Natural Bioactive Compounds from Marine-Derived Fungi

marine drugs

Review Potential Pharmacological Resources: Natural Bioactive Compounds from Marine-Derived Fungi

Liming Jin, Chunshan Quan *, Xiyan Hou and Shengdi Fan College of Life Science, Dalian Nationalities University, No. 18, LiaoHe West Road, Dalian 116600, China; [email protected] (L.J.); [email protected] (X.H.); [email protected] (S.F.) * Correspondence: [email protected]; Tel.: +86-411-8765-6219; Fax: +86-411-8764-4496

Academic Editor: Vassilios Roussis Received: 27 January 2016; Accepted: 29 March 2016; Published: 22 April 2016

Abstract: In recent years, a considerable number of structurally unique metabolites with biological and pharmacological activities have been isolated from the marine-derived fungi, such as polyketides, alkaloids, peptides, lactones, terpenoids and steroids. Some of these compounds have anticancer, antibacterial, antifungal, antiviral, anti-inflammatory, antioxidant, antibiotic and cytotoxic properties. This review partially summarizes the new bioactive compounds from marine-derived fungi with classification according to the sources of fungi and their biological activities. Those fungi found from 2014 to the present are discussed.

Keywords: marine-derived fungi; fungal metabolites; bioactive compounds; natural products

1. Introduction The oceans, which cover more than 70% of the earth’s surface and more than 95% of the earth’s biosphere, harbor various marine organisms. Because of the special physical and chemical conditions in the marine environment, almost every class of marine organism displays a variety of molecules with structurally unique features. However, unlike the long historical medical uses of terrestrial plants, marine organisms have a shorter history in pharmacological application [1]. In recent years, a significant number of novel metabolites with pharmacological potential have been discovered from marine organisms, such as polyketides, alkaloids, peptides, proteins, lipids, shikimates, glycosides, isoprenoids and hybrids, which exhibit biological activity including anticancer, antitumor, antiproliferative, antimicrotubule, cytotoxic, photo protective, as well as antibiotic and antifouling properties [2]. Among them, marine microorganisms, such as bacteria, actinomycetes, fungi and cyanobacteria have attracted more attention as potential lead compound producers. In comparison to marine invertebrates, they are a renewable and a reproducible source, as they can be cultured and can even be envisaged as amazing microbial factories for natural products [3]. Previously, scientists always focused on actinomycetes for their abilities to produce antibiotics. In fact, many fungal metabolites in the pharmaceutical market indicates the potential of microorganisms as valuable sources of lead drugs, e.g., the antibiotic polyketide griseofulvin (Likuden M®), the antibacterial terpenoid fusidic acid (Fucidine®), semi-synthetic or synthetic penicillins and cephalosporins, macrolides, statins as well as the ergot alkaloids such as ergotamine (Ergo-Kranit®)[4]. In 1949, the first secondary metabolite isolated from a marine-derived fungal strain, famous cephalosporin C, was produced by a culture of a Cephalosporium sp. isolated from the Sardinian coast. However, this was a more or less accidental discovery. Despite the discovery of such important drug from marine fungi, the number of bioactive natural products originated from marine fungi increased extremely slowly. It is only from the late 1980s that researchers have focused on marine-derived fungi. In fact, marine-derived fungi are very important sources for novel bioactive secondary metabolites that could potentially be used as

Mar. Drugs 2016, 14, 76; doi:10.3390/md14040076 www.mdpi.com/journal/marinedrugs Mar. Drugs 2016, 14, 76 2 of 25

Mar.important Drugs 2016 sources, 14, 76 for novel bioactive secondary metabolites that could potentially be used as drugs.2 of 25 Blunt et al., mentioned that marine‐derived fungi have a greater proportion of marine natural drugs.compoundsBlunt etwith al., mentionedmore desirable that marine-derived oral‐bioavailability fungi have and a greaterphysico proportion‐chemical ofproperties marine natural with compoundsmolecular weight with more (MW) desirable < 400 and oral-bioavailability clogP (calculated and octanol physico-chemical‐water logP) properties< 4 [5]. Compounds with molecular that weightmeet these(MW) criteria < 400 andcan clog suggestP (calculated the optimum octanol-water combinations logP) < for 4 [5 ].potential Compounds pharmaceuticals that meet these [5]. criteriaCurrently, can thousands suggest the of optimum structurally combinations unique and for biologically potential pharmaceuticals active compounds [5]. Currently, have been thousands reported offrom structurally marine fungi. unique and biologically active compounds have been reported from marine fungi. According to a classical definition,definition, marine fungi are divided intointo obligateobligate marinemarine fungi and facultative marine fungi [6]. [6]. In fact, marine fungi often live as symbionts in algae, mangrove, coral, sea anemone,anemone, starfish,starfish, seasea urchin,urchin, seagrass,seagrass, and,and, especially,especially, sponges.sponges. Collection of marine fungifungi usually requires the collection of the host or supportingsupporting material (e.g., algae, marine invertebrates, sediment or water, andand eveneven driftwood).driftwood). Herein, a neutral term “marine-derived“marine‐derived fungi” was used, whichwhich includesincludes any any fungal fungal strain strain obtained obtained from from marine marine environment environment using using cultivation cultivation techniques techniques with “marine”with “marine” media, whichmedia, do which not differentiate do not betweendifferentiate facultative between marine facultative strains and marine contaminants strains fromand terrestrialcontaminants habitats. from terrestrial habitats. The aim of thisthis reviewreview isis toto givegive anan overviewoverview onon secondarysecondary metabolitesmetabolites fromfrom marine-derivedmarine‐derived fungi and theirtheir biologicalbiological activities,activities, focusing on thethe periodperiod fromfrom 20142014 toto thethe present.present. In similarsimilar published reviews, assignments of a given metabolite to a certain category were generally based on structural considerations. It It is is obvious that classifications classifications of the enormous structural diversity of marine fungal-derivedfungal‐derived metabolites metabolites are are different different in in various various literature literature reports, reports, which which only only represents represents the authors’the authors’ personal personal judgments. judgments. In this In article, this article, these metabolitesthese metabolites were classified were classified according according to the sources to the ofsources marine of fungi. marine fungi.

2. Metabolites Metabolites from from Marine Marine-Derived‐Derived Fungi Fungi

2.1. Marine Animals

2.1.1. Sponge Two newnew 4-hydroxy-2-pyridone4‐hydroxy‐2‐pyridone alkaloids, arthpyrones (1–2), were isolated from thethe fungusfungus Arthrinium arundinis ZSDS1ZSDS1-F3,‐F3, which which obtained obtained from from sponge sponge (Xisha (Xisha Islands, Islands, China). China). Compounds Compounds 1 1andand 2 2hadhad signi significantficant inin vitro vitro cytotoxicitiescytotoxicities against against the the K562, K562, A549, A549, Huh Huh-7,‐7, H1975, MCF MCF-7,‐7, U937, BGC823, HL60,HL60, Hela Hela and and MOLT-4 MOLT cell‐4 lines,cell withlines, IC with50 values IC50 rangingvalues fromranging 0.24 tofrom 45 µ0.24M. Furthermore, to 45 μM. compoundFurthermore,2 displayed compound significant 2 displayed AchE significant inhibitory AchE activity inhibitory (IC50 =activity 0.81 µ M),(IC50 whereas = 0.81 μ compoundM), whereas1 showedcompound modest 1 showed activity modest (IC50 activity= 47 µM) (IC (Figure50 = 471 μ)[M)7]. (Figure 1) [7].

Figure 1. Structures of compounds 1–2. Figure 1. Structures of compounds 1–2.

Chemical examination of the solid culture of the endophytic fungus Stachybotrys chartarum Stachybotrys chartarum isolatedChemical from the examination sponge Niphates of the recondita solid culture (Weizhou of the Island endophytic in Beibuwan fungus Bay, Guangxi Province of isolatedChina) resulted from the in sponge the isolationNiphates of reconditaseven new(Weizhou phenylspirodrimanes, Island in Beibuwan named Bay, chartarlactams Guangxi Province (3–9). ofCompounds China) resulted 3–9 exhibited in the isolation potent lipid of seven‐lowering new phenylspirodrimanes,effects in HepG2 cells in named a dose chartarlactams of 10 μM (Figure (3– 92)). µ Compounds[8]. 3–9 exhibited potent lipid-lowering effects in HepG2 cells in a dose of 10 M (Figure2)[ 8].

Mar. Drugs 2016,, 14,, 76 76 3 of 25 Mar. Drugs 2016, 14, 76 3 of 25 O O HO HO O HO NH NH HO ONH NH HO HO HO HO NH NH NH NH O O O O O HO O O O HO O O O HO AcO HO H H H H O HO AcO HO H H H H 3 45 6 3 45 6

HO HO O O H O OH O HO O H OH N-CH CH OH OH O O HO 2 2 HO O O OH N-CH2CH2OH NH HO HO OHO NH NH O OH HO NH O O O OH O O O HN OH O HN O HO HO HO O HO H HO H HO H H H H 7 8 9 7 8 9 Figure 2. Structures of compounds 3–9. FigureFigure 2.2. Structures of of compounds compounds 33––99. .

TheThe extract extract of of a astrain strain of of Aspergillus Aspergillus versicolor MF359MF359 (from(from the the sponge sponge of of Hymeniacidon Hymeniacidon perleve perleve, , BohaiBohaiThe Sea, Sea, extract China) China) of yielded ayielded strain one one of Aspergillusnew new secondarysecondary versicolor metabolites,MF359 named named (from 5 the 5‐methoxydihydrosterigmatocystin‐methoxydihydrosterigmatocystin sponge of Hymeniacidon perleve , Bohai(10(10). ).Compound Sea, Compound China) yielded10 10 showed showed one newpotentpotent secondary activityactivity metabolites,against StaphylococcusStaphylococcus named 5-methoxydihydrosterigmatocystin aureus aureus ( S.(S. aureus aureus) and) and Bacillus Bacillus (subtilis10subtilis). Compound (B. (B. subtillis subtillis10) with)showed with MIC MIC potent values values activity ofof 12.512.5 against and 3.125Staphylococcus μ μg/mL,g/mL, respectively respectively aureus (S. (Figure (Figure aureus 3)) and 3)[9]. [9]. Bacillus subtilis (B. subtillisTheThe fungus) fungus with Diaporthaceae MIC Diaporthaceae values of sp. sp. 12.5 PSUPSU and‐‐SP2/4SP2/4 3.125 fromµg/mL, marinemarine respectively sponge sponge (Trang (Trang (Figure city, city,3)[ Thailand)9 Thailand)]. generated generated a a newnew Thepentacyclic pentacyclic fungus Diaporthaceaecytochalasin cytochalasin sp. (diaporthalasin,(diaporthalasin, PSU-SP2/4 from 11).). marine CompoundCompound sponge 1111 (Trang displayeddisplayed city, potent Thailand)potent antibacterial antibacterial generated aactivity newactivity pentacyclic against against both both cytochalasin S. S. aureus aureus and and (diaporthalasin, methicillinmethicillin‐resistant11). Compound S.S. aureusaureus (MRSA) (MRSA)11 displayed with with equal equal potent MIC MIC values antibacterial values of 2of 2 activityμg/mLμg/mL (Figure against (Figure 3) both 3) [10]. [10].S. aureus and methicillin-resistant S. aureus (MRSA) with equal MIC values of 2 µg/mLA Anew new (Figure chevalone chevalone3)[10]. derivative, derivative, namednamed chevalone EE ((1212),), waswas isolated isolated from from the the ethyl ethyl acetate acetate extractextractA newof of the chevalonethe undescribed undescribed derivative, marinemarine named spongesponge chevalone‐associated E ( 12 fungusfungus), was Aspergillus isolatedAspergillus from similanensis similanensis the ethyl KUFA acetate KUFA 0013, extract 0013, which was collected from the Similan Islands, Phang Nga Province, Southern Thailand. Compound 12 ofwhich the undescribedwas collected marine from the sponge-associated Similan Islands, Phang fungus NgaAspergillus Province, similanensis Southern Thailand.KUFA 0013, Compound which was 12 was found to show synergism with the antibiotic oxacillin against methicillin‐resistant S. aureus collectedwas found from to theshow Similan synergism Islands, with Phang the Nga antibiotic Province, oxacillin Southern against Thailand. methicillin Compound‐resistant12 was S. aureus found (Figure 3) [11]. to(Figure show 3) synergism [11]. with the antibiotic oxacillin against methicillin-resistant S. aureus (Figure3)[11]. Xylarianaphthol‐1 (13), a new dinaphthofuran derivative, was isolated from an Indonesian Xylarianaphthol-1Xylarianaphthol‐1 ( 13(13),), a newa new dinaphthofuran dinaphthofuran derivative, derivative, was isolatedwas isolated from anfrom Indonesian an Indonesian marine marine sponge‐derived fungus of order Xylariales on the guidance of a bioassay using the transfected sponge-derived fungus of order Xylariales on the guidance of a bioassay using the transfected human marine sponge‐derived fungus of order Xylarialesluc+ on the guidance of a bioassay using the transfected human osteosarcoma MG63 cellsluc+ (MG63 ). Compound 13 activated p21 promoter stably osteosarcoma MG63 cells (MG63 ). Compoundluc+ 13 activated p21 promoter stably transfected in humantransfected osteosarcoma in MG63 cellsMG63 with cellsdose ‐dependent(MG63 ). pattern.Compound Expression 13 activatedof p21 protein p21 inpromoter the wild‐ typestably MG63 cells with dose-dependent pattern. Expression of p21 protein in the wild-type MG63 cells was transfectedMG63 cells in MG63was also cells promoted with dose by‐dependent xylarianaphthol pattern.‐1 treatment,Expression indicating of p21 protein compound in the 13wild was‐type also promoted by xylarianaphthol-1 treatment, indicating compound 13 was expected to contribute to MG63expected cells to was contribute also promoted to cancer prevention by xylarianaphthol or treatment‐1 (Figuretreatment, 3) [12]. indicating compound 13 was cancerexpectedA prevention newto contribute polyketide or treatment to withcancer a (Figurenew prevention carbon3)[12 skeleton,].or treatment lindgomycin (Figure 3) (14 [12].), was extracted from mycelia andA culture newnew polyketidepolyketide broth of different with with a a new newLindgomycetaceae carbon carbon skeleton, skeleton, strains, lindgomycin lindgomycin which were (14 (),14 wasisolated), was extracted extractedfrom a from sponge from mycelia ofmycelia the and cultureandKiel culture Fjord broth brothin of the different of Baltic different LindgomycetaceaeSea (Germany)Lindgomycetaceae and strains,from strains, the which Antarctic. which were wereCompound isolated isolated from 14 from ashowed sponge a sponge antibiotic of the of Kiel the FjordKielactivities Fjord in the inwith Baltic the IC SeaBaltic50 value (Germany) Sea of 5.1(Germany) (±0.2) and μ fromM andagainst the from Antarctic. MRSA the Antarctic.(Figure Compound 3) [13] Compound. 14 showed 14 antibioticshowed antibiotic activities withactivities IC50 withvalue IC of50 5.1 value (˘0.2) of 5.1µM (±0.2) against μM MRSA against (Figure MRSA3 )[(Figure13]. 3) [13].

Figure 3. Structures of compounds 10–14. Figure 3. Structures of compounds 10–14. Figure 3. Structures of compounds 10–14.

