w w w . s b f g n o s i a . o r g . b r / r e v i s t a
Review
Article
C
15
acetogenins
from
the
Laurencia
complex:
50
years
of
research
–
an
overview
Tauana
Wanke
a,
Ana
Cláudia
Philippus
a,
Gabriele
Andressa
Zatelli
a,
Lucas
Felipe
Oliveira
Vieira
b,
Cintia
Lhullier
a,
Miriam
Falkenberg
a,∗aProgramadePós-graduac¸ãoemFarmácia,UniversidadeFederaldeSantaCatarina,Florianópolis,SC,Brazil bCursodeGraduac¸ãoemFarmácia,UniversidadeFederaldeSantaCatarina,Florianópolis,SC,Brazil
a
r
t
i
c
l
e
i
n
f
o
Articlehistory: Received30April2015 Accepted21July2015 Availableonline9October2015
Keywords: Acetogenins Redalgae Laurenciacomplex Halogenatedmetabolites Bromoethers
a
b
s
t
r
a
c
t
Acetogenins are secondary metabolites derived from the polyketidepathway and their potential roleaschemotaxonomicalmarkersforredalgaebelongingtotheLaurenciacomplexhasbeenlong pointedout.C15acetogeninsfromalgaearequitedifferentfromplantacetogenins:theyareusually
halogenated,and haveanenyneora bromoalleneterminal group.Sincethey werefirstreported, laurencinandotheralgalacetogeninshaveinspiredgreatcuriosityamongnaturalproductchemists and also those working with synthesis. This paper reviews the literatureabout C15 acetogenins,
focusing on theirdistribution, chemical and biologicalaspects,including theirreported biological activities.
©2015SociedadeBrasileiradeFarmacognosia.PublishedbyElsevierEditoraLtda.Allrightsreserved.
Introduction
Acetogeninsarealargegroupofnonterpenoidmoleculesthat originate in the polyketide pathway (Dembitsky et al., 2003). Theyarerelativelycommonincertainplantfamilies, especially Annonaceae,and are wellknown for theirbiological activities. Annonaceousacetogeninsarelargermolecules(C35orC37)
bear-ingethergroups,butusuallynohalogen(Liawetal.,2010).Among marinealgae,acetogeninsaremostly halogenated,andare gen-erallythoughttooriginatefromacommonC15precursorderived
fromaC16fattyacid(Wangetal.,2013).Acetogeninsare
recog-nizedaschemotaxonomicmarkersforredalgaebelongingtothe familyRhodomelaceae,inparticular,tothegenusLaurencia(Stout andKubanek,2010).
It iswellknownthat halogenatedmetabolitesare abundant inredalgae,especiallyinLaurencia(Fenical,1981).Nevertheless, itstaxonomyisconsideredachallenge,andhasundergone sub-stantialrevision.Thisgenushasbeensubstantiallydividedsince itsoriginaldescriptioninthe19thcentury,andthedifferent gen-eraacceptedascomponentsoftheLaurenciacomplexhavebeen distinguishedas:Laurenciasensustricto,Palisada,Chondrophycus,
∗ Correspondingauthor.
E-mail:miriam.falkenberg@ufsc.br(M.Falkenberg).
YuzuruaandOsmundea(Furnarietal.,2001).Afurther monospe-cific genus was recently added: Laurenciella (Cassano et al., 2012).
Despite of a few linear compounds, most algal C15
aceto-geninsarecyclicethermetaboliteswithdifferentringsizesanda conjugatedenyne(C C C CH)orbromoallene(C C CHBr) ter-minus. Until the 1960s, alkyne groups were considered to be rare in the nature, but nowadays, it is well known that com-pounds withthe acetylenicgroupare alsoprevalent in marine organisms,particularlymicrorganismsandsponges,suchas Pet-rosiapolyacetylenesrangingfromC44toC47(MintoandBlacklock, 2008).
Currentlytherearemorethan22,000compoundsderivedfrom marinemacro-ormicrorganismsandsomemoleculesarequite stunning in their complexity (Carter and Crews, 2011). There have been comprehensive reviews of marine natural products organizedphylogenetically,whicharepublishedannually(Blunt et al., 2015and previousreports in this series). Thereare also reviewsintheliteratureonmarinepolyacetylenes(Legraveetal., 2015), bioactive compounds from marine invertebrates (Datta etal.,2015),andhalogenatedmetabolitesfromLaurencia(Cabrita etal.,2010),butthesedonotfocusonacetogenins,orelsethey omit some important points about this group of metabolites. Nevertheless,someintriguingacetogeninstructureshaveinspired several groups of chemists to explore this field, through both
http://dx.doi.org/10.1016/j.bjp.2015.07.027
biosyntheticandsyntheticapproaches,withthetwoapproaches frequently converging. Dembitsky et al. (2003) reviewed the literatureonacetogeninsupto1999,but sincethen, a number of new acetogenins have been described in the literature, and the structures of some known compounds have been revised (Suyamaetal.,2011).Wangetal.(2013)includedacetogeninsin theirreviewofhalogenatedmetabolitesfromRhodomelaceae,but excludedthenon-halogenatedmetabolitesanddidnotconsider thetaxonomicreviewofthegenusLaurencia.Thepresentreview aimstoprovideageneraloverviewof50yearsofchemical and biological research on algal acetogenins, including their distri-bution, structural features, biological activities and potential ecological roles, highlighting new compounds isolated in the last15years, aswellasthetaxonomicaspectsof theLaurencia complex.
Firstreports
Laurencin(1)wasisolatedfromanalgaidentifiedasLaurencia glanduliferacollectedinJapan,anditwasthefirstC15acetogeninto
bereported(Irieetal.,1965).Sinceitsisolation,50yearsago,more than200acetogeninshavebeendescribed,mostlyofthefamily Rhodomelaceae(Dembitskyetal.,2003;Wangetal.,2013),which includestheLaurenciacomplex,butalsofromseahare(inthiscase, adietaryoriginisassumed).
It is noteworthy that the structure elucidation of the first acetogeninwasbasedoncarefulandsystematicanalysis,with com-binationofpartialstructuresdeductedfromrelativelyfewspectral data(bytoday’sstandards):1HNMR,MS,infrared(IR)andstrongly
onderivatizationprocedureswithanalysisofsuccessivereaction adductstoeliminateotherpossiblehypotheses(Irieetal.,1965, 1970).
Thecharacteristic bandsin theinfrared (IR)spectraare still usefulfordiagnosis:about3300cm−1for( C H)andfrom2000
to2300cm−1 for(C C)ofenyneorabout2000cm−1 for(=C=C)
of alleniccompounds. The NMR signals for theenyne are also
characteristic, rangingfrom 2.7 to 3.1ppm for thealkyne pro-ton and about 75–83ppm for the carbons on the triple bond (Rückeretal., 2001;Gutiérrez-Cepedaetal.,2011a,b).The bro-moallenicpartialstructure (BrHC=C=CH )canberecognizedby thecharacteristic chemical shiftsof thecarbon atoms: approx-imately 70ppm for C-1, about 200ppm for C-2, and about 100ppm for C-3; thehydrogenatoms ofC-1 and C-3correlate withacouplingconstantofabout6Hz(Gutiérrez-Cepedaetal., 2011a,b).
