Recent Advances in the Isolation, Synthesis and Biological Activity of Marine Guanidine Alkaloids

19 Pages·2017·2.71 MB·English

marine drugs
Review
Recent Advances in the Isolation, Synthesis and
Biological Activity of Marine Guanidine Alkaloids
JinLiu1,2 ID,Xu-WenLi1,* ID andYue-WeiGuo1,* ID
1 StateKeyLaboratoryofDrugResearch,ShanghaiInstituteofMateriaMedica,ChineseAcademyofSciences,
555ZuChongZhiRoad,ZhangjiangHi-TechPark,Shanghai201203,China;[email protected]
2 NanoScienceandTechnologyInstitute,UniversityofScienceandTechnologyofChina,166RenAiRoad,
Suzhou215123,China
* Correspondence:[email protected](X.-W.L.);[email protected](Y.-W.G.);
Tel.:[phone](X.-W.L.&Y.-W.G.)
Received:8September2017;Accepted:16October2017;Published:24October2017
Abstract: Marineorganismsareprolificresourcesofguanidine-containingnaturalproductswith
intriguingstructuresandpromisingbiologicalactivities. Thesemoleculeshavethereforeattractedthe
attentionofchemistsandbiologistsfortheirfurtherstudiestowardspotentialdrugleads. Thisreview
focusedontheguanidinealkaloidsderivedfrommarinesourcesanddiscussedtherecentprogress
ontheirisolation,synthesisandbiologicalactivities,coveringtheliteraturefromtheyear2010to
thepresent.
Keywords: marineguanidinealkaloids;sponge;mollusk;ascidian;totalsynthesis;biologicalactivity
1. Introduction
The marine environment has been regarded as one of the most complex biospheres on earth
duetoitshugerangesoflight(completedarknesstoextensivebrightness),temperature(−2◦Cto
over 300 ◦C), pressure (1 to more than 1000 atmospheres), nutrient conditions (sparse to rich), etc.
Such circumstances enable the existence of numerous species to produce extremely diverse and
complex secondary metabolites with a wide range of significant biological activities [1]. Over the
pastfewdecades,atleastninemarinenaturalproduct(MNP)-deriveddrugshavebeensuccessfully
developed,ofwhichsevenarenitrogenouscompounds[2]. Therefore,althoughtheyhaveonlybeen
studiedforoverhalfacentury,MNPshavealreadyshowngreatpotentialinnewdrugdiscovery.
Guanidineisconsideredtobeoneofthestrongestorganicbases(pK =13.6)[3]. Suchabasic
a
propertyenablesthismoleculetobindtocarboxylates,phosphatesandmetals. Itsguanidiniumcation
canengageinthespecialinteractionsbetweenligand/receptororenzyme/substrate[4]. Therefore,
theguanidinegroupisofgreatinterestinmedicinalchemistryandhasbecomeakeymotifinmany
clinicaldrugssuchasthefamousanti-diabeticdrugdimethyldiguanide(1)andthepepticulcerdrug
cimetidine(2)(Figure1). Guanidinederivativesarewidelydistributedinnatureandhaveattracted
a lot of attention due to their chemical diversity and broad biological activities. Due to this fact,
several groups have summarized the chemical and biological characteristics of natural guanidine
productswithdifferentemphasesandscopes. Forinstance,Chenandco-workerspublishedareview
paper in Tetrahedron in 2015, which mainly discussed the synthesis of cyclic guanidine-containing
naturalproducts[5]. NetzandOpatzpublishedageneralreviewofmarineindolealkaloidsfrom
2003to2015,inwhichsomeguanidinecompoundswerealsoincluded[6]. Berlinckandco-workers
havebeencontinuouslyreviewingthechemistryandbiologyofnaturalguanidineproductsinthe
journalNat. Prod. Rep. since1996,andthemostrecentonein2016[7]summarizedsomeisolation
andsynthesisofmarineguanidinecompoundsfrom2012to2014,includingguanidinepeptidesand
alkaloids. Inthisreview, peptideswillnotbediscussed, whiletherecent(2010–2017)advancesin
Mar.Drugs2017,15,324;doi:10.3390/md15100324 www.mdpi.com/journal/marinedrugs
Mar. Drugs 2017, 15, 324 2 of 19
Mar.Drugs2017,15,324 2of19
synthesis of marine guanidine compounds from 2012 to 2014, including guanidine peptides and
alkaloids. In this review, peptides will not be discussed, while the recent (2010–2017) advances in
gguuaanniiddiinnee aallkkaallooiiddss ffrroomm mmaarriinnee ssoouurrcceess wwiillll bbee ssppeecciifificcaallllyy ffooccuusseedd oonn,, aaiimmiinngg ttoo pprroovviiddee iinnssiigghhtt
iinnttoo tthhee ffuurrtthheerr ddiissccoovveerryy aanndd pprreeppaarraattiioonn ((ee..gg..,, ssyynntthheessiiss)) ooff iinntteerreessttiinngg bbiiooaaccttiivvee mmaarriinnee gguuaanniiddiinnee
ccoommppoouunnddss ffoorr ffuuttuurree mmeeddiicciinnaall aapppplliiccaattiioonnss..

Figure 1. Structures of the represented guanidine compounds containing drugs or toxins.
Figure1.Structuresoftherepresentedguanidinecompoundscontainingdrugsortoxins.
Marine organisms are the richest sources of natural products that have guanidine functionality,
Marineorganismsaretherichestsourcesofnaturalproductsthathaveguanidinefunctionality,
which is probably due to their special living environments. Many well-known toxins with guanidine
whichisprobablyduetotheirspeciallivingenvironments. Manywell-knowntoxinswithguanidine
groups have been found in marine resources, such as tetrodotoxin (TTX, 3) from tetraodontidae (puffer
groupshavebeenfoundinmarineresources,suchastetrodotoxin(TTX,3)fromtetraodontidae(puffer
fishes) [8], saxitoxin (STX, 4) from shellfish [9], and neosaxitoxin (NSTX, 5) from algae (Figure 1) [10].
fishes)[8],saxitoxin(STX,4)fromshellfish[9],andneosaxitoxin(NSTX,5)fromalgae(Figure1)[10].
These toxic marine natural products have high medical research value. In recent years, the impressive
Thesetoxicmarinenaturalproductshavehighmedicalresearchvalue. Inrecentyears,theimpressive
diversity and complexity of cyclic and/or linear guanidine MNPs were observed as PKS (polyketide
diversityandcomplexityofcyclicand/orlinearguanidineMNPswereobservedasPKS(polyketide
synthase) and/or NRPS (nonribosomal peptide synthetase) derivatives, terpene and/or peptide
synthase) and/or NRPS (nonribosomal peptide synthetase) derivatives, terpene and/or peptide
conjugates, etc. [7,11]. These metabolites were mainly derived from various beautiful marine sponges,
conjugates,etc.[7,11]. Thesemetabolitesweremainlyderivedfromvariousbeautifulmarinesponges,
mollusks, and ascidians in different locations. This review will summarize the recent progress on the
mollusks,andascidiansindifferentlocations. Thisreviewwillsummarizetherecentprogressonthe
isolation, synthesis and biological activities of marine guanidine alkaloids (MGAs) according to their
isolation,synthesisandbiologicalactivitiesofmarineguanidinealkaloids(MGAs)accordingtotheir
different origins.
differentorigins.
2. MGAs from Sponges
2. MGAsfromSponges
Although many reports of guanidine alkaloids from marine algae, mollusks, microorganisms,
Althoughmanyreportsofguanidinealkaloidsfrommarinealgae,mollusks,microorganisms,etc.,
etc., the richest sources of such molecules are marine sponges. To the best of our knowledge, during
therichestsourcesofsuchmoleculesaremarinesponges. Tothebestofourknowledge,duringthe
the last 7 years, over 90% MGAs were discovered in sponges, such as those of the genera Monanchora,
last7years,over90%MGAswerediscoveredinsponges,suchasthoseofthegeneraMonanchora,
Crambe, Clathira, Acanthella, Halichondria, etc. Among these, Monanchora was the most popular genus
Crambe,Clathira,Acanthella,Halichondria,etc. Amongthese,Monanchorawasthemostpopulargenusto
to have been chemically investigated, with diverse and complex cyclic or linear MGAs being isolated
havebeenchemicallyinvestigated,withdiverseandcomplexcyclicorlinearMGAsbeingisolated
and determined. Accordingly, this section will be described based on the MGAs from different
anddetermined. Accordingly,thissectionwillbedescribedbasedontheMGAsfromdifferentsponge
sponge genera [7,11].
genera[7,11].