Mar. Drugs 2016, 14, 76 4 of 25 Mar. Drugs 2016, 14, 76 4 of 25 2.1.2. Coral 2.1.2.The CoralMar. fungus Drugs 2016 Aspergillus, 14, 76 terreus SCSGAF0162 was isolated from gorgonian corals Echinogorgia4 of 25 aurantiaca (the South China Sea). Three lactones including three territrem derivatives (15–17) and a The2.1.2.Mar. fungusDrugs Coral 2016 , 14Aspergillus, 76 terreus SCSGAF0162 was isolated from gorgonian4 of 25 corals butyrolactone derivative (18) were isolated from the fungus under solid‐state fermentation of rice. EchinogorgiaThe aurantiaca fungus Aspergillus(the South terreus China SCSGAF0162 Sea). Three was lactonesisolated from including gorgonian three corals territrem Echinogorgia derivatives Among2.1.2. them, Coral compounds 15 and 16 showed strong inhibitory activity against acetylcholinesterase (15–17)aurantiaca and a butyrolactone(the South China derivativeSea). Three lactones (18) were including isolated three territrem from the derivatives fungus (15 under–17) and solid-state a with IC50 values of 4.2 ± 0.6 and 4.5 ± 0.6 μM, respectively. This was the first report that compounds fermentationbutyrolactoneThe of fungus rice. derivative Among Aspergillus ( them,18 )terreus were compounds isolatedSCSGAF0162 from15 thewasand fungus isolated16 showed under from solid gorgonian strong‐state inhibitory fermentation corals Echinogorgia activity of rice. against 17 and aurantiaca18 had evident (the South antiviral China Sea).activity Three towards lactones HSVincluding‐1, with three IC territrem50 values derivatives of 16.4 ±(15 0.6–17 and) and 21.8 a ± 0.8 acetylcholinesteraseAmong them, compounds with IC 15values and 16 of showed 4.2 ˘ strong0.6 and inhibitory 4.5 ˘ 0.6 activityµM, against respectively. acetylcholinesteraseThis was the first –1 50 μg∙mL butyrolactonewith, respectively. IC50 values derivative Moreover,of 4.2 ± 0.6 (18 and )compound were 4.5 ±isolated 0.6 μ 15M, from hadrespectively. theobvious fungus This antifouling under was solidthe first activity‐state report fermentation with that ECcompounds50 ofvalues rice. of 12.9 report that compounds 17 and 18 had evident antiviral activity towards HSV-1, with IC50 values of ± 0.5 μgAmong17∙mL and–1 toward 18them, had compounds evidentbarnacle antiviral Balanus 15 and activity 16 amphitrite showed towards strong larvae HSV inhibitory‐1, (Figure with IC activity50 4) values [14]. against of 16.4 acetylcholinesterase± 0.6 and 21.8 ± 0.8 16.4 ˘ 0.6 and 21.8 ˘ 0.8 µg¨ mL–1, respectively. Moreover, compound 15 had obvious antifouling μwithg∙mL IC–150, respectively. values of 4.2 Moreover, ± 0.6 and compound4.5 ± 0.6 μM, 15 respectively.had obvious antifoulingThis was the activity first reportwith EC that50 values compounds of 12.9 –1 activity±17 with 0.5 and μ ECg ∙18mL50 had–1values toward evident of barnacle 12.9antiviral˘ Balanus0.5 activityµg ¨amphitritemL towardstoward larvae HSV‐1, barnacle(Figure with IC 4)50 Balanus[14]. values of amphitrite 16.4 ± 0.6larvae and 21.8 (Figure ± 0.8 4) [ 14]. μg∙mL–1, respectively. Moreover, compound 15 had obvious antifouling activity with EC50 values of 12.9 ± 0.5 μg∙mL–1 toward barnacle Balanus amphitrite larvae (Figure 4) [14].

Figure 4. Structures of compounds 15–18. Figure 4. Structures of compounds 15–18.. Two new dihydrothiopheneFigure‐condensed 4. Structures chromones, of compounds oxalicumones 15–18. (19–20) were isolated from a Two new dihydrothiophene‐condensed chromones, oxalicumones (19–20) were isolated from a Twoculture new broth dihydrothiophene-condensed of the marine gorgonian‐associated chromones, fungus oxalicumones Penicillium oxalicum (19–20 )SCSGAF were isolated 0023. from culture broth of the marine gorgonian‐associated fungus Penicillium oxalicum SCSGAF 0023. a cultureCompounds brothTwo new of 19 dihydrothiophene the and marine20 showed gorgonian-associated significant‐condensed cytotoxicity chromones, against fungus oxalicumones severalPenicillium carcinoma (19–20) were oxalicum cell isolated lines withSCSGAF from IC 50a 0023. Compoundsculture 19 broth and of20 theshowed marine significant gorgonian cytotoxicity‐associated fungus against Penicillium several carcinomaoxalicum SCSGAF cell lines 0023. with IC50 Compoundsless than19 10and μM (Figure20 showed 5) [15]. significant cytotoxicity against several carcinoma cell lines with less thanCompounds 10 μM (Figure 19 and 5) 20 [15]. showed significant cytotoxicity against several carcinoma cell lines with IC50 IC50 lessless than than 10 10µ μMM (Figure(Figure 5)5)[ [15].15].

Figure 5. Structures of compounds 19–20.

The fungal strain NigrosporaFigure 5.oryzae Structures SCSGAF of compounds 0111 (from 19–20 . marine gorgonian Verrucella Figure 5. Structures of compounds 19–20. umbraculum, South China Sea)Figure yielded 5. Structures two new citrinins,of compounds nigrospins 19–20 B. and C (21–22). Compounds 21–22The showed fungal weak strain antifungal Nigrospora activity oryzae against SCSGAF Aspergillus 0111 versicolor (from withmarine inhibition gorgonian zone ofVerrucella 8 cm at The50umbraculum fungal μfungalg/paper strain , disc,strainSouth Nigrosporawith China Nigrospora a positive Sea) oryzae yielded control oryzaeSCSGAF two thiram newSCSGAF of 0111 citrinins, 8 cm (from at0111 5nigrospins μg/paper marine (from discB gorgonian andmarine (Figure C (21 –6)Verrucella22gorgonian [16].). Compounds umbraculum Verrucella , Southumbraculum China21–22Two, showed Sea)South nucleoside yielded Chinaweak antifungal derivatives twoSea) new yielded activity citrinins, (23– 24two )against were new nigrospins isolated Aspergillus citrinins, from B andversicolor nigrospins the C fungus (21 with–22 Aspergillus Binhibition). and Compounds C versicolor(zone21–22 of). 218 whichCompoundscm–22 atshowed weak21–22 antifungalshowedwas50 μ g/paperderived weak activity disc,from antifungal with the against gorgoniana positive Aspergillusactivity controlDichotella against thiram versicolor gemmacea Aspergillusof 8 cmwith in at the 5 inhibition μ Southversicolorg/paper China disc zone with Sea.(Figure of inhibitionCompounds 8 cm 6) [16]. at 50 zone µ23g/paper/24 of (a 8 cm disc, at Two nucleoside derivatives (23–24) were isolated from the fungus Aspergillus versicolor which with50 μg/paper a positivemixture disc, of control compoundwith thirama positive 23:compound of 8 control cm at 24 5 thiram µatg/paper a ratio of 8of disccm 7:10) at (Figure exhibited5 μg/paper6)[ selective16 ].disc (Figureantibacterial 6) [16]. activity wasagainst derived Staphylococcus from the epidermidisgorgonian withDichotella an MIC gemmacea value of in 12.5 the μ SouthM (Figure China 6) Sea.[17]. Compounds 23/24 (a Twomixture nucleosidenucleoside of compound derivatives 23:compound (23–24 24) were at a ratio isolatedisolated of 7:10) fromfrom exhibited thethe fungusfungus selective AspergillusAspergillus antibacterial versicolor activity which was derivedagainst from Staphylococcus the gorgonian epidermidis DichotellaDichotella with an MIC gemmacea gemmacea valueO of in12.5in the the μM South South(Figure China China6) O[17]. Sea. Sea. Compounds Compounds 2323/24/ 24(a (amixture mixture of ofcompound compound 2323:compound:compoundOH 2424 atat a aratio ratio NHof of 7:10) 7:10) exhibited exhibited selective NH antibacterial activity R2 ON O O HO HO N O against Staphylococcus epidermidis with an MICMIC valuevalueO NH ofof 12.512.5 μµMM (Figure(FigureO 6 6))[ 17[17].]. HO OH NH R2 OH ON OO O O OH R O HO HO N O 1 O O O OO O HO O OH O NHO 21:R1=OH R2=COOH O O OH NH R1 O O R OH OH O OH O 22:R2 1= R =H N O N O O 2 HO 23HO 24 21:R1= R2=COOH O O HO O OH 22:R = Figure 6. Structures ofOH compounds 21–24. OH 1 R2=H OH O O O O OH R O 23 24 1 O O O Figure 6. Structures of compounds 21–24. 21:R = R =COOH 1 2 O OH OH OH 22:R1= R =H 2 23 24

Figure 6. Structures of compounds 21–24..

Mar. Drugs 2016, 14, 76 5 of 25

TwoMar. Drugs new 2016 sulfur-containing, 14, 76 benzofuran derivatives, eurothiocin A and B (25 and 26) were5 of isolated 25 from theTwo fungus newEurotium sulfur‐containing rubrum SH-823benzofuran which derivatives, was obtained eurothiocin from aA Sarcophytonand B (25 andsp. 26 soft) were coral in the Southisolated China from Sea.the fungus The compounds Eurotium rubrum (25 SHand‐82326 )which shared was a obtained methyl thiolesterfrom a Sarcophyton moiety, sp. which soft was quitecoral rare in in the natural South secondary China Sea. The metabolites. compounds Both (25 and of them 26) shared exhibited a methyl more thiolester potent moiety, inhibitory which effects againstwasα -glucosidasequite rare in natural activity secondary than acarbose, metabolites. which Both was of the them clinical exhibitedα-glucosidase more potent inhibitor. inhibitory Further mechanisticeffects against analysis α‐glucosidase demonstrated activity that than both acarbose, of them which exhibited was the competitive clinical α‐ inhibitionglucosidase characteristics inhibitor. (FigureFurther7)[18 ].mechanistic analysis demonstrated that both of them exhibited competitive inhibition Chondrostereumcharacteristics (Figuresp. was 7) [18]. isolated from the inner tissue of a soft coral Sarcophyton tortuosum, which Chondrostereum sp. was isolated from the inner tissue of a soft coral Sarcophyton tortuosum, was collected from the Hainan Sanya National Coral Reef Reserve, China. When this fungus was which was collected from the Hainan Sanya National Coral Reef Reserve, China. When this fungus cultured in a liquid medium containing glycerol as the carbon source, a new metabolite, chondrosterin was cultured in a liquid medium containing glycerol as the carbon source, a new metabolite, 27 waschondrosterin obtained. Compound 27 was obtained.27 exhibited Compound potent 27 exhibited cytotoxic potent activities cytotoxic against activities the cancer against cell the lines cancer CNE-1 and CNE-2cell lines with CNE the‐1 and IC50 CNEvalues‐2 with of 1.32the IC and50 values 0.56 µofM 1.32 (Figure and 0.567)[ μ19M]. (Figure 7) [19].

FigureFigure 7. 7.Structures Structures of compounds 2525–29–29. .

A steroid derivative, compound 28 was isolated from the fermentation broth of a Agorgonian steroid‐derived derivative, Aspergillus compound sp. fungus.28 was The isolated fungus was from isolated the fermentation from the inner broth part of the a gorgonian- fresh derivedgorgonianAspergillus M. abnormalissp. fungus., which The was fungus collected was from isolated the Xisha from Islands the inner coral part reef ofof the South fresh gorgonianChina M. abnormalisSea. Compound, which 28 was inhibited collected the from larval the settlement Xisha Islands of barnacle coral Balanus reef of amphitrite the South with China EC50 Sea. 18.40 Compound ± 2.0 μg/mL (Figure 7) [20]. 28 inhibited the larval settlement of barnacle Balanus amphitrite with EC50 18.40 ˘ 2.0 µg/mL (Figure7)[A20 new]. diphenyl ether derivative, talaromycin A (29) was isolated from a gorgonian‐derived fungus, Talaromyces sp. The fungal strain was isolated from a piece of fresh tissue from the inner part A new diphenyl ether derivative, talaromycin A (29) was isolated from a gorgonian-derived of the gorgonian Subergorgia suberosa, collected from the Weizhou coral reef in the South China Sea. fungus, Talaromyces sp. The fungal strain was isolated from a piece of fresh tissue from the inner Compound 29 showed potent antifouling activities against the larval settlement of the barnacle part of the gorgonian Subergorgia suberosa, collected from the Weizhou coral reef in the South China Balanus amphitrite with the EC50 value 2.8 ± 0.2 μg/mL (Figure 7) [21]. Sea. Compound 29 showed potent antifouling activities against the larval settlement of the barnacle Balanus2.1.3. amphitrite Starfish with the EC50 value 2.8 ˘ 0.2 µg/mL (Figure7)[21]. Liang et al. [22] investigated the influence on secondary metabolites with variety of cultivation 2.1.3. Starfish parameters of marine fungus, Neosartorya pseudofischeri, which was isolated from the inner tissue of Liangstarfishet Acanthaster al. [22] investigated planci. Glycerol the‐peptone influence‐yeast on extract secondary (GlyPY) metabolites and glucose with‐peptone variety‐yeast of extract cultivation parameters(GluPY) of media marine were fungus, appliedNeosartorya to culture this pseudofischeri fungus. A novel, which gliotoxin was ( isolated30) was produced from the with inner GluPY tissue of starfishmedium.Acanthaster Compound planci 30. Glycerol-peptone-yeast displayed significant inhibitory extract activities (GlyPY) against and glucose-peptone-yeast three multidrug‐resistant extract bacteria, S. aureus (ATCC29213), MRSA (R3708) and Escherichia coli (E. coli) (ATCC25922), as well as (GluPY) media were applied to culture this fungus. A novel gliotoxin (30) was produced with GluPY cytotoxicities against some cell lines including human embryonic kidney (HEK) 293 cell line and medium. Compound 30 displayed significant inhibitory activities against three multidrug-resistant human colon cancer cell lines, HCT‐116 and RKO (a poorly differentiated colon carcinoma cell line) bacteria,(FigureS. aureus8). (ATCC29213), MRSA (R3708) and Escherichia coli (E. coli) (ATCC25922), as well as cytotoxicitiesA novel against isobenzofuranone some cell linesderivative, including pseudaboydins human embryonic A (31) was kidney isolated (HEK) from 293 the cellmarine line and humanfungus, colon Pseudallescheria cancer cell lines, boydii HCT-116, associated and with RKO the starfish, (a poorly Acanthaster differentiated planci. colonCompound carcinoma 31 showed cell line) (Figure8).

A novel isobenzofuranone derivative, pseudaboydins A (31) was isolated from the marine fungus, Pseudallescheria boydii, associated with the starfish, Acanthaster planci. Compound 31 showed moderate Mar. Drugs 2016, 14, 76 6 of 25 Mar. Drugs 2016, 14, 76 6 of 25 Mar. Drugs 2016, 14, 76 6 of 25 cytotoxicmoderate activitycytotoxic against activity HONE1, against HONE1, SUNE1 SUNE1 and GLC82 and GLC82 with IC with50 values IC50 values of 37.1, of 46.537.1, and46.5 87.2and µ87.2M, moderate cytotoxic activity against HONE1, SUNE1 and GLC82 with IC50 values of 37.1, 46.5 and 87.2 respectively (Figure8)[23]. μM, respectivelyrespectively (Figure(Figure 8) [23].[23].

Figure 8. Structures of compounds 30–31. Figure 8. StructuresStructures of compounds 30–31.

2.1.4. Bryozoan Three new cyclohexadepsipeptides of the the isaridin isaridin class including including isaridin isaridin G ( (32),), desmethylisaridin GG( 33((33),),), and and desmethylisaridin desmethylisaridin C1 (34 C1) were ((34 isolated)) were and isolatedisolated identified and from identifiedidentified the marine fromfrom bryozoan- thethe derivedmarine bryozoanfungus Beauveria‐‐derived felina fungusfungusEN-135. Beauveria Compounds felinafelina EN32–‐‐135.34 showed Compounds inhibitory 32–34 activity showed against inhibitoryinhibitoryE.coli with activity MIC againstvalues of E.coli 64, 64,with and MIC 8 µ g/mL,values repectively. of 64, 64, and This 8 is μ μ theg/mL, first repectively.repectively. report on antibacterial This isis thethe activitiesfirstfirst reportreport of theon antibacterialisaridins (Figure activities9)[24 ]. of thethe isaridinsisaridins (Figure(Figure 9) [24].[24]. BioassayBioassay-guided‐‐guided fractionation fractionation of a culture extract of Beauveria felina felina ENEN-135,‐‐135, an entomopathogenic fungusfungus isolatedisolatedisolated from fromfrom an unidentifiedan unidentified marine marine bryozoan, bryozoan, led to the isolationledled toto ofthethe a newisolationisolation cyclodepsipeptide, of a new cyclodepsipeptide,iso-isariin D (35); two isoiso‐‐isariinisariin new O D-containing ((35);); twotwo heterocyclicnew O‐‐containing compounds heterocyclic felinones compounds A and B felinones (felinones36 and 37 A). and B (36 and 37). Compound 35 exhibited potent lethality against brine shrimp (Artemia salina), andCompound B (36 and35 exhibited37). Compound potent 35 lethality exhibited against potent brine lethality shrimp against (Artemia brine salina shrimp), with (Artemia LD50 values salina of), with LD50 values of 26.58 μΜ, notably stronger than that of the positive control colchicine, while with26.58 LDµM,50 notablyvalues of stronger 26.58 μΜ than, notably that of stronger the positive than control that of colchicine, the positive while control compounds colchicine,36 and while37 compoundspossessed weak 36 and activity. 37 possessed Only compound weak activity.37 showed Only compound inhibitory 37 activity showed (MIC inhibitoryinhibitory value ofactivity 32 µg/mL) (MIC(MIC valuehigher of than 32 μ μ thatg/mL) of the higher chloramphenicol thanthan thatthat of controlthethe chloramphenicol (MIC value of 4controlµg/mL) (MIC(MIC against valuePseudomonas of 4 μ μg/mL) aeruginosa against Pseudomonas(Figure9)[25 ].aeruginosa (Figure(Figure 9) [25].[25].