In the 1960s, these structural features were not common, thereforeitisnotsurprisingthatlaurencin(1)andthesubsequent
isolated acetogenins attracted great curiosity from natural product chemists. Besides spectral data from natural com-poundsandtheirderivatives,totalsynthesisbecamea common approach to structure confirmation, and some Japanese groups developed expertise in acetogenin chemistry. Irie et al. (1970) reportedalso theisolation oflaureatin (2)and isolaureatin (3) a few years later, with a similarapproach to theone used for laurencin(1).
Somedifficultiesemergedconcerningthenewnaturalproduct class after the structure of laurefucin, isolated from
Lauren-cia nipponica Yamada (Fukuzawa et al., 1972), was revised 1
year later (Furusaki et al., 1973), when X-ray crystallography established the absolute configuration, and showed that the moleculehasanoxolanering(4)insteadoftheinitiallyproposed structure(5).
In a very interesting review, Faulkner (1977, p. 1423) com-mentedabouttheacetylenesisolatedfromredalgae:“...itisnot surprisingthatseveralincorrectstructureswerecorrectedusing X-rayanalysis...Becausethesignalsduetoprotons␣tooxygen, bromineandchlorineoftenoccurinthesameregionofthe spec-trum,itisdifficulttoassignsignalsinthisregion,eventhoughit maybepossibletodetermineallvicinalandgeminalrelationships betweenprotons throughcareful spindecoupling....themajor problemwastodeterminewhichfourofsixpossiblemethine car-bonatomswereinvolvedinetherlinkagesandtodeterminethe ringsizes”.
Themaneonenes(6–9)andisomaneonenes(10and11)groups werereportedinthe1970s(Waraszkiewiczetal.,1976;Sunetal., 1976).By theearly1980s, there were about25 described ace-togenins,includingsomediscoveredout ofJapan,likethatof a LaurenciaspeciesfromtheGulfofCalifornia,Mexico(Fenical,1981). WhenErickson(1983)reviewedconstituentsofLaurencia,she ded-icatedabouta quarterof her chaptertoacetogenins thatwere alreadyconsideredchemicalmarkersofthisgenus.Itwasrecently estimatedthatacetogeninsrepresent26%(180)of697halogenated moleculesofRhodomelaceaeorigin(Wangetal.,2013)andabout 18%(32)of173non-halogenatedmetabolitesfromthecomplex Laurencia(JiandWang,2014).
Classificationofacetogenins
Acetogeninsaregenerallyclassifiedbasedonstructuralfeatures suchasthepresenceofringsandtheirsize,orthenatureofthe ter-minalgroup(enyneorbromoallene).BesidestheC15acetogenins,
afewC12acetogeninshavealsobeenreportedinalgaesofar(Li etal.,2012;Liangetal.,2012).
prevalent. One of the few exceptions is the class of linear acetogenins.
Linear
Thisclassofcompoundswasreportedinjustafewspecies,and includesnon-halogenated(Kigoshietal.,1986;JiandWang,2014) andhalogenatedmetabolites(Jietal.,2009).Mosthalogenated lin-earacetogenins beara chlorineat C-6,anoxygenatedgroupat C-7,andZ-geometryattheisolated doublebonds(Wangetal., 2013).
Tetrahydrofuran
ThisclasswasreportedmainlyforL.nipponica,Chondrophycus glandulifer(asL.glandulifera)andL.obtusa.Mostcompoundsinthis grouppresentacis-ortrans-enyneasterminus,likein laureepox-ide(12),butsomebromoallenesarealsoseen.Thecompoundsare generallybrominated,butsomehavechlorineastheonlyhalogen atom,whileothersarebromochlorinated.Becausethesidechain bearssmallringsitiseasier,inthisgroup(thaninmorecomplex acetogenins),toidentifytheoriginalacycliccompoundthatcould betheprecursorbeforethecyclizationthroughthehydroxylgroups inthesidechain.
Bis-tetrahydrofuran
ThisclasswasreportedforLaurenciaspeciesdistributedfrom theMediterraneanSeatothePacificOcean.Again,mostcompounds are brominated,and enynesare more prevalentthan bromoal-lenes.Thestructureofatleastthreecompoundsofthisgroupwas revisedafterachievingtotalsynthesis,e.g.elatenyne(previously reportedas 13, had itsstructure revisedto14)(Suyamaet al., 2011).Itisnotablethatacetogeninswithpartialstructures2,2′ -bis-tetrahydrofuranand2,7-dioxabicyclo[4.4.0]decanepresentthe sameCandHconnectivity,thereforeunambiguousstructure elu-cidation by NMR analysisalone is quite a challenge (Faulkner, 1977).
2,6-Dioxabicyclo[3.3.0]octaneand2,7-dioxabicyclo[4.3.0]nonane
Obtusin(15)wasthefirstmembertobedescribedforthe diox-abicyclooctane class, which includes just over ten compounds, mostly bromoallenic compounds, and was mainly found in L. obtusaandL.intricata.Thesecondclassincludesthevery unsta-blejaponenynesA–C(16–18)fromL.japonensis(Takahashietal., 1999).
Tetrahydropyran
Justfewmembersofthissix-memberedcyclicetherclasshave beenreportedfor theLaurenciacomplex todate:scanlonenyne (19)fromL. obtusa(Suzuki et al., 1997) andbisezakyne B (20) fromanundescribedJapaneseLaurencia(Suzukietal.,1999).Some
acetogeninsbelongingtothisclasshavebeenreportedforAplysia species,suchasthedactylyne-relatedcompounds(seeAcetogenins ofseahare).
Seven-memberedcyclicethers
These acetogenins maybemonocyclic (oxepane) or bearan additional6,9-epoxidering,asinisoprelaurefucin(21).Most com-poundsaredihalogenatedandhaveanenyneastheterminalgroup (Kurosawaetal.,1973).
Eight-memberedcyclicethers
Thisclass is themostabundant,includingthefirst reported acetogenin, laurencin (1), as well as more than 70 other metabolites. Accordingtotheringclosure system(whichmight include epoxy rings in different positions and different termi-nalgroups),itcanbedividedintosevensubclasses(Wangetal., 2013).
Nine-to12-memberedcyclicethers
Acetogeninsoftheseclassesmayalsocontainepoxyring sys-tems,and havebeenfoundamongotherspecies inL.obtusa,L. okamurae,L.nipponica,Osmundeapinnatifida(asL.pinnatifida)and Laurenciaintricata(asL.implicata),whichaffordedtheonlyknown 10-memberedcyclicether(22)(CollandWright,1989apudWang etal.,2013).Most12-memberedcyclicetherswerereportedfor L.obtusa,butsofar,therehavebeennoreportsof11-membered cyclicethers(Wangetal.,2013).
Maneonenesandisomaneonenes
This class differs from the other because the carbon chain cyclisesbackonitselftoformacarbocyclicringinmaneonenes (6–9) (Waraszkiewicz et al., 1976, 1978; Sunet al., 1976) and biscarbocyclic rings in isomaneonenes (10–11) (Waraszkiewicz etal.,1978).BothclasseswerefirstdescribedforL.nidificafrom Hawaii.
Branched
TheseacetogeninshavebeensofarreportedjustforL.
micro-cladia from Il Rogiolo, Italy, and the compounds were named
afteritas“rogiolenynes”(Guellaetal.,1992b;GuellaandPietra, 1991).
