Recent Researches of Bioactive Metabolites in ...

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identified as Streptomyces sp. (BL2492582005) , .... centrotus intermedius with MIC50 range from 2.7 to ... Strongylocentrotus intermedius ( M IC50 equal to 5.0.
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J o ur n al of O c e a n Uni v e rs it y of Chi n a ( Oceanic and Coastal Sea Research ) ISS N 167225182 , October 31 ,2004 , Vol.3 , N o.2 ,pp.1502156 http:// www. ouc. edu. cn/ xbywb/ E2mail: xbywb @mail. ouc. edu. cn

Recent Researches of Bioactive Metabolites in Marine Organisms2associated Microorganisms GU Qianqun1) , L U J ia1) , CU I Chengbin1) ,2) , 3 , Z HU Tianjiao1) , FAN G Yuchun1) , 1) 1) L IU Hongbing , Z HU Weiming 1) Key L aboratory of Marine Drug , Chinese Ministry of Education , Instit ute of Marine Drug and Food , Ocean University of China , Qingdao 266003 , P. R. China 2) Beijing Instit ute of Pharmacology and Toxicology , AMMS , Beijing 100850 , P. R. China

( Received April 16 ,2004 ; accepted J uly 5 ,2004 ) A bs t r a c t  Rece nt resea rc hes have s how n t hat s ome comp ounds is olate d f r om ma ri ne orga nis ms have st ri ki ng st ruct ural si mi2 la rities wit h t he met a bolites f r om know n micr oorga nis ms . It is i nf e r re d f r om t he resea rc hes t hat t he s ymbiotic or ass ociate d ma ri ne micr oorga nis ms may be t he t rue s ources of t hose comp ounds or at least i nvolve d i n t he biosynt hesizi ng p r ocess . This view has bee n f urt he r evide nce d by t he resea rc hes f or ma ny sp onges a nd sp onge2ass ociate d micr oorga nis ms . I mp ort a ntly , gr owi ng evide nce has highlighte d t hat t he symbiotic or ass ociate d ma ri ne micr oorga nis ms live i n t he micr oe nvir onme nt wit hi n t he hosts , a nd t hey als o p r oduce seconda ry met a bolites w hic h a re new a nd origi nal i n st ruct ure a nd unique i n activit y. All t hese suggest t hat t he micr oorga nis ms ass ociate d wit h ma ri ne orga nis ms a re t he s ources wit h ve ry high p ote ntial t o be new nat ural bioactive age nts . This a rticle reviews brief ly t he resea rc h a dva nces i n t he st udy of new bioactive met a bolites f r om ma ri ne orga nis ms2ass ociate d micr oorga nis ms si nce 2000 . Ke y w or ds  ma ri ne micr oorga nis m ; symbiont ; bioactive ; met a bolite Num be r  ISS N 167225182 (2004) 022150207

1  Int r o d u c ti o n  Since t he early 1960 s , ocean has been considered as a new and untouched source of potentially usef ul com2 pounds. The result s f rom t he researches on t he organ2 isms such as sponges , soft corals , algae , ascidians , bryozoans and mollusks , have demonst rated t hat ma2 rine organisms can produce unique secondary metabo2 lites different f rom t hose found in terrest rial organisms ( Murray et al. , 1999 ) . In recent years , marine mi2 croorganisms have att racted increasing attention in t he search for new p harmaceutical or agrochemical lead st ruct ures ( Faulkner , 2001 ) . Indeed , marine mi2 croorganisms have been shown to be able to produce a large number of bioactive substances. This might be due to t heir living conditions and f unctions in t he e2 cosystem. Many marine microorganisms are symbiotic wit h marine sponges and ot her invertebrates. Their secondary metabolites might cont ribute to protecting t heir host s by chemically mediated defense mecha2 nisms f rom dangers like predation. In some cases , t here are evidences t hat symbiotic or associated marine microorganisms are t he t rue sources of bioactive metab2 3 Corresponding aut hor. Tel :0086253222032065 E2mail :cuicb @sohu. com

olites originally isolated f rom t heir host s. Thus , t he microorganisms associated wit h marine plant s and ani2 mals are expected to be potential sources for new nat u2 ral bioactive agent s. The purpose of t his article is to review t he st udies on t he secondary metabolites and biological activities of bacteria and f ungus which have been isolated f rom marine organisms.

