Polycyclic Guanidine Alkaloids from Poecilosclerida Marine Sponges

24 Pages·2016·3.57 MB·English

marine drugs
Review
Polycyclic Guanidine Alkaloids from Poecilosclerida
Marine Sponges
EstelleSfecci1,ThierryLacour2,PhilippeAmade1andMohamedMehiri1,*
1 NiceInstituteofChemistry,MarineNaturalProductTeam,UniversityNiceSophiaAntipolis,ParcValrose,
28avenuedeValrose,06108NiceCedex02,France;[email protected](E.S.);[email protected](P.A.)
2 Biopreserv,4traverseDupont,06130Grasse,France;[email protected]
* Correspondence:[email protected];Tel.:[phone]
AcademicEditor:KirstenBenkendorff
Received:2February2016;Accepted:1April2016;Published:9April2016
Abstract: Sessile marine sponges provide an abundance of unique and diversified scaffolds.
Inparticular,marineguanidinealkaloidsdisplayaverywiderangeofbiologicalapplications. Alarge
numberofcyclicguanidinealkaloids,includingcrambines,crambescins,crambescidins,batzelladines
ornetaminshavebeenisolatedfromPoeciloscleridamarinesponges. Inthisreview,wewillexplore
thechemodiversityoftri-andpentacyclicguanidinealkaloids. NMRandMSdatatoolswillalso
beprovided,andanoverviewofthewiderangeofbioactivitiesofcrambescidinsandbatzelladines
derivativeswillbegiven.
Keywords: marine sponges; Poecilosclerida; alkaloids; crambescidins; batzelladines;
analyticaltools;bioactivity
1. Introduction
The most primitive benthic marine organisms are also among the most chemodiversified
producersofsecondarymetabolites(SM).Thesecompoundsareusedforpredationandcompetition
for space, as well as for communication, and protection against potential surrounding aggressors.
Duetothehighwaterdilution,theproducedmetabolitesexhibitseveralpotentbiologicalactivities[1].
Severalreviewsdealingwithbioactivemarinenaturalproducts,inparticular,alkaloidshavebeen
published in the last few decades [2–19]. Of the many different marine species that have been
researched,spongesarelikelytobethemoststudiedsourcesofmarinenaturalproductsduetothe
largeamountofstructurallydiverseSMscaffoldstheyproduce. Evenso,thelastfewyearshaveseen
aslightdeclineinthenumberofnewlydescribedmetabolites[17,18].
Inthisreview,wefocusedonthechemodiversityandbiologicalactivitiesofbatzelladine-and
crambescidin-likeguanidinealkaloidsisolatedfromPoeciloscleridamarinesponges. Thesepolycyclic
guanidine alkaloids are extremely versatile SM [20]. Since their original isolation in 1989, several
revisionshavebeenmadeandmanyaspectsremaintobestudied. However,whatisclearisthatthey
seemtobespecifictoPoeciloscleridamarinesponges. Over53derivativeshavebeenisolatedand
theiroriginalstructures,basedonchemicaldegradationstudiesandextensiveNMRandMSstudies,
havebeenrevisedsincethedevelopmentoftheirtotalsynthesis. Thestructuralandstereochemical
complexity of this class of natural products have inspired the development of a number of new
syntheticmethodologies[21–34],whichinturnhasledtoseveraltotalsyntheses[31,33,35–50]beyond
thescopeofthisreview. Finally,theseuniqueandfascinatingstructuresarecoupledwithawiderange
ofbiologicalactivitiesduetothetypicalshapeoftheirtricyclicskeleton. However,littleisknown
abouttheirexactmechanismofaction.
Mar.Drugs2016,14,77;doi:10.3390/md14040077 www.mdpi.com/journal/marinedrugs
Mar.Drugs2016,14, 77 2of24
Mar. Drugs 2016, 14, 77 2 of 24
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aCnladthMrioan caanllcah, oarnada rMbuosncaunlach(Toraab alerb2u)s.cula (Table 2).
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Cina trhibeb CeaarnibSbeeaan(F Siegau r(eFi1g)u.re 1).

Figure 1. Geographical repartition of new TGA (triazaacenaphthylene guanidine alkaloids)
Figure1.GeographicalrepartitionofnewTGA(triazaacenaphthyleneguanidinealkaloids)discovered
fdriosmco1v9e8re9dt ofr2o0m15 1.9G8r9a tpoh 2ic01©5.d G-mraapphsi.cco ©m d-[m72a]p.sU.csoemdw [i7t2h].p eUrsmedis swiointh. permission.
Mar.Drugs2016,14, 77 3of24
Table1.Reviewedcrambescidin-likeGA(guanidinealkaloids)from1989to2015.
Discovery Guanidine Biological Synthesis
Metabolite Species SamplingSite Ref.