Miscellaneous
Biosynthesis
Kurosawaetal.(1972)isolatedfromL.nipponicathe nonhalo-genatedtrans-andcis-laurediols(23and24),whichwereregarded asbiosyntheticprecursorsofvariousnonterpenoidC15metabolites.
Fouracetylenicpolyenes(25–28)closelyrelatedtolaurediols(23 and24)wereisolatedfromL.okamurae(Kigoshietal.,1986)and werealsofoundtobeofbiogeneticsignificance.
Duetothecomplexvariationsthatacetogeninsmaypresent, each structural grouprequired specific studies,but those early findingswereessentialtoestablishthefirstcommonstepsofthe biosyntheticalprocess.
Eight-memberedcyclicethersarethemostabundantand struc-turally diverse C15 acetogenins. They can be divided into two
subclasses:lauthisantype,aslaurencin(1)andlaurenantype,as laureatin(2)andlaurallene(29)(Sugimotoetal.,2007).Aseries ofstudiesbytheMuraigroupledtotheproposalofabiogenetic pathwayforlaurenancompounds,includingthebromo-cationic cyclization of an acyclic precursor cis-laurediol (24) to afford prelaureatin(30),whichisconvertedtolaureatin(2)andseveral bicycliccompoundsbythesubsequentbromo-cationiccyclization (Muraietal.,1977).FukuzawaandMurai’sproposedbiosynthesis ofvariousbromoethersstemmingfrombromoniumionisshownin Scheme1.Muraihasalsoshownthatlactoperoxydasecancatalyze theformationof5-memberedethersfromlinearpolyenes,asin Scheme2(TaylorandFox,2015).Theideathatatransient bromo-niumspeciescouldbetheintermediarykeyforthebiosynthesisof severalacetogenins,throughintramolecularbromoetherification
inspiredothergroups.Accordingtothisbiogeneticpathway,the firsttotalsynthesisoflaureatin(2)wasproposedsomeyearslater (Sugimotoetal.,2007).Bromoniumionswerealsousedrecentlyto proposeabromine-inducedskeletalrearrangementofanoxocene precursortoobtaintheepoxytetrahydrofuranlaureepoxide(12) (TaylorandFox,2015).
Distributionbyspecies
Somealgaespeciesareparticularlyproficuousonthesynthesis ofacetogenins,liketheoneshighlightedabove.Speciesnotclearly
identified,butthatalsocontaininterestingstructures,areincluded onthetopic“Otherspecies”.
Chondrophycusglandulifer(asLaurenciaglandulifera)
Laurenciaglandulifera (Kützing)Kützing is a taxonomic syn-onymforChondrophycusglandulifer(Kützing)Lipkin&P.C.Silva (currentacceptednameaccordingtotheAlgaebase).Itisreported mainly in Europe,but also in theAtlantic Islands (Canary and Madeira),Indianand PacificOceans,and Asia.IntheAlgaebase, thereisjustonerecordofthis speciescollectedinJapan(Guiry andGuiry,2015).
O Br HO
H
H O Br
HO H H
Bromonium
O Br
H
Br O
H O
Br O
O
H H
OH
OO
Br
H H2O
Laurefucin
O
Cl
O
Br H
H
Notoryne Br
Et
O Br
H O
Laureoxanyne Br+
Br+
CI–
H
+
Scheme1.FukuzawaandMurai’sproposedbiosynthesisofvariousbromoethersstemmingfrombromonium.
Scheme2.ProposedbiosynthesisofbrominatedTHF’sfromlinearpolyenes.
asL.glandulifera,collectedinOshoroBay,Hokkaido,Japan(1965). Inapaperonthebiosynthesisofbrominatedmetabolites,Suzuki andcoauthors(2009)affirmthatlaurencin(1)wasisolatedfrom achemicalraceofL.nipponicaYamadathatwasidentified asL. glanduliferaKützing(seeLaurencianipponica).Thesampleafforded laurencin(1)inrelativelyhighquantities(4.5gfrom8.5kgdried algaaccordingtoIrieetal.,1968c),whichallowedthescientists toperformseveral reactionsuntilits structure elucidation(Irie
et al.,1965,1968c).Investigationof this compound withX-ray crystallography enabled its stereochemistry to be established (Cameronetal.,1965), andthefirsttotal synthesisoflaurencin (1) in a racemic form was achieved in 1977 by Murai et al. (1977).Biologicalinvestigations showedthat laurencin(1) pro-longed pentobarbitone-inducedsleep time in mice(Kaulet al., 2011).
Laurenciachondrioides
L.chondrioidesBørgesenisreportedinEurope(mostly Mediter-ranean Sea), Atlantic Islands, Caribbean Islands, Israel and Philippines (Guiry and Guiry, 2015). The material collected in Kefalonia Island (Greece) was submitted to a dereplication approachusingUHPLC-PDA-HRMSand2DHSQCNMR.Twonew bromoalleneacetogeninswereisolated:marilzallene B(42)and chondrioallene(43)alongwithknownacetogenins3-E-laurenyne (44),trans-pinnatifidenyne(45),obtusenyne(46)andobtusallenes II(47),III(48),V(49)andVI(50)(Kokkotouetal.,2014).
Laurenciadecumbens
L.decumbensKützing(syn.L.pygmaeaWeber–vanBosse)is reportedinseverallocationsofAmerica,Africa,AsiaandOceania, butnotinEurope(GuiryandGuiry,2015).
AccordingtoStout andKubanek(2010)it isnot commonto see bromoallene and enyne metabolites co-occurring, but this wasreportedforL.decumbensfromChina,thatbesideselatenyne (14)presentslaurendecumenynes A (51)and B(52)as wellas laurendecumallenes A (53) and B (54) (Ji et al., 2007, 2010). Their structures and relative stereochemistry were established byspectroscopicanalysisincluding1Dand2DNMRtechniques, but two compounds had their structures revised (Ji et al., 2010).
Laurenciaelata
Laurenciaelata(C.Agardh)J.D.Hooker&Harveywasreported inAfrica,South-WestAsia,AustraliaandNewZealand(Guiryand Guiry,2015).Elatenynewasisolatedin1986fromL.elataandits structurededucedas13 onthebasis of1Hand 13C NMR
spec-troscopicanalysis(HallandReiss,1986).However,morerecently elatenynewasisolatedfromsampleofL.elatacollectedinSt.Paul’s Beach, Sorrento, Victoria (Australia), with 3-Z-chlorofucin (55)
(DiasandUrban,2011).Inthiscase,theelucidationofelatenyne was performed in comparison withdata reported by Hall and Reiss(1986);therelative configurationwasrevisedto14using synthesis of several derivatives togetherwith onand off reso-nance decoupling, double resonance and lanthanideshift NMR experiments(BrkljacaandUrban,2013;Wrightetal.,1993). More-over,elatenynehasalsobeenreportedfromthemarineredalgae L. majuscula (Wright et al., 1993) and L. decumbens (Ji et al., 2007).