2  Bi o a c ti v e Me t a b olit e s f r o m Ma ri n e O r 2 g a ni s m s 2a s s o ci a t e d B a c t e ri a  Recent researches have demonst rated t hat bacteria isolated f rom marine organisms have greater antit umor activities t han t hose isolated f rom sediment s. Below is a summary of t hese researches.  Lomaiviticins A and B ( 1 and 2 in Fig. 1 ) are two potent antit umor antibiotics wit h t he st ruct ure of dimeric diazobenzo2fluorene glycoside. They were isolat2 ed f rom an actinomycete st rain identified as a new species of t he genus M icromonos pora on t he basis of it s morp hological characteristic and 16 S DNA se2 quence , M icromonos pora lom ai vitiensis ( He et al. , 2001 ) . This actinomycete st rain was isolated f rom t he inner core of t he host ascidian. Lomaiviticins A and B were demonst rated potent DNA damaging agent s by B IA , bot h wit h a minimum induction concent ration

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GU Q. Q. et al. : Rece nt Resea rc hes of Bi oact ive Met a bolites i n Ma ri ne Sym bi ot ic Microorga nis ms 151   less t han or equal to 0 . 1 ng per spot . The more abun2 dant lomaiviticin A was also tested against a number of cancer cell lines and showed cytotoxicity wit h IC50 val2 ues ranging f rom 0.01 to 98 ng mL - 1 . Lomaiviticins A and B were also potent antibiotics against Gram2posi2 tive bacteria , S t aphylococcus au reus and Enterococcus f aeci u m wit h M IC values f rom 6 to 25 ng per spot in a plate assay. The discovery of t he potent antit umor lomaiviticins provides an example of a marine2inverte2 brate2associated microorganism as an excellent re2 source for new bioactive nat ural product s.  Three new cytotoxic 3 , 62disubstit uted indoles ( 3 5 in Fig.1 ) were isolated f rom t he mycelium of a st rain identified as S t reptom yces sp. (BL2492582005 ) , which was obtained f rom a Mexican marine invertebrate (Jose et al. , 2003 ) . Cytotoxic assays for these com2 pounds were performed against 14 different t umor cell lines. Compound ( 3 ) showed significant cytotoxicity against K2562 ( leukemia ) wit h a GI50 value of 8. 46 μmol L - 1 . Aldoxime mixt ure ( 4 ) showed activity wit h GI50 values wit hin 1 micromolar range against L N2caP

(prostate cancer ) , HM EC1 ( endot helial cancer ) , K2 562 (leukemia) , PANC1 (pancreas cancer) , and LO2 VO and LOVO2DOX ( colon cancer ) . It showed slightly higher values against t he rest of t he t umor cell lines , without any particular specificity. Bioassays per2 formed wit h nit rile ( 5 ) showed no activity.  An acidic polysaccharide isolated f rom Pseu doal 2 teromonas disti nct a f rom a marine sponge contained two unusual acidic amino sugars , 22acetamido222 de2 oxy2D2galact uronic acid and 52acetamido23 , 5 , 7 , 92 tet radeoxy272formamido2L2 glycero2L2 m an no2nonu2 losonic acid ( Muldoon and Shashkov , 2001 ) . Howev2 er , t he bioactivities of t hese compounds were not re2 ported.  The alkaloid Harman ( 6 in Fig. 1 ) , previously ob2 tained f rom some marine invertebrates , was identified as t he antibiotic substance of t he t unicate2associated bacterium , Enterococcus f aeci u m ( Assila and Bour2 guet2 Kondracki , 2003 ) . It exhibited t he antibacterial activity ( M IC , 0 . 017 mmol L - 1 ) against t he icht hy2 opat hogenic st rain V ibrio anguill aru m.