Figure 9. Structures of compounds 32–37. Figure 9. StructuresStructures of compounds 32–37. 2.1.5. Sea Urchin 2.1.5. Sea Urchin The Penicillium sp. SF‐‐6013 was isolatedisolated fromfrom thethe sea urchin Brisaster latifronslatifrons,, which was collectedThe Penicilliumfrom the Seasp. of SF-6013 Okhotsk. was Chemical isolated from investigation the sea urchin of strainBrisaster SF‐6013 latifrons resulted, which in the was discovery collected collectedfrom the Seafrom of the Okhotsk. Sea of Okhotsk. Chemical Chemical investigation investigation of strain SF-6013of strain resulted SF‐6013 inresulted the discovery in the discovery of a new of a new tanzawaictanzawaic acid derivative, 2E,4,4Z‐‐tanzawaictanzawaic acid D ((38).). Screening forfor anti‐‐inflammatoryinflammatory tanzawaiceffects in lipopolysaccharide acid derivative, 2E ,4(LPS)Z-tanzawaic‐activated acid microglial D (38). ScreeningBV‐2 cells for indicated anti-inflammatory that compound effects 38 in effectslipopolysaccharide in lipopolysaccharide (LPS)-activated (LPS)‐ microglialactivated BV-2microglial cells indicatedBV‐2 cells that indicated compound that38 compoundinhibited the38 inhibited the production of nitric oxide (NO) with IC50 values of 37.8 μM (Figure 10) [26]. inhibited the production of nitric oxide (NO) with IC50 values of 37.8 μM (Figure 10) [26]. production of nitric oxide (NO) with IC50 values of 37.8 µM (Figure 10)[26]. 2.1.6. Fish 2.1.6. Fish Two new rubrolides, rubrolides R (39) and S (40), were isolated from the fermentation broth of Two new rubrolides, rubrolides R ( 39) and S (40), were isolated from the fermentation broth of the marine‐derived fungus Aspergillus terreus OUCMDZ‐1925, which was isolated from the viscera the marine-derivedmarine‐derived fungusfungus AspergillusAspergillus terreus terreusOUCMDZ-1925, OUCMDZ‐1925, which which was was isolated isolated from from the the viscera viscera of of C. haematocheilus grown in the waters of the Yellow River Delta. Compound 39 showed ofC. haematocheilusC. haematocheilusgrown grown in the in waters the ofwaters the Yellow of the River Yellow Delta. River Compound Delta. 39Compoundshowed comparable 39 showed or comparable or superior antioxidation against ABTS radicalsradicals toto thosethose of troloxtrolox and ascorbic acid with an IC50 value of 1.33 μM. Compound 40 showed comparable or superior anti‐influenza A (H1N1) an IC50 value of 1.33 μM. Compound 40 showed comparable or superior anti‐influenza A (H1N1)

Mar. Drugs 2016, 14, 76 7 of 25

superiorMar. Drugs antioxidation2016, 14, 76 against ABTS radicals to those of trolox and ascorbic acid with an IC50 value7 of of25 1.33 µM. Compound 40 showed comparable or superior anti-influenza A (H1N1) virus activity to that ofvirus ribavirin activity with to that an IC of50 ribavirinvalue of with 87.1 anµM. IC Compounds50 value of 87.139 μandM. Compounds40 showed weak 39 and cytotoxicity 40 showed against weak thecytotoxicity K562 cell against line with the IC K56250 values cell line of 12.8with and IC50 10.9 valuesµM, of respectively, 12.8 and 10.9 while μM, wererespectively, inactive while against were the A549,inactive HL-60, against Hela the and A549, HCT-116 HL‐60, cell Hela lines and (Figure HCT‐116 10)[ cell27]. lines (Figure 10) [27].

OH O

O O OH O O

O

HO

38 39 40 OH OH Figure 10. Structures of compounds 38–40.

2.1.7. Prawn The fungal fungal strain, strain, AspergillusAspergillus flavus flavus OUCMDZOUCMDZ-2205,‐2205, was obtained was obtained from the from prawn, the Penaeus prawn, Penaeusvannamei, vannamei from the, Lianyungang from the Lianyungang sea area, Jiangsu sea Province area, Jiangsu of China. Province Two new of China.indole‐diterpenoids Two new indole-diterpenoids(41 and 42) were isolated (41 and from42) were the isolatedfermentation from the broth fermentation of the fungus. broth ofCompound the fungus. 41 Compound exhibited 41antibacterialexhibited antibacterialactivity against activity S. aureus against withS. aureusa MIC withvalue a of MIC 20.5 value μM ofand 20.5 showedµM and PKC showed‐beta inhibition PKC-beta with an IC50 value of 15.6 μM. Both 41 and 42 could arrest the A549 cell cycle in the S phase at a inhibition with an IC50 value of 15.6 µM. Both 41 and 42 could arrest the A549 cell cycle in the S phase atconcentration a concentration of 10 of μ 10M µ(FigureM (Figure 11) [28].11)[ 28].

2.1.8. Others The marine-derivedmarine‐derived fungus fungusEurotium Eurotium amstelodami amstelodamiwas was isolated isolated from from an unidentified an unidentified marine marine animal collectedanimal collected from the from Sungsan the coastSungsan in Jeju coast Island, in Jeju Korea. Island, An anthraquinone Korea. An anthraquinone derivative, questinol derivative, (43) wasquestinol successfully (43) was isolated successfully from the isolated broth extract from ofthe the broth fungus extract for the of first the time. fungus Questinol for the ( 43first) did time. not exhibitQuestinol cytotoxicity (43) did not in LPS-stimulated exhibit cytotoxicity RAW in 264.7 LPS cells‐stimulated up to 200 RAWµM while264.7 couldcells up significantly to 200 μM inhibit while NOcould and significantly PGE2 production inhibit atNO indicated and PGE concentrations.2 production at Furthermore, indicated concentrations. it could inhibit Furthermore, the production it ofcould pro-inflammatory inhibit the production cytokines, of includingpro‐inflammatory IL-1β, TNF- cytokines,α, and IL-6including and suppress IL‐1β, TNF the‐α expression, and IL‐6 level and ofsuppress iNOS inthe a dose-dependentexpression level manner of iNOS through in a dose the western‐dependent blot manner analysis. through All these the results western suggest blot thatanalysis. questinol All these might results be selected suggest as a that promising questinol agent might for the be prevention selected as and a promising therapy of inflammatoryagent for the diseaseprevention (Figure and 11therapy)[29]. of inflammatory disease (Figure 11) [29]. A novelnovel aspochalasin, aspochalasin, 20- 20β-methylthio-aspochalsin‐β‐methylthio‐aspochalsin Q (namedQ (named as aspochalasin as aspochalasin V, 44) wasV, 44 isolated) was fromisolated culture from broth culture of brothAspergillus of Aspergillussp., which sp., was which obtained was obtained in the gut in of the a marinegut of a isopod marineLigia isopod oceanica Ligia (Dinghaioceanica in(Dinghai Zhoushan, in ZhejiangZhoushan, Province Zhejiang of China). Province This isof the China). first report This about is the methylthio-substituted first report about aspochalasinmethylthio‐substituted derivative. aspochalasin Apochalasin Vderivative. showed moderate Apochalasin cytotoxic V showed activity moderate against the cytotoxic prostate activity cancer PC3against cell the line prostate and HCT116 cancer cell PC3 line cell with line IC and50 values HCT116 of 30.4cell andline 39.2withµ ICM,50 respectivelyvalues of 30.4 (Figure and 39.2 11)[ μ30M,]. respectivelyTwo new (Figure cerebrosides, 11) [30]. penicillosides A (45) and B (46) were isolated from the marine-derived fungusTwoPenicillium new cerebrosides,species, which penicillosides were gained A (45 from) and the B ( Red46) were Sea tunicate, isolated fromDidemnum the marinespecies‐derived in the Mangrove.fungus Penicillium Penicilloside species, A displayedwhich were antifungal gained from activity the against Red SeaCandida tunicate, albicans Didemnumwhile penicilloside species in the B illustratedMangrove. antibacterial Penicilloside activities A displayed against antifungalS. aureus activityand E. coliagainst. Additionally, Candida albicans both compounds while penicilloside showed weakB illustrated activity antibacterial against HeLa activities cells (Figure against 11)[ 31S.]. aureus and E. coli. Additionally, both compounds showed weak activity against HeLa cells (Figure 11) [31].

Mar. Drugs 2016, 14, 76 8 of 25 Mar. Drugs 2016, 14, 76 8 of 25 Mar. Drugs 2016, 14, 76 8 of 25

Figure 11. Structures of compounds 41–46. Figure 11. Structures of compounds 41–46. 2.2. Mangrove 2.2. Mangrove Six new compounds with polyketide decalin ring, peaurantiogriseols A–F (47–52), were Six newnew compounds compounds with with polyketide polyketide decalin decalin ring, ring, peaurantiogriseols peaurantiogriseols A–F ( 47A–F–52 ),(47 were–52 isolated), were isolated from the fermentation products of mangrove endophytic fungus Penicillium isolatedfrom the fermentationfrom the productsfermentation of mangrove products endophytic of mangrove fungus Penicillium endophytic aurantiogriseum fungus 328#,Penicillium which aurantiogriseum328#, which was collected from the bark of Hibiscus tiliaceus in the Qi’ao Mangrove wasaurantiogriseum collected from328#, the which bark ofwasHibiscus collected tiliaceus fromin the the bark Qi’ao of Mangrove Hibiscus tiliaceus Nature in Reserve the Qi’ao of Guangdong Mangrove Nature Reserve of Guangdong Province, China. Compounds 47–52, showed low inhibitory activity NatureProvince, Reserve China. of Compounds Guangdong47 Province,–52, showed China. low Compounds inhibitory activity 47–52, against showed human low inhibitory aldose reductase activity against human aldose reductase (at a concentration of 50 μM), the corresponding value of percent (atagainst a concentration human aldose of 50 reductaseµM), the corresponding(at a concentration value of of 50 percent μM), the inhibitions corresponding were 16%, value 6%, of 31%, percent 22%, inhibitions were 16%, 6%, 31%, 22%, 26%, 2%, respectively (Figure 12) [32]. inhibitions26%, 2%, respectively were 16%, (Figure6%, 31%, 12 22%,)[32 ].26%, 2%, respectively (Figure 12) [32].

O OH O OH O OH O OH O OH O OH H H H H H H S S S S S S S S S S S S S S S S S SR S S R S R S R R S R S R R H H OH H OH H OH H OH H 47 OH 48 49 OH 47 48 49

O OH O O OH O OH O O OH H H H H H O H R R O S S R R R R S S S R S R OH S S R OH S R OH R RR HO R S OH S R R R HO R S OH H H H OH H 50 OH H 51 H 52 50 OH 51 52 Figure 12. Structures of compounds 47–52. Figure 12. Structures of compounds 47–52. Aspergifuranone (53), isocoumarin derivatives (±) 54 were separated from the mangrove Aspergifuranone (53), isocoumarin derivatives (±) 54 were separated from the mangrove endophyticAspergifuranone fungus Aspergillus (53), isocoumarin sp. 16‐5B, which derivatives was isolated (˘) 54 werefrom separatedthe leaves fromof Sonneratia the mangrove apetala endophytic fungus Aspergillus sp. 16‐5B, which was isolated from the leaves of Sonneratia apetala fromendophytic Dongzhaigang fungus AspergillusMangrove Nationalsp. 16-5B, Nature which Reserve was isolated in Hainan from Island, the leaves China. of BothSonneratia of them apetala were from Dongzhaigang Mangrove National Nature Reserve in Hainan Island, China. Both of them were evaluatedfrom Dongzhaigang for their α‐ Mangroveglucosidase National inhibitory Nature activities, Reserve and in Hainan compound Island, 53 China. showed Both significant of them evaluated for their α‐glucosidase inhibitory activities, and compound 53 showed significant wereinhibitory evaluated activity for with their ICα50-glucosidase value of 9.05 inhibitory ± 0.60 μM. activities, Kinetic analysis and compound showed that53 showed compound significant 53 was inhibitory activity with IC50 value of 9.05 ± 0.60 μM. Kinetic analysis showed that compound 53 was ainhibitory noncompetitive activity inhibitor with IC ofvalue α‐glucosidase. of 9.05 ˘ 0.60 CompoundµM. Kinetic 54 exhibited analysis showed moderate that inhibitory compound activities,53 was a noncompetitive inhibitor50 of α‐glucosidase. Compound 54 exhibited moderate inhibitory activities, witha noncompetitive IC50 value of inhibitor90.4 ± 2.9 μ ofMα -glucosidase.(Figure 13) [33]. Compound 54 exhibited moderate inhibitory activities, with IC50 value of 90.4 ± 2.9 μM (Figure 13) [33]. withA IC newvalue alkaloid, of 90.4 brocaeloid˘ 2.9 µM (Figure B (55), 13 containing)[33]. C‐2 reversed prenylation, was isolated from A 50new alkaloid, brocaeloid B (55), containing C‐2 reversed prenylation, was isolated from culturesA new of Penicillium alkaloid, brocaeloid brocae MA B‐ (192,55), containingan endophytic C-2 reversed fungus prenylation,obtained from was the isolated fresh fromleaves cultures of the cultures of Penicillium brocae MA‐192, an endophytic fungus obtained from the fresh leaves of the marineof Penicillium mangrove brocae plantMA-192, Avicennia an endophytic marina in Hainan fungus island, obtained China. from Compound the fresh leaves 55 showed of the lethality marine marine mangrove plant Avicennia marina in Hainan island, China. Compound 55 showed lethality againstmangrove brine plant shrimpAvicennia (Artemia marina salinain) Hainanwith an island,LD50 value China. of 36.7 Compound μM (Figure55 showed13) [34]. lethality against against brine shrimp (Artemia salina) with an LD50 value of 36.7 μM (Figure 13) [34]. brineThe shrimp fungus (Artemia Phoma salina sp. )OUCMDZ with an LD‐1847,value which of 36.7 wasµ Misolated (Figure from 13)[ a34 mangrove]. fruit sample of The fungus Phoma sp. OUCMDZ‐1847,50 which was isolated from a mangrove fruit sample of KandeliaThe candel fungus (Wenchang,Phoma sp. Hainan OUCMDZ-1847, Province, China), which was generated isolated a new from thiodiketopiperazine, a mangrove fruit sample named of Kandelia candel (Wenchang, Hainan Province, China), generated a new thiodiketopiperazine, named Kandeliaphomazines candel B ((Wenchang,56). Compound Hainan 56 showed Province, cytotoxicity China), generated against the a new MGC thiodiketopiperazine,‐803 cell line with IC50 named value phomazines B (56). Compound 56 showed cytotoxicity against the MGC‐803 cell line with IC50 value of 8.5 μM (Figure 13) [35]. of 8.5 μM (Figure 13) [35].

Mar. Drugs 2016, 14, 76 9 of 25 phomazines B (56). Compound 56 showed cytotoxicity against the MGC-803 cell line with IC value Mar. Drugs 2016, 14, 76 50 9 of 25 of 8.5 µM (Figure 13)[35]. Four newnew disulfide-bridged disulfide‐bridged diketopiperazine diketopiperazine derivatives, derivatives, brocazines brocazines (57 –(6057)– were60) were isolated isolated from Penicilliumfrom Penicillium brocae brocaeMA-231, MA a‐231, fungus a fungus obtained obtained from thefrom fresh the tissuefresh tissue of the of marine the marine mangrove mangrove plant Avicenniaplant Avicennia marina marinathat was that collected was collected at Hainan at Island,Hainan China. Island, Compounds China. Compounds57–60 showed 57–60 cytotoxic showed activitiescytotoxic againstactivities nine against tumor nine cell tumor lines, includingcell lines, including Du145, HepG2, Du145, HeLa, HepG2, NCI-H460, HeLa, NCI MCF-7,‐H460, SGC-7901, MCF‐7, SW1990,SGC‐7901, U251 SW1990, and SW480, U251 and with SW480, IC50 values with IC ranging50 values from ranging 0.89 to from 9.0 µ0.89M (Figure to 9.0 μ 13M)[ (Figure36]. 13) [36].

OH

O O OH O

HO N O H O O O NH O O HO

OH O HO

53 54 55

S O O R H H N O O NH OH H OH S H H HO N N S S R S N N H H S OH OH O O H H O OH

57:R=OMe 59:R=αOH,βH 56 58:R=H 60:R= =O Figure 13. Structures of compounds 53–60.