Laurenciafiliformis
Laurencia filiformis (C. Agardh) Montagne is found mainly
in Australia and New Zealand, but it is also reported from Europe,Florida, Brazil,Belize (Central America), Tanzania, Pak-istan,Japan,IndonesiaandPacificIslands(GuiryandGuiry,2015). FromL.filiformiscollectedalongthewesterncoastofAustralia, eight-memberedetherringacetogeninswereisolated,suchascis -dihydrorhodophytin(56)(BrennanandErickson,1982),alsofound inOsmundeapinnatifida(asL.pinnatifida)(Norteetal.,1989a), Lau-rencianangii(VairappanandTan,2009)andfrommolluskspecies Aplysiabrasiliana(Kinneletal.,1979).Therelatedmetabolitecis -epi-dihydrorhodophytin(57)alsowasisolatedfromthisspecies (BrennanandErickson,1982).
Laurenciaintricata
ThesamplescollectedinJapanpresentedacetogenins belong-ing to three different classes: tetrahydrofuran derivatives such asitomanalleneB(61)andnine-memberedcyclicetherssuchas itomanalleneA(62)(Suzukietal.,2002).Thetotalsynthesisfor itomanalleneA(62)wasobtainedthroughintermolecularamide enolatealkylationandring-closingmetathesis(Jeongetal.,2010). L.implicata J.Agardhisregardedasataxonomicsynonymof L.intricataJ.V.Lamouroux,which isthecorrect nameaccording totheAlgaebase(GuiryandGuiry,2015).Therearetworeports of studies under the non-correct epithet, both from Australia. The samples collected in Magnetic Island, Australia, presented acetogeninsbelongingtotwodifferentclasses:eight-membered cyclic ethers such as 3-Z-bromofucin(63)and nine-membered cyclicetherssuchas64(CollandWright,1989apudWangetal., 2013).Twoother acetogenins wereisolated from material col-lectedfromBritomartReef,Australia,alsopresentingeight-and nine-memberedcyclic etherssuchas 65 and 66 (Wright etal., 1991).
Laurenciamajuscula
Laurencia majuscula (Harvey) A.H.S. Lucas is regarded as a taxonomicsynonymofL.dendroideaJ.Agardh,whichisthe cur-rentlyacceptedname,accordingtotheAlgaebase.Thisspecieswas describedinEurope;AtlanticIslands,Africa,IndianOceanIslands; Asia(China,Japan,Korea);South-eastAsia(Indonesia,Malaysia, Philippines,Vietnam);Australia,NewZealandandPacificIslands (GuiryandGuiry,2015).
acetogenin,67 (Kim etal.,1989)whichwastotallysynthesized throughanefficientsyntheticrouteforhalogenated pyrano[3,2-b]pyrans(Sheldrakeetal.,2006).MaterialfromHawaiiafforded acetogeninsbelongingtothe2,2-bis-tetrahydrofuran class(68), twolinearacetogenins(69–70)andthreebelongingto miscella-neousacetogenins(71–73)(Wrightetal.,1993).
Laurenciamicrocladia
Laurencia microcladia Kützing occurs in the Atlantic Ocean, Pacific Islands, Asia, and Mediterranean Sea (Guiry and Guiry, 2015).The samplescollected atTorrent IlRogiolo,Italy, in the MediterraneanSeapresentedacetogeninsoftheseven-membered cyclicetherclasssuchasrogioloxepanesA–C(74–76)(Guellaetal., 1992a),andbranchedacetogeninslikerogiolenyneA–D(77–80) (Guellaetal.,1992b;GuellaandPietra,1991).Curiously,the rogi-olenynesA–C(77–79)werealsoidentifiedforaspongespeciesin thesamearea,whichfeedonthealgae(GuellaandPietra,1991).The samplecollectedintheFrenchcoastatCapeFerrat,Mediterranean Seapresentstheeight-memberedcyclicethersmicrocladallenesA andB(81–82)(Kennedyetal.,1984).
Laurencianidifica
LaurencianidificaJ.AgardhoccursmainlyintheSouthPacific andIndian Ocean, especially inHawaii, butalsoin theAtlantic Islands,China,AustraliaandNewZealand(GuiryandGuiry,2015). ThesamplecollectedfromtheIslandofOahu,Hawaii,presented cis-maneonene A (6) (Waraszkiewicz et al., 1976; Sun et al., 1976), cis-maneonene B (7) (Waraszkiewicz et al., 1976), cis -maneoneneC(8)(Waraszkiewiczetal.,1978),trans-maneonene B(9)(Waraszkiewiczetal.,1976,1978)andisomaneonenesAand
B(10and11)(Waraszkiewiczetal.,1978).Holmesetal.(1983) reportedthetotalsynthesisof10and11;1yearlater,thesame groupsynthesized9(Holmesetal.,1984).Laurenidificin(83)was reportedforthespeciescollectedinHainann Island,China,and belongtothe2,6-dioxabicyclooctaneclass(Liuetal.,2010).
Laurencianipponica
LaurencianipponicaYamada,knowninJapanbythename “Ura-sozo”(Irieetal.,1970)isreportedonlyinAsiancountries(Guiry andGuiry,2015).SamplescollectedinHakodateBayJapan, pre-sented specially acetogenins belonging to the eight-membered cyclicetherclass,suchaslaureatin(2)andisolaureatin(3),which wereobtainedinrelativelyhighquantitiesfromthesameextract andhadtheirstructureselucidatedalsobyacombinationof1H
NMR,IR,MSandchemicalreactions(Irieetal.,1970;Kurosawa etal.,1972).Asoccurredwithlaurencin(1),thestructureswere reportedfirst(Irieetal.,1968a,b),andthenmorecompletedetails
oftheisolationandstructuralelucidationwerepublished(Irieetal., 1970).TotalsynthesisofbothwasachievedbyKimetal.(2007).
Further investigations led to the isolation of the eight-memberedcyclicethersdeacetyllaurencin(84)(Kurosawaetal., 1972), prelaureatin(30)(Fukuzawa etal., 1991), laurefucin (4), acetyllaurefucin(85),(Fukuzawaetal.,1972)andlaurallene(29) (FukuzawaandKurosawa,1979).
L.nipponicaalsocontainsacetogeninsbelongingtothe tetrahy-drofuran class: laureepoxide (12) (Fukuzawa and Kurosawa,
cis-deacetylkumausyne (88 and 89) (Suzuki et al., 1983c), laureoxolane(90)(Fukuzawaetal.,1989).
Someotheracetogenins havealsobeenreported:the seven-membered isoprelaurefucin (21) (Kurosawa et al., 1973) and neoisoprelaurefucin(91)(Suzukietal.,1996a);thenine-membered isolaurallene(92)(Kurataetal.,1982;Furusakietal.,1985); noto-ryne(93)belongingtothe2,2′-bis-tetrahydrofuranclass(Kikuchi etal.,1991);the2,6-dioxabicyclo[3.3.0]octanekumausallene(94) (Pradillaetal.,1998;Suzukietal.,1983b);andthelinear aceto-geninstrans-andcis-laurediols(23and24)(Kurosawaetal.,1972).
This extraordinary chemical diversity may be explained by theoccurrence of severalraces, which produce differentmajor metabolites(sesquiterpenesoracetogenins)withadistinctrange ofgeographical distribution(Masudaet al.,1997).Thedifferent populationswerestudied,alsoincrossabilityexperiments,which alsoshowed that ...”occurrence ofmixed types of metabolites betweenexperimentalinterpopulationhybrids andseveralwild plants at thesympatric locality strongly suggests that the lat-terplantsarenatural hybridsbetweentwo chemicallydifferent populations”.Furthermore,theauthorsconsiderthis finding“an answertothequestionposedbyErickson(1983)...thatspecies of Laurencia producing different sets of halogenated secondary metabolitesmay include several different species or varieties”. Based onMasuda’s groupresults (Masuda et al., 1997), Suzuki etal.(2009)usedlaurencin-andlaureatin-producingracesintheir biosynthesisstudiesonL.nipponica.