Fig. 1 Compounds isolated from marine organisms2associated bacteria

3  Bi o a c ti v e Me t a b olit e s f r o m Ma ri n e O r 2 g a ni s m s 2a s s o ci a t e d Fu n gi 3. 1   Bioactive Metabol ites from Fungi Isolated from Sponges

 Fungi obtained f rom marine invertebrates , especial2 ly sponges , have yielded novel metabolites wit h potent antibacterial , anticancer or ot her bioactivities.  Xestodecalactones A , B and C ( 7 - 9 in Fig.2 ) were purified f rom t he f ungus Penicilli u m cf . mont anense isolated f rom marine sponge Xestos pongia ex i gua ( E2

drada , 2002 ) . Compound 8 was found to be active a2 gainst t he yeast Can di da albicans. In t he agar diff u2 sion assay , it caused inhibition zones of 25 , 12 and -1 7 mm at concent rations of 100 , 50 and 20μmol L re2 spectively. All t he isolated compounds were found to be inactive toward t he bacteria B acill us subtilis , S t aphylococcus au reus and Escherichia coli. According to t he similar lactones f rom microorganisms , t he xestodecalactones should be formed via an acetogenic pat hway , as evidenced f rom t he periodically arranged oxygen atoms , which should be t he remainders of a polyketide precursor. From X. ex i gua collected in In2

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donesia , t he f ungus As pergill us versicolor was isolat2 ed. Seven new angular t ricyclic chromone derivatives ( 10 - 16 in Fig.2) were obtained f rom t he cult ure of t he

2004 , Vol . 3 , No. 2

f ungus ( Lin et al. , 2003 ) . Compound 10 displayed only moderate antibacterial activity against B. subtilis and was inactive against E. coli and S. cerevisiae.

Fig. 2 Compounds isolated from sponges2associated fungi

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GU Q. Q. et al. : Rece nt Resea rc hes of Bi oact ive Met a bolites i n Ma ri ne Sym bi ot ic Microorga nis ms 153  

 An undescribed fungus of the genus Microsphaeropsis, isolated from the Mediterranean sponge A plysina aerophoba , produced two new betaenone derivatives (17 and 18 in Fig . 2 ) and three new 1 , 3 , 6 , 82tetrahydroxyanthra2quinone congeners (19 - 21 in Fig.2) (Brauers et al. , 2000) . More2 over , it was shown that compounds 17 , 19 , 20 and 21 are inhibitors of PKC2 , CDK42 and EGF receptor tyrosine ki2 nases. The range of the IC50 values was from 18.5 to 54.0 μmolL - 1 .  Two new metabolites , microsp haerones A and B ( 22 and 23 in Fig. 2 ) , were identified f rom t he acetic et her ext ract of t he cult ure of an undescribed f ungus of t he genus M icros phaeropsis, which was isolated f rom t he Mediterranean sponge A plysi na aerophoba ( Wang et al. , 2002 ) . Bot h compounds , 22 and 23 , exhibited no significant antiproliferative activity against HL260 and NB24 cell lines. When tested against larvae of polyp hageous pest insect S podoptera littoralis and brine shrimp , A rtem ia sali na, bot h compounds dis2 played no or only moderate activity.  Chemical investigations were conducted for a Peni 2 cilli u m brocae obtained f rom a tissue sample of a Fi2 jian sponge Zyz yya sp . The result s indicated t hat t he ext ract yielded t hree novel cytotoxic polyketides , bro2 caenols A2C ( 24 - 26 in Fig. 2 ) (Bugni et al. , 2003 a , Bugni et al. , 2003 b) . All t he t hree compounds were tested in HCT2116 cell line wit h M T T assay and showed moderate cytotoxicity. The IC50 values for 24 , 25 , and 26 were 20 , 50 and beyond 50μgmL - 1 respectively.  Two new macrolide metabolites , pandangolide ( 27 and 28 in Fig.2 ) , were identified f rom t he organic ex2 t ract of Cl ados pori u m herbaru m isolated f rom marine sponge Callyspongia aeriz usa (J adulco et al. , 2001 ) . The two compounds were inactive when tested against Gram2positive and Gram2negative bacteria.  One new ant hraquinone ( 29 in Fig. 2 ) was isolated f rom Cu rv ul aria l u nat a; two new R2pyrones ( 30 and 31 in Fig.2 ) and one new p ht halide ( 32 in Fig.2 ) were obtained respectively f rom two st rains of Cl ados pori2 u m herbaru m isolated f rom two sponges , A plysi na aerophoba and Callyspongia aeriz usa (J adulco et al. , 2002 ) . Compound 29 was found active against S. au2 reus, E. coli , and B. subtilis but inactive against C. albicans. Compounds 30 and 31 showed activity a2 gainst A rtem ia sali na. Compound 30 gave mortality rates of 85 % and 75 % at 100μg and 50μg dose lev2 els , respectively , while compound 31 gave 80 % and 65 % mortality rates at t he two dose levels , respec2 tively. However , compound 32 showed no activity in t he test against A. sali na and human leukemia cell line HL260 .   New compounds , varit riol , varioxirane , dihy2 droterrein and varixant hone ( 33 - 36 in Fig. 2 ) , were isolated f rom a marine2derived st rain of f ungus E2 mericell a v ariecolor isolated f rom a sponge collected in t he Venezuelan waters of t he Caribbean Sea

