereale. The unique compound 49 is produced only by P. carneus, which was grouped in the rst cluster. Considering the several possibilities for branching in the phylogenetic tree, ITS2 regions might not be sufficient to reconstruct the phylogenetic tree and more genes may be

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needed for a better resolution of the phylogeny with respect to compounds produced. However, all genes are not available in the Genbank at present to accurately draw the phylogeny for additional genes, and true horizontal gene transfer from plants to fungi may exist for different pathway enzyme genes from distant lineages, which would complicate the analysis.114 Study of polyketide synthase genes could shed some light on the mechanisms involved in the production of metabolites combined with multigene concatenation and supertree analysis of fungal genomes. The majority of phylogenetic analyses of fungi are derived from rDNA, whereas protein-coding genes such as RNA polymerases (RPB1 and RPB2), a and b -tubulin, gactin, ATP synthase (ATP6), and elongation factor EF-1 a (TEF1a) are rarely used in fungal phylogenetics and would provide good resolution of phylogenetic relationships.115

12 Conclusion Phenaloenones, a unique class of bioactive natural products with diverse structural features, are mostly produced by the fungi belonging to several genera such as Penicillium, Polytolypa, Aspergillus, Talaromyces, Sclerophora, Phaesphaeria, Cytalidium, Paecilomyces, Neonectria, Sirococcus, Godronia and Coniothyrium. About 72 molecules of this class have been reported until August 2013 from fungal sources. The rich nucleophilic chemistry of the phenalenone nucleus, wherein all

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positions of this nucleus are susceptible to electrophilic attack has been extensively exploited by fungi to cra a bewildering array of structurally intriguing natural substances. This was accomplished through the use of the basic polyketide and isoprene building blocks coupled with some simple oxidative nishing work on the prenylated substrates. The characteristics of phenalenones will encourage the pharmacologists and the organic chemists to devise chemical syntheses to prepare more analogues and create a library of novel compounds to screen and develop them for future medicine for treatment of various diseases. The racemic mixture of (/+) sclerodin (20/21) was also reported to have been isolated from the roots of a plant Peucedanum praeruptorum.56 Also, sclerodione (28) was isolated from the acetone leaf extract of the plant Casimiroa edulis (Rutaceae).116 These two examples are considered as exceptions because the plant phenalenones usually contain a phenyl group at C-11 instead of methyl one and, consequently, it is suspected that in these cases, the compounds were produced by a symbiotic fungus within the plant. The phylogenetic analyses of 32 fungal sequences producing over 60 compounds were analyzed and the majority of the fungi were distributed to two main clusters, irrespective of the compounds produced by them. The unique metaboliteproducing fungi could not be differentiated by using only ITS2 region for the phylogeny, and a multiple gene phylogenetic analysis awaits for further accumulation of structural biosynthesis genes in the Genbank.

13 References 1 Main IPC: C12N001-14.; Secondary IPC: C12R001-80; C07C049-755; C07D307-92. Pat., WO2003068946, 0821; Patent Application Date: 20030204.; Priority Application Date: 20020218. 2 J. Nanclares, J. Gil, B. Rojano, J. Saez, B. Schneider and F. Otalvaro, Tetrahedron Lett., 2008, 49(24), 3844–3847. 3 Y. R. Lee and J. Y. Suk, Tetrahedron Lett., 2000, 41(24), 4795– 4799. 4 B. Meltzheim, K. Kilway, M. Lignell, B. Waegell and F. Tort, Bull. Soc. Chim. Fr., 1996, 133(10), 979–985. 5 G. A. Morrison and P. A. Bradley, J. Chem. Res., Synop., 1996, 8, 360–361. 6 T. Hayashi, T. Takido and K. Itabashi, Nippon Kagaku Kaishi, 1992, 415–419. 7 A. F. Zaher, M. Y. H. Essawi and H. M. R. El-Moua, Bull. Fac. Pharm. (Cairo Univ.), 1990, 28(2), 59–62. 8 R. C. Haddon, S. V. Chichester and S. L. Mayo, Synthesis, 1985, 639–641. 9 M. Noguchi, N. Tanigawa, T. Tamamoto and S. Kajigaeshi, Chem. Lett., 1985, 14(7), 873–876. 10 Y. Miki, N. Nishikubo, Y. Nomura, H. Kinoshita, S. Takemura and M. Ikeda, Heterocycles, 1984, 22(11), 2467–2470. 11 T. Sato and M. Yokote, J. Synth. Org. Chem. Jpn., 1982, 40(9), 839–843.