2.1. Monanchora
2.1. Monanchora
Monanchora, of the order Poecilosclerida and the family Crambeidae, is one of the richest sources of
Monanchora, of the order Poecilosclerida and the family Crambeidae, is one of the
MGAs, especially complex polycyclic guanidines, such as crambescidins, ptilomycalins, fromiamycalins,
richest sources of MGAs, especially complex polycyclic guanidines, such as crambescidins,
celeromycalins, batzelladines, monanchomycalins, monanchocidins, normonanchocidins, neofolitispates,
ptilomycalins,fromiamycalins,celeromycalins,batzelladines,monanchomycalins,monanchocidins,
etc. Most of the recently reported MGAs were derived from this genus, with a wide range of biological
normonanchocidins, neofolitispates, etc. Most of the recently reported MGAs were derived from
activities such as cytotoxic, antimicrobial, antimalarial, and anti-HIV properties [12].
Mar.Drugs2017,15,324 3of19
thisgenus, withawiderangeofbiologicalactivitiessuchascytotoxic, antimicrobial, antimalarial,
andanti-HIVproperties[12].
PentacyclicMGAsareoneofthemostcomplexmarineguanidine-containingnaturalproducts
that have intriguing structures (Figure 2). Monanchocidin (6) is a novel pentacyclic guanidine
derivative that was isolated by Makarieva and co-workers in 2010 from the sponge M. pulchra,
collected near Urup Island at a depth of 66 m [13]. In fact, the novelty of this molecule is the
presenceofanunprecedentedbis-spiro-pentacyclicguanidineringsystem(includingtwocontiguous
1-oxa-6-azaspiro[4,5]decane and 1-oxa-7-azaspiro[5,5]undecane spiro-ring systems), a long chain
moiety derived from a polyketide precursor (ω-3)-hydroxy fatty acid, and a 2-aminoethyl- and
3-aminopropyl- substituted morpholine hemiketal ring. Thus, monanchocidin is believed to be
a PKS-derived MGA. Biological evaluation revealed that 6 exhibited cytotoxicity against human
leukemia THP-1, human cervix epithelioid carcinoma HeLa, and mouse epidermal JB6 Cl41 cell
lines, with IC values of 5.1, 11.8, and 12.3 µM, respectively. This derivative also showed 66%
50
apoptosis-inducingeffectinTHP-1cellsataconcentrationof3.0µM.Inthefollowingyear,thesame
author discovered a series of monanchocidin analogs from the same species collected in the same
location,including6[14]. Inordertoavoidfutureconfusion,theyre-designated“monanchocidin”
as“monanchocidinA”. ThefournewisolateswerenamedmonanchocidinsB–E(7–10). Amongthe
fivecompounds,6,9,and10sharedthemostsimilarstructures,withtheonlydifferencebeingthe
lengthofthelinkedchain(14for6and9,13for10)betweenthepentacyclicguanidineringandthe
morpholine hemiketal ring or the loss of an ethyl group on C-23 position for 9. Monanchocidins
B and C (7 and 8) differed from 6 by the replacement of 1-oxa-6-azaspiro[4,5]decane in 6 with
an 1-oxa-8-azaspiro[6,5]dodecane in 7 and 8 in the bis-spiro-pentacyclic ring system. In fact,
thepentacyclicringsystemof7and10wasthecrambescidinskeleton. AllfiveMGAs6–10displayed
strongcytotoxicityagainsthumanpromyelocyticleukemiaHL-60cellswithIC valuesof540,200,110,
50
830,and650nM,respectively.Intriguingly,forthestructuresofthisseriesofcompounds,Kashman[15]
pointedoutthatthebis-spiro-polycyclicalkaloidslooklikeavessel,andMakarievareferredtothe
morpholinehemiketalringofcompounds6–10asananchor;thus,thelonghydrocarbonchaincould
actasananchoragecabletolinkbothvesselandanchor.
In2012,twonewmonanchocidinanalogs,monanchomycalinsA(11)andB(12)fromthedeepsea
spongeM.pulchrawereisolatedbyMakarieva’sgroupnearUrupIslandatadepthofapproximately
150m[16]. TheirstructuresdifferedfromthatofmonanchocidinAmainlybythevariationofthe
“anchor”moiety. Infact, a spermidineresidueacted asthe anchorin thesecompounds insteadof
themorpholinehemiketalringinmonanchocidins. MonanchomycalinsA(11)andB(12)exhibited
stronger cytotoxicity than the previous analogs, with IC values of 120 and 140 nM, respectively,
50
against HL-60 cells. Monanchomycalin C (13), an analog of the above two MGAs, was isolated
by the same group from the same species in the sea near Kunashir Island in 2013 at a depth of
114m[17]. ItwasfoundtobecytotoxicagainsthumanbreastcancerMDA-MB-231cellswithanIC
50
valueof8.2µM.Mostrecently,in2016,Aliandco-workersisolatedthreecrambescidinderivatives,
i.e., crambescidin 786 (14), crambescidin 814 (15), and norcrambescidic acid (16), from a French
PolynesianMonanchoran. sp. spongecollectedoffthecoastofHivaOaata20-mdepth[18]. Allthree
compounds exhibited significant cytotoxic activities against KB tumor cell lines (a subline of the
ubiquitous KERATIN-forming tumor cell line HeLa), with IC values of 0.3, 0.005, and 0.5 µM,
50
respectively. In 2017, Gauvin-Bialecki and co-workers discovered four ptilomycalin derivatives,
i.e.,ptilomycalinsE–H(17–20),fromthespongeM.unguiculatecollectedat2–6minMitsioIslands,
Madagascar[19]. Structurally,allthesecompoundscomprisethecyclicguanidinegroupaswellasone
ortwoacyclicguanidinegroupsasthe“anchor”moiety. Itisworthmentioningthatisomers19and
20wereobtainedasa2:1mixture,whichcouldnotbeseparatedbutcouldbestructurallyidentified
bytheauthors. Biologically,17andthemixtureof19/20showedstrongcytotoxicityagainstKBcell
lineswithIC valuesof0.85and0.92µM,respectively,while18displayedpromisingactivityagainst
50
PlasmodiumfalciparumwithanIC valueof0.23µM.
50
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Mar. Drugs 2017, 15, 324 4 of 19

Figure 2. Structures of pentacyclic MGAs (6–20) from sponges of the genus Monanchora.
Figure2.StructuresofpentacyclicMGAs(6–20)fromspongesofthegenusMonanchora.