Year Moiety Activity Described
Hemimycalesp.Ptilocaulis
ptilomycalinA(1) Redsea 1989 1 Av,Am,At Yes [42,51,73]
spiculifer
crambescidin800(2) Crambecrambe PalmadeMallorca,Mediterraneansea 1991 1 Av,Am,At Yes [54–56,73,74]
Av,At,Ca2+
crambescidin816(3) Crambecrambe PalmadeMallorca,Mediterraneansea 1991 1 No [52,55,56,75]
antagonist
crambescidin830(4) Crambecrambe PalmadeMallorca,Mediterraneansea 1991 1 n.t. No [55]
crambescidin844(5) Crambecrambe PalmadeMallorca,Mediterraneansea 1991 1 Av No [55,56]
13,14,15-isocrambescidine800(6) Crambecrambe Banyuls,Mediterraneansea 1993 1 Notactive Yes [36,42,56]
crambidine(7) Crambecrambe Banyuls,Mediterraneansea 1993 1 n.t. Yes [45,49,52]
neofolitispate1(8) Neofolitispadianchora AndamanIslands,IndianOcean 1999 1 Av No [57]
neofolitispate2(9) Neofolitispadianchora AndamanIslands,IndianOcean 1999 1 Av Yes [57]
neofolitispate3(10) Neofolitispadianchora AndamanIslands,IndianOcean 1999 1 Av No [57]
crambescidin359(11) Monanchoraungiculata Belize,NorthAtlanticOcean 2000 1 n.t. Yes [33,41,48,53]
crambescidin431(12) Monanchoraungiculata Belize,NorthAtlanticOcean 2000 1 n.t. No [53]
crambescidin826(13) Monanchorasp. Palau,PacificOcean 2003 1 Av No [54]
crambescidinacid(14) Monanchoraungiculata MaldiveIslands,IndianOcean 2004 1 At No [58]
Monanchoraunguifera
crambescidicacid(15) Panama,Caribbeanside,AtlanticOcean 2005 1 n.t. No [59]
Monanchoradianchora
16β-hydroxycrambescidin359(16) Monanchoraunguifera Jamaica,NorthAtlanticOcean 2007 1 Am No [73]
ptilomycalinD(17) Monanchoradianchora Madagascar,IndianOcean 2007 1 n.t. No [60]
monanchocidinA(18) Monanchorapulchra UrupIsland,NorthPacificOcean 2010 1 At No [61]
monanchocidinB(19) Monanchorapulchra UrupIsland,NorthPacificOcean 2011 1 At No [62]
monanchocidinC(20) Monanchorapulchra UrupIsland,NorthPacificOcean 2011 1 At No [62]
monanchocidinD(21) Monanchorapulchra UrupIsland,NorthPacificOcean 2011 1 At No [62]
monanchocidinE(22) Monanchorapulchra UrupIsland,NorthPacificOcean 2011 1 At No [62]
monanchomycalinA(23) Monanchorapulchra UrupIsland,NorthPacificOcean 2012 1 At No [63]
monanchomycalinB(24) Monanchorapulchra UrupIsland,NorthPacificOcean 2012 1 n.t. No [63]
monanchomycalinC(25) Monanchorapulchra UrupIsland,NorthPacificOcean 2013 1 n.t. No [64]
Am,antimicrobialactivity;Av,antiviralactivity;At,antitumoralactivity;andn.t.,nottested.
Mar.Drugs2016,14, 77 4of24
Table2.Reviewedbatzelladine-likeGAfrom1989to2015.
Discovery Guanidine Biological Synthesis
Metabolites Species SamplingSite Ref.
Year Moiety Activities Described
batzelladineA(26) Batzellasp. Bahamas,NorthAtlanticOcean 1996 3 Am,Av Yes [32,46,66]
batzelladineB(27) Batzellasp. Bahamas,NorthAtlanticOcean 1996 3 Av No [66]
batzelladineC(28) Batzellasp. Bahamas,NorthAtlanticOcean 1996 2 Av,Am,At No [66,73]
batzelladineD(29) Batzellasp. Bahamas,NorthAtlanticOcean 1996 2 Av,Am Yes [37,40,46,47,66]
batzelladineE(30) Batzellasp. Bahamas,NorthAtlanticOcean 1996 2 n.t. Yes [35,66]
batzelladineF(31) Batzellasp. Jamaica,NorthAtlanticOcean 1997 2 Am Yes [30,39,42,67]
batzelladineG(32) Batzellasp. Jamaica,NorthAtlanticOcean 1997 2 Av No [67]
batzelladineH(33) Batzellasp. Jamaica,NorthAtlanticOcean 1997 2 Av No [67]
batzelladineI(34) Batzellasp. Jamaica,NorthAtlanticOcean 1997 2 Av No [67]
dehydrobatzelladineC(35) Monanchoraarbuscula Belize,NorthAtlanticOcean 2000 2 Av,Am,At Yes [43,53,73]
batzelladineJ(36) Monanchoraunguifera Panama,NorthAtlanticOcean 2005 3 n.t. No [59]
batzelladineK(37) Monanchoraunguifera Jamaica,NorthAtlanticOcean 2007 1 n.t. No [73]
batzelladineL(38) Monanchoraunguifera Jamaica,NorthAtlanticOcean 2007 2 Av,Am,At No [73]
batzelladineM(39) Monanchoraunguifera Jamaica,NorthAtlanticOcean 2007 2 Av,Am,At No [73]
batzelladineN(40) Monanchoraunguifera Jamaica,NorthAtlanticOcean 2007 2 Av,At No [73]
clathriadicacid(41) Clathriacalla Martinique,NorthAtlanticOcean 2009 1 Am No [68]
merobatzelladineA(42) Monanchorasp. Amami-OshimaIsland,NorthPacificOcean 2009 1 Am No [50,69]
merobatzelladineB(43) Monanchorasp. Amami-OshimaIsland,NorthPacificOcean 2009 1 Am Yes [69]
norbatzelladineA(44) Monanchoraarbuscula GuadeloupeIsland,NorthAtlanticOcean 2009 3 Am,At No [68]
norbatzelladineL(45) Clathriacalla Martinique,NorthAtlanticOcean 2009 2 Am,At No [68]
dinorbatzelladineA(46) Monanchoraarbuscula Guadeloupeisland,NorthAtlanticOcean 2009 3 Am,At No [68]
dinorbatzelladineB(47) Monanchoraarbuscula Guadeloupeisland,NorthAtlanticOcean 2009 3 n.t. No [68]
dinordehydrobatzelladineB(48) Monanchoraarbuscula Guadeloupeisland,NorthAtlanticOcean 2009 3 Am,At No [68]
dihomodehydrobatzelladineC(49) Monanchoraarbuscula Guadeloupeisland,NorthAtlanticOcean 2009 2 Am,At No [68]
batzellamideA(50) Monanchoraarbuscula RiodeJaneirostate,SouthAtlanticOcean 2015 2 n.t. No [70]
hemibatzelladineJ(51) Monanchoraarbuscula RiodeJaneirostate,SouthAtlanticOcean 2015 2 n.t. No [70]
∆19-hemibatzelladineJ(52) Monanchoraarbuscula RiodeJaneirostate,SouthAtlanticOcean 2015 2 n.t. No [70]
∆200-hemibatzelladineJ(53) Monanchoraarbuscula RiodeJaneirostate,SouthAtlanticOcean 2015 2 n.t. No [70]
Am,antimicrobialactivity;Av,antiviralactivity;At,antitumoractivity;andn.t.,nottested.