Regardingtheeight-memberedcyclicetherclass,some com-pounds, laureatin (2) and isolaureatin (3), showed insecticidal activityagainstmosquitolarvae(Culexpipienspallens)(Watanabe et al., 1989); isolaureatin (3) and laurefucin (4) prolonged sleep-time in mice induced by pentobarbitone (Kaul et al., 2011).
Laurenciaobtusa
Laurenciaobtusa (Hudson) J.V. Lamouroux is a species with
widespreaddistributionworldwide.It wasdescribedin Europe, theAtlanticIslands,CentralAmerica, theCaribbeanIslands,the WesternAtlantic,SouthAmerica,Africa,theIndianOceanIslands, South-WestAsia,South-EastAsia,Australia,NewZealandandthe
Pacific Islands(Guiry and Guiry,2015).This species is theone withthe highest number of isolated compounds for the genus Laurencia,includingmorethanthirtyacetogenins.Theseinclude compoundsbelongingtothetetrahydrofuranclass,isolatedfrom materialcollectedintheCanaryIslands,Spain,suchasgraciosin (95),graciosallene(96)(Norteetal.,1988)andalsofromtheRed Sea, Egypt,suchashurgadenyne(97)(Ayyadet al.,1990).Two belongtothe2,2′-bis-tetrahydrofuranclass:98frommaterial col-lectedinLaGraciosa,CanaryIslands,Spain(Norteetal.,1989b)and
99fromalgaecollectedinGüvercinlik,nearBodrum,inthe Mediter-ranean(Imreetal.,1995).Obtusin(15)wasobtainedfrommaterial collectedinTossadeMar,intheMediterranean,andbelongstothe 2,6-dioxabicyclo[3.3.0]octaneclass;itsstructurewasestablished byX-raycrystallography(Howardetal.,1979)andcontainsa bro-moproparglycterminus,astructuralfeaturethatwasreportedso farjustforacetogeninsfromL.obtusa(as95,98,106and107).
Scanlonenyne(19)wasisolatedfromLaurenciaobtusacollected intheScanlonIslands,Irelandandbelongstothesix-membered cyclicetherclass(Suzukietal.,1997).Eight-memberedcyclicether acetogenins werereportedfromalgae collectedin Sicily,in the Mediterranean,includinglaurencienyne(100),whichwasactive againstBacillussubtilisandEscherichiacoli(Caccameseetal.,1980); 3-Z-laurenyne(44), frommaterialcollectedin Gökceada,in the AegeanSea(Falshawetal.,1980);epoxyisodihydrorhodophytin (101)wasisolatedfromorganismsfoundintheSeaofMarmara, Turkey,intheMediterranean(Imreetal.,1987).Fromacollectionin SymiIsland,intheAegeanSea,Greece,compounds102–105were obtained(Iliopoulouetal.,2002);fromLaGraciosa,intheCanary Islands,Spain,compounds106and107werereported(González etal.,1984;Norteetal.,1989b).
LaurenciaobtusacollectedintheSaudiArabiaRedSeaCoast atJeddah alsoaffordedacetogenins fromthemaneoneneclass: 12-Z-cis-maneoneneD(114),12-E-cis-maneoneneE(115),and 12-Z-trans-maneoneneC (116);compounds 114and 115inhibited apoptosis of blood neutrophils, suggesting that they may be involvedinregulationofprogrammeddeathintheinitiationand propagationofinflammatoryresponses(Ayyadetal.,2011). Com-pound117belongstothemiscellaneousacetogeninsanditwas isolatedfromalgaecollectedinLaGraciosa,intheCanaryIslands, Spain(Norteetal.,1989b).
Laurenciaokamurae
(120)(SuzukiandKurosawa,1982),andachlorohydrin(121)that isananalogueofkamurallene(Suzukiet al.,1989).Their struc-tures(118–121)weresubsequentlyconfirmed(Suzukietal.,1991). OthermetaboliteswereisolatedfromL.okamurae,alsocollected inHokkaidoBay,Japan:neolaurallene(122)belongstothe nine-memberedcyclicetherclass(Suzukietal.,1984;Jietal.,2008), compound123isaneight-memberedcyclicether(Suzukietal., 1989)and fouracetylenicpolyenes(25–28)consideredtobeof biogeneticsignificance(Kigoshietal.,1986).
Laurenciapannosa
LaurenciapannosaZanardiniisreportedinAsia(India,Taiwan, Indonesia)andAustralia(GuiryandGuiry,2015).Someacetogenins belongingtotheeight-memberedetherringclasswereisolated inthis species.From L.pannosacollectedatAnThoi, PhuQuoc Island(Vietnam)3-E-chlorofucin(124)anditsdibromo-containing analogue(125)wereisolated,togetherwiththebromoallene pan-nosallene(126)(Suzukietal.,1996b).Thelatterwassubsequently reportedinL.okamurae(Lietal.,2012)andL.nipponicaas epilaural-lene(Abeetal.,1999)anditwasalsoreportedforL.nangii(Kamada andVairappan,2012).Recently,compound125wasalsoobtained bysynthesis(Kimetal.,2012).
Theisomer3-Z-chlorofucin(55)wasreportedforthisspeciesin asamplecollectedinPulauTalang-TalangKecil(Kuching,Sarawak, Malaysia)(Suzukietal.,2001).ItwaspreviouslyreportedforL. sny-derae(Howardetal.,1980;Youngetal.,1980),redalgaDasyphila plumariodes(Denysetal.,1993),andalsoforunrecordedspecies collectedatPulauNyireh,Terengganu(Malaysia)(Vairappanetal., 2008).Compound55wasalsoisolatedfromL.elata(DiasandUrban, 2011)andshowedantibacterialactivityagainstChromobacterium violaceum(Suzukietal.,2001),butnoappreciableantitumor activ-ity(DiasandUrban,2011).
Laurenciasnyderae
Laurenciasnyderae E.Y.DawsonoccursinNorth Americaand South-West Asia(Guiryand Guiry,2015).The eight-membered cyclicether3-E-chlorofucin(124)wasisolatedfromasample col-lected in La Jolla, California (Howard et al., 1980); it was also
reportedfor L.elata(Diasand Urban,2011), L.pannosa(Suzuki et al.,1996b)and otherLaurenciaspecies collectedin Malaysia (Vairappanetal.,2008).
Laurenciathyrsifera
Laurenciavenusta
LaurenciavenustaYamada wasreportedin America (Mexico,
Brazil),Africa,Asia,AustraliaandNewZealand,andalsoinPacific Islands(Fiji)(GuiryandGuiry,2015).Allacetogeninsisolatedsofar fromthisspeciesbelongtotheeight-memberedcyclicetherclass. ThefirstreportedacetogeninswerevenustinA(132)andB(133) (Suzuki and Kurosawa,1980)obtainedfroma samplecollected at Moheji, Hakodate Bay, Hokkaido (Japan). These metabolites were renamed as 3-E-epoxyvenustin and 3-E-venustin (Suzuki etal.,1983a),respectively.Arelatedmetabolite3-Z-epoxyvenustin (134),majorcomponentcomprising10%oftheextract,andalso 3-Z-venustin(135)and3-Z-venustinene(136)werereportedinJapan forasamplecollectedatMoura,nearAsamushi,AomoriPrefecture (Suzukietal.,1983c).