The chemical diversity and complexity of the genus Monanchora was not only exemplified by
mTohneancchheomciidcianl-ldikiev epresnittyacyacnldic cMoGmApsl,e bxuitty aolsfo tthriecygcelinc uosneMs osnuachn cahso rbaatwzeallsadnionteso, nbliycyeclxice monpelsi fied
by msuocnha ansc uhropcoicdiidnin-lsi,k aenpd eanctyaccliycc olincesM suGcAh sa,s bpuutlcahlrsaonintr iAcy. Tclhiec monosets frseuqcuhenatslyb daitszceolvleardeidn etrsi,cybcilcicy clic
onesMsGuAchs awseruer pmoicraidbiilnins, aannadlogasc,y wclihcicohn ceosmspurcihse aas [p6u,6l,c5h]-rsaynn-ifnusAed. Ttrhiecymcliocs rtinfrge qsyusetnemtly wdiitshc othvee red
tricygculiacniMdiGneA gsrowuper ien mthier acebniltienr [a2n0]a.l Iong fsa,cwt, shuicchh ac otrmicypcrliisce staru[c6t,u6r,a5l] -sskyenle-tfouns eladckteridc yocnlliyc trwinog spsiyros tem
ether rings compared with that of pentacyclic MGAs, and thus these tricyclic MGAs were considered
withtheguanidinegroupinthecenter[20]. Infact,suchatricyclicstructuralskeletonlackedonly
to be the precursor of the related pentacyclic ones (Figure 3). In 2011, by using a bioassay-guided
two spiro ether rings compared with that of pentacyclic MGAs, and thus these tricyclic MGAs
approach, Costa-Lotufo and co-workers isolated five known tricyclic MGAs, i.e., mirabilin B (21),
were considered to be the precursor of the related pentacyclic ones (Figure 3). In 2011, by using
8bβ-hydroxyptilocaulin (22), ptilocaulin (23), and a mixture of the 8β- and 8α-epimers of 8-
a bioassay-guided approach, Costa-Lotufo and co-workers isolated five known tricyclic MGAs,
hydroxymirabilin B (24 and 25), from M. arbuscula colonies collected off the coast of Ceará State,
i.e., mirabilin B (21), 8bβ-hydroxyptilocaulin (22), ptilocaulin (23), and a mixture of the 8β- and
Brazil, at a depth of 18 m [21]. The authors focused on the biological investigation of the isolates. In
8α-etphiem cyertostooxfi8c- ahsysdayro oxfy amll ifriavbe iclionmBpo(2u4ndans dag2a5in),sft rfoomur Mdi.ffaerrbeunstc tuulmaocor lcoenllise [sHcLo-l6le0c, tHedCTo-f8f t(hhuemcoaans tof
CearcáolSotna tcea,nBcrear zciel,lla),t MaDdeAp-tMhBo-f43158 (mhu[m21a]n. Tbhreeasatu ctahnocresr fcoeclul)s, eSdF-o2n95t h(heubmioalno gXiGca lmianlvigensatingta gtiloionmoaf the
isolacteelsl).] Inantdh eocnyet ontoorxmicala shsuamyaonf aplelrfiipvheecraolm bploooudn dmsoangoaniuncslteafor ucreldl i(fPfeBrMenCt)t,u 2m2 oerxhceiblliste[dH aLc-t6iv0i,tHiesC T-8
(humagaanincsot loHnL-c6a0n, cMerDcAel-lM),BM-4D35A w-MithB -I4C3550 v(haulumesa nofb 7r.e8a9s tancadn 1c1e.r34c eμllM),,S rFe-s2p9e5ct(ihveulmy, awnhXilGe 2m3 awliagsn ant
gliomcyatocteolxl)i]c aangdaionnset nHoLrm-60a,l hHuCmTa-8n, pMerDipAh-eMraBl-4b3lo5 owdimtho nICo5n0 uvcaleluaresc eollf (P5.B7M7, C1)7,.6292, eaxnhdib i7te.5d8 aμctMiv,i ties
agairnesstpeHctLiv-6el0y,. MNeDitAhe-Mr cBo-m43p5ouwndit h22I Cnor vcoamlupeosuonfd7 2.839 shaonwde1d1 c.3y4toµtoMxic,irtye sapgeacitnisvte PlyB,MwCh, ilweh2ic3hw as
50
cytowtoaxrircaangtsa ifnusrtthHerL s-6tu0d,Hy. CInT -f8a,cMt, tDheA a-MuthBo-4rs3 5pewrfitohrmICed av maluecehsaonfis5t.i7c7 s,t1u7d.y69 o,fa tnhde 7c.y5t8otµoMxic, reefsfepcetc otifv ely.
50
Neithercompound22norcompound23showedcytotoxicityagainstPBMC,whichwarrantsfurther

study.Infact,theauthorsperformedamechanisticstudyofthecytotoxiceffectof23onHL-60leukemia
Mar.Drugs2017,15,324 5of19
cells,includingantiproliferativeactivity,morphologicalchanges,andcaspaseactivationusingflow
cytometry. 23wasconfirmedtoinduceapoptosisoftheHL-60cells. Inaddition,compounds22and
Mar. Drugs 2017, 15, 324 5 of 19
23weretestedforhemolyticactivityandshowedmoderateeffectswithEC valuesof577.95and
50
352.9213µ oMn H,rLe-s6p0 elecutikveemlyi.a Bcealtlzs,e ilnlaclduidniensg aarnetiaprsoelirfieersatoivfet raicctyivciltiyc, MmoGrpAhodliomgiecrasl cphoasnsgeesss,i anngdt cwasoptarsiec yclic
ringsayctsitveamtiosnc ousninngec ftloewd bcyytoamloentrgy.e 2s3t ewracsh caoinnfi.rTmheed fitor sintdeuxcaem appolepstoosfiss oufc thhea HskLe-6le0 tcoenllsa. rIen abdadtziteilolna,d ines
A-E,cwomhipcohuwndesr e22d iasncdo v2e3r wederbey tePstaetdil faonr dhecmo-owlyotirck aecrtsiviintya aBnadh sahmowaseds pmoondgeeraBtea tezfeflelcatss pw.iitnh 1E9C9550 [22].
Monavnaclhuoersa osfp o57n7g.9e5s aarnedr i3c5h2i.9n1b μatMze, lrleasdpiencetsiv.eIlny.2 0B1a4tz,eblalatdzeinlleasd ainree aL s(2er6i)esw oafs tirsioclyactleicd MfroGmA Mdi.maerbrsu scula
possessing two tricyclic ring systems connected by a long ester chain. The first examples of such a
andwasfoundtohaveantifungalactivityagainstAspergillusflavusstrainswithminimalinhibitory
skeleton are batzelladines A-E, which were discovered by Patil and co-workers in a Bahamas sponge
concentration (MIC) values ranging from 1.9 to 7.8 µg/mL and minimal fungicide concentrations
Batzella sp. in 1995 [22]. Monanchora sponges are rich in batzelladines. In 2014, batzelladine L (26) was
(MFCs)rangingfrom3.9to15.6µg/mL[23]. Theseresultsindicatedthatbatzelladinesarepotential
isolated from M. arbuscula and was found to have antifungal activity against Aspergillus flavus strains
drugleadsagainstaflatoxigenicfungi. FromthesameMonanchoraspongespeciesbutcollectedoff
with minimal inhibitory concentration (MIC) values ranging from 1.9 to 7.8 μg/mL and minimal
thecofuansgtiocfidCe acbooncFernitor,aBtioranzs i(lM,BFeCrsli)n rcakngainndg cfroo-mw o3r.9k etor s1i5s.o6 lμatge/dmLa t[o23ta].l Tohfeeslee vreesnulbtsic iyncdliiccaatendd thtraitc yclic
MGAbsatazfetlelradHinPeLs Car-eU pVo-tEenLtSiaDl -dMruSg- gleuaiddse adgafirnasctt aioflnaatotxioignenoifci ftusnagni.t iF-rpoamra tshieti scaemxet rMacotn[a2n4ch].orAa mspoonngget hem,