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12 S. L. Solodar and V. A. Kochkin, Zh. Org. Khim., 1982, 18(8), 1779–1780. 13 T. Sato and M. Yokote, J. Synth. Org. Chem. Jpn., 1981, 39(7), 654–658. 14 D. A. Frost, D. D. Halton and G. A. Morrison, J. Chem. Soc., Perkin Trans. 1, 1977, 2443–2448. 15 D. A. Frost and G. A. Morrison, J. Chem. Soc., Perkin Trans. 1, 1973, 2388–2396. 16 D. A. Frost and G. A. Morrison, J. Chem. Soc., Perkin Trans. 1, 1973, 2159–2169. 17 D. D. Halton and G. A. Morrison, J. Chem. Res. (S), 1979, 1, 4–5. 18 R. G. Cooke and J. M. Edwards, Prog. Chem. Org. Nat. Prod., 1981, 40, 153–190. 19 J. L. Durant, W. F. Busby Jr., A. L. Laeur, B. W. Penman and C. L. Crespi, Mutat. Res., Genet. Toxicol., 1996, 371(3–4), 123–157. 20 J. Wang and W. F. Busby Jr, Fundam. Appl. Toxicol., 1996, 33(2), 212–219. 21 K. Winters, J. C. Batterton and C. Van Baalen, Environ. Sci. Technol., 1977, 11(3), 270–272. 22 R. Thomas, Pure Appl. Chem., 1973, 34(3–4), 515–528. 23 D. H. R. Barton, P. De Mayo, G. A. Morrison and H. Raistrick, Tetrahedron, 1959, 6, 48–62. 24 N. Narasimhachari, K. S. Gopalkrishnan, R. H. Haskins and L. C. Vining, Can. J. Microbiol., 1963, 9, 134–136. 25 Y. Ishikawa, K. Morimoto and S. Iseki, J. Am. Oil Chem. Soc., 1991, 68(9), 666–668. 26 I. C. Paul and G. A. Sim, J. Chem. Soc., 1965, 1097– 1112. 27 W. A. Ayer, Y. Hoyano, M. S. Pedras, J. Clardy and E. Arnold, Can. J. Chem., 1987, 65(4), 748–753. 28 J. S. Brooks and G. A. Morrison, J. Chem. Soc., Perkin Trans. 1, 1974, 2114–2119. 29 N. Narasimhachari, B. N. Vasavada and S. Viswanathan, Experientia, 1965, 21(7), 376. 30 N. Narasimhachari and L. C. Vining, J. Antibiot., 1972, 25(3), 155–162. 31 N. Imamura, T. Ishikawa, K. Takeda, H. Fukami, A. Konno and R. Nishida, Biosci., Biotechnol., Biochem., 2001, 65(9), 1965–1969. 32 R. G. Cooke, E. L. Ghisalberti, B. L. Johnson, C. L. Raston, B. W. Skelton and A. H. White, Aust. J. Chem., 2006, 59(12), 925–930. 33 N. Tabata, H. Tomoda and S. Omura, J. Antibiot., 1998, 51(7), 624–628. 34 H. Tomoda, N. Tabata, R. Masuma, S. Y. Si and S. Omura, J. Antibiot., 1998, 51(7), 618–623. 35 Main IPC: C07D307-77.; Secondary IPC: A61K031-34; C12N001-14; C12P017-04; C12P017-16; C12R001-80. Pat., JP10287662, 1027; Patent Application Date: 19970408.; Priority Application Date: 19970408. 36 J. A. Galarraga, K. G. Neill and H. Raistrick, Biochem. J., 1955, 61, 456–464. 37 Y. Fujimoto, T. Takahashi, E. Yokoyama, J. Uzawa, H. Tsunoda and T. Tatsuno, Tennen Yuki Kagobutsu Toronkai Koen Yoshishu, 1983, 26, 166–172.

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View Article Online

Published on 01 April 2014. Downloaded by Ondoku Mayis Universitesi on 25/04/2014 03:51:36.