A new isochroman, (3R,4S)‐3,4‐dihydro‐8‐hydroxy‐4‐methoxy‐3‐methylisocoumarin (61), was A new isochroman, (3R,4S)-3,4-dihydro-8-hydroxy-4-methoxy-3-methylisocoumarin (61), was isolated from the marine fungus Phomopsis sp. (No. Gx‐4), which was obtained from the mangrove isolated from the marine fungus Phomopsis sp. (No. Gx-4), which was obtained from the mangrove sediment of ZhuHai, Guangdong, China. Primary bioassays and preliminary pharmacological tests sediment of ZhuHai, Guangdong, China. Primary bioassays and preliminary pharmacological tests indicated that compound 61 could accelerate the growth of subintestinal vessel plexus (SIV) indicated that compound 61 could accelerate the growth of subintestinal vessel plexus (SIV) branches branches markedly (Figure 14) [37]. markedly (Figure 14)[37]. Penicillium brocae MA‐231, an endophytic fungus, was obtained from the fresh tissue of the Penicillium brocae MA-231, an endophytic fungus, was obtained from the fresh tissue of the marine mangrove plant Avicennia marina. After investigation, five new sulfide diketopiperazine marine mangrove plant Avicennia marina. After investigation, five new sulfide diketopiperazine derivatives, namely, penicibrocazines A–E (62–66) were isolated and identified. In the antimicrobial derivatives, namely, penicibrocazines A–E (62–66) were isolated and identified. In the antimicrobial experiments, compounds 63–65 showed activity against S. aureus, with MIC values of 32.0, 0.25 and experiments, compounds 63–65 showed activity against S. aureus, with MIC values of 32.0, 0.25 and 8.0 μg/mL, respectively. Compound 64 also showed activity against Micrococcus luteus with MIC 8.0 µg/mL, respectively. Compound 64 also showed activity against Micrococcus luteus with MIC value of 0.25 μg/mL. Moreover, compounds 63, 65 and 66 implied activity against plant pathogen value of 0.25 µg/mL. Moreover, compounds 63, 65 and 66 implied activity against plant pathogen Gaeumannomyces graminis with MIC values of 0.25, 8.0, and 0.25 μg/mL, respectively (Figure 14) [38]. Gaeumannomyces graminis with MIC values of 0.25, 8.0, and 0.25 µg/mL, respectively (Figure 14)[38].

Mar. Drugs 2016, 14, 76 10 of 25 Mar. Drugs 2016, 14, 76 10 of 25 Mar. Drugs 2016, 14, 76 10 of 25 O OH O O H OH O H S O S S O O OH O S O H OH O OH N N H H OH H N N N N H OH H H N N OCH 3 OH O H OH H OCH3 OH O H H O H H O O H H 61 62 O 63 H O 62 61 63 O

OH O O OH H O H O H H H S O H S O S O S S O OH S O OH O OH H OH H OH H OH N N H N H N N H N N N H N H N N H N OH H OH H OH H OH OH O S OH O S O S O O S H O S H S H H OH H O H O OH O O 64 65 66 64 65 66 Figure 14. Structures of compounds 61–66. Figure 14. Structures of compounds 61–66. Two new biogenetically related compounds (67–68) have been isolated from a fungus Two new biogenetically related compounds ( 67–68) have been isolated from a fungus Penicillium dipodomyicola HN4‐3A from mangrove of South China Sea. Compounds 67 and 68 Penicillium dipodomyicoladipodomyicolaHN4-3A HN4‐3A from from mangrove mangrove of Southof South China China Sea. CompoundsSea. Compounds67 and 6768 showedand 68 showed strong inhibitory activity against Mycobacterium tuberculosis protein tyrosine phosphatase B showedstrong inhibitory strong inhibitory activity againstactivityMycobacterium against Mycobacterium tuberculosis tuberculosisprotein tyrosine protein tyrosine phosphatase phosphatase B (MptpB) B (MptpB) with IC50 values of 0.16 ± 0.02 μM and 1.37 ± 0.05 μM, respectively (Figure 15) [39]. (MptpB)with IC50 withvalues IC50 of values 0.16 ˘ of0.02 0.16µ M± 0.02 and μ 1.37M and˘ 0.05 1.37µ ±M, 0.05 respectively μM, respectively (Figure (Figure15)[39]. 15) [39]. Investigation of the marine mangrove‐derived fungal strain Penicillium sp. MA‐37 resulted in Investigation of the marine mangrove-derivedmangrove‐derived fungal strain Penicillium sp. MA MA-37‐37 resulted in the isolation of one new benzophenone, iso‐monodictyphenone (69) and two new diphenyl ether the isolation of one new benzophenone, iso‐-monodictyphenonemonodictyphenone ( (6969)) and two new diphenyl ether derivatives penikellides A (70) and B (71). Compounds 69–71 exhibited brine shrimp lethality, with derivatives penikellides A A ( (7070)) and B ( 71). Compounds 6969––7171 exhibited brine shrimp lethality, lethality, with LD50 values of 25.3, 14.2 and 39.2 μM, respectively, while the positive control colchicine had LD50 LD50 valuesvalues of of 25.3, 25.3, 14.2 14.2 and and 39.2 μµM, respectively, while thethe positivepositive controlcontrol colchicinecolchicine hadhad LDLD5050 value of 1.22 μM. Compound 69 showed antibacterial activity against Aeromonas hydrophilia with value ofof 1.221.22µ μM.M. Compound Compound69 69showed showed antibacterial antibacterial activity activity against againstAeromonas Aeromonas hydrophilia hydrophiliawith with MIC MIC 8 μg/mL, while the positive control, chloromycetin exhibited a MIC of 4 μg/mL (Figure 15) [40]. MIC8 µg/mL, 8 μg/mL, while while the positive the positive control, control, chloromycetin chloromycetin exhibited exhibited a MIC a MIC of 4 µofg/mL 4 μg/mL (Figure (Figure 15)[ 15)40]. [40].

Figure 15. Structures of compounds 67–71. Figure 15. StructuresStructures of compounds 67–71. A new naphthalene derivative, vaccinal A (72), was isolated from Pestalotiopsis vaccinii A new naphthalene derivative, vaccinal A (72), was isolated from Pestalotiopsis vaccinii (cgmcc3.9199)A new naphthalene endogenous derivative,with the mangrove vaccinal plant A (72 Kandelia), was isolatedcandel (L.) from DrucePestalotiopsis (Rhizophoraceae). vaccinii (cgmcc3.9199) endogenous with the mangrove plant Kandelia candel (L.) Druce (Rhizophoraceae). (cgmcc3.9199)Compound 72 endogenousexhibited in vitro with anti the‐ mangroveenterovirus plant 71 (EV71)Kandelia with candel IC50 value(L.) Druce of 19.2 (Rhizophoraceae). μM and potent Compound 72 exhibited in vitro anti‐enterovirus 71 (EV71) with IC50 value of 19.2 μM and potent 50 CompoundCOX‐2 inhibitory72 exhibited activity inwith vitro ICanti-enterovirus value of 1.8 μM 71 (Figure (EV71) 16) with [41]. IC 50 value of 19.2 µM and potent COX‐2 inhibitory activity with IC50 value of 1.8 μM (Figure 16) [41]. COX-2The inhibitory fungus Astrocystis activity with sp. IC BCCvalue 22166 of 1.8 wasµM isolated (Figure 16from)[41 a]. mangrove palm, Nypa, at Hat The fungus Astrocystis sp. BCC50 22166 was isolated from a mangrove palm, Nypa, at Hat KhanomThe‐Mu fungus Ko ThaleAstrocystis Tai Nationalsp. BCC Park, 22166 Nakhon was isolated Si Thammarat from a Province mangrove of palm, Thailand. Nypa, Two at new Hat Khanom‐Mu Ko Thale Tai National Park, Nakhon Si Thammarat Province of Thailand. Two new Khanom-Mucompounds, phthalide Ko Thale 73 Tai, dihydroisocoumarin National Park, Nakhon 74 were Si Thammarat separated Provincefrom the offungus. Thailand. Compound Two new 73 compounds, phthalide 73, dihydroisocoumarin 74 were separated from the fungus. Compound 73 compounds,exhibited antibacterial phthalide 73activity, dihydroisocoumarin against Bacillus 74cereuswere (IC separated50 = 12.5 from μg/mL), the fungus. while Compoundcompound 7374 exhibited antibacterial activity against Bacillus cereus (IC50 = 12.5 μg/mL), while compound 74 50 exhibitedshowed cytotoxicity antibacterial to activity KB and against VeroBacillus cells with cereus values(IC50 =of 12.5 ICµ g/mL),22.6 and while 48.2 compound μg/mL respectively74 showed showed cytotoxicity to KB and Vero cells with values of IC50 22.6 and 48.2 μg/mL respectively cytotoxicity(Figure 16) [42]. to KB and Vero cells with values of IC 22.6 and 48.2 µg/mL respectively (Figure 16)[42]. (Figure 16) [42]. 50 A new aromatic amine, pestalamine A (75) was isolated from mangrove‐derived endophytic A new aromatic amine, pestalamine A (75) was isolated from mangrove‐derived endophytic fungus Pestalotiopsis vaccinii that was isolated from a branch of Kandelia candel (L.) Druce fungus Pestalotiopsis vaccinii that was isolated from a branch of Kandelia candel (L.) Druce (Rhizophoraceae), a usual viviparous mangrove species in coastal and estuarine areas of southern (Rhizophoraceae), a usual viviparous mangrove species in coastal and estuarine areas of southern

Mar. Drugs 2016, 14, 76 11 of 25

A new aromatic amine, pestalamine A (75) was isolated from mangrove-derived endophytic fungus Pestalotiopsis vaccinii that was isolated from a branch of Kandelia candel (L.) Druce Mar. Drugs 2016, 14, 76 11 of 25 (Mar.Rhizophoraceae Drugs 2016, 14),, 76 a usual viviparous mangrove species in coastal and estuarine areas of southern11 of 25 China. Pestalamine A ( 75) showed moderate cytotoxicities against human cancer cell lines lines (MCF-7,(MCF‐7, China. Pestalamine A (75) showed moderate cytotoxicities against human cancer cell lines (MCF‐7, HeLa, and HepG2) with ICIC5050 valuesvalues of 40.3, 22.0, and 32.8 μµM, respectively (Figure 1616))[ [43].43]. HeLa, and HepG2) with IC50 values of 40.3, 22.0, and 32.8 μM, respectively (Figure 16) [43].

Figure 16. Structures of compounds 72–75.. Figure 16. Structures of compounds 72–75. A new aromatic butyrolactone, flavipesins A (76), was isolated from marine‐derived A new aromatic butyrolactone, flavipesins A (76), was isolated from marine-derived endophytic endophyticA new fungus aromatic Aspergillus butyrolactone, flavipes. AIL8.flavipesins This was A isolated(76), was from isolated the inner from leaves marine of mangrove‐derived fungus Aspergillus flavipes. AIL8. This was isolated from the inner leaves of mangrove plant endophyticplant Acanthus fungus ilicifolius Aspergillus (Daya flavipes. Bay, Shenzhen AIL8. This City, was Guangdong isolated from Province, the inner China). leaves Compound of mangrove 76 Acanthus ilicifolius (Daya Bay, Shenzhen City, Guangdong Province, China). Compound 76 plantdisplayed Acanthus significant ilicifolius antibacterial (Daya Bay, activity Shenzhen against City, S. aureus Guangdong (MIC = 8.0Province, μg/mL) China). and B. subtillisCompound (MIC 76 = displayed significant antibacterial activity against S. aureus (MIC = 8.0 µg/mL) and B. subtillis displayed0.25 μg/mL). significant Compound antibacterial 76 also showed activity the against unique S. aureusantibiofilm (MIC activity = 8.0 μ g/mL)of decreasing and B. subtillis the number (MIC of = (MIC = 0.25 µg/mL). Compound 76 also showed the unique antibiofilm activity of decreasing the 0.25living μg/mL). cells embed Compound in the 76 biofilm also showed matrix the from unique 390.6 antibiofilm to 97.7 μ g/mLactivity (p of< decreasing0.01). This theindicates number that of number of living cells embed in the biofilm matrix from 390.6 to 97.7 µg/mL (p < 0.01). This indicates livingcompound cells 76embed could in penetrate the biofilm the biofilmmatrix frommatrix 390.6 and tokill 97.7 the μ livingg/mL bacteria (p < 0.01). inside This mature indicates S. aureus that that compound 76 could penetrate the biofilm matrix and kill the living bacteria inside mature S. aureus compoundbiofilm (Figure 76 could 17) [44]. penetrate the biofilm matrix and kill the living bacteria inside mature S. aureus biofilm (Figure 17)[44]. biofilmA new(Figure prenylated 17) [44]. phenol vaccinol I (77) was isolated from endogenous fungi Pestalotiopsis A new prenylated phenol vaccinol I (77) was isolated from endogenous fungi Pestalotiopsis vaccinii vacciniiA new(cgmcc3.9199) prenylated of phenol mangrove vaccinol plant IKandelia (77) was candel isolated (L.) Drucefrom endogenous(Rhizophoraceae fungi). Compound Pestalotiopsis 77 (cgmcc3.9199)vaccinii (cgmcc3.9199) of mangrove of mangrove plant Kandelia plant candelKandelia(L.) candel Druce (L.) (Rhizophoraceae Druce (Rhizophoraceae). Compound). Compound77 exhibited 77 exhibited potent COX‐2 inhibitory activity (IC50 = 16.8 μM) (Figure 17) [45]. potent COX-2 inhibitory activity (IC = 16.8 µM) (Figure 17)[45]. exhibitedPenicibilaenes potent COX A ‐(278 inhibitory) and B ( 79activity50), two (IC sesquiterpenes50 = 16.8 μM) (Figurepossessing 17) [45].a tricyclo[6.3.1.0 1,5] dodecane Penicibilaenes A (78) and B (79), two sesquiterpenes possessing a tricyclo[6.3.1.01,51,5] dodecane skeleton,Penicibilaenes were characterized A (78) and Bfrom (79), Penicilliumtwo sesquiterpenes bilaiae MApossessing‐267, a afungus tricyclo[6.3.1.0 obtained] dodecanefrom the skeleton, were characterized from Penicillium bilaiae MA-267, a fungus obtained from the rhizospheric skeleton,rhizospheric were soil characterizedof the mangrove from plant Penicillium Lumnitzera bilaiaeracemosa MA. Both‐267, of thema fungus exhibited obtained selective from activity the soil of the mangrove plant Lumnitzera racemosa. Both of them exhibited selective activity against rhizosphericagainst the plantsoil of pathogenic the mangrove fungus plant ColletotrichumLumnitzera racemosa gloeosporioides. Both of them(MIC exhibited = 1.0 and selective 0.125 μ activityg/mL, the plant pathogenic fungus Colletotrichum gloeosporioides (MIC = 1.0 and 0.125 µg/mL, respectively) againstrespectively) the plant (Figure pathogenic 17) [46]. fungus Colletotrichum gloeosporioides (MIC = 1.0 and 0.125 μg/mL, (Figure 17)[46]. respectively)Three new (Figure resveratrol 17) [46]. derivatives, resveratrodehydes A–C (80–82), were isolated from the Three new resveratrol derivatives, resveratrodehydes A–C (80–82), were isolated from the mangroveThree endophyticnew resveratrol fungus derivatives, Alternaria sp.resveratrodehydes R6. All compounds A–C showed (80–82 broad), were‐spectrum isolated inhibitoryfrom the mangrove endophytic fungus Alternaria sp. R6. All compounds showed broad-spectrum inhibitory mangroveactivities against endophytic human fungus breast Alternaria MDA‐MB sp.‐435, R6. humanAll compounds liver HepG2, showed and broadhuman‐spectrum colon HCT inhibitory‐116 by activities against human breast MDA-MB-435,MDA‐MB‐435, human liver HepG2, and human colon HCT HCT-116‐116 by MTT assay (IC50 < 50 μM). Especially, compounds 80 and 81 both exhibited marked cytotoxic MTT assayassay (IC (IC5050< < 50 50µM). μM). Especially, Especially, compounds compounds80 and 8081 andboth 81 exhibited both exhibited marked cytotoxicmarked cytotoxic activities activities against HCT‐116 and MDA‐MB‐435 cell lines (IC50 < 10 μM). Additionally, compounds 80 against HCT-116 and MDA-MB-435 cell lines (IC < 10 µM). Additionally, compounds 80 and 82 activitiesand 82 showed against moderate HCT‐116 antioxidant and MDA‐ effectMB‐435 by cell DPPH 50lines radical (IC50

Figure 17. Structures of compounds 76–82. Figure 17. Structures of compounds 76–82. The strategy that co‐cultivation of two mangrove fungi, Phomopsis sp. K38 and Alternaria sp. The strategy that co‐cultivation of two mangrove fungi, Phomopsis sp. K38 and Alternaria sp. E33 (LeizhouThe strategy Peninsula, that co-cultivation Guangdong ofProvince, two mangrove China) in fungi, a singlePhomopsis confinedsp. environment K38 and Alternaria generatedsp. E33 (Leizhou Peninsula, Guangdong Province, China) in a single confined environment generated E33new (Leizhou active Peninsula, natural Guangdong products, Province, including China) inthree a single confinednew environmentcyclic tetrapeptides, generated new active natural products, including three new cyclic tetrapeptides, cyclo(D‐Pro‐L‐Tyr‐L‐Pro‐L‐Tyr) (83), cyclo(Gly‐L‐Phe‐L‐Pro‐L‐Tyr) (84) and cyclo(D‐Pro‐L‐Tyr‐L‐Pro‐L‐Tyr) (83), cyclo(Gly‐L‐Phe‐L‐Pro‐L‐Tyr) (84) and cyclo(L‐leucyl‐trans‐4‐hydroxy‐L‐prolyl‐D‐leucyl‐trans‐4‐hydroxy‐L‐proline) (85). Compounds 83–85 cyclo(showedL‐leucyl moderate‐trans ‐4to‐hydroxy high ‐antifungalL‐prolyl‐D ‐leucylactivities‐trans (‐Candida4‐hydroxy albicans‐L‐proline), Gaeumannomyces (85). Compounds graminis 83–85, showedRhzioctonia moderate cerealis, Helminthosporiumto high antifungal sativum activities and Fusarium(Candida graminearumalbicans, Gaeumannomyces) as compared graminiswith the, Rhzioctoniapositive control cerealis (Figure, Helminthosporium 18) [48,49]. sativum and Fusarium graminearum) as compared with the positive control (Figure 18) [48,49].