monaslpideciniees Abu(t2 7co)lilsecate[d5, 6o]f-ff uthsee dcobaiscty ocfl iCcaMboG AFr,ioa,r bBuraszciul,l iBdeirnlien(c2k8 a)nrdep croe-swenortksetrhse isfiorlsattetrdi cay ctolitcalM oGf Ato
posseeslsevaebne nbizceyncleicr inangd, atnrdicyhcelimc iMbaGtzAesl laadftienre sHAPL–CC-U(2V9–-E3L1S)Dan-MdSb-gautzidelelda dfirnaectDion(3at2i)ona reoff oiutsr eaxnatim- ples
oftripcyarcaliscitiMc eGxAtralcitn [k2e4d]. Atomaotnegr mthienma,l macoyncalliicdignue aAn i(d27in) eis gar [o5u,6p]-fbuysead lboincgycelisct eMrGcAha, ianrb.uAscllutlihdeinoet hers,
(28) represents the first tricyclic MGA to possess a benzene ring, and hemibatzelladines A–C (29–31)
including batzellamide A (33), batzelladines F (34), L (26), J (35), and nor-batzelladine L (36) are
and batzelladine D (32) are four examples of tricyclic MGA linked to a terminal acyclic guanidine
batzelladine-liketricyclicMGAdimers,ofwhichbatzelladineJ(35)comprisestwotricyclicguanidine
group by a long ester chain. All the others, including batzellamide A (33), batzelladines F (34), L (26),
ring systems plus one terminal guanidine group. It is worth mentioning that the authors have
J (35), and nor-batzelladine L (36) are batzelladine-like tricyclic MGA dimers, of which batzelladine J
accomplishedthetotalsynthesisofmonalidineAtoconfirmitsstructure,whichwillbediscussedinthe
(35) comprises two tricyclic guanidine ring systems plus one terminal guanidine group. It is worth
followmienngtiosencintigo nth.aItn ththe isaurtehsoerasr chhav,teh aeccaoumthpolirssheadls othien tvoetastl isgyantethdesains toi-fl emisohnmaliadniniael ,Aa ntot ic-tornyfpiramn oitsso mal,
and csytrtuocttouxreic, awchtiicvhit iwesillo fbeth deismcuasjsoerdc oinm tphoe ufnodllosw2i6n,g2 7se,c3ti2o,n3. 4I,na nthdis 3r6e.seAarllcht,h ethtee satuetdhocrosm aplsoou nds
showiendvessttrigoantgeda annttii--lleeiisshhmmaanniiaal,l aancttii-vtriytipeasnaogsoaminaslt, aTn.dc rcuyztoitwoxitich aacntivIiCties ovfa tlhuee moafj2or– 6co4mµpMou,nadnsd 2266, was
50
them2o7,s 3t2a,c 3t4iv, aencdo 3m6.p Aolul tnhde t(e2stµeMd c)o.mWpitohunredssp sehcotwteodt hsteroanngt ia-ntrtiy-lpeaisnhomsaonmiaal laactcitviiotinesa aggaaiinnsstt TL.. cirnufzain tum,
batzewllaitdhi anne IFC(503 v4a)lduies opfl a2y–6e4d μaMn,a acntidv 2e6I Cwas othfe4 mµoMst, awcthivilee caolmloptohuenrds p(2e μrfMor)m. Wedithb reetstpere,cwt tiot hthIeC antiv-alues
50 50
of 2 µtrMyp.aWnoistohmraels apcetciotnt oagcayintostt oLx. iicniftayntaugma, ibnasttzeLllLaCdi-nMe KF 2(34c)e ldlissp(Glaaynedg easn Racitviveer ImC5o0 nokf e4y μkMid, wnehyilec ells),
onlya3l4l oetxhherisb ipteerdfomrmoedde braettteera, cwtiivthit IyCw50 vitahluaens oIfC 2 μMva. lWueitho fre1s0peµcMt to, aclyltoottohxeicristyp aogsasienssste LdLCIC-MKv2a lues
cells (Ganges River monkey kidney cells), only 3504 exhibited moderate activity with an IC50 valu5e0 of
higherthan20µM.
10 μM, all others possessed IC50 values higher than 20 μM.

Figure 3. Structures of tricyclic MGAs (21–36) from sponges of the genus Monanchora.
Figure3.StructuresoftricyclicMGAs(21–36)fromspongesofthegenusMonanchora.
Mar.Drugs2017,15,324 6of19
Mar. Drugs 2017, 15, 324 6 of 19
BBiiccyycclliicc MMGGAAss hhaavvee bbeeeenn lleessss ffrreeqquueennttllyy rreeppoorrtteedd ffrroomm MMoonnaanncchhoorraa ssppoonnggeess iinn rreecceenntt yyeeaarrss
((FFiigguurree 44)).. OOtthheerr tthhaann tthhee aabboovvee--mmeennttiioonneedd mmoonnaalliiddiinnee AA,, uurruuppoocciiddiinnss aarree tthhee rreepprreesseenntteedd bbiiccyycclliicc
MMGGAAss.. ThTehye cyomcopmripsrei sae 5,a6-5fu,6s-efdu sceydcliccy gculiacngiduiannei driinnge sryisntgems,y wsthemich, iws hcoicnhneicstecdo nton ethctreede atloipthharteiec
saildipeh cahtiacinssid aet cCh-a1i0n,s Ca-t1C4,- 1a0n,dC -C1-41,5a npdosCit-io15nsp. oTshiteio Cn-s1.4T shiedeC -c1h4aisnid ies clhinakinedi stoli nak etedrmtoinaatle armcyicnlaicl
gacuyacnliidcignue agnrioduipn.e Ugrruopuopc.idUinrus pAo acinddin Bs (A37 aanndd B38()3 w7earned fi3r8st) iwsoelraetefidr sbtyi Msoalaktaerdiebvya aMnadk caor-iwevoarkaenrds
fcroo-mw othrkee dresefpro smeat shpeodnegeep Mse. apuslpchornag neeMar. Upruulcph rIaslannedar aUt aru dpepIstlha nofd 1a8t3a md ienp 2th01o4f [12853]. mUriunp2o0c1id4i[n2 5A].
(U3r7u) pwocaisd ifnouAn(d3 7t)ow ianscrfoeausned ntoitrinicc roexaisdeen iptrriocdouxcidtieonp riond umctuiorinnein mmaucrrionpehmagacerso pbhya ginedsubcyiningd iuNciOnSg
(iiNnOduSci(binled nuictirbicle oxniidtrei csyonxtihdaeses)y enxtphraesses)ioenx aptr e1s0s.0io annda t1.100 μ.0Ma ncodnc1e.0ntµraMtiocnosn. Icne n2t0r1a6ti,o enxsc.epItn fo2r 0t1h6e,
aebxocevpet-mfoerntthioenaebdo vpee-mnteancyticolnice dMpGenAtsa,c yAclliic ManGdA sc,oA-wlioarknedrsc o-iwsoolartkeedr sfisooulra tendewfo ubrincyecwlicb icoyncelisc,
monoensa,nmcohnoarnadchinosr aAdi–nCs A(3–9C–4(13)9,– a4n1)d, adnedhdydehroycdrraomcrbaemscbiens cAin2 A42184 1(842(4),2 )f,rofrmom ththe eFFrreenncchh PPoollyynneessiiaann
MMoonnaanncchhoorraa nn.. sspp.. ssppoonnggee [[1188]].. TThhee ssttrruuccttuurreess ooff tthheessee ccoommppoouunnddss aarree lleessss ccoommpplleexx tthhaann tthhoossee ooff
uurruuppoocciiddiinnss,, wwiitthh tthhee ssiimmiillaarr ccyycclliicc rriinngg ssyysstteemm lliinnkkeedd ttoo oonnllyy oonnee aalliipphhaattiicc ssiiddee cchhaaiinn.. AAllll ffoouurr
ccoommppoouunnddss wweerree tteesstteedd ffoorr ccyyttoottooxxiicc aaccttiivviittiieess aaggaaiinnsstt KKBB ttuummoorr cceellll lliinneess,, aanndd 3399 aanndd 4422 sshhoowweedd
ssttrroonngg aaccttiivviittiieess wwiitthh IICC5500 vvaalluueess ooff 77..77,, aanndd 00..11 μµMM,, rreessppeeccttiivveellyy..

FFiigguurree 44.. SSttrruuccttuurreess ooff bbiiccyycclliicc aanndd aaccyycclliicc MMGGAAss ((3377––4466)) ffrroomm ssppoonnggeess ooff tthhee ggeennuuss MMoonnaanncchhoorraa..