(Malmst r g m et al. , 2002 ) . Varit riol ( 33 ) displayed increasing potency of activity toward selected renal , CNS , and breast cancer cell lines but was inactive a2 gainst t he remaining cell lines at a concent ration of -4 - 1 10 mol L . When tested in an antimicrobial assay , varit riol did not inhibit t he growt h of bacteria and yeast at 100μg mL - 1 . Varixant hone ( 36 ) was tested toward P388 ( mouse lymp homa) , A549 ( human lung carcinoma) and H T29 ( human colon carcinoma) cell lines and found inactive at 1μg mL - 1 . However , var2 ixant hone displayed antimicrobial potency against Gram2positive and Gram2negative bacteria. 3. 2   Bioactive Metabol ites from the Fungi Associated with Other Marine Animals and Plants

 In addition to sponges , many ot her invertebrates such as mollusks , t unicates , crustacean and algae are also rich sources of f ungus isolates.  From t he green alga U l v a sp . , t he endop hytic ma2 rine f ungus Ascochyt a salicorniae was isolated ( Oster2 hage et al. , 2002 ) . A. salicorniae was mass cultivat2 ed and found to produce t he unprecedented and st ruc2 t urally unusual tet ramic acid containing metabolites ascosalipyrrolidinones A , B ( 37 a and 37 b in Fig. 3 ) . Additionally , a new nat ural product ascosalipyrone ( 38 in Fig. 3 ) and many known metabolites were ob2 tained. Ascosalipyrrolidinone A ( 37 a ) had antiplas2 modial activity toward Pl as modi u m f alci paru m st rains K1 and N F 54 , antimicrobial activity and in2 hibiting activity toward tyrosine kinase p 56lck.  Two p henalenone2skeleton2based compounds , scule2 zonone2A ( SCUL2A ) and sculezonone2B ( SCUL2B ) (39 and 40 in Fig. 3 ) , were purified f rom a brot h of t he f ungus Penicilli u m sp . isolated f rom Okinawa marine bivalve M ytil us coruscus ( Perpelescu et al. , 2002) . Bot h compounds inhibited bovine DNA poly2 merases α and γ and moderately affected t he activity of DNA polymerase ε. However , t hey had almost no effect on HIV2reverse t ranscriptase and E. coli DNA polymerase I Klenow f ragment . Most notably , SCUL2 A inhibited pol β ( IC50 = 17μmol L - 1 ) , while SCUL2 B had only a weak influence upon t his polymerase ( IC50 = 90μmol L - 1 ) . Kinetic st udies also showed t hat SCUL2A or SCUL2B could inhibit DNA polymerases α and γ , and t he inhibitive action was competitive wit h respect to d T TP subst rate and noncompetitive wit h t he template2primer. Whereas polymerases α in2 hibition by SCUL2B was competitive wit h respect to dATP , t he inhibition by SCUL2A was found to be a mixed type wit h dATP subst rate. The calculated Ki values of SCUL2B were 1.8 and 6 .8μmol L - 1 for DNA polymerases α and ε, respectively. The Ki of DNA polymerase γ for SCUL2Awas 12μmolL - 1 and t hat for DNA polymerase α was 16μmol L - 1 . Therefore , re2 moval of t he O H2group at C12 enhanced t he inhibition of DNA polymerase β.

