Marine fungal metabolites as a rich source of bioactive compounds

This paper reviews the recent results of bioactive compounds derived from marine fungi, which are highly diversified and are less explored. Researchers are showing keen interest in isolating novel bioactive compounds with clinical applications. Hence, here we discussed most of the bioactive compounds isolated from marine derived fungi and their possible roles in various efficient biological activities.


INTRODUCTION
The main emphasis of this review is on bioactive compound producing marine fungi and their biological active compounds. Marine secondary metabolites can easily impede other micro organisms (Jeffrey et al., 2011). Among marine microorganisms, particularly fungi have gained an important role as a source of biologically active secondary metabolites (Amira et al., 2009). Marine fungi are prolific resources of natural products. But only a limited potential of marine fungi have been investigated to an extent. True marine fungi have the ability to grow and sporulate exclusively in sea water, where facultative marine fungi are able to adapt away from their natural habitat.

Unique features of marine environment and their relevance to marine fungi
The unique properties of the marine environment are considered important for marine biotechnology for several reasons: 1) A good adaptation of ecosystem will help in development of novel genes and 2) biotechnological production processes are influenced by the special adaptations of organisms to their environment.
The physical factors that influence the marine fungi are a) salinity and pH, b) low water potential, c) high concen-trations of sodium ions, d) low temperature, e) oligotrophic nutrient conditions and f) high hydrostatic pressure, the last three parameters being unique to the deep-sea environment (Raghukumar, 2008).
In recent years, marine fungi have been explored more intensely to obtain novel and biologically active compounds, when compared with marine sponges, bacteria. Marine fungi are still less explored. Nevertheless, success in marine fungi research is less. Cephalosporin C was the first bioactive compound from Cephalosporium acremonium which was isolated from a sewage outlet of the Sardinian coast.
Marine fungi have been explored to a much lesser extent than their terrestrial counterparts, such as those for use in treatment of human diseases as well as several others in biotechnological applications (Aline et al., 2008). Hence, we tried to review the research carried out so far regarding marine fungi and their bioactive compounds.
Previous literature shows that marine-derived fungi have been recognized as one of the tapped sources for new biologically active secondary metabolites including antitumor, antibacterial, antiviral, antifungal, anti-inflammatory and anticancer activities and enzyme inhibitor compounds. Clodepsipeptide (1) isolated from the marine fungus, Clonostachys sp. is having anti cancer activity (Samuel et al., 2011). Until 1991, only 321 species of obligate marine fungi had been described, of which 11 belong to the class Ascomycete, which are found in shallow waters. Facultative marine fungi have been explored to a lesser extent, and only 56 species have been described until 1999 (Aline et al., 2008). Between 2000 and 2005, approximately 100 marine fungal metabolites were described and between 2006 and 2010, a total of 690 natural products were reported as being isolated from fungi in marine habitats (Katia et al., 2012). Marine fungi have attracted great attention as considerable resources from only few decades. Recent investigations on marine filamentous fungi looking for biologically active secondary metabolites indicate their tremendous potential as a source of new medicines even at low concentrations of their secondary metabolites (Table 5) .
Continuous investigations demonstrated that marine microorganisms are an unlimited source of novel biologically active secondary metabolites. Marine-derived fungi, in particular, have yielded an increasing number of biologically active natural products.
The structure and absolute stereochemistry of S)-8methoxy-3,5-dimethylisochroman-6-ol, isolated from Penicillium steckii obtained from an algae belonging to the genus Sargassum, could be established by analysis of spectroscopic data and also by comparison with literature data.
A Penicillium sp. strain DG M3) 6'C, isolated from the ascidian Didemnum granulatum, yielded 13-desoxyphomenone. Roridin A was isolated from Trichoderma sp. obtained from the sponge Mucale angulosa and also identified by analysis of spectroscopic data and comparison with literature data. The fungal strain Ma G) K, obtained from the sponge M. angulosa and identified as Penicillium paxilli, gave an extract which was cytotoxic against MDA-MB435 human mammalian cancer cells (HCT8 human colon), CNS 295 central nervous system cancer cells and HL60 leukemia cells. Fractionation of this crude extract yielded three 2-pyrones, belonging to Pyrenocines the class of pyrenocines, of which two were known and one was a new natural product, Pyrenocine J. Swathi et al. 185 B and A were first isolated from Pyrenochaeta terrestris and identified by spectroscopic and X-ray diffraction analysis (Miriam et al., 2012). Two new indole alkaloids, 2-3, 3-dimethylprop-1-ene)-costaclavine and 2-3, 3dimethylprop-1-ene)-epicosta-clavine, together with the known compounds costaclavine, fumgaclavine A and C, were isolated from the marine-derived fungus Aspergillus fumigates (2) (Dahai et al., 2012). Penicillium commune SD-118, a fungus obtained from a deep-sea sediment sample, resulted in the isolation of a known antibacterial compound, xanthocillin X (3) , and 14 other known compounds comprising three steroids, two ceramides, six aromatic compounds and three alkaloids (Table 1). Xanthocillin X was isolated for the first time from a marine fungus. In the bioassay, xanthocillin X displayed significant cytotoxicity against MCF-7, HepG2, H460, Hela, Du145 and MDA-MB-231 cell lines. Meleagrin exhibited cytotoxicity against HepG2, Hela, Du145 and MDA-MB-231 cell lines. This is the first report on the cytotoxicity of xanthocillin X (Shang et al., 2012). Khouloud and Yousry (2012) isolated new biologically active metabolites against some virulent fish pathogens Edwardsiella tarda, Aeromonas hydrophila, Vibrio ordalli and Vibrio angularuim. Aspergillus terreus var. Africanus was identified as the most potent isolate by Khouloud and Yousry (2012). Acremolin (5) , a novel modified base, was isolated from the culture broth of the marine fungus Acremoniu strictum. Based on combined spectroscopic analyses, the structure of this compound was that of a methyl guanine base containing an isoprene unit. In addition, the presence of a 1H-azirine moiety is unprecedented among natural products. This compound exhibited weak cytotoxicity against an A549 cell line (Elin et al., 2012).