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38 A. Quick, R. Thomas and D. J. Williams, J. Chem. Soc., Chem. Commun., 1980, 1051–1053. 39 T. Yoshioka, T. Hirata, T. Aoki and T. Suga, Chem. Lett., 1981, (12), 1729–1732. 40 T. Yoshioka, T. Hirata, T. Aoki and T. Suga, Bull. Chem. Soc. Jpn., 1982, 55(12), 3847–3851. 41 Y. Ishikawa, K. Morimoto, T. Sada and T. Fujiwara, Yukagaku, 1992, 41(11), 1107–1110. 42 Y. Ishikawa, T. Hamasaki, Y. Ueda and T. Fujiwara, Biosci., Biotechnol., Biochem., 1992, 56(9), 1486–1487. 43 Main IPC: C12P001-02.; Secondary IPC: A23L003-3472; C09K015-34.; Index IPC: C12P001-02; C12R001-80. Pat., JP02079985, 0320; Patent Application Date: 19880919.; Priority Application Date: 19880919. 44 W. A. Ayer and Y. T. Ma, Can. J. Chem., 1992, 70(7), 1905– 1913. 45 W. A. Ayer, Y. Hoyano, M. Soledade Pedras and I. Van Altena, Can. J. Chem., 1986, 64(8), 1585–1589. 46 Novel and Bioactive Natural Products from the Marine-Derived Endophytic Fungi, Coniothyrium cereale, Phaeosphaeria spartinae and Auxarthron reticulatum, PhD Thesis, M. F. E. Moustafa, 2011, Bonn University, Germany. 47 S. Nakanishi, S. Toki, Y. Saitoh, E. Tsukuda, K. Kawahara, K. Ando and Y. Matsuda, Biosci., Biotechnol., Biochem., 1995, 59(7), 1333–1335. 48 J. Z. Xiao, S. Kumazawa, H. Tomita, N. Yoshikawa, C. Kimura and T. Mikawa, J. Antibiot., 1993, 46(10), 1570– 1574. 49 Pat., CN102093187, 0615; Patent Application Date: 20101203.; Priority Application Date: 20101203. 50 Main IPC: A01N043-90.; Secondary IPC: C12P015-00.; Additional IPC: A01N063-02. Pat., JP06321710, 1122; Patent Application Date: 19930512.; Priority Application Date: 19930512. 51 Main IPC: C07D307-92.; Secondary IPC: C07D307-94; C12P001-02; C12P015-00; C12P017-04; A61K031-34.; Index IPC: C12R001-80. Pat., DE19516521, 1107; Patent Application Date: 19950505.; Priority Application Date: 19950505. 52 K. Shiomi, R. Matsui, M. Isozaki, H. Chiba, T. Sugai, Y. Yamaguchi, R. Masuma, H. Tomoda, T. Chiba, H. Yan, Y. Kitamura, W. Sugiura, S. Omura and H. Tanaka, J. Antibiot., 2005, 58(1), 65–68. 53 W. A. Ayer, M. Kamada and Y. T. Ma, Can. J. Chem., 1989, 67(12), 2089–2094. 54 M. F. Elsebai, S. Kehraus, U. Lindequist, F. Sasse, S. Shaaban, M. Guetschow, M. Josten, H. Sahl and G. M. Koenig, Org. Biomol. Chem., 2011, 9(3), 802–808. 55 W. Ayer, Y. Hoyano, I. Van Altena and Y. Hiratsuka, Can. Revista Latinoamericana de Quimica, 1982, 13(3–4), 84–87. 56 C. Zhang, Y. Xiao, M. Taniguchi and K. Baba, Zhongguo Zhongyao Zazhi, 2006, 31(16), 1333–1335. 57 N. Robinson, K. Wood, P. J. Hylands, T. M. Gibson, C. J. Weedon and N. Covill, J. Nat. Prod., 1992, 55(6), 814– 817. 58 G. W. Van Eijk, Phytochemistry, 1971, 10(12), 3263–3265.