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Fig. 3 Compounds isolated from fungi associated wit h marine animals and plants

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GU Q. Q. et al. : Rece nt Resea rc hes of Bi oact ive Met a bolites i n Ma ri ne Sym bi ot ic Microorga nis ms 155  

 Two new diterpenic altrosides , virescenosides M and N ( 41 and 42 in Fig.3 ) , have been isolated f rom a ma2 rine st rain of A cremoni u m st riatis poru m KMM 4401 associated wit h t he holot hurian Eu pent act a f rau da2 t ri x ( Afiyat ullov et al. , 2000 ) . In addition to t he new compounds , t hree ot her known diterpenic alt rosides , virescenosides A , B and C , have also been isolated. Virescenosides A , B , C , M and N showed cytotoxic effect s on developing eggs of sea urchin S t rongylo2 cent rot us i ntermedi us wit h M IC50 range f rom 2. 7 to -1 20μmol L , and t heir activities decreased in t he order of C , M , B , A and N . It was shown t hat t hese glyco2 sides exhibited cytotoxic action against t umor cells of Ehrlich carcinoma ( IC50 range f rom 10 to 100μmolL - 1 ) i n vit ro. Furt her investigations for metabolites of t his f ungal strain Acremonium st riatisporum KMM 4401 led to t he isolation of t hree new cytotoxic glycosides , virescenosides O , P and Q ( 43 - 45 in Fig.3 ) ( Afiyat2 ullov et al. , 2002 ) . It was shown t hat virescenosides O , P and Q exhibited cytotoxic action against t umor cells of Ehrlich carcinoma wit h IC50 range f rom 20 to 100 μmol L - 1 in vit ro. Virescenoside P showed cytotoxic ef2 fect s on t he developing eggs of t he sea urchin S t ron gylocent rot us i ntermedi us ( M IC50 equal to 5. 0 μmol L - 1 ) .  Trichodermamides A and B ( 46 and 47 in Fig. 3 ) , two modified dipeptides , have been isolated f rom t he cult ures of marine f ungus Trichoderm a vi rens ( Garo et al. , 2003 ) . The f ungal st rains were obtained f rom a sample of marine ascidian Di dem n u m molle and green alga Hali meda sp. respectively. Compound 47 dis2 played significant cytotoxicity against HCT2116 hu2 man colon carcinoma wit h an IC50 of 0 . 32μg mL - 1 i n vit ro. This metabolite also exhibited moderate antimi2 crobial activities against amp hoterocinresistant C. al 2 bicans, met hacillin2resistant S. au reus and van2 comycin2resistant E. f aeci u m wit h M IC values of about 15μg mL - 1 . Compound 46 was completely inac2 tive in all t hese bioassays , suggesting t hat t he chlorine atom was an essential part of p harmacop hore.  Three new oxepin2containing metabolites , named oxepinamides A2C ( 48 - 50 in Fig. 3 ) , as well as two new members of t he f umiquinazoline class of com2 pounds , f umiquinazolines H and I (51 and 52 in Fig.3 ) , were purified f rom a f ungus of genus A cremoni u m isolated f rom t he surface of Caribbean t unicate Ectei nasci dia t u rbi nate collected in Bahamas (Belofsky et al. , 2000 ) . Compounds 51 and 52 were found to have weak antif ungal activities toward Can di da albi2 cans in brot h microdilution assay and exhibit t he activ2 ities in a dilution of 0.5 mg mL - 1 ( 1 mm) . Oxepinamide A ( 48 ) showed good topical anti2inflammatory activity in t he resiniferatoxin ( R TX) 2induced mouse ear ede2 ma assay , a test for neurogenic inflammation. Ox2 epinamide A exhibited 82 % inhibition of edema ( in2 duced by R TX at 0.1μg per ear) at t he standard test2 ing dose of 50μg per ear.