AAccyycclliicc MMGGAAss,, wwhhiicchh hhaavvee sseellddoomm bbeeeenn ddiissccoovveerreedd iinn MMoonnaanncchhoorraa ssppoonnggeess ((FFiigguurree 44)),, aarree mmuucchh
lleessss ccoommpplleexx aanndd ddiivveerrssee tthhaann tthhee ccyycclliicc oonneess.. TThhee rreepprreesseenntteedd aaccyycclliicc MMGGAAss aarree ppuullcchhrraanniinnss AA––CC
((4433––4455)),, ffeeaattuurreedd bbyy aa tteerrmmiinnaall gguuaanniiddiinnee wwiitthh aa lloonngg uunnssaattuurraatteedd aalliipphhaattiicc cchhaaiinn,, wwhhiicchh hhaavvee bbeeeenn
iissoollaatteedd ffrroomm tthhee ffaarr--eeaassteterrnn mmaarirninee spsponongeg eMM. p.upluchlcrhar anenaera UrrUurpu IpslIasnladn adt aatboaubto u17t51 7m5 dmepdthep btyh
MbyakMaarikeavrai eavnada cnod-wcoor-kweorsrk ienr 2s0i1n3 2[02163,27[2].6 T,2h7e].y Thahveey bheaevne fboueennd ftoou bned thtoe fbierstt heexafimrsptleesx aomf mplaersinoef
nmoanr-ipneepntiodne- ipnehpibtiidtoersin ohf iTbRitPorVs-1o (ftrTaRnPsiVen-1t r(etrcaenpstoiern ptorteecnetpiatlo cratpioonte cnhtiaanlncealt siounbfachmainlyn Vel msuebmfbameri 1ly)
cVhamnenmelbs ewrit1h) EchCa50n vnaellusews oitfh 41E.C2,5 905v aanldu e1s83o fμM41,. 2re,s9p5ecatnivde1ly8.3 Inµ 2M01,7r,e aslpoencgti wveitlhy. thIne a2b0o1v7e,-amloenngtiownietdh
ptheentaabcoyvcleic-m MeGntAiosn, Gedaupveinnt-aBciaylcelcickiM anGdA cso,-wGaourkveirns- Bisioallaetcekdi aann daccyoc-lwic oornkee, rusnigsouliactueldin aAn 4a6c,y fcrloicmo tnhee,
supnognugiec uMli.n unAgu4i6c,uflraotem. Itt shheoswpeodn gmeoMde.ruatneg cuyictoutloatxei.ciIttys ahgoawinesdt KmBo cdelelr lainteesc ayntodt oanxitcipitlyasamgoaidniastl aKcBtivcietyll
alignaeisnsatn Pd. faanlctiippalrausmm o(3dDia7l) awcittihv iItCy5a0 gvaailunests Po.f f7a.l6c6ip aanrudm 12(.38D9 7μ)Mw, irtehspICec50tivveallyu [e1s9o].f 7.66and12.89µM,
respectively[19].
2.2. Crambe
2.2. Crambe
Crambe, of the order Poecilosclerida and the family Crambeidae (the same as Monanchora), has
the oCrirgaimnb ea,so wftehlel-korndoewrnP oMecGiloAssc lseuricdha aasn dcrtahmebfaemsciilnysC arnamd bceriadmaebe(tshceidsianms.e CarsaMmboen acnrachmobrea ),ish aas rtehde
moraigriinnea sspwoenlgl-ek, nmowainnlMy GdiAstsrisbuuctheda sincr athmeb wesecsintesrnan Mdecdraitmerbreasnceidanin sS.eCa.r aBmrabeekcmraamnb eainsda croed-wmorakrienres
csopmonpglee,temda tihnely fidrsist tcrihbeumteicdailn sttuhdeyw oefs ttehrins Mspeodnigteer irna n1e9a9n0 Saenad. B19ra9e2k [m28a,2n9a],n ldeacdoi-nwgo trok etrhsec doimscpolveeterdy
othf ecrfiarmstbcihneems Aic a(l47st, u5d,6y-foufstehdi sbsicpyocnligce MinG1A99),0 Ba (n4d8,1 59,962-s[p2i8r,o2 9b]i,clyecaldici nMgGtoAt)h, eCd1 i(s4c9o)v, earnydo Cf2cr (a5m0)b. iInt eiss
wAo(r4t7h, m5,6en-ftuiosendingb icthyactl ic49M aGndA )5,0B ar(e4 8r,ar5e,6 m-sponiroocybcicliycc MlicGMAGs. AM),eaCn1w(h49il)e,, atnhde gCr2ou(5p0s) .of IBtriasewkmoratnh
amnedn Rtiionneihnagrtt hdaistc4o9vearnedd t5h0ea wreelrla-krenomwonn poocylyccliycclMicG MAGsA. sM, ceraanmwbheislcei,dtihnes 8g0r0o u(5p1s),o 8f1B6 r(a5e2k),m 83a0n (a5n3)d,
8R4i4n e(h5a4r),t idsiosccroavmerbeedsctihdeinw 8e0l0l- k(5n5o)w anndp oclryacmycbliidcinMeG (A56s), [c3r0a,m31b]e, swcihdiicnhs a8t0t0ra(c5te1d), 8a1 l6ot( 5o2f) ,a8tt3e0n(ti5o3n),
because of their total synthesis and biological studies (Figure 5). In recent years, the chemical
investigation of sponges of the genus Crambe was not as frequent as Monanchora, which might be due
Mar.Drugs2017,15,324 7of19
8M4a4r.( D54ru)g,si s2o01c7r,a 1m5,b 3e24s cidin800(55)andcrambidine(56)[30,31],whichattractedalotofattentionbec7a ouf s1e9
oftheirtotalsynthesisandbiologicalstudies(Figure5). Inrecentyears,thechemicalinvestigationof
to the previous intensive study of this genus and also because of its limited distribution. There is only
spongesofthegenusCrambewasnotasfrequentasMonanchora,whichmightbeduetotheprevious
one report on the chemical reinvestigation of Crambe by the French group of Thomas in 2012, and one
intensivestudyofthisgenusandalsobecauseofitslimiteddistribution. Thereisonlyonereporton
biological study was conducted by the Spanish group of Botana in collaboration with Thomas in 2015.
thechemicalreinvestigationofCrambebytheFrenchgroupofThomasin2012,andonebiologicalstudy
Thomas and co-workers isolated 11 crambescin derivatives (57–67), and crambescidin 816 (52) (Figure
wasconductedbytheSpanishgroupofBotanaincollaborationwithThomasin2015. Thomasand
5), from the Villefranche-Sur-Mer (France) at 10–20 m depth [32]. The 11 crambescins can be divided
co-workersisolated11crambescinderivatives(57–67),andcrambescidin816(52)(Figure5),fromthe
into three types. The first type, including 57–61, is of a crambescin A skeleton, which is characterized
Villefranche-Sur-Mer(France)at10–20mdepth[32]. The11crambescinscanbedividedintothree
by a 5,6-fused bicyclic ring system connected to one aliphatic side chain at the C-13 position and
types. The first type, including 57–61, is of a crambescin A skeleton, which is characterized by
another one with a terminal guanidine group at the C-7 position. Compounds 62–64 represent the
a5,6-fusedbicyclicringsystemconnectedtoonealiphaticsidechainattheC-13positionandanother
second type of crambescin B skeleton, featured by a [4,5]decane spiro-ring system with similar side
onewithaterminalguanidinegroupattheC-7position. Compounds62–64representthesecond
chains as crambescin A. The last type, exemplified by 65–67, is from the crambescin C family, with a
typeofcrambescinBskeleton,featuredbya[4,5]decanespiro-ringsystemwithsimilarsidechainsas
monocyclic guanidine ring linked to two side chains. The absolute configurations of compounds 57,
crambescinA.Thelasttype,exemplifiedby65–67,isfromthecrambescinCfamily,withamonocyclic
63 and 67 were determined by the TDDFT (time-dependent density functional theory) ECD
guanidine ring linked to two side chains. The absolute configurations of compounds 57, 63 and
(electronic circular dichroism) method. All the compounds were tested for their cytotoxicity against
67 were determined by the TDDFT (time-dependent density functional theory) ECD (electronic
cortical neurons, with the known one 52 found to be the most toxic. In fact, crambescidins have been
circular dichroism) method. All the compounds were tested for their cytotoxicity against cortical
widely biological investigated, while there are not many biological reports on crambescins. Thus,
neurons,withtheknownone52foundtobethemosttoxic. Infact,crambescidinshavebeenwidely
Botana and co-workers cytotoxically examined crambescins A1 (60) and C1 (66) against human
biologicalinvestigated,whiletherearenotmanybiologicalreportsoncrambescins. Thus,Botanaand
hepatoblastoma cell HepG2, including mechanistic studies, such as proliferation, apoptosis, and
co-workerscytotoxicallyexaminedcrambescinsA1(60)andC1(66)againsthumanhepatoblastomacell
antioxidant activities [33]. The results revealed that 66 was able to induce MTs (metallothioneins)
HepG2,includingmechanisticstudies,suchasproliferation,apoptosis,andantioxidantactivities[33].
transcription and synthesis in HepG2 cell lines, protecting cells from oxidative damage at
Theresultsrevealedthat66wasabletoinduceMTs(metallothioneins)transcriptionandsynthesisin
concentrations that retained cell viability. Such an observation provided the first comprehensive
HepG2celllines,protectingcellsfromoxidativedamageatconcentrationsthatretainedcellviability.
method regarding the various bioactivities of crambescins on tumor cells and gave a biological clue
Suchanobservationprovidedthefirstcomprehensivemethodregardingthevariousbioactivitiesof
for the future investigation of such compounds.
crambescinsontumorcellsandgaveabiologicalclueforthefutureinvestigationofsuchcompounds.