Laurenciellamarilzae(asLaurenciamarilzae)
Laurenciamarilzae was described some years ago as a new
species of thegenus Laurencia(Gil-Rodríguez et al., 2009), but after phylogenetic analyses it was reclassified as a new genus (Laurenciella),whichissofarmonospecific(Cassanoetal.,2012). Therefore, thecurrentlyaccepted name accordingto Algaebase (Guiry and Guiry,2015), isLaurenciella marilzae (Gil-Rodríguez, Sentíes,Díaz-Larrea,Cassano&M.T.Fujii)Gil-Rodríguez,Sentíes, Díaz-Larrea, Cassano &M.T. Fujii. It has been identified in the CanaryIslands,SoutheasternBrazilandintheMexicanCaribbean (Cassanoetal.,2012).
Co-occurrenceofenyneandalleneswasreportedfor Lauren-ciellamarilzae collectedin Tenerife (Canary Islands). Gutiérrez-Cepeda et al. (2011a) reported the isolation of eight new acetogenins (mostly eight- and 12-membered cyclic ethers),
besidestheknownobtusalleneIV(109).Newcompoundsincluded marilzallene(137)andtwoacetoxyderivativesofit,besides lin-ear acetogenins Z- (138)and E-adrienyne (139).The structural elucidationwas obtainedby theauthorsusing HECADE experi-ment.Asecondreportdescribednew12-memberedcyclicethers, marilzabicycloallenes A–D (140–143). The framework of these metabolitesreinforcedthehypothesisthatbiosynthesisof obtusal-lenesoccursthroughelectrophilicbromination(Gutiérrez-Cepeda etal.,2011b).
Osmundeapinnatifida(asLaurenciapinnatifida)
AccordingtotheAlgaebase,thecurrentacceptednameforL. pinnatifidaisOsmundeapinnatifida(Hudson)Stackhouse(Guiryand Guiry,2015).Thisspecieswasreportedunderitspreviousnamein allcontinents,notablyinthecountriesofEurope(GuiryandGuiry, 2015).Inadditiontolinearacetogenins(144–151)(Gonzálezetal., 1982;Norteetal.,1991),someacetogeninsbelongingtothe eight-memberedetherringsclasswereisolatedfromalgaecollectedon theIslandofTenerife(CanaryIslands),astheisomerscis-(152)and trans-pinnatifidenyne(45)(Gonzálezetal.,1982;Norteetal.,1991) and trans- (153) and cis-dihydrorhodophytin (56)(Norte et al., 1989a),aswellasstructureswithanine-memberedetherring(154 and155)(Norteetal.,1991).Theabsoluteconfigurationsof152 and45havebeenreassignedonthebasisofX-rayanalysis(Norte etal.,1991),and45wasisolatedalsofromAplysiadactylomela col-lectedintheSouthChinaSea(Manzoetal.,2005).Pinnatifidine (156)hasbeenisolatedfromsamplecollectednearKarachi,and representsthefirstdiacetylateddibromobelongingtothe eight-membered ether ring class (Atta-ur-Rahman,1989).Metabolite cis-dihydrorhodophytin(56)presentedantifeedantactivity(Kinnel etal.,1979)andsignificantantibacterialactivityagainstthetested foodpathogens(VairappanandTan,2009).Recently,thetotal syn-thesisof 152 (Kim et al., 2003)and 56 (Kim et al.,2011) was performed.
Yuzuruapoiteaui(asLaurenciapoitei)
Otherspecies
InvestigationsonLaurenciasp.cf.L.graciliscollectedinNew Zealandwatersallowedtheisolationofthefirstexamplesfrom LaurenciaspeciesofnonhalogenatedC15acetogenins(158and159)
belongingto theeight-memberedcyclic ether class(König and Wright,1994).Therelatedchlorine-containingmetabolite160was alsoreported(KönigandWright,1994).Noreportunderthisname wasfoundintheAlgaebase(GuiryandGuiry,2015).
AsampleofLaurenciasp.fromPhilippineswasreportedto con-tainthreediasteromericpairsofcyclicetheracetogeninsnamed laurefurenynesA–F(161–166).Thestructureswereassignedonthe basisofextensive1Dand2DNMRexperiments,NOESYand molec-ularmodelling.Thematerialwasprovidedthroughcollaboration withtheAmericanNCI(NationalCancerInstitute);laurefurenynes C(163)andF(166)weremoderatelycytotoxicagainstsolidtumors
andleukaemiaL1210cells,butnon-selective(Abdel-Mageedetal., 2010).Accordingtotheauthors,itwasthefirstreportof cytotox-icityforvinylacetylenicacetogenins.Nevertheless,structuresof laurefurenynesA(161)andB(162)wererevisedafternew evi-dencesbased onDFTcalculationsandtotal synthesis(Shepherd etal.,2013;HolmesandBritton,2013).
Acetogeninsofseahare
Theseahares,opistobranch mollusksbelongingtotheorder Aplysiomorpha,aresoft-bodiedandslow-movingbenthicmarine animals.Theyarestrictlyherbivorous,usuallyfeedingona vari-etyofmarinealgae,andwithwidedistributioninbothtemperate andtropicalwaters(Manzoetal.,2005;Ioannouetal.,2009).These molluskshavebeenproventoactassourceofbioactivecompounds thatareoftenconsideredtobeofdietaryorigin.Theaccumulation ofsecondarymetabolitesmayplayaroleasadefensemechanism againstpredators,andthischemicalrelationshipbetweenseahares andalgaehasbeentheobjectofinterestamongscientists(Manzo etal.,2005;Ioannouetal.,2009;PalanivelooandVairappan,2014). SpeciesbelongingtothefamilyAplysiidae,includingthegenera Aplysia,havebeenstudied,resultingintheidentificationofalarge numberofdietarymetabolites,typicallyalgalhalogenated com-pounds(Bluntetal.,2015andpreviousreportsofthisseries).
Aplysiaspp.areusuallygrazingspeciesoftheLaurencia com-plex,thereforeawiderangeofhalogenatedmetaboliteshavebeen isolatedfromthismollusk.Differentspeciescollectedfromvarious locationshaveaffordednewandknownhalogenatedcompounds, mainlyterpenesandacetogenins(Ioannouetal.,2009),thelatter beingthefocusofthisreview.