Mar.Drugs2016,14, 77 5of24
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A A
R1 R1
5O HN 5ONHNO19N O19
8 815 15
H10 NH131H0 NO1O3HR2OnOR R2 nR
R = ORH =ON OOHOHHONNOHHO2H NH2 R = R =N N NNHH22 NNHH22
O O
H2N H2N monamncohnoamncyhcoamliny cAa l(i2n3 A): ( 23):
monamncohnoacnidchino cAid (i1n8 A): R(11 8=) :H R,1 R =2 H= ,E Rt,2 n= =E1t3, n =13 R1 = ERt,1 R= 2E =t ,H R,2 n = =H14, n =14
monamncohnoacnidchino cDid (i2n1 D): R(21 1=) :H R,1 R =2 H= ,H R,2 n = =H13, n =13 monamncohnoamncyhcoamliny cBa (l2in4 )B: ( 24):
monamncohnoacnidchino cEid (2in2 )E: R(21 2=) :H R,1 R =2 H= ,E Rt,2 n= =E1t2, n =1 2 R1 = HR,1 R =2 H= ,H R,2 n = =H14, n =14
FigureF i3g. uCroen 3t.. Cont.
Figure3.Cont.
Mar.Drugs2016,14, 77 6of24
Mar. Drugs 2016, 14, 77 6 of 24
Mar. Drugs 2016, 14, 77 6 of 24
B
B
R3
R3
3 OH O19
3 O8HN NO1915
8 N10 NN1315
crambescidin 359 (1H1H1)0: NR11 3=R R1R2R 12=R 2R 3 = H
crcarmambebsecsidciidni n35 493 (11 (11)2: )R: 1R =1 =R 2R =3 =R 3H =, HR2 = COOEt
crcarmambebsecsidciidni n43 a1c i(d12 ()1:4 R):1 R= 1R =3 R=3 H = ,H R,2 R=2 C=O COOEOt H
crambescidin acid (14): R1 = R3 = H, R2 = COOH
R =2 = O nR4
R2 OO nR4
O
neofolitispate 1 (8): R1 = R3 = H, R4 = COOMe, n = 15
nenoefoofloitliistpisaptaet e1 2(8 ()9: )R: 1R =1 =R R3 =3 =H H, R, R4 =4 =C COOOOMMe,e n, n = =1 51 4
nenoefoofloitliistpisaptaet e2 3(9 ()1: 0R)1: R= 1R =3 R= 3H =, HR,4 R= 4C =O COOMOeM, ne ,= n 1 =4 13
necorafomlibtiesspcaidtei c3 a (c1i0d) :( 1R51) =: RR13 == RH3 ,= R H4 ,= R C4 O= OCMOOe,H n, =n 1 =3 14
R2 =R2 = OOO HmHOHOH NHN2H2 cprtpailmtoilmboemyscycaicdlainilci n Da cD (i1d (7 1()71: )5R:) 1R: =R1 =1R =R3 =R3 =H3 =H, RH, R4, =4R =M4 =Me C,e n,O n=O =1H 41, 4R n = 14
O mO N OH = R NH2
O N OH R =4 N NHN2H2
H2N R4 ON NH2
monancHh2Nocidin B (19): ptilomycalOin A (1):
moRn1 a=n Rc3h =o cHid, imn B= 1(139 ) : O ptRil1o =m Ry3c =a lRin = A H (,1 n) := 14
RmR11omR ==n1 o RRa=nn 33Ra c==n3h HHc=oh c,,Ho immdc, ii md==n i 11C=n34 1C (42 0(2)0: ) : cRr4a R=m4 =beOscONidNin 8O26NN (HHNN122HH3 22): RcRcrrRcRc11aa rr==11mmaa ==mmRRbb RR33eebb ==3 ssee= cc =ssRH iiOcc ddH ii,=ddH iiRnn, iiH,Rnn 88=R, 10 88=nO36010 O= 60H=(( 23 HH((1,))23 4n::,,)) nn:: = ==1 411 44
crRam1 =b Res3 c=id Hin, n8 2=6 1 (61 3): Rc1 r=a mR b=e OscHid, iRn3 8 =3 0H (,4 n): = 14

R1 = R3 = H, n = 16 crRa1m =b Re s=c iOdHin, 8R330 = ( 4H):, n = 15

Rc1 r=a mR b=e OscHid, iRn3 8 =4 4H (,5 n): = 15
crRa1m =b Re s=c iOdHin, 8R434 = ( 5H):, n = 16
Rm1 =o Rna =n OchHom, Ry3c =a lHin, Cn =(2 156):
mRo1n =a nRc =h oHm, Ryc3 a=l iEnt ,C n ( =2 51)4:

R1 = R = H, R3 = Et, n = 14
Figure 3. Related (A) C-8 cycloheptanic spiro ring and (B) C-8 cyclopentanic spiro ring
Figure 3. Related (A) C-8 cycloheptanic spiro ring and (B) C-8 cyclopentanic spiro ring
Figcurarme b3e.s ciRdeinla-tleikde G(AA). C-8 cycloheptanic spiro ring and (B) C-8 cyclopentanic spiro ring
crambescidin-likeGA.
crambescidin-like GA.
OHNOHNNNONO O ONH(OS)H NNHH22 OOHNHN NNN O19(R1O9)(RHO)H NO4(HO3S4)H3 NNHH22
H H 14 (S) NH2 H 14 (S) NH2
N OO ON NH2 N OO ON NH2
H H 14 H 14
O O O O
13,14,15-isocrambescidin 800 (6) Crambidine (7)
13,14,15-isocrambescidin 800 (6) Crambidine (7)
3 O H O19
8 N N
38ON10 NHN1O31519OH
H 15 H
10 N 13
OH
16β-hydroxyHcrambeHscidi n 359 (16)
F1ig6uβr-eh 4y.d Nroonx-yrcelraatmedb cersacmidbiens c3id5i9n -(l1ik6e) GA.