644 | Nat. Prod. Rep., 2014, 31, 628–645

Review

59 K. Homma, K. Fukuyama, Y. Katsube, Y. Kimura and T. Hamasaki, Agric. Biol. Chem., 1980, 44(6), 1333–1337. 60 O. Bachmann, B. Kemper and H. Musso, Liebigs Ann. Chem., 1986. 61 K. Krohn, M. H. Sohrab, H. Aust, S. Draeger and B. Schulz, Nat. Prod. Res., 2004, 18(3), 277–285. 62 C. Rossi and R. Ubaldi, Ann. Ist. Super. Sanita, 1973, 9(pt 4), 320–322. 63 N. J. McCorkindale, McRitchie Allan and S. A. Hutchinson, J. Chem. Soc., Chem. Commun., 1973, 108–109. 64 N. J. McCorkindale, S. A. Hutchinson, A. C. McRitchie and G. R. Sood, Tetrahedron, 1983, 39(13), 2283–2288. 65 N. Narasimhachari and L. C. Vining, J. Antibiot., 1972, 25(3), 155–162. 66 T. J. Simpson, J. Chem. Soc., Chem. Commun., 1976, 258–260. 67 T. J. Simpson, J. Chem. Soc., Perkin Trans. 1, 1979, 1233– 1238. 68 M. Perpelescu, J. Kobayashi, M. Furuta, Y. Ito, S. Izuta, M. Takemura, M. Suzuki and S. Yoshida, Biochemistry, 2002, 41(24), 7610–7616. 69 K. Komatsu, H. Shigemori, Y. Mikami and J. Kobayashi, J. Nat. Prod., 2000, 63(3), 408–409. 70 J. Inokoshi, K. Shiomi, R. Masuma, H. Tanaka, H. Yamada and S. Omura, J. Antibiot., 1999, 52(12), 1095–1100. 71 J. Zhan, G. M. K. B. Gunaherath, E. M. K. Wijeratne and A. A. L. Gunatilaka, Phytochemistry, 2007, 68(3), 368–372. 72 L. E. Zawadzke, P. Wu, L. Cook, L. Fan, M. Casperson, M. Kishnani, D. Calambur, S. J. Hofstead and R. Padmanabha, Anal. Biochem., 2003, 314(2), 243–252. 73 M. A. Ernst-Russell, C. L. L. Chai, J. A. Elix and P. M. McCarthy, Aust. J. Chem., 2000, 53(12), 1011–1013. 74 A. Mathey, B. Steffan and W. Steglich, Liebigs Ann. Chem., 1980, 779–785. 75 L. Y. Sun, Z. L. Liu, T. Zhang, S. B. Niu and Z. T. Zhao, Chin. Chem. Lett., 2010, 21(7), 842–845. 76 M. F. Elsebai, M. Nazir, S. Kehraus, E. Egereva, K. N. Ioset, L. Marcourt, D. Jeannerat, M. Guetschow, J. Wolfender and G. M. Koenig, Eur. J. Org. Chem., 2012, (31), 6197–6203. 77 M. F. Elsebai, L. Natesan, S. Kehraus, I. E. Mohamed, G. Schnakenburg, F. Sasse, S. Shaaban, M. Gutschow and G. M. Konig, J. Nat. Prod., 2011, 74(10), 2282–2285. 78 T. Shibata, M. Nishikawa, Y. Tsurumi, S. Takase, H. Terano and M. Kohsaka, J. Antibiot., 1989, 42(9), 1356–1361. 79 Z. Lin, T. Zhu, Y. Fang, Q. Gu and W. Zhu, Phytochemistry, 2008, 69(5), 1273–1278. 80 W. R. Gamble, J. b. Gloer, J. A. Scott and D. Malloch, J. Nat. Prod., 1995, 58(12), 1983–1986. 81 N. Otomo, H. Sato and S. Sakamura, Agric. Biol. Chem., 1983, 47(5), 1115–1119. 82 W. A. Ayer and M. S. Pedras, Can. J. Chem., 1987, 65(4), 754– 759. 83 S. Shibata, Y. Ogihara, N. Tokutake and O. Tanaka, Tetrahedron Lett., 1965, 6(18), 1287–1288. 84 F. O. Bryant, H. G. Cutler and J. M. Jacyno, J. Pharm. Sci., 1993, 82(12), 1214–1217. 85 IPC: C12D009-04. Pat., CS178477, 0415; Patent Application Date: 19720921.; Priority Application Date: 19720921.