 Pestalone ( 53 in Fig. 3 ) , a new chlorinated ben2 zop henone antibiotic , was produced by cult ured ma2 rine f ungus ( Cueto et al. , 2001 ) . The f ungus , isolat2 ed f rom t he surface of brown alga Rosenvi n gea sp . collected in Bahamas Islands , was identified as an un2 described member of t he genus Pest alotia. Compound 53 was found to exhibit moderate cytotoxicity i n vit ro in t he National Cancer Instit ute’s human t umor cell line screen ( mean GI50 = 6.0μmL - 1 ) . More important 2 ly , it showed potent antibacterial activity against me2 t hicillin2resistant S taphylococcus aureus ( MIC = 37 ng mL - 1 ) and vancomycin2resistant Enterococcus f aeci u m ( M IC = 78 ng mL - 1 ) .

4  Co n cl u s i o n  Marine organism2associated microorganisms produce rich secondary metabolites wit h chemical diversities. These metabolites include alkaloids , glycosides , diones , peptides , polyketides , macrolides , unusual aroma rings and so on. Many of t hem show antibacte2 rial or antit umor activities. It is well known t hat t he o2 cean is a source of a large group of st ruct urally unique nat ural product s t hat are mainly accumulated in inver2 tebrates such as sponges , t unicates , bryozoans and molluscs. Some of t hese compounds show pronounced p har2 macological activities and are interesting candi2 dates for new drugs primarily in t he area of cancer t reat ment . Numerous nat ural product s f rom marine in2 vertebrates show st riking st ruct ural similarities to known metabolites of microbial origin , suggesting t hat microorganisms are at least involved in t heir biosyn2 t hesis or are in fact t he t rue sources of t hese respective metabolites. This observation has been corroborated by several st udies on nat ural product s f rom sponges , which prove t hat t hese compounds are localized in symbiotic microorganisms. However , it is a challenge to develop and apply t he novel bioactive nat ural prod2 uct s because it is very difficult to collect t he marine sample , t he content of active compounds in samples is ext remely low , and t he chemical st ruct ures of t hese active compounds are too complex to be synt hesized. A large number of novel bioactive product s are to be explored and research on t he active component s found in marine microorganisms has become a hot area of marine nat ural product . In particular , f ungi obtained f rom marine invertebrates have yielded novel metabo2 lites wit h potent antibacterial and anticancer activi2 ties.  The aut hors have been working on novel bioactive nat ural product s f rom marine microorganisms since 2001 . In our continuous search for nat ural product s wit h potential anticancer activity , ext ract s of microor2 ganisms associated wit h marine plant s and animals are screened for novel cell cycle inhibitors and apoptosis inducers by using mouse cdc2 mutant cell lines , t s2 FT210 . Several st rains of f ungi and actinomycetes

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showed inhibitory activities and apoptosis inducers a2 gainst t he cell cycle of t sF T210 . Now , bioassay2guided f ractionation of t he et hyl esters ext ract of isolated st rains is under investigation in our laboratory.

A c k n o wl e d g e m e nt s  This work was supported by t he National Nat ural Science Foundation of China ( No . 39825126 ) , t he Cheung Kong Scholar f rom t he Cheung Kong Scholars Program of Minist ry of Education of China , t he Hi2 Tech Research and Develop ment Program of China ( Nos. 2002 AA628130 and 2003 AA624020 ) , t he Nat2 ural Science Foundation of Shandong Province ( No . Z2001 C01 ) , and t he High Technology Research and Develop ment Program of Shandong Province ( No . 0121100107 ) .

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