Figure 4. Non-related crambescidin-like GA.
Figure4.Non-relatedcrambescidin-likeGA.
Mar.Drugs2016,14, 77 7of24
Mar. Drugs 2016, 14, 77 7 of 24
Mar. Drugs 2016, 14, 77 7 of 24
CCoommppaarreedd ttoo ccrraammbbeesscciiddiinn--lliikkee GGAA,, bbaattzzeellllaaddiinneess--lliikkee GGAA pprreesseenntt mmoorree ssttrruuccttuurraall vvaarriiaattiioonnss..
SSttrruuccttuurrCaallollymy,, paaallllr eoodff ttthohe ec rbbaaamttzzbeeelllslaacddidiinninee-ssl iskshhea aGrreeA aa, dbdaeetcczaaehhllyyadddrriono-e- soo-rlri kooecct taGahhAyy ddprrrooe-s-55e,,n66,t,8 8mbb--ottrrrieiaa zszataraauccceetnnuaarpaplhh vtthhaaarlileaenntieeo ns.
ccoorrSee twwruiictthhtu ddraiifflflfyeerr, eeannltlt dodfee ggthrreeeee ssb aootffz oeolxxliaidddaaitntiieoosnn ..s hBBaaarttezz eealll laadddeiicnnaeehssy AdAr––oII -( (2o266r– –o33c44t))a aahllyll dpproooss-ss5ee,6sss,s8 baatt- tllreeiaaazsstta aoocnneeen attrrpiicchyythccllaiilcce ne
gguuaacnnoiirddeii nnweei ctchoo rrdeeit fhtfhearatetc noctno dntaetiagnirsnesee iset hiotehfr eoarx saiyd nsaytonior noanr. tBaianstttzie erseltloeardreeionla ertseio lAants–ihoI in(ps2h6o–ifp3t h4o)ef aatlnhl gepu oalanssrgehusylsa darr toh lgyeedansrsto gtohenanets flt rtahicnayktc lic
tfhlaengpkuy atrhnreoid lpiidnyiernr eocolnirdietir notheg aentni tcr[o7on6gt]ea.niTn o[s7 t6eh]ii.ts hT,etorr i tcahy iscsyl,i nctr ogicruy aacnnliitcdi gisntueearcneooidr erinealera etciocoornens naheripect ceoodfn ,tnthheerc otaeundgg,h uthalanrro euhsgytehdr raloinng ekenastsge ert,h at
alinndkflaaagndekd, iatthnioedn paadylrdgriuotialoindniiadnlie ng neuiaftrrnaoigdgmeinnee n[ f7tr6sa]go. mfTvoe antrhtysi ison, fgt vricacorymycilnpicgl e gcxuoitamyn.pidBleianxtizet eycl.ol aBrdea itanzreeels lcaFodn(i3nn1ee)sc, tFGe d(3(,3 1t2)h,) r,Goau n(g3d2h)L ,a an(3n 8eds) ter
aLl l(3lpi8no) skasalelg spes,o aasnsnedas dsa ddanidt iiaotidnodanilatitlor gincuayalc ntlriicdicihynyceld ifcrr oahxgyymd-rgeonuxtaysn -ogidfu ivananeriydfriinanggem cfroeamngtmp,lweenxhitit,l yew. thBhiaeltezs teihmlleap sdliiemnsetpsml eFse t(m 3m1b)ee,m rGsb o(e3fr2st) ho, eaf nd
fthameL fi la(y3m,8bi)la yat,lz lbe plalotazsdseielnlsaesds aiCnn ea(s2d 8Cd)i ,t(Di2o8n()2,a 9lD )t, r(ai2cn9yd)c,l Eiacn (h3dy0 )dE,r p(o3ox0sy)s-,e gpsusoasansciedosismn aem cforoanmg4mm-geounnat ,n4 w-idghuinialoen -tibhdueint syoilm-bupunltieyts.lt T umhneeitmm. Tboherrees of
cmoomtrhepe lc efoxammbpaitllyzeex, l blbaaadttzizneelellsala,ddAinin(e2es6s ,C) aA (n2 d(82)B6, )D( 2a 7n(2)d,9 a)B,r e a(na2t7dt)a ,E ca h(re3ed0 a)t,t otpaaocnshseaedns ast loao gacuonem aomnfaoclrnoag m4u-beg euosafcn icnirdaAimn(ob5-4eb)suc(tiFynil g Auun r(ei5t5.4 ))T. he
B(Faitgmzueorllerae d5 c)i.no eBmsaptFzlee(x3ll 1ab)daaitnnzdeesllJ aF(d3 (i6n3)1ea)s r,a eAncd o( m2J6 p()3 oa6sn)e dda roBef c(t2ow7mo),p 5ao,r6se,e6 daa t-ottarfi cathwzeado- a 5tco,e6 n,a6anap -ahtrntihaaazlolaeg-nauceee cnooafr pecshratlhimnakbleeendscevi nciao Arae ns( 54)
alilnipk(hFedaigt viucirace h a5an)i .na B.liapthzaetlilac dcihnaeisn .F (31) and J (36) are composed of two 5,6,6a-triaza-acenaphthalene cores
linTTkhheeed ss vttrriauu ccattnuu rraeelsisp oohffa stsieecvv ceehrraaailln mm. eemmbbeerrss ooff tthhee bbaattzzeellllaaddiinneess hhaavvee bbeeeenn rreevviisseedd ssiinnccee tthheeiirr oorriiggiinnaall
iissoollaattiioonnT.. hTTeh hseet rouorcriitgguiinrneaasll llyoyf ppsreroovppeoroasslee dmd sestmtrruubccettruusr reoesfs twwheeer rebe abbtzaaesselelddad ooinnne csch hheeammviiecc aablle dednee ggrrreaavddisaaettiidoo nns inssttcuuedd tiiheeessi,, rN NoMMrigRRin al