FFiigguurree 55.. SSttrruuccttuurreess ooff MMGGAAss ((4477––6677)) ffrroomm ssppoonnggeess ooff tthhee ggeennuuss CCrraammbbee..
22..33.. OOtthheerr SSppoonnggeess
AAlltthhoouugghh nnuummeerroouuss ccoommpplleexx MMGGAAss wweerree oobbttaaiinneedd ffrroomm MMoonnaanncchhoorraa aanndd CCrraammbbee,, tthheeiirr ddiivveerrssiittyy
iiss nnoott tthhaatt wwiiddee.. MMaarriinnee cchheemmiissttss ttuurrnneedd ttoo tthhee cchheemmiiccaall iinnvveessttiiggaattiioonn ooff ootthheerr ssppoonnggeess ffrroomm ddiiffffeerreenntt
llooccaattiioonnss ssuucchh aass tthhoossee ffrroomm tthhee ggeennuuss CCllaatthhrriiaa iinn VVaannuuaattuu,, HHaalliicchhoonnddrriiaa iinn OOkkiinnaawwaa,, PPsseeuuddaaxxiinneellllaa iinn
Bahamas, Acanthella in Australia, Agelas in Solomon Islands, etc. In 2011, Wagoner and co-workers
isolated four new tris-bromoindole cyclic guanidine alkaloids, araiosamines A–D (68–71) (Figure 6),
from the marine sponge, Clathria (Thalysias) araiosa, collected from Vanuatu [34]. The structures of
Mar.Drugs2017,15,324 8of19
Bahamas,AcanthellainAustralia,AgelasinSolomonIslands,etc. In2011,Wagonerandco-workers
Mar. Drugs 2017, 15, 324 8 of 19
isolatedfournewtris-bromoindolecyclicguanidinealkaloids,araiosaminesA–D(68–71)(Figure6),
tfhroemse thceommparoiunendsps onargee ,tColtaatlhlryi ad(Tifhfearlyesnita sf)raormai ostah,ec oallfeocrteemdefrnotmionVeadn uMatuG[A3s4.] .TThheeys trcuocmtuprreisseo ftthhreesee
bcorommpooiunnddoslea rreintgost,a lcloyndnieffcetirneng ttfor osmix-tmheemafboerreemde anntido nfievde-MmGemAsb.eTrehde ygcuoamnipdrinisee rthinrgees. bTrhome aouinthdoorles
treinstgesd, tchoen npehcetninogtytpoics eixff-emctesm abgeariendst aznedbrafifviseh-m emembrbyeores,d agnutiabnaicdteinriealr aincgtisv.ityT hageaainustht oSrtasptheysltoecdoctchues
apuhreenuos,t yapnicd efHfeIcVts iangfaeicntisotnz eobfr atfihseh eamrabiorsyaoms,inaenst,i bwacittehroiault aschtiovwityinagg aainnyst sSitganpihfyicloacnotc caucstiavuirtieeuss.,
NanedveHrtIhVeliensfse, catrioaniosoafmthineeas rraeiopsraemseinnte as ,nwovitehlo suctafsfhooldw ionfg MaGnyAss igdnisicfiocvaenrtedac ftrivoimtie ms.arNineev esrptohnelgeesss.,
Taryapioicsaalm triinceysclriecp MreGseAnst, amniroavbeillisnc aGff o(7ld2),o nfeMtaGmAinsed Misc (o7v3e)r, eadndfr ommirambailriinn eKs (p7o4n),g heasv.eT ybpeiecna lotbrtiacyincelidc
fMroGmA tsh,em SioraubthileinasGter(n7 2A),usntertaalimanin sepMong(7e3 A),caanndthemlliar aCbailvinernKos(a7 4[)3,5h].a vTehebseee mniorabbtailiinne ddefrriovmativthees
wSoeurteh eevaastleuranteAdu fsotrra alicatnivsitpyo naggaeiAnscta ntuthmeollra sCuapvperrensossoar [P35D]C.TDh4e s(Permogirraabmilimnedde rcievlal tdiveeasthw perreoetevianl u4a),t eodf
wfohriaccht i7v2i tayndag 7a3i ndsistptulamyeodr ssturponpgre isnshoirbPitDorCyD ac4ti(vPirtoiegsr ianm thmee cdelcluelllard deaetghrapdraottieoinn o4f) ,PoDfCwDh4i cwhit7h2 EaCn5d0
v73alduiessp olafy 1e.d8 satnrdon 2g.8i nμhgi/bmitLor, yreascpteivcittiiveeslyin. Tthoe thceel lauulathrodresg’ rbaedsat tkionnowoflePdDgCe,D 742 wanitdh 7E3C a50rev tahlue efsirostf
1M.8NaPnsd r2e.8poµrgt/edm Lto,r esstpabeciltiizvee lyP.DTCoDth4e auuntdheorr st’ubmesotrk nporwomleodtgine,g7 2coannddi7ti3onarse. tBhiecyficrlsitc MMNGPAssre poof rtthede
ctorasmtabbeisliczine PskDeCleDto4nu, enxdeemrptulimfieodr pbyro cmraomtibnegsccoinnsd Ait2io 3n9s2. (B7i5c)y, c4l0ic6 M(7G6)A, 4s2o0f (t7h7e), carnadm Sbcehsc 5in75s9k4e8l e(7to8n),,
wexeerme pdliisficeodvebryedcr ianm tbhees BcianhsaAm2a3s9 s2p(o7n5g),e4 P06se(u7d6a)x,i4n2e0lla(7 r7e)t,icaunldatSe cchol5l7ec5t9e4d8 i(n7 8S)w,weeetriendgiss cCoavye raetd a i1n7t-hme
dBeaphtahm (aFsigspuoren g6e) P[3se6u] dbaxyi nMelolalirnestikciu laantedc oclole-wctoedrkienrsS wine e2t0in1g5s. CAally tahtea c1o7m-mpoduepntdhs (Fwigeruer ete6s)t[e3d6 ]fboyr
aMnotilfiunnskgiaal nadcticvoi-twy oargkaeinrssti nth2e0 1p5a.thAollgtehneicc ostmrapinosu nCdasndwidear ealtbeisctaends faonrda nCtrifyupntogcaolccaucst ivspit.y, wagitahin MstItCh5e0
rpaanthgiongge nfriocmst r1a.1in tso C39an μdgid/maaLl baincadn MsaInCd90 Cfrroympt o2c.o3c tcou s59s pμ.g,/wmitLh. TMhIeC l5e0nrgatnhg oifn tghfer oalmky1l. s1idtoe 3c9haµign/ wmaLs
raensdpoMnIsCib9l0ef rfoomr t2h.3e tova5r9iaµtigo/nm oLf. Tahcteivleitniegst.h Ionf tthhee aslkaymles idyeeacrh, atihnew garsoruepsp oonf sAibllie afonrdt hceo-vwaroiraktieorns
ionfvaecsttiivgaittieeds. a PInactihfiec sspamonegey eAagr,elaths ecf.g mroauupritoiafnAa flrioamn dSocloo-mwoonr kIeslrasnidnsv aets t1i8g–a3te0d ma dPepacthifi, cresspuoltningge
iAng tehlaes icsfo.lmataiuorni taiannda efrluocmidSaotiloomn oofn dIeslbarnodmsoakte1r8a–m30admindee (p7t9h), (rFeisguulrtien 6g) i[n37th].e Ciosomlaptoiounnadn 7d9,e bluecloidnagtiinogn
toof dtheeb ropmyrorkoeler-a2m-aamdiinneoi(m79i)d(aFziogluer e(P6-)2[-3A7I]).,C ios map doeubnrdom79o, bperloondguicntg otfo ktheerapmyarrdoilnee-2 -(a8m0)i, nwoihmicidha wzoalse
i(sPo-l2a-tAedI) ,bisy aKdoebbaryoamshoi parnodd uccot-wofokrekrearms fardoimne a(n80 O),kwinhaicwhawn aSseias oslpaotendgeb yAKgeolbasa ysaps. h[i38a]n. dTchoe- wauotrhkoerrss
afrcohmievanedO tkoitnaal wsyanntSheeasissp oofn 7g9e aAngdel a8s0s tph.r[o3u8]g.hT ha ekaeuyt hreogrisoascehleiecvtievde tooxtaidlsaytinvteh easdisdoitfio7n9 aonf da 8g0utahnrioduignhe
daekreivyarteivgeio soenl eNct-iavceyolpxyidrarotilvee daidhdyidtiroonpyorfiadignueasn. iTdhinise mdeertihvoadti vweaosn aNp-palciyedlp yforrro tlheed ishyyndthroepsiysr iodfi nthees.