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new active natural products, including three new cyclic tetrapeptides, cyclo(D-Pro-L-Tyr-L-Pro-L-Tyr) (83), cyclo(Gly-L-Phe-L-Pro-L-Tyr) (84) and cyclo(L-leucyl-trans-4-hydroxy-L-prolyl-D-leucyl-trans- 4-hydroxy-L-proline) (85). Compounds 83–85 showed moderate to high antifungal activities (Candida albicans, Gaeumannomyces graminis, Rhzioctonia cerealis, Helminthosporium sativum and FusariumMar. Drugs 2016 graminearum, 14, 76 ) as compared with the positive control (Figure 18)[48,49]. 12 of 25

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Figure 18. Structures of compounds 83–85. Figure 18. Structures of compounds 83–85. Figure 18. Structures of compounds 83–85. 2.3. Sediment 2.3. Sediment Penicillium chrysogenum PJXPJX-17,‐17, which was separated from marine sediment (South China Sea) generated two novel sorbicillinoids combining a bicyclo[2.2.2] octane with a 2‐methoxyphenol generatedPenicillium two novel chrysogenum sorbicillinoids PJX‐17, combining which was a bicyclo[2.2.2] separated from octane marine with sediment a 2-methoxyphenol (South China Sea) moiety, moiety, sorbicatechols A (86) and B (87) respectively. Compounds 86 and 87 exhibited activities sorbicatecholsgenerated Atwo (86 novel) and sorbicillinoids B (87) respectively. combining Compounds a bicyclo[2.2.2]86 andoctane87 withexhibited a 2‐methoxyphenol activities against againstmoiety, influenza sorbicatechols virus A (H1N1),A (86) and with B (IC8750) respectively.values of 85 Compoundsand 113 μM, 86 respectively and 87 exhibited (Figure activities 19) [50]. influenza virus A (H1N1), with IC50 values of 85 and 113 µM, respectively (Figure 19)[50]. Theagainst fungal influenza strain virus Penicillium A (H1N1), sp. withF446, IC which50 values was of 85isolated and 113 from μM, marinerespectively sediments (Figure at 19) the [50]. depth of The fungal strain Penicillium sp. F446, which was isolated from marine sediments at the depth of 25 m collectedThe fungal from strainGeomun Penicillium‐do (Island), sp. F446, Korea, which generated was isolated a novel from marinemeroterpenoid, sediments atpenicillipyrones the depth of B 25 m collected from Geomun-do (Island), Korea, generated a novel meroterpenoid, penicillipyrones B (88). Compound25 m collected 88 from showed Geomun significant‐do (Island), induction Korea, generated of quinone a novel reductase meroterpenoid, (Figure 19)penicillipyrones [51]. B (88). Compound(88). Compound88 showed 88 showed significant significant induction induction ofof quinone reductase reductase (Figure (Figure 19) 19 [51].)[51 ].

O O O O O O HO HO HO O HO HO O O HO O O H H O O OH O O OH HH OHOH

H H O O OO OH H H OH 8686 87 87 88 88

Figure 19. Structures of compounds 86–88. Figure 19. Structures of compounds 86–88. An epidithiodiketopiperazine, N‐methyl‐pretrichodermamide B (89) was isolated from the Anfungus epidithiodiketopiperazine,epidithiodiketopiperazine, Penicillium sp. WN‐11‐1‐3N-‐ 1N‐methyl-pretrichodermamide2,‐methyl derived‐pretrichodermamide from the sediment of B ( a89B hyper )( was89) saline isolatedwas isolatedlake from located the from fungusat the PenicilliumfungusWadi Penicillium Elsp.‐Natrun WN-11-1-3-1-2, sp. in Egypt,WN‐11 80‐ 1km‐ derived3‐ 1northwest‐2, derived from of Cairo. the from sediment Compoundthe sediment of 89 a hypershowed of a hyper saline pronounced saline lake located cytotoxicitylake located at Wadi at WadiEl-Natrunagainst El‐Natrun in the Egypt, murine in Egypt, 80 kmlymphoma 80 northwest km northwestL5178Y of Cairo. mouse of Cairo. Compound lymphoma Compound cell89 showedline, 89IC 50showed pronounced= 2 μM (Figurepronounced cytotoxicity 20) [52]. cytotoxicity against against theOne murine new polyketide lymphoma (90 L5178Y) was isolated mouse from lymphoma the lipophilic cell line,extract IC of50 =the 2 μ marineM (Figure‐derived 20) fungus [52]. the murine lymphoma L5178Y mouse lymphoma cell line, IC50 = 2 µM (Figure 20)[52]. OneIsaria new felina polyketide KMM 4639 ( 90from) was marine isolated sediments from the at lipophilica depth of extract 10 m (South of the marine-derivedmarineChina Sea,‐derived coast fungusof Vietnam). Compound 90 exhibited cytotoxicity against HL‐60 and THP‐1 cell lines with IC50 values Isaria felinafelina KMMKMM 4639 4639 from from marine marine sediments sediments at a at depth a depth of 10 mof (South10 m China(South Sea, China coast Sea, of Vietnam).coast of of 4.3 and 37.4 μM, respectively (Figure 20) [53]. Vietnam). Compound 90 exhibited cytotoxicity against HL‐60 and THP‐1 cell lines with IC50 values CompoundOne90 newexhibited indolediketopiperazine cytotoxicity against peroxide, HL-60 13 and‐O‐prenyl THP-1‐26 cell‐hydroxyverruculogen lines with IC50 values (91), of was 4.3 and of 4.3 and 37.4 μM, respectively (Figure 20) [53]. 37.4 µisolatedM, respectively and identified (Figure from 20 the)[53 culture]. extract of the marine sediment‐derived fungus Penicillium One new indolediketopiperazine peroxide, 13‐O‐prenyl‐26‐hydroxyverruculogen (91), was Onebrefeldianum new indolediketopiperazine SD‐273. Compound 91 peroxide, showed potent 13-O-prenyl-26-hydroxyverruculogen lethality against brine shrimp (Artemia (91), was salina isolated), isolated and identified from the culture extract of the marine sediment‐derived fungus Penicillium and identifiedwith LD50 fromvalue theof 9.44 culture μΜ, comparing extract of thewith marine the positive sediment-derived control colchicine fungus (LD50Penicillium = 99.0 μΜ) brefeldianum(Figure brefeldianum SD‐273. Compound 91 showed potent lethality against brine shrimp (Artemia salina), SD-273.20) Compound[54]. 91 showed potent lethality against brine shrimp (Artemia salina), with LD50 value with LD50 value of 9.44 μΜ, comparing with the positive control colchicine (LD50 = 99.0 μΜ) (Figure of 9.44 µM, comparing with the positive control colchicine (LD50 = 99.0 µM) (Figure 20)[54]. 20) [54].

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Figure 20. Structures of compounds 89–91. Figure 20. Structures of compounds 89–91.. Fungus Spicaria elegans KLA03 was derived from marine sediments collected in Jiaozhou Bay, Fungus Spicaria elegans KLA03 was derived from marine sediments collected collected in in Jiaozhou Jiaozhou Bay, Bay, China. Eleganketal A (92), a naturally occurring aromatic polyketide possessing a rare highly China. Eleganketal Eleganketal A A ( (9292),), a a naturally naturally occurring occurring aromatic aromatic polyketide polyketide possessing possessing a a rare highly oxygenated spiro[isobenzofuran‐1,3′‐isochroman] ring system, was isolated from the fungus by oxygenated spiro[isobenzofuran-1,3spiro[isobenzofuran‐1,3′‐1-isochroman]isochroman] ring ring system, system, was was isolated isolated from from the fungus by culturing it in a modified mannitol‐based medium. The synthetic (±)‐92a and its separated culturing itit in in a modified a modified mannitol-based mannitol‐based medium. medium. The synthetic The synthetic (˘)-92a and (±) its‐92 separateda and its enantiomers separated enantiomers showed no cytotoxicity against HL‐60 and K562 cells (IC50 > 50 μM). Only compound showedenantiomers no cytotoxicity showed no against cytotoxicity HL-60 andagainst K562 HL cells‐60 (IC and50 >K562 50 µ cellsM). Only (IC50 compound > 50 μM). (Only´)-92 compounda exhibited (−)‐92a exhibited activity against the influenza A H1N1 virus with an IC50 = 149 μM (Figure 21) [55]. activity(−)‐92a exhibited against the activity influenza against A H1N1 the influenza virus with A anH1N1 IC50 virus= 149 withµM an (Figure IC50 = 21 149)[55 μM]. (Figure 21) [55]. Two novel tetracyclic oxindole alkaloids, speradines G (93) and H (94), were isolated from the Two novelnovel tetracyclictetracyclic oxindole alkaloids, speradines G ( 93) and H (94), were isolated from the marine‐derived fungus Aspergillus oryzae, isolated from marine sediments (Langqi Island, Fujian, marine-derivedmarine‐derived fungus Aspergillus oryzae ,, isolated isolated from from marine sediments (Langqi Island, Fujian, China). This is the first report on cyclopiazonic acid (CPA)‐type alkaloids with a hexacyclic skeleton. China). This is the first first report on cyclopiazonic acid acid (CPA) (CPA)-type‐type alkaloids with a a hexacyclic hexacyclic skeleton. skeleton. The compounds 93–94 showed unconspicuous cytotoxic effects on the Hela, HL‐60 and K562 cell The compoundscompounds93 93––9494showed showed unconspicuous unconspicuous cytotoxic cytotoxic effects effects on theon the Hela, Hela, HL-60 HL and‐60 K562and K562 cell lines, cell lines, IC50 values larger than 30 μg/mL (Figure 21) [56]. IClines,50 values IC50 values larger larger than 30thanµg/mL 30 μg/mL (Figure (Figure 21)[56 21)]. [56]. OR OR OR H OR H OR NH N O OR O OR NH N O RO O OR RO O H O O O N H O N O O O N OH O N O RO OOH O RO O O 92:R=H 92:R=H 93 94 92a:R=CH3 93 94 92a:R=CH3 Figure 21. Structures of compounds 92–94. Figure 21. Structures of compounds 92–94.. One new cyclic peptide, psychrophilins (95), possessing a rare amide linkage between the One new cyclic peptide, psychrophilins (95), possessing a rare amide linkage between the carboxylicOne new acid cyclicin anthranilic peptide, acid psychrophilins (ATA) and the (95 nitrogen), possessing from an a indole rare amide moiety, linkage was obtained between from the carboxylic acid in anthranilic acid (ATA) and the nitrogen from an indole moiety, was obtained from carboxylicthe culture acidof the in marine anthranilic‐derived acid fungus (ATA) Aspergillus and the nitrogenversicolor ZLN from‐60, an isolated indole moiety, from the was mud obtained (depth, the culture of the marine‐derived fungus Aspergillus versicolor ZLN‐60, isolated from the mud (depth, from20 m) the of the culture Yellow of the Sea. marine-derived Compound 95 fungusshowedAspergillus potent lipid versicolor‐loweringZLN-60, effects isolated at a dose from of 10 the μM mud as 20 m) of the Yellow Sea. Compound 95 showed potent lipid‐lowering effects at a dose of 10 μM as (depth,assessed 20 by m) Oil of Red the Yellow O staining Sea. Compound(Figure 22) [57].95 showed potent lipid-lowering effects at a dose of 10 µM assessed by Oil Red O staining (Figure 22) [57]. as assessedTwo new by Oilprenylated Red O staining indole (Figure alkaloids, 22)[ including57]. a β‐carboline, penipalines B (96), and one Two new prenylated indole alkaloids, including a β‐carboline, penipalines B (96), and one indoleTwo carbaldehyde new prenylated derivative, indole alkaloids, penipaline including C (97), a βwere-carboline, obtained penipalines from the B (96deep), and‐sea one‐sediment indole indole carbaldehyde derivative, penipaline C (97), were obtained from the deep‐sea‐sediment carbaldehydederived fungus derivative, Penicillium penipaline paneum CSD (97‐44), werecultured obtained in a from500‐L the bioreactor. deep-sea-sediment Compounds derived 96 and fungus 97 derived fungus Penicillium paneum SD‐44 cultured in a 500‐L bioreactor. Compounds 96 and 97 Penicilliumshowed potent paneum cytotoxicSD-44 cultured activities in against a 500-L two bioreactor. tumor cell Compounds lines, A‐54996 and and97 HCTshowed‐116. potentThe IC cytotoxic50 values showed potent cytotoxic activities against two tumor cell lines, A‐549 and HCT‐116. The IC50 values activitiesof compounds against 96 twoand tumor97 against cell HCT lines,‐116 A-549 were and 14.88 HCT-116. and 18.54 The μM, IC50 whilevalues those of compoundsagainst A‐54996 wereand of compounds 96 and 97 against HCT‐116 were 14.88 and 18.54 μM, while those against A‐549 were 9720.44against and 21.54 HCT-116 μM, respectively were 14.88 and (Figure 18.54 22)µM, [58]. while those against A-549 were 20.44 and 21.54 µM, 20.44 and 21.54 μM, respectively (Figure 22) [58]. respectivelyThe fungal (Figure strain 22)[ Aspergillus58]. versicolor HDN08‐60, isolated from the sediments in the South The fungal strain Aspergillus versicolor HDN08‐60, isolated from the sediments in the South ChinaThe Sea, fungal was fermented strain Aspergillus on liquid versicolor cultureHDN08-60, (60 L) for 30 isolated days and from extracted the sediments three intimes the with South EtOAc. China China Sea, was fermented on liquid culture (60 L) for 30 days and extracted three times with EtOAc. Sea,A novel was versicamide fermented on H liquid (98) was culture obtained. (60 L) forCompound 30 days and 98 exhibited extracted moderate three times activity with EtOAc. against A HL novel‐60 A novel versicamide H (98) was obtained. Compound 98 exhibited moderate activity against HL‐60 versicamidecells (IC50 = H8.7 ( μ98M)) was and obtained. selective Compound PTK inhibitory98 exhibited activities moderate in further activity investigation against HL-60with target cells cells (IC50 = 8.7 μM) and selective PTK inhibitory activities in further investigation with target (ICscreening50 = 8.7 (FigureµM) and 22) selective [59]. PTK inhibitory activities in further investigation with target screening screening (Figure 22) [59]. (Figure 22)[59].