ssppeeiccsttorrlooasstcciooonpp.yy Taahnneaa lloyyrssiiigssi n((11aDDlly aa nnpddro 22pDDos)),,e daann sddtr ccuoocmmtuppreaasrr iisswooennr eoo ffb ttahhseee ddd aaottnaa tctooh eppmrreeivcvaiiool uudssellgyyr rareedppaootirrotteendd s ptpuoodllyyieccsyy,c cNlliiccM R
gguuaasnnpiieddciitnnreeo sscusoucphcyha saanpsat illypostmiislyo (mc1aDylic naaAnlidn( 12)AD. S),i( n1ac)n.e dtS hcienocmoerp igatihrnieas olonisr oioglfai tntihaoeln dwisaootalrak tt,ioot hnpe rsewtvroiuorcuktu,s lryteh sreeo pfsobtrratutezcdet ullpraoedsliy nceoysfc lic
Aba(t2gz6eu)lal,anDdidi(ni2ne9es) ,AEs u((2c3h60)) ,, aaDsn (d2p9Fti)l,(o 3Em1 )(y3hc0aa)v,l ieann adlAl Fb e((1e3n)1. )r ehSvianivsceee d alttlho bete heoenri rirgceiuvnriasrlee dni sttooslt artuhtiecotinru rcewusrorarefknte,t r stththreue icrstutprrauercstt iuaafrlteoesrr of
ttohteabilra stpyzanerlttlhiaaedls iionsre[ s2t o7A–ta 3(l02 s,63y)5,n ,D3th9 e](.2si9As) s,[ 2Ea7 c(–o330n0)s,,3e aq5n,u3de9 n]F.c eA(3os1 f)a th hcaeovsnees reaeqlalu sbeseingecnnem roeefv ntithssee,dsthe t eore rteahlsaestiiirgv nceumsrtereenrnetsto ,c sththreuem crtieusltrareytsiv oaeff ter
sbtaetrtzeheoellciarhd epimnareitssitaGrly o(o3rf2 t)bo,atHtazle( 3slly3a)nd,taihnneedssi sIG ([ 32(437)2–)h3, 0aH,s3 b5(3,e33e9)n,] .ar eAnedsx aIa m (c3io4nn)e shdeaq[s3u b0ee]n.ecne roefe xthamesien ereda [s3s0ig].n ments, the relative
steTTrhheeeo ccchuuerrrrmeennisttt rssyttrr uoufcc ttbuuarrteezsse ololfaf d2222in rreeesll aaGttee (dd3 2bb)aa, ttHzzee (lll3laa3dd),ii nnaene--dllii kkI ee(3 GG4A)A h aaarrsee b sseuuemmn mmreaearxriiazzmeeddin iinend FF i[ig3gu0u]rr.e e 66..
OOtthhTeehrre bb caauttzzrreeelllnlaatdd siitnnreue--cllitikukere eGGs AoAf h2h2aa vvreee lbabteeeeednn biisasotozllaeatlteleaddd sisnuuecc-hhli kaaess GbbaAattz zaeerllella asdduiinmneem CCa r((i22z88e)d),, KiKn ((F33i77g))u,, raaenn 6dd. EE ((3300));;
ddeehhyyddrrooObbtaahttzzeere lllblaaaddtziinneeell aCCd ((i33n55e))-;;l icckllaeat thGhrrAiiaa ddhiiaccv aaecc iibdde e((44n11 )i);s; oaalnnaddte bbdaa tstzzueecllhllaa mamsi iddbeaet AAze ((l5l5a00d)) i((nFFeiig gCuu rr(ee2 787))).,. K (37), and E (30);
dehydrobatzelladine C (35); clathriadic acid (41); and batzellamide A (50) (Figure 7).
NH
O O
NH NHN2H
O O
8 NH NH2
HN N
NHH8N N
crambNeHscin A (54)
crambescin A (54)
Figure 5. Crambescin A (54).
Figure5.CrambescinA(54).
Figure 5. Crambescin A (54).
A
A R1 O H H
R2 n OR1 O HN H
R2 n O N NHN m
NH R2 = N NRN RNH m
R2 =R2 = HONH NHHONHON ON3NH 3NHNHN2H NH2 batzelladiRn2e =H F (HN31N):NH N H NH
bRa1 t=bz eaHltlz,a endl li=an d8e, i Anme N ( H=2A 68 )( :2 6 ) : bRa1 t=Rbz eaC1 lt=lHza eCd3l,lHi aRnd3e ,= i GRn He =( ,3F nH2 ( )=3,: 1n7 ) ,=: m 7 ,= m 6 = 6 batzeRl2l =aRd2 i=nNHe DNHNH N(2H2 N9H)2:
norRb1a =tz Hel,l and =in 8e, Am (=4 84 ): Rba1 t=Rbz eaC1 lt=lHza eCd3l,lH iRand3e ,= iRL nO e (=H 3G O8, )(nH:3 =2 , )n7: ,= m 7 ,= m 8 = 8 R1 =b Hat,z mel l=a d7i,n ne =D 3 (29):
R1 =n oHr,b na t=z e8l,l amd =in 7e A (44): R1 = H, m = 7, n = 3
dinRo1r b=a Htz,e nll a=d 8i,n me A= 7(4 6): R1 =b aCtHze3l,l aRd =in He ,L n (=3 87),: m = 8
norRb1a t=z CelHla3d, iRn e= LH (,4 n5 )=: 7 , m = 8
R1 =d Hin,o nrb =a t8z, emll a=d 6in e A (46):
R1 = H, n = 8, m = 6 R1 =n oCrHba3,t zRe =ll aHd,i nne = L 7 ,( 4m5 )=: 7
R1 = CH3, R = H, n = 7, m = 7

Figure 6. Cont.
Figure 6. Cont.
Figure6.Cont.