Kirschsteiniothelia maritima
To study the potential of Trichoderma species in controlling nematodes, fungal filtrates of 329 Trichoderma strains were evaluated for their nematicidal activity against Panagrellus redivivus and Caenorhabditis elegans. Fifteen strains exhibited nematicidal activity against P. redivivus, and 14 strains showed activity against C. elegans (Zhong-Shan et al., 2010). Fungi Phialocephala sp. FL30r) have strong cytotoxic activities inhibition rate of 50%. Nine cytotoxic compounds belonging to phenazine, indole, polyether and ester were isolated from them through bioassay-guided chromatography and identified by spectral methods (Xiang et al., 2010). Marine fungus Aspergillus glaucus produces anti-tumor polyketide compound aspergiolide A (18) (Xueqian et al., 2010) and statistical methodologies were employed to optimize submerged culture medium for the production of this novel compound from Aspergillus glaucus HB1-19 . A marine-derived fungus, Cladosporium sp. F14, was studied for its ability to produce antibiotic and antifouling compounds on different cultivation media. The fungus grew well on tryptone or yeast extract media, slowly on ammonium or nitrate media, and not at all on urea media. In nutrient-enriched cultivation media, this strain produced antibiotic and antifouling compounds in the presence of glucose or xylose. These bioactive compounds were rarely produced in the absence of the sugars, even though the fungal cells grew well under these conditions. Fungal extracts decreased the attachment of bryozoan larvae Bugula neritina and showed antibiotic activity towards 6 tested bacterial species. Metabolite profiles of the fungus revealed by gas chromatographymass spectrometry GCeMS) showed clear differences when glucose was present in or absent from the culture medium. This study provides evidence that marine fungus has the ability to produce antibiotic and antifouling compounds (Hairong et al., 2009). Six new ergosterols, including 3β-hydroxyl-22E, 24R)-ergosta-5,8,22-trien-7,15-dione (19) , 3β-hydroxyl-22E, 24R)-ergosta-5,8,14,22tetraen-7-one 20 , 3β,15α-dihydroxyl-22E, 24R)-ergosta-5,814),22-trien-7-one (21) , 3β,15α-dihydroxyl-22E, 24R)ergosta-5,814),22-trien-7-one (22) , 3β-hydroxyl-22E, 24R)ergosta-5,814),22-trien-7,15-dione (23) and 5α,8α-epidioxy-23,24R)-dimethylcholesta-6,911),22-trien-3β-ol, have been isolated from the marine derived fungus Rhizopus sp., along with four known ones. The structures of the new compounds were determined on the basis of extensive spectroscopic data. All compounds were eva-luated for their cytotoxic activities against P388, A549, HL-60 and BEL-7420 cell lines by the MTT and SRB methods (Fazuo et al., 2008). Chemical investigation of the cytotoxic and anti-tuberculosis is active butanone extract obtained from the growth media of the marine-derived fungus Beauveria felina led to the isolation of two new destruxins, (b -Me-Pro) destruxin E chlorohydrins (24) and pseudodestruxin C (25) , along with five known cyclic depsipeptides. The structures of the new destruxin derivatives were established by analysis of spectroscopic data, while the absolute configuration of the common amino acid residues was established by Marfey's analysis (Simone et al., 2006). The potential activity of domic acid, a neurotoxin released from marine fungi was studied against from Dipteral larvae (Nicolas et al., 2010).
A new cytotoxic cyclodepsipeptide 26 was isolated from extracts of marine fungus Clonostachys sp.. The amino acid sequence was determined by spectrometric studies and the sequence was revealed to be a cyclic dimer formed by two chains of L-N,N-Me2Leu-L-Ser-L-N-MeLeu-L-N-MePhe bound by the two esters formed between the carboxylic acid of the L-N-MePhe and the hydroxyl function of the L-Ser. IB-01212 is highly cytotoxic to different tumour cell lines (Luis et al., 2006). The new metabolite cillifuranone 27 was isolated from Penicillium chrysogenum strain LF066. The structure of cillifuranone was elucidated based on 1D and 2D NMR analysis and turned out to be a previously postulated intermediate in sorbifuranone biosynthesis. Only minor antibiotic bioactivities of this compound were found so far (Jutta et al., 2011). Protulactones A and B 4) , two new polyketide-derived fungal metabolites, have been isolated from an EtOAc extract of the marine-derived fungus Aspergillus sp. SF-5044 by various chromatographic methods (Jae and Hyuncheol, 2010). Marine fungi belonging to the genus Aspergillus, Pencillium and Fusarium were isolated from mangrove forest and these fungal derived compounds were tested for antibacterial activity with E. coli, K. pneumonia and P. aurogenosa and antimycobacterial activity against M. tuberculosis H37 RV. These fungal compounds showed best antibacterial and antimycobacterial activities when extracted with n-hexane, methanol and ethyl acetate (Punyasloke et al., 2006). Two new sesquiterpenes, one new monocyclofarnesane type 3,7,10-trihydroxy-6,11 cyclofarnesane-1-ene 28 and acorane type sesquiterpene,8-hydroxymethyl)-1-2hydroxy-methylethyl)-4-methylspirol(4.5)-dec-8-en-7-ol 29 and three known terpenes were isolated from Eutypella scoparia which shows cytotoxic activities against the SF-268, MCF-7, NCL-H460 tumor cell lines . Mohamad et al. (2007) isolated marine derived fungi that produce spiromassaritone 30 and massariphenone 31 , as well as the previously reported fungal metabolites 6-epi-