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Mar. Drugs 2016, 14, 76 14 of 25

Figure 22. Structures of compounds 95–98. Figure 22. Structures of compounds 95–98. After modified diethyl sulphate mutagenesis procedure, a marine‐derived fungus Penicillium After modified diethyl sulphate mutagenesis procedure, a marine-derived fungus purpurogenum G59 (the tideland of Bohai Bay, Tianjin, China) yielded four new antitumor PenicilliumAfter modified purpurogenum diethylG59 sulphate (the tidelandmutagenesis of Bohaiprocedure, Bay, a Tianjin, marine‐derived China) yieldedfungus Penicillium four new compounds named penicimutanolone (99), penicimutanin A (100), penicimutanin B (101), and purpurogenumantitumor compounds G59 (the named tideland penicimutanolone of Bohai Bay, (99 Tianjin,), penicimutanin China) Ayielded (100), penicimutaninfour new antitumor B (101), penicimutatin (102). Compounds 99–101 inhibited several human cancer cell lines (K562, HL‐60, compoundsand penicimutatin named (102 penicimutanolone). Compounds 99 –(99101), inhibitedpenicimutanin several A human (100), cancerpenicimutanin cell lines (K562,B (101 HL-60,), and HeLa, BGC‐823, and MCF‐7) with IC50 values lower than 20 μM, compound 102 also inhibited the penicimutatinHeLa, BGC-823, (102 and). Compounds MCF-7) with 99 IC–101 valuesinhibited lower several than human 20 µM, cancer compound cell lines102 (K562,also inhibited HL‐60, cell lines to some extent [60]. In addition,50 three new C25 steroids (103–105) with an unusual HeLa,the cell BGC lines‐823, to someand MCF extent‐7) [with60]. IC In50 addition, values lower three than new 20 C25 μM, steroids compound (103– 105102) also with inhibited an unusual the bicyclo[4.4.1]A/B ring with the Z‐configuration of 20,22‐double bond were isolated. All of them cellbicyclo[4.4.1]A/B lines to some ring extent with [60]. the InZ-configuration addition, three of new 20,22-double C25 steroids bond ( were103–105 isolated.) with Allan unusual of them weakly inhibited several human cancer cell lines (K562, HL‐60 and HeLa) to varying extents (Figure weaklybicyclo[4.4.1]A/B inhibited ring several with human the Z‐configuration cancer cell lines of 20,22 (K562,‐double HL-60 bond and were HeLa) isolated. to varying All of extents them 23) [61]. Furthermore, seven new (106–112) lipopeptides were isolated from the extract of mutant, (Figureweakly inhibited23)[61]. Furthermore,several human seven cancer new cell ( 106lines–112 (K562,) lipopeptides HL‐60 and were HeLa) isolated to varying from extents the extract (Figure of which showed weak cytotoxicity (Figure 23) [62]. These results provided the way to discover new 23)mutant, [61]. whichFurthermore, showed seven weak cytotoxicitynew (106–112 (Figure) lipopeptides 23)[62]. Thesewere isolated results provided from the the extract way toof discovermutant, compounds by activating silent fungal metabolic pathways. which showed weak cytotoxicity (Figure 23) [62]. These results provided the way to discover new new compounds by activating silent fungalHO metabolic pathways. O H compounds by activating silent fungalH metabolic pathways. N HO O O NH O H H HN N NH O OO O N H O HN O O HOO N H 99O O 102 HOO 99H 102 R OH O NH OR H 100:R=H N H OH 101:R=OH R NH OR N H H 100:R=H N O H HH 101:R=OH H N N OH H HO OO H O H H ON OO O HO 103:23H S,24S;R=H O 104:23O S,24R;R=H 105:23S,24S/R;R=Me O HOO O 103:23S,24S;R=H 104:23S,24R;R=H 105:23S,24S/RNH;R=Me NH2 HO 2 O NHO OH O NH2 OH O 2 O H H ON ON OH O N N R OH O N O NH2 H H H H H O N O N 106,107:R=OCH2CH3,C-2 epimerN N R N NH2 H 108,109:R=OCH3,C-2 epimer H H O 110:R=CONH ,2S(L-leucine amide) O O NH 106,107:R=OCH2 2CH3,C-2 epimer O NH2 112 2 111:R=CONH ,2R(D-leucine amide) 108,109:R=OCH2 3,C-2 epimer O NH 110:R=CONH2,2S(L-leucine amide) O NH2 112 2 111:R=CONH2,2R(D-leucine amide)Figure 23. Structures of compounds 99–112. Figure 23. Structures of compounds 99–112. Ascotricha sp. ZJ‐M‐5, is a Figurefungus 23. isolatedStructures from of compoundsa mud sample,99–112 which. was collected on a coastal beach in Fenghua County, Zhejiang Province, China. Chemical investigations were found to Ascotricha sp. ZJ‐M‐5, is a fungus isolated from a mud sample, which was collected on a coastal produceAscotricha cyclonerodiolsp. ZJ-M-5, analogues, is a fungus a 3,4 isolated‐seco lanostane from a mud triterpenoid, sample, which and was diketopiperazines collected on a coastal in an beach in Fenghua County, Zhejiang Province, China. Chemical investigations were found to beacheutrophic in Fenghua medium County, by the one Zhejiang strain Province,‐many compounds China. Chemical (OSMAC) investigations analysis. Two were new found caryophyllene to produce produce cyclonerodiol analogues, a 3,4‐seco lanostane triterpenoid, and diketopiperazines in an cyclonerodiolderivatives (113 analogues,–114) were a produced 3,4-seco lanostane in an oligotrophic triterpenoid, medium, and diketopiperazinesCzapek Dox broth inwith an or eutrophic without eutrophic medium by the one strain‐many compounds (OSMAC) analysis. Two new caryophyllene mediumMg2+. (+)‐ by6‐O the‐Demethylpestalotiopsin one strain-many compounds A (113 (OSMAC)) and (+)‐ analysis.6‐O‐demethylpestalotiopsin Two new caryophyllene C (114 derivatives), which derivatives (113–114) were produced in an oligotrophic medium, Czapek Dox broth with or without have a five‐membered hemiacetal structural moiety, showed growth inhibitory abilities against Mg2+. (+)‐6‐O‐Demethylpestalotiopsin A (113) and (+)‐6‐O‐demethylpestalotiopsin C (114), which K562 and HL‐60 leukemia cell lines with the lowest GI50 value of 6.9 ± 0.4 μM. This indicated that have a five‐membered hemiacetal structural moiety, showed growth inhibitory abilities against K562 and HL‐60 leukemia cell lines with the lowest GI50 value of 6.9 ± 0.4 μM. This indicated that

Mar. Drugs 2016, 14, 76 15 of 25

(113–114) were produced in an oligotrophic medium, Czapek Dox broth with or without Mg2+. (+)-6-O-Demethylpestalotiopsin A (113) and (+)-6-O-demethylpestalotiopsin C (114), which have

Mar.a five-membered Drugs 2016, 14, 76 hemiacetal structural moiety, showed growth inhibitory abilities against K56215 of and 25 HL-60Mar. Drugs leukemia 2016, 14, cell76 lines with the lowest GI50 value of 6.9 ˘ 0.4 µM. This indicated that modification15 of 25 modificationof the culture of media the culture was effective media was in the effective discovery in the of discovery novel bioactive of novel fungal bioactive secondary fungal metabolites secondary (Figuremetabolitesmodification 24)[ 63(Figure of]. the culture24) [63]. media was effective in the discovery of novel bioactive fungal secondary metabolitesThe marine (Figure fungus 24) [63]. CladosporiumCladosporium sp. was was isolated isolated from from a a sediment sample collected from YangshashanThe marine Bay, fungus Ningbo,Ningbo, Cladosporium ZhejiangZhejiang Province,Province, sp. was China.China. isolated Two from newnew sulfur-containingsulfura sediment‐containing sample diketopiperazines collected from (DKPs),Yangshashan cladosporin Bay, Ningbo, A ( 115 )Zhejiang and cladosporin Province, B China.( 116), were Two separated new sulfur from ‐containing the fungus diketopiperazines by high high-speed‐speed countercounter-current(DKPs),‐ currentcladosporin chromatography A (115) and cladosporin (HSCCC). Cytotoxic B (116), were activity separated tests showed from the that fungus compounds by high 115‐speed and counter‐current chromatography (HSCCC). Cytotoxic activity tests showed that compounds 115 and 116 exhibitedexhibited moderate cytotoxic activities to HepG2 cell line, withwith valuesvalues ofof ICIC5050 21 andand 4242 μµg/mLg/mL (Figure116 exhibited 2424))[ [64].64 moderate]. cytotoxic activities to HepG2 cell line, with values of IC50 21 and 42 μg/mL (Figure 24) [64]. O O O O Ha Hb Ha Hb CH3 CH O 3 SCH SCH3 O Ha Hb 3O Hb CH3 Ha O O CH3 OH SCH3 H C HO O SCH3O 3 H3C H H O CH3 CH3 OH H C O HO N N N H 3C HH3CC H H N 3 CH3 3 CH H H O OH 3 N H H H C O N H C O N N H3C H3C OH 3 3 OH H H O H H O H H H C O H C O H3CS H OH 3 H CS 3 H'a OH O O 3 H'a O O H HO HOH H'b H3CS H'b H H CS H'a OH O 3 H'a O HO HO H'b H'b 113 114 115 116 113 114 115 116 Figure 24. Structures of compounds 113–116. Figure 24. Structures of compounds 113–116. A novel cyclic dipeptide, 14‐hydroxy‐cyclopeptine (117), was purified from a deep sea derived A novel cyclic dipeptide, 14-hydroxy-cyclopeptine (117), was purified from a deep sea derived fungusA novelSCSIOW2 cyclic identified dipeptide, as 14 an‐hydroxy Aspergillus‐cyclopeptine sp. Fungus (117 SCSIOW2), was purified was isolated from afrom deep deep sea derivedmarine fungus SCSIOW2 identified as an Aspergillus sp. Fungus SCSIOW2 was isolated from deep marine sedimentfungus SCSIOW2 sample collectedidentified in as the an SouthAspergillus China sp. Sea Fungus at a depth SCSIOW2 of 2439 was m. isolated Compound from 117deep inhibited marine sediment sample collected in the South China Sea at aa depthdepth ofof 24392439 m.m. Compound 117 inhibitedinhibited nitric oxide production with IC50 value at 40.3 μg/mL in a lipopolysaccharide and recombinant nitric oxide production with IC value at 40.3 µg/mL in a lipopolysaccharide and recombinant mouse mousenitric oxide interferon production‐γ‐activated with macrophage50IC50 value at‐like 40.3 cell μ line,g/mL RAW in a 264.7lipopolysaccharide (Figure 25) [65]. and recombinant interferon-γ-activated macrophage-like cell line, RAW 264.7 (Figure 25)[65]. mouseTrichobotrysins interferon‐γ‐activated (118–120 macrophage), a class of ‐newlike celltetramic line, RAW acid derivatives264.7 (Figure with 25) [65].a decalin ring, were Trichobotrysins (118–120), a class of new tetramic acid derivatives with a decalin ring, were characterizedTrichobotrysins from the (118 culture–120), of a Trichobotrysclass of new effuse tetramic DFFSCS021 acid derivatives derived from with the a deepdecalin sea ring, sediment were characterized from the culture of Trichobotrys effuse DFFSCS021 derived from the deep sea sediment collectedcharacterized from from the South the culture China of Sea. Trichobotrys Compounds effuse 118 DFFSCS021–120 exhibited derived significant from the selective deep sea cytotoxicity sediment collected from the South China Sea. Compounds 118–120 exhibited significantsignificant selective cytotoxicity against human carcinoma KG‐1a cell line with IC50 values of 5.44, 8.97, and 6.16 μM, and obvious µ against human human carcinoma carcinoma KG KG-1a‐1a cell cell line line with with IC50 ICvalues50 values of 5.44, of 8.97, 5.44, and 8.97, 6.16 and μM, 6.16 and obviousM, and antiviral activity towards HSV‐1 with IC50 values of 3.08, 9.37, and 3.12 μM, respectively (Figure 25) obvious antiviral activity towards HSV-1 with IC values of 3.08, 9.37, and 3.12 µM, respectively [66].antiviral activity towards HSV‐1 with IC50 values of50 3.08, 9.37, and 3.12 μM, respectively (Figure 25) (Figure[66]. 25)[66].

Figure 25. Structures of compounds 117–120. Figure 25. Structures of compounds 117–120.. 2.4. Alga 2.4. Alga 2.4. AlgaThe Aspergillus ustus cf‐42 strain, which was obtained from the fresh tissue of the marine green alga TheC. fragile Aspergillus (Zhoushan ustus cf-42cfIsland,‐42 strain, China), which generated was obtained a new from ergosteroid the fresh derivative, tissue of the isocyathisterol marine green alga C. fragile (Zhoushan Island, China), generated a new ergosteroid derivative, isocyathisterol (alga121).C. Compound fragile (Zhoushan 121 exhibited Island, China),weak antibacterial generated a newactivity ergosteroid against S. derivative, aureus and isocyathisterol E. coli (inhibitory (121). (121). Compound 121 exhibited weak antibacterial activity against S. aureus and E. coli (inhibitory diametersCompound of121 5.7exhibited and 6.7 mm, weak respectively) antibacterial at activity 30 mg/disc against (FigureS. aureus 26) [67].and E. coli (inhibitory diameters diameters of 5.7 and 6.7 mm, respectively) at 30 mg/disc (Figure 26) [67]. of 5.7Five and 6.7new mm, polyketides respectively) (122 at– 30126 mg/disc) have (Figurebeen isolated 26)[67 ].from the lipophilic extracts of the marineFive‐derived new fungipolyketides Penicillium (122 thomii–126) andhave Penicillium been isolated lividum from isolated the fromlipophilic superficial extracts mycobiota of the ofmarine the brown‐derived alga fungi Sargassum Penicillium miyabei thomii (Lazurnaya and Penicillium Bay, the lividum Sea of isolatedJapan). Compoundfrom superficial 123 was mycobiota able to of the brown alga Sargassum miyabei (Lazurnaya Bay, the Sea of Japan). Compound 123 was able to inhibit the transcriptional activity of the oncogenic nuclear factor AP‐1 with IC50 value of 15 μM after 50 12inhibit h of thetreatment. transcriptional Compound activity 125 of exhibited the oncogenic cytotoxicity nuclear against factor splenocytesAP‐1 with IC with value a IC of50 15value μM ofafter 38 μ12M. h Itof wastreatment. shown Compoundthat compounds 125 exhibited 124 and cytotoxicity126 at a non against‐toxic concentration splenocytes with (10 μ aM) IC 50inhibited value of the 38 adhesionμM. It was of shownmacrophages that compounds (30%–40% 124 of inhibition).and 126 at aIn non addition,‐toxic concentration compounds 122(10 μandM) 125 inhibited exhibited the adhesion of macrophages (30%–40% of inhibition). In addition, compounds 122 and 125 exhibited

Mar. Drugs 2016, 14, 76 16 of 25

Five new polyketides (122–126) have been isolated from the lipophilic extracts of the marine-derived fungi Penicillium thomii and Penicillium lividum isolated from superficial mycobiota of the brown alga Sargassum miyabei (Lazurnaya Bay, the Sea of Japan). Compound 123 was able to inhibit the transcriptional activity of the oncogenic nuclear factor AP-1 with IC50 value of 15 µM after 12 h µ ofMar. treatment. Drugs 2016, Compound14, 76 125 exhibited cytotoxicity against splenocytes with a IC50 value of 3816 ofM. 25 ItMar. was Drugs shown 2016, that 14, 76 compounds 124 and 126 at a non-toxic concentration (10 µM) inhibited the adhesion16 of 25 ofradical macrophages scavenging (30%–40% activity against of inhibition). DPPH with In addition,IC50 values compounds of 100 and 50122 μM,and respectively125 exhibited (Figure radical 26) radical scavenging activity against DPPH with IC50 values of 100 and 50 μM, respectively (Figure 26) scavenging[68]. activity against DPPH with IC50 values of 100 and 50 µM, respectively (Figure 26)[68]. [68].

HO OAc H HO O OAcO H HO O O O HO O H OH H O AcO O OH H OH O OH AcO O OAc H OH OAc O OH OH O O OH O 121 122 123 121 122 123 O OAc OH O OAcO O OHO HO O HO O HO O HO HO OH HO O HO O OH HO O O OAc HO O HO O OAc OAc OAc O O O O 124 O 125 O 126 124 125 126 Figure 26. Structures of compounds 121–126. Figure 26. Structures of compounds 121–126. Seven new austalide meroterpenoids (127–133) were isolated from the alga‐derived fungi Seven new austalideaustalide meroterpenoids (127–133) were isolatedisolated fromfrom thethe alga-derivedalga‐derived fungifungi Penicillium thomii KMM 4645 and Penicillium lividum KMM 4663, which was isolated from superficial PenicilliumPenicillium thomii KMM 4645 and Penicillium lividum KMM 4663, which was isolated from superficialsuperficial mycobiota of the brown alga Sargassum miyabei (Lazurnaya Bay, the Sea of Japan). Compounds 127, mycobiota of the the brown brown alga alga SargassumSargassum miyabei miyabei (Lazurnaya(Lazurnaya Bay, Bay, the the Sea Sea of Japan). of Japan). Compounds Compounds 127, 128, 132 and 133 could inhibit AP‐1‐dependent transcriptional activity in JB6 Cl41 cell lines at 127128,, 128132, 132andand 133133 couldcould inhibit inhibit AP AP-1-dependent‐1‐dependent transcriptional transcriptional activity activity in in JB6 JB6 Cl41 Cl41 cell cell lines atat noncytotoxic concentrations. Compounds 127–133 exhibited significant inhibitory effects against noncytotoxic concentrations. Compounds Compounds 127127––133133 exhibited significant significant inhibitory effects againstagainst endo‐1,3‐β‐D‐glucanase from a crystalline stalk of the marine mollusk Pseudocardium sachalinensis endo-1,3-endo‐1,3‐β‐β-DD‐-glucanaseglucanase from from a a crystalline stalk of thethe marinemarine molluskmollusk PseudocardiumPseudocardium sachalinensissachalinensis (Figure 27) [69]. (Figure(Figure 2727))[ [69].69].