Mar.Drugs2016,14, 77 8of24
Mar. Drugs 2016, 14, 77 8 of 24
B
R1 O H
R2 n O N
N N
H 6
= H
R2 N N
R = HN N
2 NH N
N O H H
H O 3NH NH2 batzelladine M (39): R1 = H, n = 6
batzelladine J (36): R1 = H, n = 6 batzelladine N (40): R1 = CH3, n = 7

C
O
H
R1 O N
R N N
2 H n
NH
O O
OH OH NH H 3NH NH2
R1 = 6 N N N R1 = 6 N N N R1 = NH NH2 R1 = H6N N
H H H H Dihomodehydro- NH
batzelladine H (33): batzelladine I (34): batzelladine C (49): dinordehydro-
R2 = CH3, n = 6 R2 = CH3, n = 6 R2 = C5H11, n = 8 batzelladine B (48):
R2 = CH3, n = 6
D E
NH
H H
N N NH O
H H
R
NH NH n H H n O N
H2N N O O N N
NH 3 H 5
merobatzelladine A (42): R = , n = 5
batzelladine B (27): n = 8
merobatzelladine B (43): R = Et, n = 3
dinorbatzelladine B (47): n = 6

F
O
H H
H2N N O N
NH
NH NH R
hemibatzelladine J (51): R = OH

OH
Δ19-hemibatzelladine J (52): R =
Δ20-hemibatzelladine J (53): R = OH

FFigiguurere6 .6.R Reelalateteddb baatztzelellaladdinine-el-ilkikeeG GAAw witihthd dififfefreernenttr irgihght-th-hanadndededtr tirciyccylcelse.s.
Mar.Drugs2016,14, 77 9of24
Mar. Drugs 2016, 14, 77 9 of 24
H O H H OH H H O H
H2N N O N H2N N O N H2N N O N
NH NH NH
Mar. Drugs 2016, 14, 77 N HN 5 N NH N N 95 o f 24
batzelladine C (28) batzelladine E (30) dehydrobatzelladine C (35)
H O H H O H H H O H
H2NNHNbatzeHllaNHdONinNeH CN 4N( 2HN8) 5 H2NNHNbat5zeHllaNHOdNinNe NEON (O3NHH0 ) H2dNeNNHhHyNNdNHroba7tzOOelOlaHdNNinNNe NNCH (3O5 ) 5
batzelladine K (37) clathriadic acid (41) batzellamide A (50)
H H NH N N O
NHNN 4 FigFuigruere7 .7U. Unnrreel5laattHeedd bbNaattzzeelllOaladOdiHni en-eli-kleik GeAG. A. NH NH 7 O HNNNH O
In summary, the structurally unique tricyclic guanidinium ring system
In(hydrsoub-5ma,t6zm,6ealaltarrdyia,iznaea Kcet (hn3ae7p) thasletrnue)c ttuharta dllceylfainthersiu atnhdiiisqc cualcaeisds (o4ft1 rn)i actyucralilc prodguuctabsna ctiazdnei lnblaieum fmoiduen dA ir(ni5n 0og)v er 53sy stem
(hydrod-i5ff,e6r,e6natt railakzalaoaidces.n Waphtihlea leeanche F)oigft uhtrhaeet 7s.e dU nenafirtenulaertaseld pt bhraoitsdzeulcclaltads sinsshe-aolrikfee t nGhaiAst .u croamlmporno dsturucctsturcaal nmobteif, ftohue nd in
over5s3udbsitfifteureenntts aalrkoaulnodi dths.e Wtrihcyilcelice accohreo offt thheessee nmaotluercaulleps rloedadusc ttos sah saigrenitfhiciasnct osmtrumctounrasl tdruivcetrusirtayl, motif,
thesuwbshtiictIhun erenlatsstuea mtroom au awnrdyid, teh-reatnthrgeie c yofc slbiticroulcocotguriecraaolll fpytr hopeseuerntimieqsuo. eFle ocru inltersistcaylneccaleidc, as ltaogrguaeas nnigiudnminibfiieucrma on ft thsterrsiune gcmt uorleasclyusdlteiesvm e rsity,
(ihnycdlurdo-in5,g6 ,b6aattzreiallzaadaicneen Fa p(t3h1a) laennde) pthtialot mdeyfcianleins tAh i(s1 c) lfaesast uofr en aestuterrasl tphraotd tuetchtse rc athne b ter ifcoyucnlidc cinor oev teor a5 3
whichrelatetoawide-rangeofbiologicalproperties. Forinstance,alargenumberofthesemolecules
ddiifvfeerresne ta rarlakya loofi ddsi.f fWerehnilte f ueancchti oonfa tl hgersoeu pnsa,t uinrcallu pdrinogd uoctthse rs htraircey ctlhicis g cuoamnimdionne ssutrbuucntuitrsa. lT mheo otitfh, etrh e
includingbatzelladineF(31)andptilomycalinA(1)featureestersthattetherthetricycliccoretoa
saurbesat iotuf esntrtus caturorauln ddi vtheres ittryic wyciltihci nc otrhei so ffa tmheilsye omf oallekcauloleids sl eisa dbso ttho tah esi gCn1i faicnadn tt hset rCuc8t ualrkayl ld cihvearinsist,y ,
diversearrayofdifferentfunctionalgroups,includingothertricyclicguanidinesubunits. Theother
wwhhiicchh rvealartye itno tae wrmids eo-fr alnengget ohf, buinoiltosg oicf aul npsraotpuerarttiieosn. ,F aonrd i nosxtaidnacteio, an .l aRregme ontuem obxeidr aotfi othne osfe tmheo laelckuylle s
area oibnfrcaslutnrdcuhincetgsu briasa tlzcdehlilavardeacrintseeirt iyFs t(iw3c 1i)to haf inntdh teph tiicslroafmammybceialslycinido Aifn a(1lak)l kafealoalotiuiddrsse, iesisntbecorlust dhthintahgt etepCtthi1leorma tnhydeca ttlrihince yAcCl i8c( 1aco)l kreay nltodc ha ains,
whichdcirvvaaemrrsybee isancrirdtaeiynr m o3f5s 9do i(ff1f1elre),en wngth tfhiuc,hnu cftneiaoittnusarloe g ftrwuonou spsapst,i urionrccayltucidolicinn ,hgea omntdhiaemor xitnridiaclayst cailosic nw g.euRlal enamisd tiohnteee tsrouicxbyiudcnlaiictt isgo. unTahnoeifd otitnhheee ra lkyl
brancahfrreeasam iosefwc hsotarrkura.c ctIunter raailds ddtiiictvioeornfs tithtoye swctrriauthmcitnub retahslc isdi difvainemrasililytky a,o lfbo aaidtlzksea,lllioanidcdilsnu eidssi -nlbikogethp G ttihAloe m aCny1dc aacnlridanm tAhbee( s1Cc)i8da inanldsk-ylcilkr aecmh GabiAne ss,c idin
359 (1wa1lh)k,iacwlho hivdiascr hyfe fainetu atrteeur mrdeisf tfoewfr eolnents pgsttiherro, ecuoyncchitlesim coifhc uaelmn csiaoatnumfirgainutiaroalntsi, oaansnsd wo ofe xltilhdeaa sttirotihcnye. cRltiercim ccyoorcteel i. ocBxgoidtuhaa ttnihoined itonrfae nthsf-er aaamnlkdey wl ork.