Fromspecimens of A. dactylomelacollectedin the Bahamas, twoacetogeninsofthenine-memberedcyclicetherclass,3-Z-and 3-E-12-epi-obtusenyne(170and 171)have been isolatedalong with3-Z-and3-E-dactomelyne(172and173)(Gopichandetal., 1981).Thetrans-isomer(173)hasbeenfoundasametaboliteofL. obtusacollectedinTurkey(Aydo˘gmus¸etal.,2004).Investigation ofanothercollection,alsointheBahamas,affordedacetogeninsof thehydropyransubclass:3-Z-dactylyneand3-E-isodactylyne(174 and175)(McDonaldetal.,1975;VanderahandSchmitz,1976); 3-Z-dactylynehasalsobeenisolatedfromaLaurenciaspeciesfrom Japan(Suzukietal.,1999)andhaspresentedpronounced activ-ityinincreasingbloodlevelsofpentobarbitalinadose-dependent manner.Itincreasedboththehalf-lifeandthedurationofaction ofthedrug,possiblyduetotheinhibitionofmetabolic elimina-tionofpentobarbitalcausedby3-Z-dactylyneitself,orperhapsby ametabolite(KaulandKulkarni,1978).
FromspecimensofA.dactylomelacollectedinHainanIsland,in theChinaSea,othernine-memberedcyclicetherswerereported, suchas3-Z-and3-E-6R,7R-obtusenyne(176and177)(Manzoetal., 2005).Isomersofpinnatifidenyne(152,153and178), represent-ativesofeight-memberedcyclicetheracetogenins,wereisolated fromA.dactylomela(Manzoetal.,2005;PalanivelooandVairappan, 2014)andalsofromthealgaeOsmundeapinnatifida(asL. pinnat-ifida)(Gonzálezetal.,1982)andL.claviformis(Norteetal.,1991). Someof the isomerswere tested as feeding-deterrents against goldfishCarassiusauratus,178presentingactivity,aswellas3-Z -laurenyne(44),thelastonebeingalsotoxictowardsbrineshrimp, butinactivewhentestedforantibacterialactivityagainstmarine bacteria(Manzoetal.,2005;Takahashietal.,2002).Theacetogenin 44hasbeenreportedforA.dactylomela(Manzoetal.,2005)andfor thealgaL.yanoguniensisfoundinJapan(Takahashietal.,2002).The latterwaspresentedasanewspeciesofLaurencia,butnoreportwas foundunderthisnameattheAlgaebase(GuiryandGuiry,2015).
Palaniveloo and Vairappan (2014) collected samples of A. dactylomelafromdifferentislandsof Malaysia,and isolated 12-Z-lembyneA(167),whichwasalsoreportedforanon-identified Laurenciasp.fromMalaysia(Vairappanetal.,2001a)and 12-E -lembyneA(179)whichwasalsoisolatedfromL.mariannensisfrom Japan(Vairappanetal.,2001b).Bothpresentedprominent antibac-terialactivityagainstmarinebacteria(Vairappanetal.,2001a,b). Dactylallene(180)wasfirstreportedforA.dactylomelafromthe CanaryIslands;thiscompoundhasnotbeenfoundinalgae,but itsdiastereoisomerobtusalleneII(47)haspreviouslybeenisolated
fromL.obtusa(Ciavattaetal.,1997).AnothercompoundfoundinA. dactylomelaiscis-maneoneneC(8)(Sakaietal.,1986),ametabolite firstreportedforL.nidifica(Waraszkiewiczetal.,1978).
Ioannouetal.(2009)investigatedthechemicalprofileofthe speciesA.fasciata,collectedinAlfacsBay,Catalonia,Spain.Two linearacetogenins(182)and(144)wereidentified;thefirstoneis anewnaturalproductandthelatterwaspreviouslyreportedfor L.pinnatifidafromtheCanaryIslands(Gonzálezetal.,1982;Norte etal.,1991).Ioannouetal.(2009)alsoidentifiedthreeacetogenins oftheeight-memberedcyclicetherclass:3-Z-venustinene(136), previouslyisolatedfromL.venusta(Suzukietal.,1983a);3-Z -13-epi-pinnatifidenyne(182),previouslymentionedforA.dactylomela, and3-E-laurenyne(44),alsoisolatedfromL.obtusa(Öztunc¸etal., 1991a).
Aplysia brasiliana is considered a synonym for A.
fasci-ata (accepted name according to the database WoRMS). Four acetogenins were reported for the species described as A.
brasiliana collected in the Gulf of Florida, USA. Two of them
are the diastereoisomers cis-dihydrorhodophytin (56) and cis -isodihydrorhodophytin(183)(Kinneletal.,1979).Acetogenin56 hasalreadybeenidentifiedassecondarymetaboliteofsome Lau-renciaspecies(Brennanand Erickson,1982;Norte etal.,1989a; VairappanandTan,2009),andhasshownantifeedantproperties inbioassayswithswordtailfish(Xiphophorushelleri)(Kinneletal., 1977)andsignificantantibacterialactivityagainstfoodpathogens, besides Vibrio cholerae, Staphylococcus aureus, Escherichia coli, Salmonellaenteritidis,S.typhiandS.thyphimurium(Vairappanand Tan,2009).Metabolite183hasalsobeenisolatedfromL.obtusa (Imreetal.,1981).Anothertwometaboliteswereisolatedfrom materialidentifiedasA.brasiliana:brasilenyne(184)(Kinneletal., 1979)andpanacene(185)(Kinneletal.,1977),whosecomplete structural elucidation was started by Feldman (1982) withthe assignmentofrelativestereochemistryofthebromoalleneportion achievedbyBoukouvalasetal.(2006),whenthefirstpathwaysfor anasymmetrictotalsynthesiswereestablished.Brasilenyne(184) isanine-memberedcyclicetherandpresentedantifeedantactivity inabioassaywithswordtailfish(Kinneletal.,1979).
Otherspecies of Aplysiapresented acetogeninsas secondary metabolites.InvestigationofspecimensofA.oculiferafoundinSri LankaandOahuIsland,Hawaiiledtotheisolationofthree ace-togenins,srilankenyne(186), Z-andE-ocellenyne(187and188) (Schulteetal.,1981;Silvaetal.,1983).FromA.parvulaitwas pos-sibletoidentifyanewacetogenin,aplyparvunin(189),acompound that presentsichthyotoxicactivity,withLC100 of 3ppm in24h
(Myiamotoetal.,1995).Themetabolite3-Z-bromofucin(63)was alsoreportedforA.parvula(McPhailandDavies-Coleman,2005) andpreviouslyforL.intricata(asL.implicata)(CollandWright,1989 apudWangetal.,2013).ForthespeciesA.kurodaifromthecoastof Fukui,Japan,anewbromoallenewithpromisingactivityasNa, K-ATPaseinhibitorhasbeenreportedandnamedasaplysiallene(190) (Okamotoetal.,2001).ItsstructurehasbeenreviewedbyOkamoto etal.(2003),andwasfoundtobethesameasabromoalleneisolated fromL.okamurae(SuzukiandKurosawa,1985).In2007,Wangand Pagenkopfachievedthetotalsynthesisofaplysiallene,thereforeits stereochemistrycouldbeunambiguouslyreassigned.
Chemotaxonomy
identifiedasL.glandulifera,butwas,infact,L.nipponica,according toSuzukietal.(2009).Therefore,halogenatedsecondary metabo-litesmaybeausefultaxonomictoolatthespecieslevel,afterthe investigationofthenaturalvariabilityfactors(Stengeletal.,2011). Fujiietal.(2011)reviewedthetaxonomyandthemajor metabo-litesoftheLaurenciacomplexfromBrazil,andnoacetogeninwas reportedforthespecies citedin thereview,but thosemustbe consideredpreliminarydata.