R O R O O R O R O R O R O O O O O O O O H H H H HO H H H OH O O O O O H O O O H H OH H H O HOHO H H O H OH O O O O O H O O O HOOH O HO O O O 127:R=OH HO 128:R=OH O 131 O 132:R=OH O 129:R=H127:R=OH O 130:R=H128:R=OH O 133:R=H 131 132:R=OH 129:R=H O 130:R=H 133:R=H

Figure 27. Structures of compounds 127–133. Figure 27. Structures of compounds 127127––133133.. The fungal strain Penicillium echinulatum pt‐4 was isolated from marine red alga Chondrus The fungal strain Penicillium echinulatum pt‐4 was isolated from marine red alga Chondrus ocellatusThe fungalthat was strain collectedPenicillium from echinulatum the coastpt-4 of wasPingtan isolated Island, from marineChina. redOne alga newChondrus meroterpene, ocellatus ocellatus that was collected from the coast of Pingtan Island, China. One new meroterpene, thatarisugacin was collected K (134) from was theisolated coast from of Pingtan the culture Island, of China. strain Onept‐4. new Compound meroterpene, 134 showed arisugacin inhibitory K (134) arisugacin K (134) was isolated from the culture of strain pt‐4. Compound 134 showed inhibitory wasactivity isolated against from E. thecoli culturewith an of inhibition strain pt-4. diameter Compound 8 mm134 at 30showed μg/disk inhibitory (Figure 28) activity [70]. against E. coli activity against E. coli with an inhibition diameter 8 mm at 30 μg/disk (Figure 28) [70]. withA an new inhibition nitrobenzoyl diameter sesquiterpenoid, 8 mm at 30 µg/disk 6b,9a‐ (Figuredihydroxy 28)[‐1470‐].p‐nitrobenzoylcinnamolide (135) was A new nitrobenzoyl sesquiterpenoid, 6b,9a‐dihydroxy‐14‐p‐nitrobenzoylcinnamolide (135) was isolatedA new from nitrobenzoyl extracts of the sesquiterpenoid, culture of marine 6b,9a-dihydroxy-14-‐derived fungus Aspergillusp-nitrobenzoylcinnamolide ochraceus Jcma1F17, (135 which) was isolated from extracts of the culture of marine‐derived fungus Aspergillus ochraceus Jcma1F17, which isolatedwas derived from from extracts a marine of the alga culture Coelarthrum of marine-derived sp. in Paracel fungus Islands,Aspergillus South China ochraceus Sea.Jcma1F17, Compound which 135 was derived from a marine alga Coelarthrum sp. in Paracel Islands, South China Sea. Compound 135 wasdisplayed derived significant from a marine cytotoxicities alga Coelarthrum against 10sp. cancer in Paracel cell lines Islands, (K562, South H1975, China U937, Sea. Molt Compound‐4, BGC‐823,135 displayed significant cytotoxicities against 10 cancer cell lines (K562, H1975, U937, Molt‐4, BGC‐823, displayedHL60, MCF significant‐7, A549, cytotoxicities Hela, and Huh against‐7), with 10 cancer IC50 cellvalues lines of (K562, 1.95 μ H1975,M to U937,6.35 μ Molt-4,M. In BGC-823,addition, HL60, MCF‐7, A549, Hela, and Huh‐7), with IC50 values of 1.95 μM to 6.35 μM. In addition, HL60,compound MCF-7, 135 also A549, showed Hela, antiviral and Huh-7), activities with against IC valuesEV71 and of H3N2 1.95 µ (FigureM to 6.35 28) µ[71].M. In addition, compound 135 also showed antiviral activities against50 EV71 and H3N2 (Figure 28) [71]. compoundA structurally135 also unique showed 3 antiviralH‐oxepine activities‐containing against alkaloid, EV71 andvarioxepine H3N2 (Figure A (136 28), )[characterized71]. by a A structurally unique 3H‐oxepine‐containing alkaloid, varioxepine A (136), characterized by a condensed 3,6,8‐trioxabicyclo[3.2.1]octane motif, was isolated from the marine algal‐derived condensed 3,6,8‐trioxabicyclo[3.2.1]octane motif, was isolated from the marine algal‐derived endophytic fungus Paecilomyces variotii. Compound 136 was evaluated for antimicrobial activity endophytic fungus Paecilomyces variotii. Compound 136 was evaluated for antimicrobial activity against several human‐ and aqua‐pathogenic bacteria (Aeromonas hydrophila, S. aureus, Vibrio against several human‐ and aqua‐pathogenic bacteria (Aeromonas hydrophila, S. aureus, Vibrio anguillarum, E. coli, Micrococcus luteus, Vibrio harveyi, and Vibrio parahemolyticus). The results revealed anguillarum, E. coli, Micrococcus luteus, Vibrio harveyi, and Vibrio parahemolyticus). The results revealed that compound 136 has diverse antibacterial activities with the MIC values ranging from 16 to 64 that compound 136 has diverse antibacterial activities with the MIC values ranging from 16 to 64 μg/mL. Furthermore, it inhibited plant pathogenic fungus Fusarium graminearum, with an MIC value μg/mL. Furthermore, it inhibited plant pathogenic fungus Fusarium graminearum, with an MIC value of 4 μg/mL (Figure 28) [72]. of 4 μg/mL (Figure 28) [72].

Mar. Drugs 2016, 14, 76 17 of 25

A structurally unique 3H-oxepine-containing alkaloid, varioxepine A (136), characterized by a condensed 3,6,8-trioxabicyclo[3.2.1]octane motif, was isolated from the marine algal-derived endophytic fungus Paecilomyces variotii. Compound 136 was evaluated for antimicrobial activity against several human- and aqua-pathogenic bacteria (Aeromonas hydrophila, S. aureus, Vibrio anguillarum, E. coli, Micrococcus luteus, Vibrio harveyi, and Vibrio parahemolyticus). The results revealed that compound 136 has diverse antibacterial activities with the MIC values ranging from 16 to 64 µg/mL. Furthermore, it inhibited plant pathogenic fungus Fusarium graminearum, with an MIC value of Mar.4 µg/mL Drugs 2016 (Figure, 14, 76 28 )[72]. 17 of 25 Mar. Drugs 2016, 14, 76 17 of 25 O O O O O O O O O O N O O N NH OH NH OH N N O O H O O O O O O H OH O O H O OH O H O2N HO O2N O HO OH O OH 134 135 134 136 135 136 Figure 28. StructuresStructures of compounds 134–136. Figure 28. Structures of compounds 134–136. Two new butenolides, namely, butyrolactone IX (137) and aspulvinone O (138) were isolated Two new butenolides, namely, butyrolactone IX (137) and aspulvinone O (138) were isolated from the marine‐derived endophytic fungus Paecilomyces variotii from Grateloupia turuturu, a red alga from the marine-derivedmarine‐derived endophytic fungus Paecilomyces variotii from Grateloupia turuturu , a red alga collected from the coast of Qingdao, China. The isolated butenolides were tested for the activity collected from the coast of Qingdao,Qingdao, China.China. The The isolated butenolides were were tested for the activity against DPPH radicals and the results indicated that butyrolactone (137) possessed potent activity against DPPHDPPH radicals radicals and and the the results results indicated indicated that that butyrolactone butyrolactone (137 ()137 possessed) possessed potent potent activity activity with with IC50 values 186.3 μM, while aspulvinone (138) showed significant activity with IC50 value 11.6 ICwith valuesIC50 values 186.3 186.3µM, μ whileM, while aspulvinone aspulvinone (138 )( showed138) showed significant significant activity activity with with IC valueIC50 value 11.6 11.6µM. μM.50 The author speculated that a larger conjugated aromatic system gave aspulvinone50 (138) more TheμM. authorThe author speculated speculated that a that larger a larger conjugated conjugated aromatic aromatic system system gave aspulvinone gave aspulvinone (138) more (138 stronger) more stronger DPPH radical scavenging activity than that of butyrolactone (137) (Figure 29) [73]. DPPHstronger radical DPPH scavenging radical scavenging activity than activity that than of butyrolactone that of butyrolactone (137) (Figure (137 29) (Figure)[73]. 29) [73]. A new benzamide derivative (methyl 4‐(3,4‐dihydroxybenzamido) butanoate (139) was isolated A new benzamide derivative (methyl 4 4-(3,4-dihydroxybenzamido)‐(3,4‐dihydroxybenzamido) butanoate (139) was isolated from themarine brown alga‐derived endophytic fungus Aspergillus wentii EN‐48. Compound 139 from themarinethemarine brown alga-derivedalga‐derived endophyticendophytic fungusfungus AspergillusAspergillus wentiiwentii EN-48.EN‐48. Compound 139 showed significant scavenging activity against DPPH with IC50 values of 5.2 μg/mL, which was showed significantsignificant scavenging activity against DPPHDPPH withwith ICIC5050 values of 5.25.2 μµg/mL,g/mL, which was significantly stronger than BHT (IC50 = 36.9 μg/mL) (Figure 29) [74]. significantlysignificantly stronger than BHT (IC(IC5050 == 36.9 36.9 μµg/mL)g/mL) (Figure (Figure 29) 29 )[[74].74]. OH OH O O O O O OH O O HO OMe O OH O HO N OMe O HN HO OH H O HO HO HO OHOH HO O HO 137 HO OH 138 HO 139 137 138 139 Figure 29. Structures of compounds 137–139. Figure 29. Structures of compounds 137–139. Two new oxepine‐containing diketopiperazine‐type alkaloids, varioloids A and B (140 and Two new oxepine‐containing diketopiperazine‐type alkaloids, varioloids A and B (140 and 141), Twowere new isolated oxepine-containing from the fungus diketopiperazine-type Paecilomyces variotii EN alkaloids,‐291, which varioloids was isolated A and from B (140 Grateloupiaand 141), 141), were isolated from the fungus Paecilomyces variotii EN‐291, which was isolated from Grateloupia turuturuwere isolated, a marine from the red fungus algae Paecilomycescollected from variotii the EN-291,coast of whichQingdao, was China. isolated Compounds from Grateloupia 140 turuturuand 141, turuturu, a marine red algae collected from the coast of Qingdao, China. Compounds 140 and 141 exhibiteda marine redpotent algae activity collected against from the the plantpathogenic coast of Qingdao, fungus China. Fusarium Compounds graminearum140 and with141 MICexhibited values exhibited potent activity against the plantpathogenic fungus Fusarium graminearum with MIC values ofpotent 8 and activity 4 μg/mL, against respectively the plantpathogenic (Figure 30) [75]. fungus Fusarium graminearum with MIC values of 8 and of 8 and 4 μg/mL, respectively (Figure 30) [75]. 4 µg/mL,A new respectively eudesmane (Figure sesquiterpenoid, 30)[75]. eudesma‐4(15),7‐diene‐5,11‐diol (142) has been isolated A new eudesmane sesquiterpenoid, eudesma‐4(15),7‐diene‐5,11‐diol (142) has been isolated from Athe new red eudesmane alga Laurencia sesquiterpenoid, obtusa, which eudesma-4(15),7-diene-5,11-diolwas collected off the Saudi Arabia (142 Red) has Sea been Coast isolated at Jeddah. from from the red alga Laurencia obtusa, which was collected off the Saudi Arabia Red Sea Coast at Jeddah. Boththe red qualitative alga Laurencia and quantitative obtusa, which antifungal was collected assays off therevealed Saudi that Arabia compound Red Sea Coast142 exhibited at Jeddah. a good Both Both qualitative and quantitative antifungal assays revealed that compound 142 exhibited a good antifungalqualitative effect and quantitative against Candida antifungal albicans assays, Candida revealed tropicals that, compoundAspergillus 142flavusexhibited and Aspergillus a good antifungal niger; the antifungal effect against Candida albicans, Candida tropicals, Aspergillus flavus and Aspergillus niger; the MICeffect values against wereCandida 2.92, albicans 2.10, 2.92,, Candida 6.5 μg/mL, tropicals respectively, Aspergillus (Figure flavus and30) [76].Aspergillus niger; the MIC values MIC values were 2.92, 2.10, 2.92, 6.5 μg/mL, respectively (Figure 30) [76]. were 2.92, 2.10, 2.92, 6.5 µg/mL, respectively (Figure 30)[76]. OMe OMe O N O N O N NH O N NH NH NH N N N O N O O O O O O O HO O O HO O HO O HO 140 141 142 140 141 142 Figure 30. Structures of compounds 140–142. Figure 30. Structures of compounds 140–142. 2.5. Sea Water 2.5. Sea Water

Mar. Drugs 2016, 14, 76 17 of 25

O O O O O O N NH OH N O O H O O O OH O H O2N HO OH O 134 135 136 Figure 28. Structures of compounds 134–136.

Two new butenolides, namely, butyrolactone IX (137) and aspulvinone O (138) were isolated from the marine‐derived endophytic fungus Paecilomyces variotii from Grateloupia turuturu, a red alga collected from the coast of Qingdao, China. The isolated butenolides were tested for the activity against DPPH radicals and the results indicated that butyrolactone (137) possessed potent activity with IC50 values 186.3 μM, while aspulvinone (138) showed significant activity with IC50 value 11.6 μM. The author speculated that a larger conjugated aromatic system gave aspulvinone (138) more stronger DPPH radical scavenging activity than that of butyrolactone (137) (Figure 29) [73]. A new benzamide derivative (methyl 4‐(3,4‐dihydroxybenzamido) butanoate (139) was isolated from themarine brown alga‐derived endophytic fungus Aspergillus wentii EN‐48. Compound 139 showed significant scavenging activity against DPPH with IC50 values of 5.2 μg/mL, which was significantly stronger than BHT (IC50 = 36.9 μg/mL) (Figure 29) [74].

OH O O O OH O HO OMe O N H HO OH O HO HO OH HO 137 138 139 Figure 29. Structures of compounds 137–139.

Two new oxepine‐containing diketopiperazine‐type alkaloids, varioloids A and B (140 and 141), were isolated from the fungus Paecilomyces variotii EN‐291, which was isolated from Grateloupia turuturu, a marine red algae collected from the coast of Qingdao, China. Compounds 140 and 141 exhibited potent activity against the plantpathogenic fungus Fusarium graminearum with MIC values of 8 and 4 μg/mL, respectively (Figure 30) [75]. A new eudesmane sesquiterpenoid, eudesma‐4(15),7‐diene‐5,11‐diol (142) has been isolated from the red alga Laurencia obtusa, which was collected off the Saudi Arabia Red Sea Coast at Jeddah. Both qualitative and quantitative antifungal assays revealed that compound 142 exhibited a good Mar. Drugsantifungal2016, 14 effect, 76 against Candida albicans, Candida tropicals, Aspergillus flavus and Aspergillus niger; the18 of 25 MIC values were 2.92, 2.10, 2.92, 6.5 μg/mL, respectively (Figure 30) [76].

OMe O N O N NH NH N N O O O O O HO O HO

140 141 142 FigureFigure 30. 30.Structures Structures of compounds 140140–142–142. . Mar. Drugs 2016, 14, 76 18 of 25 2.5. Sea Water 2.5. Sea Water OneMar. Drugs unusual 2016, 14 pyridone,, 76 trichodin A (143), was extracted from the marine fungus, Trichoderma18 of 25 sp. strainOne unusualMF106 pyridone,isolated from trichodin the Greenland A (143), was Seas. extracted Compound from the 143 marine showed fungus, antibioticTrichoderma activitiessp. againststrain MF106 StaphylococcusOne unusual isolated pyridone,epidermidis from the trichodin Greenland with IC A50 ( Seas.value143), was Compoundof 24 extracted μM (Figure 143fromshowed 31)the [77].marine antibiotic fungus, activities Trichoderma against sp. strain MF106 isolated from the Greenland Seas. Compound 143 showed antibiotic activities StaphylococcusThe fungus epidermidis Penicilliumwith 303# IC 50wasvalue isolated of 24 fromµM (Figure sea water, 31)[ 77which]. was collected from Zhanjiang against Staphylococcus epidermidis with IC50 value of 24 μM (Figure 31) [77]. MangroveThe fungus NationalPenicillium Nature303# Reserve was isolated in Guangdong from sea water,Province, which China. was collectedThree new from metabolites Zhanjiang The fungus Penicillium 303# was isolated from sea water, which was collected from Zhanjiang (compounds 144–146) were isolated from the fungus fermentation medium. Those compounds MangroveMangrove National National Nature Nature Reserve Reserve in in Guangdong Guangdong Province, China. China. Three Three new new metabolites metabolites showed(compounds(compounds weak144 to– moderate146144–)146 were) were cytotoxic isolated isolated from activities from the fungusthe against fungus fermentation MDA fermentation‐MB‐435 medium. (Figuremedium. Those 31) Those [78]. compounds compounds showed weakshowed to moderate weak to cytotoxic moderate activities cytotoxic againstactivities MDA-MB-435 against MDA‐MB (Figure‐435 (Figure 31)[78 31)]. [78].

Figure 31. Structures of compounds 143–146. FigureFigure 31. 31.Structures Structures of compounds compounds 143143–146–146. .