Pycnidiophora dispersa
Neuroactivity cytotoxicity 50-hydroxy-mycosporulone 32 and enalin A 33 from Massarina sp. strain CNT-016) (Mohamed et al., 2007). Marine derived fungi Mucor racemosus CBMAI 847 has relevant potential features producing laccase, manganese peroxidise and lignolytic enzymes (Rafaella et al., 2010). Mi-Hee et al. (2008) isolated a novel yeast strain that produce a large amount of squalene 43 and several polyunsaturated fatty acids from Pseudozyma sp. JCC 207 of marine fungi   (Table 3). Oda and colleagues (2005) described the pharmacology of verrucarin A, a compound isolated from the culture broth of the Palauan marine fungus Myrothecium roridum. Verrucarin A significantly inhibited interleukin-8 production from human promyelocytic leukemia cells, by a mechanism that involved inhibition of the activation of the mitogen activated kinases c-JUN and p38 (Alejandro et al., 2009). Wei et al. (2011 investigated a novel polyketide shimalactone A isolated from the cultured marinederived fungus Emericella variecolor GF10. Shimalactone A induced neuritogenesis in a neuroblastoma Neuro 2A cell line at 10 μg/ml by a none yet undetermined mechanism (Alejandro et al., 2009). Marine fungi strains of genera Pencillium and Cladosporium show strong antibacterial activity (Ya-Nan et al., 2011). A marine fungal isolate, Penicillium sp. isolated from seaweed, Ulva sp. led to the isolation of a new chromone derivatives, 2hydroxymethyl)-8-methoxy-3-methyl-4H-chromen-4-one chromanone A 44 which act as an active tumour anti-  (Amira et al., 2009). The marine fungi are highly diversified and their potential to produce bioactive compounds clearly demonstrates their role in clinical applications and further drug designing pharmaceuticals. New method of isolation and screening of fungi and its metabolites is essential to generate a novel compound (Table 4). The main goal of this review was to investigate the potential bioactive compounds isolated from marine fungi and their contribution towards modern medicine.