Inaddbcriitsai-nocconhnetfoisg suitrsra utcicohtnuasrr aaoclft edtrhiives teiprcys riotryof ,libtdhainetz e ecslrulaabmdubinneites cshi-daliviknee baGelekAna laroenipddos,rc treiadnmc ilnub detshincisgid cilpnatssis-l oloimkf eyncGaatAulinraa ll Akpa rol(od1i)ud cstasnf.e da ture
cBraamtzeblelascdiidnien F3 5(93 1(1) 1h),i gwhhliigchh tfse athtuisr es ttweroe oscphieromciyccalli cd hiveemrsiaitmy inasa lsit acso wntealiln ass ttwheo trdicisytcinlicct gturiacnyicdliicn e
different stereochemical configurations of the tricyclic core. Both the trans- and cis-configurations
fgraumaneiwdionrek .s uInb uanditdsi,t iwoint ht oe ascthru fcetauturarli ndgi voenres iotyf , thbea tpzyelrlraodliidniense-l ickoen fGigAu raantidon csr. aTmhbe esstceirdeioncsh-leimkei cGalA
ofthepyrrolidinesubunithavebeenreportedinthisclassofnaturalproducts. BatzelladineF(31)
adlkivaelorsiidtys ifse agteunreer adlliyff elirmenitte dst teor ethoech ceomnfiicgaul rcaotinofnig ouf rtahteio pnysr roofl itdhien et ruincyitc, laics aclol roef. tBheo tahlk tahleo idtrsa nins -t hains d
highlicglhastss ftehaitsusrete ar etoracnhse rmelaictiaolndshivipe rbseittwyeaesni tthceo nCt4a (iannsdt/woro Cd6i)s ptirnoctotntr aicnydc ltihce gCu1a (nainddi/noer sCu8b) ualnkiytsl ,with
cis-configurations of the pyrrolidine subunit have been reported in this class of natural products.
each fcehaatiun,r iwnigth othnee eoxcfepthtieonp oyfr mroelriodbiantezeclloadnifingesu Ara (t4io2)n asn.d TBh (4e3)s.t Beoretho cnhateumrailc parlodduivcetsr sfeitayturise ag ceins erally
Batzelladine F (31) highlights this stereochemical diversity as it contains two distinct tricyclic
limiterdeltaotiotnhsehicpo bnefitwgeuerna ttihoen C6o fprtohteonp aynrdr othlied Cin8e alukynli tc,haaisn.a ll of the alkaloids in this class feature a
guanidine subunits, with each featuring one of the pyrrolidine configurations. The stereochemical
transdreivlaetrisoitnys ihs igpenbeertawllye elinmtihteed Cto4 th(aen cdon/foigruCra6t)iopnr ooft othnea pnydrrothliediCne1 u(annitd, a/so arllC of8 t)hael kalyklaclohidaisn in,w thiitsh the
2.2. TGA Classification
excepctliaosns foefatmureer oa btaratnzse lrlealdatiinonesshAip (b4e2t)waenend tBhe( 4C34) .(aBnodt/horn Ca6t)u rparoltporno adnudc ttshef eCa1tu (raenda/ocri sCr8e)l aatlikoynl ship
betwecehnaitnhD, ewifCfieth6re ptnhrte og etuoxancneiapdntiindoen t aholkef amCloe8irdoasbl kcalytazlsesclilhfaiacdaiintni.eosn sA c (a4n2 )b ea nmda Bd e(,4 a3n).d B, oatsh s uncahtu, rSaaln ptoros detu aclt.s ( 2fe0a1t5u) rhea av ec is
rdeelastciroinbeshdi pfo buert wGAee nch tehme oCt6y pperso t[o7n0] a. nTdh eth feir Cst8 c alalkssy li sc hcaoinns.t i tuted of a monocyclic pyrimidinamine
2.2. TGskAelCetloans,s iffiocr aetxioanmple, crambescin C1 (55) or the bicyclic cyclopentapyrimidinamine skeleton, such
2a.2s . cTraGmAb Cinlaes sAif ic(5a6ti)o n(F igure 8). The second one is a tricyclic triazaacenaphthylene skeleton, which
Differentguanidinealkaloidsclassificationscanbemade,and,assuch,Santosetal. (2015)have
only contains one guanidine moiety like crambescidins, and the third one possess the same skeleton
Different guanidine alkaloids classifications can be made, and, as such, Santos et al. (2015) have
descriabse fdorf ocluarssG 2A, bucht ceomntoatiynps,e ast [l7ea0s]t., Tonhee mfiorrset gcluaasnsidisinceo mnostieittuy,t eads coafn abem soeenno ciny cthliec cpasyer iomf midoisnta mine
described four GA chemotypes [70]. The first class is constituted of a monocyclic pyrimidinamine
skeletboant,zefollradeixnaems. Tphlee, fcoruarmth boensec iisn aC tr1ic(y5c5li)c ocyrctlhopeebnitcayqculiincaczyolcinloapmeinneta spkyelreitmoni dliiknea nmetianmeinske eMle (t5o7n) ,such
skeleton, for example, crambescin C1 (55) or the bicyclic cyclopentapyrimidinamine skeleton, such
as craomr bpitnileocAaul(i5n6 ()58(F). igure 8). The second one is a tricyclic triazaacenaphthylene skeleton, which