TheconfirmationofdifferentracesforL.nipponicacouldexplain the extreme high chemical diversity observed for this species withinthesamegeographicalarea.
ThechemicaldifferencesbetweenL.okamuraeandL.composita haveproventobeusefulasanaidtotheidentificationofthese species.Thesetwo speciesareconsidereddifficultto differenti-atebasedontheirmorphologicalfeaturesalone;however,itwas observedthatthelatterisnotabletosynthesizeoxygenatedand halogenatedacetogenins(possiblyduetothelackoftheenzyme activitynecessaryforoxygenating/halogenatingenynes),whileL. okamuraeaffordedseveralcomplexacetogenins(Jietal.,2009).
Investigationsperformedinthelast5 yearswiththespecies L. chondrioides and Laurenciella marilzae suggest that the co-occurrenceofenynesandbromoallenesmightbemorecommon thanwasfirstthought,thereforethetypeoflinearorcyclic struc-turemaybemorerelevantinachemotaxonomicalapproachthan thetype ofterminus. Nevertheless, it is noteworthy that com-poundswithbromoparglycterminushavebeenreportedsofarjust forLaurenciaobtusa.
Biologicalactivities
MetabolitesisolatedfromalgaebelongingtotheLaurencia com-plexhaveexhibitedmarkedantibacterial,insecticidal,antifungal, andantiviralactivity,buttheactivityofterpenesismorewidely investigated than that of acetogenins. Sea hares of the genus Aplysia(Anaspidea,Aplysiidae) areknowntopreyonLaurencia,
andsequesterhalogenatedsecondarymetabolitesfromtheirdiet (Kladietal.,2014).Curiously,manyofthemwerefirstreported forseahare,andsomelaterfoundinalgae.Thismaysuggestthese metabolitesarenotveryefficientasfeeding-deterrentformollusks, butitisnotclearwhethertheyareactiveagainstotherpotential predators.Thenaturalfunctionofmostmarinesecondary metabo-litesremains uninvestigated,butithasbeendemonstratedthat many secondarymetabolites, suchas alkaloids,sterolsand ter-penes,amongothermetabolites,canplayaroleinthedefenses againstconsumers,competitors,foulingorganisms,etc.(Hay,1996; Maia et al., 1999; Coutinho et al., 2002; Epifanio et al., 2006). It mustbeestablishedwhetheracetogeninsareincludedornot among thesechemical defensesforthealgae,but theyseem to beforAplysiaspp(Kinneletal.,1977,1979;VairappanandTan, 2009).
Inageneralway,thebiologicalactivitieswereassayedjustfora fewcompounds,probablyduetotherelativelylowamounts usu-allyisolatedinthestudiesreportedhere.Laurencin,laureatinand isolaureatinwereexceptions,but inthesecases,theamountof algalmaterial usedasthebasis for theinvestigationswasover 10kgofdriedalgae(Irieetal.,1965,1970),consideringthatthe available structure elucidation methods atthat time consumed uptograms ofisolatedcompounds.Anotherpointis thatsome acetogenins, such as elatenyne, are unstable (Dias and Urban, 2011).
Species Compounds Biological activities
Chondrophycus glandulifer = L. glandulifera
133-36 Prolongs sleep-time by pentobarbitone (Kaul et al., 2011)
Antistaphylococcal (MRSA) (Kladi et el., 2008)
L. elata 55, also isolated from
L. pannosa
Antibacterial activity against C. violaceum (Suzuki et al., 2001) but no appreciable antitumour activity (Dias et al., 2011)
L. obtusa 100 Antibacterial activity against Bacillus subtilisand E. coli (Caccamese et al., 1980)
L. obtusa 114 and 115 Apoptosis inhibition of blood neutrophils (Ayyad et al., 2011)
L.nipponica 2 and 3
3 and 4
Insecticidal against mosquito larvae (Watanabe et al., 1989) Prolongs sleep-time by pentobarbitone (Kaulet al., 2011)
Laurencia sp 168 Antibacterial activity against C. violaceum, Clostridium cellobioparumand Vibrio parahaemolyticus (Vairappan et al.,
2001a).
Laurencia sp 163and 166 Cytotoxic against solid tumours and leukaemia L1210 cells (Abd el-Mageed et al., 2010)
Osmundea pinnatifida = L.
pinnatifida
56 Antibacterial activity against food pathogens (Kinnel et al., 1979); antifeedant activity (Vairappan and Tan, 2009)
Chart1. ReportedbiologicalactivitiesofacetogeninsisolatedfromalgaebelongingtotheLaurenciacomplex.
Species of
Aplysia Compounds Biological activities
A. dactylomela 174 also isolated from
Laurencia (Suzuki et al., 1999)
Activity in increasing blood levels of pentobarbital in a dose-dependent(Kaul and Kulkarni, 1978)
A. dactylomela 178 and 45 Antifeedant against Carassius auratus (Manzo et al., 2005); toxicity to brine shrimp but inactive against marine
bacteria (Takahashi et al., 2002)
A. dactylomela 167and 179, also isolated from Laurencia
sp (Vairappan et al., 2001)
Antibacterial activity against marine bacteria (Vairappan et al, 2001a,b)
A. fasciata =A. brasiliana
56, also isolated from
Laurencia sp(Brennan and Erickson, 1982;
Norte et al., 1989; Vairappan and Tan,
2009)
Antifeedant against Xiphophorus helleri(Kinnel et al., 1977); antibacterial activity against Salmonella enteritidis,
Vibrio cholerae,Staphylococcus aureus,E. coli, S. typhi
and S. thyphimurium (Vairappan and Tan, 2009)
A. fasciata= A. brasiliana
184 Antifeedant activity (Kinnel et al., 1979)
A. kurodai 190 Inhibitor Na, K-ATPase (Okamoto et al., 2001)
A. parvula 189 Ichthyotoxic activity (Myiamoto et al., 1995)
Chart2.Reportedbiologicalactivitiesofacetogeninsisolatedprimarilyfromseahare.
Conclusionandperspectives
After50yearsofresearchontheLaurenciacomplex,hundredsof metaboliteshavebeenisolated,mainlyterpenesandacetogenins andmanymoreareexpectedtobefoundinanearfuture,since thenewdereplicationapproaches thatarebeingusedpresently areabletodetectunknowncompoundseven inlow concentra-tions.Ourpoorknowledgeabouttaxonomicalaspectsmightbea
Authors’contributions
Allauthorscontributedincollectingandanalyzingdatabesides draftingpartsofthepaper.TW(PhDstudent),ACP(Master stu-dent),GAZ(MSc),LFOV(Undergraduatestudent)andCL(postdoc fellowship)contributedalsodrawingthestructures.MF (Profes-sor)organizedthedataandcontributedtocriticalreadingofthe manuscript.Alltheauthorshave read thefinal manuscript and approvedthesubmission.
Conflictsofinterest
Theauthorsdeclarenoconflictsofinterest.
Acknowledgments
TheauthorsthankCoordenac¸ãodeAperfeic¸oamentodePessoal de NívelSuperior (Capes, Brazil) (TW, ACPand GAZ)and Con-selhoNacionaldeDesenvolvimentoCientíficoeTecnológico(CNPq, Brazil) (LFOV and CL) for their fellowships. The authors thank ManuelaBatista(CCB,UFSC)forthepictureusedinthegraphical abstract.
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