aTnhaislomgse tohfo 7d9,w wahsicahp pallileodwfeodr tthhee fsuyrnththeer sbiisoolofgthiceaal nstauldogys oof fP7-29,-AwIh dicehrivalaltoivweesd. Itnh 2e0f1u6r,t htwerob 6i,o7l-ofugsiceadl
bstiucydcylico fMPG-2A-As,I 6d-eerpivi-amtiovneasn. cInho2r0in16 (,8t1w) oan6d,7 -iftus skendobwicny cisliocmMerG mAso,n6a-necphi-omrionn (a8n2c)h (oFriignu(r8e1 6))a, nwdeirtes
iksnoolawtend isboym Yearmmaoznakani cahnodr icno(-8w2o)r(kFeirgsu rfreo6m), twhee rOekisionlaawteadn bmyaYrainmea szpaoknigaen dHcaoli-cwhoonrdkreiar spfarnoimceat haet
IOrikoimnaowtea Inslmanadr iinne Jsappoanng [e39H].a Nlicehiothnedrr icaopmanpiocueanadt eIxrihoimbiotetde Iascltainvdityi nagJaapinasnt M[39. ]s.egNmeaitthise artc 2o0m μpgo/udnisdc
nexohr icbyitteodtoaxcictiivtyit yagaagianisnts ctaMnc.esre gcmelal tliisnaets 2a0t µ10g /μdMis.c norcytotoxicityagainstcancercelllinesat10µM.

Figure 6. Structures of MGAs (68–82) from the other marine sponges.
Figure6.StructuresofMGAs(68–82)fromtheothermarinesponges.
3. MGAs from Other Marine Sources
Despite that most of MGAs are of sponge origins, a few of them were found in other marine
resources. Apparently, during the last seven years, there is no report on guanidine-containing toxins
related to TTX or STX from marine algae, while a few miscellaneous MGAs were obtained from
Mar.Drugs2017,15,324 9of19
3. MGAsfromOtherMarineSources
Despite that most of MGAs are of sponge origins, a few of them were found in other marine
resources. Apparently,duringthelastsevenyears,thereisnoreportonguanidine-containingtoxins
related to TTX or STX from marine algae, while a few miscellaneous MGAs were obtained from
marinemollusksandascidians(Figure7). In2011,incollaborationwiththegroupofGavagninin
Italy, our group isolated two novel guanidine-containing indole alkaloids, phidianidines A and B
(83and84),fromtheSouthChinaSeaopisthobranchmolluskPhidianamilitarisinHainanIsland,China.
Phidianidinescompriseanunprecedented1,2,4-oxadiazoleconnectedtoanindoleringandalong
Mar. Drugs 2017, 15, 324 9 of 19
sidechainbearingaterminalguanidinegroup[40]. Theyshowedhighcytotoxicityagainsttumor
andnomntaurimneo mrmollaumskms aanldia ansccideilalsnsw (FitihguIrCe 7). vIna l2u0e1s1, riann cgoillnagbofrraotimon 0w.1it4h ttohe1 g0r0o.u2pµ oMf G.Davuagention itnh enovel
50
Italy, our group isolated two novel guanidine-containing indole alkaloids, phidianidines A and B (83
structuresandthehighbiologicalactivities,phidianidinesattractedalotofattentionfortheirsynthesis,
and 84), from the South China Sea opisthobranch mollusk Phidiana militaris in Hainan Island, China.
whichwillbediscussedinthenextsection. Biologically,itisworthmentioningthatphidianidineA(83)
Phidianidines comprise an unprecedented 1,2,4-oxadiazole connected to an indole ring and a long
wasidentifiedasanewCXCR4(C-X-Cchemokinereceptortype4)ligandforantagonistactivityby
side chain bearing a terminal guanidine group [40]. They showed high cytotoxicity against tumor
Amodeaonadn ndoncotu-mwoorr kmearmsminal2ia0n1 3c,elwlsi twhitvha IrCio50u vsaliunetse nrasnivgeinbg iforloomg i0c.a1l4 sttou 1d0i0e.s2 tμoMc.o Dnufier mto tthhee inrorveeslu lts[41].
Inthesastmruectyueraesr ,aKnödn tihgea nhidghc ob-iwoloorgkicearls aicstoivlaittieeds, apnhiodviaenligduinaens idatitnraec-tiendt ear rluopt toefd atteternpteionno ifdo,r dtohteoirfi de(85),
fromthseymnthaersiinse, wmhoicllhu swkil(l sblue gd)isDcuostsoepdi ninn atthiefi dnaex(Gt saescttrioonp.o Bdiao,loNgiucadlliyb,r aitn icsh wiao)rctho lmleecntetidoniinngF ethrraot l,Spain.
phidianidine A (83) was identified as a new CXCR4 (C-X-C chemokine receptor type 4) ligand for
Theauthorsspeculatedthatsuchaterpenoid-MGAhybridcouldprobablyactasachemicaldefensive
antagonist activity by Amodeo and co-workers in 2013, with various intensive biological studies to
metabolite for shell-less mollusks like D. pinnatifida [42]. Recently, once again, our group and the
confirm their results [41]. In the same year, König and co-workers isolated a novel guanidine-
groupoinftGeraruvpatgedn itnerpcoenlloaibd,o draottoefdidwe (i8th5),e farcohm oththe emraarninde dmioslclousvke r(selduga) Dneotwo pdinianactyifligdau (aGnaisdtrionpeo,daac,t inofide
(86),froNmudthiberaSnocuhtiah) CcohlliencateSde ian Fmerorlolul, sSkpaAinc.t iTnhoec yaucltuhsorpsa sppiellcautluastecdo tlhleact tseudchi na tWerepienZohido-uMIGslAan hdy,brCidh ina[43].