A marineA marine strain strain Stachybotrys Stachybotrys sp. sp. MF347, MF347, whichwhich was isolated isolated from from a driftwooda driftwood sample sample collected collected at HelgolandAat Helgoland marine (North strain (North Sea,Stachybotrys Sea, Germany), Germany),sp. provided MF347, provided which aa novel was spirocyclicspirocyclic isolated drimane from drimane a driftwoodcoupled coupled by sampletwoby twodrimane collecteddrimane fragmentat Helgolandfragment building (Northbuilding blocks Sea, blocks Germany), 147 147. Compound. Compound provided 147147 a novelexhibited spirocyclic comparablecomparable drimane antibacterial antibacterial coupled activities by activities two with drimane with chloramphenicolfragmentchloramphenicol building against blocks against the147 the clinically. clinically Compound relevant relevant147 MRSAMRSAexhibited (Figure(Figure comparable 32) 32) [79]. [79]. antibacterial activities with chloramphenicolPenicilliuminePenicilliumine against (148 (148), the a), newa clinically new structure structure relevant was was MRSA isolatedisolated (Figure fromfrom the 32the )[fermentation fermentation79]. Penicillium Penicillium commune commune 366606,Penicilliumine366606, a marine a marine‐derived (148‐derived), a newfungus fungus structure isolatedisolated was fromfrom isolated thethe fromseasea waterwater the fermentationcollected collected at atQingdao,Penicillium Qingdao, China. commune China. Compound 148 was not cytotoxic against MCF‐7, SMMC‐7721, HL‐60, A‐549 and SW480 cells or no Compound366606, a marine-derived 148 was not cytotoxic fungus isolated against from MCF the‐7, SMMC sea water‐7721, collected HL‐60, at A Qingdao,‐549 and China.SW480 Compound cells or no potent inhibiting the nitric oxide release. Compound (−)‐148 and (+)‐148 could inhibit the 148 was not cytotoxic against MCF-7, SMMC-7721, HL-60, A-549 and SW480 cells or no potent potentacetylcholinesterase inhibiting the activitynitric oxideby 18.7% release. (±0.26%) Compound and 32.4% (±2.08%)(−)‐148 atand the concentration(+)‐148 could of 50inhibit μM, the inhibiting the nitric oxide release. Compound (´)-148 and (+)-148 could inhibit the acetylcholinesterase acetylcholinesteraserespectively, compared activity with by 43.6% 18.7% (±2.12%) (±0.26%) inhibition and 32.4% rate of (±2.08%) the positive at thecontrol concentration tacrine (Figure of 32)50 μM, respectively,activity[80]. by 18.7% compared (˘0.26%) with and 43.6% 32.4% (±2.12%) (˘2.08%) inhibition at the concentration rate of the positive of 50 µ controlM, respectively, tacrine (Figure compared 32) [80].with 43.6%A strain (˘2.12%) of the inhibition fungus Penicillium rate of the chrysogenum positive controlwas collected tacrine from (Figure sea water 32)[ (10–2580]. m depth), off Athe strain strain North of of Sea the the coast,fungus fungus China. PenicilliumPenicillium A new chrysogenum benzoic chrysogenum acid, was 2was‐(2 collected‐hydroxypropanamido) collected from from sea sea water water benzoic (10–25 (10–25 acid m depth),( m149 depth),), off theoff theNorthisolated North Sea from Sea coast, the coast, fermentation China. China. A A newbroth new benzoicof benzoic fungus, acid, showed acid, 2 2-(2-hydroxypropanamido)‐(2 remarkable‐hydroxypropanamido) anti‐inflammatory benzoic benzoic and analgesic acid acid ( ( 149149),), isolatedactivities from butthe exhibitedfermentation fermentation no ulcerogenic broth of fungus, fungus,effect (Figure showed 32) [81].remarkable remarkable anti anti-inflammatory‐inflammatory and analgesic activities but exhibited no ulcerogenic effect (Figure 3232))[ [81].81].

Figure 32. Structures of compounds 147–149.

2.6. Others Figure 32. Structures of compounds 147–149. Figure 32. Structures of compounds 147–149. Racemic dinaphthalenone derivatives (±)‐asperlone A (150) and (±)‐asperlone B (151) were 2.6. Othersisolated from the cultures of Aspergillus sp. 16‐5C from the leaves of S. apetala, which were collected in Hainan Island, China. Compounds 150 and 151 exhibited potent inhibitory effects against Racemic dinaphthalenone derivatives (±)‐asperlone A (150) and (±)‐asperlone B (151) were Mycobacterium tuberculosis protein tyrosine phosphatase B (MptpB) with IC50 values of 4.24 ± 0.41, isolated4.32 from ± 0.60 the μM, cultures respectively, of Aspergillus which represent sp. 16 ‐a5C new from type the of leadleaves compounds of S. apetala for the, which development were collected of in Hainannew anti Island,‐tuberculosis China. drugs Compounds (Figure 33) [82].150 and 151 exhibited potent inhibitory effects against MycobacteriumA new tuberculosis polychlorinated protein triphenyl tyrosine diether phosphatase named microsphaerol B (MptpB) (with152) and IC50 a valuesnew naphthalene of 4.24 ± 0.41, 4.32 ±derivative 0.60 μM, named respectively, seimatorone which (153 represent), were isolated a new fromtype theof lead endophtic compounds fungus forMicrosphaeropsis the development sp. of new antiand ‐tuberculosisSeimatosporium drugs sp., (Figurewhich were 33) [82]. isolated from the halotolerant herbaceous plant Salsola Aoppositifolia new polychlorinated from Playa del triphenylIngles (Gomera, diether Spain). named Preliminary microsphaerol studies revealed (152) and that a compound new naphthalene 152 derivative named seimatorone (153), were isolated from the endophtic fungus Microsphaeropsis sp. and Seimatosporium sp., which were isolated from the halotolerant herbaceous plant Salsola oppositifolia from Playa del Ingles (Gomera, Spain). Preliminary studies revealed that compound 152

Mar. Drugs 2016, 14, 76 19 of 25

2.6. Others Racemic dinaphthalenone derivatives (˘)-asperlone A (150) and (˘)-asperlone B (151) were isolated from the cultures of Aspergillus sp. 16-5C from the leaves of S. apetala, which were collected in Hainan Island, China. Compounds 150 and 151 exhibited potent inhibitory effects against Mycobacterium tuberculosis protein tyrosine phosphatase B (MptpB) with IC50 values of 4.24 ˘ 0.41, 4.32 ˘ 0.60 µM, respectively, which represent a new type of lead compounds for the development of new anti-tuberculosis drugs (Figure 33)[82]. A new polychlorinated triphenyl diether named microsphaerol (152) and a new naphthalene derivativeMar. Drugs 2016 named, 14, 76 seimatorone (153), were isolated from the endophtic fungus Microsphaeropsis sp.19 of and 25 Seimatosporium sp., which were isolated from the halotolerant herbaceous plant Salsola oppositifolia fromshowed Playa good del antibacterial Ingles (Gomera, activities Spain). against Preliminary Bacillus Megaterium studies revealed and E. thatcoli, compoundand good antilagal152 showed and goodantifungal antibacterial activities activities against against ChlorellaBacillus fusca Megateriumand Microbotryumand E. coliviolaceum, and good, respectively. antilagal and On antifungal the other activitieshand, compound against Chlorella 153 exhibited fusca and moderateMicrobotryum antibacterial, violaceum antialgal,, respectively. and antifungal On the other activities hand, compound(Figure 33) 153[83].exhibited moderate antibacterial, antialgal, and antifungal activities (Figure 33)[83].

Figure 33. Structures of compounds 150–153.

3. Future Future Perspectives Perspectives and and Concluding Concluding Remarks Remarks Based on the above literature, we can find find that marine marine-derived‐derived Aspergillus and Penicillium are the most ubiquitous genera, probably because both of them are salt tolerant, fast growing and easily obtained. As As seen in Figure 3434,, aboutabout 3/43/4 of all new compounds reported from marine fungi are derived fromfrom isolation isolation from from living living matter, matter,i.e. i.e.marine marine animals animals (30.1%) (30.1%) and marineand marine plants plants (42.5%), (42.5%), while thewhile remaining the remaining compounds compounds are obtained are obtained from non-living from non sources,‐living sources, most notably most notably sediments sediments (22.9%). Within(22.9%). the Within individual the individual groups, mangrovegroups, mangrove habitats habitats (25.5%), (25.5%), alga (14.4%), alga (14.4%), and sponges and sponges (9.2%) are (9.2%) the predominantare the predominant sources sources for fungal for diversity. fungal diversity. A newly A emerging newly emerging source is source the deep is the sea. deep The sea. extreme The environmentextreme environment encountered encountered in the form in ofthe low form temperature, of low temperature, elevated hydrostatic elevated hydrostatic pressure, absence pressure, of light,absence high of concentrations light, high concentrations of metals in hydrothermal of metals in ventshydrothermal and hypoxic vents conditions and hypoxic possibly conditions produce structurallypossibly produce unique structurally metabolites. unique Nevertheless, metabolites. very Nevertheless, few reports are very related few reports to this habitatare related because to this of scarcityhabitat because of source. of It scarcity is worth of mentioning source. It is that worth an increasing mentioning number that an of Chineseincreasing scientists number are of engaging Chinese scientists are engaging in this research field, mostly focusing on mangrove areas around South in thisMar. research Drugs 2016 field,, 14, 76 mostly focusing on mangrove areas around South China Sea. 20 of 25 China Sea. According to the structural types, of the 153 compounds included in this review, alkaloids (27.0%) and polyketides (25.7%) play a dominant role. Moreover, peptides, terpenes, lactone, and steroids are 13.8%, 9.9%, 3.9% and 3.3%, respectively (see Figure 35). As illustrated in Figure 36, biological activities of these compounds are mainly focused in the areas of cytotoxicity (37.5%) and antimicrobial activity, including antibacterial activity (18.4%), antifungal activity (7.9%) and antiviral activity (7.2%). Furthermore, other selective activities include antioxidant, anti‐inflammatory, antifouling, lipid‐lowering activities, lethality against brine shrimp effects, etc. The oceans are the largest underexploited wealthy resource of potential drugs. Marine‐derived fungi have provided a variety of potential pharmacological metabolites and thus represent a valuable resource of new drug candidates. In the period covered by the first review of this series, Figure 34. New compounds from marine‐derived fungi included in this review, divided by sources fromFigure the beginning 34. New compounds until 2002, from 272 marine-derived new structures fungi had included been reported, in this review, in 2009 divided more by sourcesthan 200 of was of the fungal strains. reachedthe fungal[2], and strains. in 2012 and 2013, the numbers were 288 and 302, respectively [3,84]. Though bioactivities of secondary metabolites from marine fungi reveal interesting levels for a number of clinical relevant targets, they are not well represented in the pipelines of drugs and none of them currently is on the market. Only Plinabulin, a synthetic cyclic dipeptide analogue of halimide, which is isolated from a marine fungus species, is in phase II clinical trial for treatment of non‐small cell lung cancer. Thus, there is still a long way to go [85].

Figure 35. New compounds from marine‐derived fungi included in this review, divided by structural types.

Figure 36. Bioactive categories of new compounds from marine‐derived fungi included in this review.

First of all, many marine‐derived fungal biosynthetic pathways are silent under common laboratory culture conditions, and activation of the silent pathways may enable access to new metabolites. One strain–many compounds (OSMAC) strategy, chemical epigenetic modification (e.g., using DNA methyltransferase inhibitor, 5‐azacytidine, histone deacetylase inhibitors, suberoylanilide hydroxamic acid and sodium butyrate [60–62,86–88]), co‐culture method [48], or gene level manipulations could be applied to access new secondary metabolites. Furthermore, as mentioned above, alterations of the culture conditions might lead to changes of the metabolic spectrum. The pharmaceutical industry should concentrate on how to appropriately maintain

Mar. Drugs 2016, 14, 76 20 of 25

Mar. Drugs 2016, 14, 76 20 of 25

Mar. Drugs 2016, 14, 76 20 of 25

According to the structural types, of the 153 compounds included in this review, alkaloids (27.0%) and polyketidesFigure 34. New (25.7%) compounds play a dominantfrom marine role.‐derived Moreover, fungi included peptides, in terpenes,this review, lactone, divided and by steroidssources are 13.8%,of 9.9%,the fungal 3.9% strains. and 3.3%, respectively (see Figure 35).

Figure 34. New compounds from marine‐derived fungi included in this review, divided by sources of the fungal strains.

FigureFigure 35. New 35. compoundsNew compounds from marine from‐derived marine-derived fungi included fungi in included this review, in this divided review, by structural divided bytypes. structural types.

As illustrated in Figure 36, biological activities of these compounds are mainly focused in the areas of cytotoxicity (37.5%) and antimicrobial activity, including antibacterial activity (18.4%), antifungal activity (7.9%) and antiviral activity (7.2%). Furthermore, other selective activities include antioxidant, anti-inflammatory,Figure 35. New compounds antifouling, from lipid-lowering marine‐derived activities,fungi included lethality in this against review, brine divided shrimp by structural effects, types.etc.

Figure 36. Bioactive categories of new compounds from marine‐derived fungi included in this review.

First of all, many marine‐derived fungal biosynthetic pathways are silent under common laboratory culture conditions, and activation of the silent pathways may enable access to new metabolites. One strain–many compounds (OSMAC) strategy, chemical epigenetic modification (e.g., using DNA methyltransferase inhibitor, 5‐azacytidine, histone deacetylase inhibitors, suberoylanilide hydroxamic acid and sodium butyrate [60–62,86–88]), co‐culture method [48], or geneFigureFigure level 36. 36.manipulations BioactiveBioactive categories categories could of ofbe new new applied compounds compounds to access from newmarine marine-derived secondary‐derived fungi metabolites. included in inFurthermore, thisthis review.review. as mentioned above, alterations of the culture conditions might lead to changes of the metabolic First of all, many marine‐derived fungal biosynthetic pathways are silent under common spectrum.The oceans The pharmaceutical are the largest underexploited industry should wealthy concentrate resource on of how potential to appropriately drugs. Marine-derived maintain laboratory culture conditions, and activation of the silent pathways may enable access to new fungi have provided a variety of potential pharmacological metabolites and thus represent a valuable metabolites. One strain–many compounds (OSMAC) strategy, chemical epigenetic modification resource of new drug candidates. In the period covered by the first review of this series, from the (e.g., using DNA methyltransferase inhibitor, 5‐azacytidine, histone deacetylase inhibitors, beginning until 2002, 272 new structures had been reported, in 2009 more than 200 was reached [2], and suberoylanilide hydroxamic acid and sodium butyrate [60–62,86–88]), co‐culture method [48], or in 2012 and 2013, the numbers were 288 and 302, respectively [3,84]. Though bioactivities of secondary gene level manipulations could be applied to access new secondary metabolites. Furthermore, as metabolites from marine fungi reveal interesting levels for a number of clinical relevant targets, they mentioned above, alterations of the culture conditions might lead to changes of the metabolic are not well represented in the pipelines of drugs and none of them currently is on the market. Only spectrum. The pharmaceutical industry should concentrate on how to appropriately maintain Plinabulin, a synthetic cyclic dipeptide analogue of halimide, which is isolated from a marine fungus species, is in phase II clinical trial for treatment of non-small cell lung cancer. Thus, there is still a long way to go [85]. Mar. Drugs 2016, 14, 76 21 of 25

First of all, many marine-derived fungal biosynthetic pathways are silent under common laboratory culture conditions, and activation of the silent pathways may enable access to new metabolites. One strain–many compounds (OSMAC) strategy, chemical epigenetic modification (e.g., using DNA methyltransferase inhibitor, 5-azacytidine, histone deacetylase inhibitors, suberoylanilide hydroxamic acid and sodium butyrate [60–62,86–88]), co-culture method [48], or gene level manipulations could be applied to access new secondary metabolites. Furthermore, as mentioned above, alterations of the culture conditions might lead to changes of the metabolic spectrum. The pharmaceutical industry should concentrate on how to appropriately maintain certain physico-chemical factors, viz., amount of oxygen available, optimum pH and temperature, avoiding variation of secondary metabolites. What is more, a better understanding of the molecular basis of biosynthesis and regulation mechanisms will contribute to making better use of the enormous chemical potential of marine derived fungi, which depends on the continuous development of the new techniques [89,90]. In addition, beyond the current in vitro bioactivity examination, further in vivo and preclinical studies, as well as side effects examinations, are required to determine the bioactive compounds with potential therapeutic applications. We believe that with the development of more automated and more affordable techniques for isolating and characterizing marine fungi bioactive metabolites, marine fungi will be promising sources for novel therapeutic agents that will be useful in controlling human diseases and protecting human health.

Acknowledgments: This work was financially supported by National Natural Science Foundation of China (NO.21272031 and NO.21372037) and Fundamental Research Fund for the Central Universities (DC201501020302, DC201502020201 and DC201501081). Author Contributions: All authors contributed as the same for the manuscript preparation and design. Conflicts of Interest: The authors declare no conflict of interest.

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