This journal is © The Royal Society of Chemistry 2014

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Review

86 Y. Ogihara, Y. Iitaka and S. Shibata, Acta Crystallogr., Sect. B: Struct. Crystallogr. Cryst. Chem., 1968, 24(8), 1037–1047. 87 K. Kawai, H. Shiojiri, T. Nakamaru, Y. Nozawa, S. Sugie, H. Mori, T. Kato and Y. Ogihara, Cell Biol. Toxicol., 1985, 1(2), 1–10. 88 J. Fuska, L. P. Ivanitskaya, L. V. Makukho and L. Y. Volkova, Antibiotiki (Moscow), 1974, 19(10), 890–893. 89 J. Fuska, I. Kuhr, P. Nemec and A. Fuskova, J. Antibiot., 1974, 27(2), 123–127. 90 J. Fuska, K. Horakova, P. Vesely and P. Nemec, Prog. Chemother. (Antibacterial, Antiviral, Antineoplast.), Proc. Int. Congr. Chemother., 8th, 1974, 3, pp. 835–840. 91 I. Kuhr and J. Fuska, J. Antibiot., 1973, 26(9), 535–536. 92 L. Kovac, E. Bohmerova and J. Fuska, J. Antibiot., 1978, 31(6), 616–620. 93 H. Shimonaka, Gifu Daigaku Igakubu Kiyo, 1978, 26(1), 96– 119. 94 H. Shiojiri, K. Kawai, T. Kato, Y. Ogihara and Y. Nozawa, Maikotokishin (Tokyo), 1983, 18, 38–41. 95 Y. Ogihara, O. Tanaka and S. Shibata, Tetrahedron Lett., 1966, 7(25), 2867–2873. 96 M. Yamazaki and E. Okuyama, Chem. Pharm. Bull., 1980, 28(12), 3649–3655. 97 Z. Guo, C. Shao, Z. She, X. Cai, F. Liu, L. L. P. Vrijimoed and Y. Lin, Magn. Reson. Chem., 2007, 45(5), 439–441. 98 X. Xia, C. Liu, W. Yuan, X. Wang, X. Meng, M. Zhang, Z. She and Y. Lin, Zhongyaocai, 2009, 32(9), 1385–1387. 99 T. Dethoup, L. Manoch, A. Kijjoa, M. S. J. Nascimento, P. Puaparoj, A. M. S. Silva, G. Eaton and W. Herz, Planta Med., 2006, 72(10), 957–960. 100 K. K. Chexal, C. Tamm, K. Hirotsu and J. Clardy, Helv. Chim. Acta, 1979, 62(6), 1785–1803.

This journal is © The Royal Society of Chemistry 2014

NPR

101 G. Snatzke and C. Tamm, Helv. Chim. Acta, 1984, 67(3), 690– 695. 102 J. Ren, F. Zhang, X. Liu, L. Li, G. Liu, X. Liu and Y. Che, Org. Lett., 2012, 14(24), 6226–6229. 103 E. Julianti, J. Lee, L. Liao, W. Park, S. Park, D. Oh, K. Oh and J. Shin, Org. Lett., 2013, 15(6), 1286–1289. 104 W. A. Ayer, M. S. Pedras and D. E. Ward, Can. J. Chem., 1987, 65(4), 760–764. 105 G. Jinming, H. Lin and L. Jikai, Steroids, 2001, 66(10), 771– 775. 106 M. Iorizzi, L. Minale, R. Riccio, J. S. Lee and T. Yasumoto, J. Nat. Prod., 1988, 51(6), 1098–1103. 107 R. Thomas, ChemBioChem, 2001, 2(9), 612–627. 108 R. Thomas, Biochem J, 1961, 78, 807–813. 109 N. Narasimhachari, V. B. Joshi and S. Krishnan, Experientia, 1968, 24(6), 538–539. 110 J. M. Edwards and U. Weiss, Tetrahedron Lett., 1972, 13(17), 1631–1634. 111 R. Nilsson, V. Veldre, M. Hartmann, M. Unterseher, A. Amend, J. Bergsten, E. Kristiansson, M. Ryberg, A. Jumpponen and K. Abarenkov, Fungal Ecol., 2010, 3, 284–287. 112 J. D. Thompson, T. J. Gibson, F. Plewniak, F. Jeanmougin and D. G. Higgins, Nucleic Acids Res., 1997, 25(24), 4876– 4882. 113 K. Tamura, D. Peterson, N. Peterson, G. Stecher, M. Nei and S. Kumar, Mol. Biol. Evol., 2011, 28(10), 2731–2739. 114 M. P. Nelsen and A. Gargas, New Phytol, 2008, 177(1), 264– 275. 115 H. T. Lumbsch, I. Schmitt, A. Mangold and M. Wedin, Mycol. Res., 2007, 111(9), 1133–1141. 116 D. A. Barakat, Aust. J. Basic Appl. Sci., 2011, 5(9), 693–703.

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Fungal phenalenones: chemistry, biology, biosynthesis and phylogeny.

Covering up to the end of August 2013. Phenalenones are members of a unique class of natural polyketides exhibiting diverse biological potential. This...
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