Actinoficdoueldis parotbearpbleyn aocitd a-sg au cahneimdiicnael dheyfbenrsidiv,ef emaettuabreodliteb yfoar sghuelal-nleidssi nmeogllruoskusp liakcey Dla. tpeindnbatyifitdwa [o42t]e. rpenoid
Recently, once again, our group and the group of Gavagnin collaborated with each other and
acidunits. Furthermore,afour-stepsynthesisofactinofideanditsanalogswasachieved,whichwill
discovered a new diacylguanidine, actinofide (86), from the South China Sea mollusk Actinocyclus
bediscussedinthenextsection.
papillatus collected in Wei Zhou Island, China [43]. Actinofide is a terpenoid-guanidine hybrid,
Marine ascidians are also a very important source of bioactive marine alkaloids. One of the
featured by a guanidine group acylated by two terpenoid acid units. Furthermore, a four-step
mostfasmynotuhsesmis aorf iancetinnoaftiuder aalnpdr iotsd auncatl-odges rwivaes dacdhrieuvgesd,, ewchteicihn awsiclli dbein d-i7s4cu3s(sEedT -in7 4th3e), nuenxtd seercttihone. tr adename
YodelisbyPMhaarirnme aasMcidaria/nJso ahrne saolsno a& veJoryh inmspoonr/taOntr stohuorBcei ootfe bciohafcotirvet hmeatrrineea atmlkaelnoitdos.f Orenfer oafc tthoer ymosostf t-tissue
sarcomfaasm,owush imchariwnea snaatpurparl opvreoddubcty-dtehrieveEdu drorupgesa, nectCeionmasmcidiisns-i7o4n3 i(nET2-704037),, uwnadserfi trhset tirsaodlea tneadmfer om the
Yodelis by PharmaMar/Johnson & Johnson/OrthoBiotech for the treatment of refractory soft-tissue
marinetunicateEcteinascidiaturbinate[44,45]. Inrecentyears,onlyonereporthasbeenobservedfor
sarcomas, which was approved by the European Commission in 2007, was first isolated from the
theMGAsfromascidians. BychemicalinvestigationofthecolonialmarineascidianEudistomasp.
marine tunicate Ecteinascidia turbinate [44,45]. In recent years, only one report has been observed for
collected in Koror/Airai Channel, Palau, Gustafson and co-workers isolated two novel polycyclic
the MGAs from ascidians. By chemical investigation of the colonial marine ascidian Eudistoma sp.
MGAs,ceoulledcitsetdi dinin KeosrAor/aAnirdaiB C(h8a7nnaenl,d P8a8la)u,,u Gsiunsgtafasobni oaansds acyo--wgourikdeersd iasoplpatreoda tcwho[ 4n6o]v.el8 7poalnycdyc8l8ic possess
anunpMreGceAdse, neuteddisttideitnraesc yAc alincdc Bo r(8e7c aonmd p88r)i,s uinsignga af ubsioeadsspayy-rgiumidieddi naep,pqrouaicnha [z4o6]l.i n87e ,aannd d88i mpoisdseaszso lering,
inwhicahn aungpuraenceiddeinnteedf utentrcatcioycnlaicl ictoyrei scoemmpbreisdindge ad f.uIsneda pbyiroim-sicdrieneen, qinuginaazsoslainye,,8 a7nedf ifmecidtiavzeollye rbinlogc, kedthe
in which a guanidine functionality is embedded. In a bio-screening assay, 87 effectively blocked the
bindingofsolubleCH1(theproteinbindingdomainoftranscriptionalcoactivatorproteinp300)to
binding of soluble CH1 (the protein binding domain of transcriptional coactivator protein p300) to
immobilizedC-TAD(theproteinbindingdomainoftranscriptionfactorHIF-1: hypoxia-inducible
immobilized C-TAD (the protein binding domain of transcription factor HIF-1: hypoxia-inducible
factor1f)a,cwtoirt h1),I wC5it0h oICf570 5ofµ 7M5 μ,Mw,h wilheil8e8 88w waassn noott aaccttiivvee. .ThTeh setrsutcrtuucrteu orfe 87o fm8a7y mpraoyvidper oav niedwe cahenmewicacl hemical
scaffoldsctaoffsotlud dtoy sptu3d0y0 p/3H00I/FH-1IFα-1iαn tinetrearcatcitoionnss ttoowwaarrddss nnovoevl ealnatincatniccaenr cderurgd druisgcodveisryco. very.

FigureFi7g.uSrter 7u. cSttururectsuorefsM ofG MAGsA(s8 (38–38–888))f frroomm ootthheer rmmarainrein seousrocuesr c(meso(llmusoklsl uansdk sasacniddiaans)c. idian).
In summary, although guanidine containing metabolites are extremely rare in nature, more than
60 MGAs have being isolated since 2010 from various marine sources located all over the global ocean
(Figure 8), with sponges as the most frequent origins. As shown in Figure 9, only 3, 2 and 1 MGAs
Mar.Drugs2017,15,324 10of19
Mar. Drugs 2017, 15, 324 10 of 19
were isolated from other marine sources, including mollusks and ascidians, in 2011, 2015, and 2017,
Insummary,althoughguanidinecontainingmetabolitesareextremelyrareinnature,morethan
respectively. These data indicated that marine sponges are the main sources of MGAs in recent years,
60MGAshavebeingisolatedsince2010fromvariousmarinesourceslocatedallovertheglobalocean
which should be attributed to their relatively larger amount and ease of collection.
(Figure8),withspongesasthemostfrequentorigins. AsshowninFigure9,only3,2and1MGAs
Mar. Drugs 2017, 15, 324 10 of 19
wereisolatedfromothermarinesources,includingmollusksandascidians,in2011,2015,and2017,
respectivelyw.eTreh iesosleatdeda tfaroimn dotihceart emdartihnea tsomuracreisn, iencslpudoinngg emsoallruesktsh aenmd aasicnidsiaonus,r icne 2s0o11f, M20G15A, asndin 20r1e7c,e ntyears,
respectively. These data indicated that marine sponges are the main sources of MGAs in recent years,
whichshouldbeattributedtotheirrelativelylargeramountandeaseofcollection.
which should be attributed to their relatively larger amount and ease of collection.

Figure 8. The global distribution of the MGA-containing marine organisms, which have been chemically
FFiigguurree 88.. TThhee gglloobbaall ddiissttrriibbuuttiioonn ooff tthhee MMGGAA--ccoonnttaaiinniinngg mmaarriinnee oorrggaanniissmmss,, wwhhiicchh hhaavvee bbeeeenn cchheemmiiccaallllyy
investigated since 2010 (red means sponges, violet means mollusks, green means ascidians).
iinnvveessttiiggaatteedd ssiinnccee 22001100 ((rreedd mmeeaannss ssppoonnggeess,, vviioolleett mmeeaannss mmoolllluusskkss,, ggrreeeenn mmeeaannss aasscciiddiiaannss))..

Figure 9. New MGAs from 2010 to 2017 (2017 data were updated on 30 June 2017).
4. Synthetic Examples of Recently Discovered Bioactive MGAs
The beautiful structures and broad biological activities of MGAs have unquestio nably attracted
many synthetic chemists with respect to their total syntheses. A range of well-known and complex
MGFFiAiggsuu hrraeev 99e. . bNNeeeenww s yMMntGGhAeAssisz fefrrdoo mmma 2n200y11 t00im ttooe s22 u00s11i7n7 g((2 2d00i1f1f77e rddenaattt aaa pwwpeerroreea cuuhppesdd, aasttueecddh ooansn t33h00e JtJouuxnniene 22fa00m1177il))y.. TTX
and STX, pentacyclic crambescidins, tricyclic batzelladines, bicyclic urpocidins, etc. [45–49]. In recent
4. Synthetiyce Earxsa, msopmlee so fo tfh eRme,c eevnetnl yth Dosies cdoisvcoevreerded B iino naacttuirvee m MorGe Athsa n 10 years ago, still underwent
4. SyntheticExamplesofRecentlyDiscoveredBioactiveMGAs
synthetic studies, such as the polycyclic dragmacidin E, massadine, axinellamines, and the TTX
The beautiful structures and broad biological activities of MGAs have unquestionably attracted
ThebeautifulstructuresandbroadbiologicalactivitiesofMGAshaveunquestionablyattracted
mmaannyy ssyynntthh eettiicc cchheemmiissttss wwiitthh rreessppeecctt ttoo tthheeiirr ttoottaall ssyynntthheesseess.. AA rraannggee ooff wweellll--kknnoowwnn aanndd ccoommpplleexx
MGAs have been synthesized many times using different approaches, such as the toxin family TTX
MGAshavebeensynthesizedmanytimesusingdifferentapproaches,suchasthetoxinfamilyTTXand
and STX, pentacyclic crambescidins, tricyclic batzelladines, bicyclic urpocidins, etc. [45–49]. In recent
STX,pentacycliccrambescidins,tricyclicbatzelladines,bicyclicurpocidins,etc.[45–49]. Inrecentyears,
years, some of them, even those discovered in nature more than 10 years ago, still underwent
someofthem,eventhosediscoveredinnaturemorethan10yearsago,stillunderwentsyntheticstudies,
synthetic studies, such as the polycyclic dragmacidin E, massadine, axinellamines, and the TTX