as crambine A (56) (Figure 8). The second one is a tricyclic triazaacenaphthylene skeleton, which
onlycontainsoneguanidinemoietylikecrambescidins,andthethirdonepossessthesameskeleton
only contains one guanidine moiety like crambescidins, and the third one possess the same skeleton
A B C D
asforasc lfaosrs c2la,sbs u2t, bcuotn cNtaoHin2ntasi,nast, alet alesat,sto, nNoHen2em moorree gguuaanniiddiinnee mmooieiteyt,y a,sa scacna nbeb seeesne einn tihne tchaesec aofs emoofstm ost
batzebllaatdzeinlleasd.inTehs.e TfHhoNeu frotNhurothn eonise ias tar itcrNiyccylNcilcicc cyyccllooppeennttaaqquuNiinHn2aazzoolilninamaminien seksekleetolent NoliHnkel inkeetanmeitnaem Min (e57M) (57)
orptiolor cpatuilloiHcnaOu(5li8n) .(58). C8H17 C10H21 HN N HN NH
A O O NH2 B O O HN NH2 C D
NH52 NH NH NH2 NH
crambeHsNcin NC1 (55) craNmbiNne A (56) neNtaHm2 ine M (57) ptiloNcHaulin (58)
HO C8H17 C10H21 HN N HN NH
Figure 8. (A) Crambescin C1 (55); (B) crambine A (56); (C) netamine M (57); and (D) ptilocaulin (58).
O O NH2 O O H
N NH2
N NH
5 H NH
crambescin C1 (55) crambine A (56) netamine M (57) ptilocaulin (58)
Figure 8. (A) Crambescin C1 (55); (B) crambine A (56); (C) netamine M (57); and (D) ptilocaulin (58).
Figure8.(A)CrambescinC1(55);(B)crambineA(56);(C)netamineM(57);and(D)ptilocaulin(58).
Mar. Drugs 2016, 14, 77 10 of 24
Mar. Drugs 2016, 14, 77 10 of 24
Mar. MDMrauraM.gr.Ds a D2rr.u0r Dug1gs6rs,u2 1g204s01 ,612 7,6071,1 416,4, ,17 7477, 77 10 of 121040 o 1of0f2 2o44f 24
Another classification can be made with the same first, second and fourth classes, and a
Another classification can be made with the same first, second and fourth classes, and a
modified third class describing pentacyclic triazaacenaphthylene skeletons like crambescidins (1–25)
AnotAhenAro ntcholteahrs esicrf liaccsalastisifosmiicnfao ictcdiaaoitfnniio e nbdc ae tcn ham inrbad edb ceeml a wasmsdi adetdh ee ws tchiwrteihbi t ishntah gmte hp eese anfsmitraasemct y, efci slreifscictr ,ots rntsi,ad ezsc eaoacannocdden ndafa onpaudhnr ttdfhho y ufclorelutanhrset s hecs klsa,ce sllaaseesntsosd,en ssaa, n laidkn eda c raa mbescidins (1–25)
(Table A3)n. o therclassificationcanbemadewiththesamefirst,secondandfourthclasses,andamodified
modimfieomddo itdfhiieifrdide td hc ltiarhsdisr cddl aecsslasc sr(dsiTbe dasinbecrlgseic b pr3iie)nb.n gint apgce ypncetlnaicct aytcrciylaicczl aitcra itcarezinaazaaapcaehcntehanypalheptnhhety hsleyknleeelne steko senklsee tllioeknteos nc lrsika lmeik cber eacsmrcaibmdeibnsecsis d(c1ii–dn2sin5 ()s1 –(12–52) 5)
thirWdcitlhaossudt etsackriinbgin ignptoe natcaccoyucnlitc atrniayz agaecneunsa prehvthisyiolenn emsakdeele, tsoonmslei koebcsrearmvabteiosncisd imnsay(1 –b2e5 o)u(Ttalibnleed3. ).
(Tabl(eT (3aT)b.al eb l3e) .3 ) . Without taking into account any genus revision made, some observations may be outlined.
AccordWinitgh toou tthtea dkaintag rienptoortaecdc,o Munotnaanncyhogrean isu sthree mviosisotn stmudaidede, gseonmues (oTbasbelrevsa 1t iaonnds 2m).a Syombee ospuetlciineesd .
WithWouWitt hittoahukotiun tgta ktiainnktgionA gianc ccticnooo rtuoadn cianct ocgacu ntonouyt tn hgate nea nydnu aygst eagrn reeuevnpsiu sorisroe tvnreeid svm,i ioMsanidoo ennm, a amnsdocahemdo, reesa ,o oismsbo stemhe reoev bmaostbeoiosrsvetn rassvtt iuamotdniaoisyen d msb geame ynoa uuyb tselb i(noeT euaodtbul.li entlsei nd1e .a dn. d 2). Some species
seAemcc otrod pinrgodtoucteh ebodtahta threep corratmedb,eMscoidnainnsc haonrda ibsatthzeelmlaodsitnsetsu cdliaesdsegse ansu iss (iTlalubsltersa1teadn wdi2t)h. SMoomneanscpheocriae s
AccoArdcAicnocgcr odtoridn tgihn etgo d ttoaht teah dreea dptsaaoe trreateme prde o,tp roMot eprodtrne,o daMdn, ucMohcnoeoar nnbaac oinhstco hthrh aot erhia sem itcsho rtesaht mm es tbomuesdots cisseittdd usi tdgnuiesde ndaiuen gdsd e (g nTbeuaansbtuz l(eesT sl(al Ta1bd alaebinnsld ee1ss 2 a1c)n .la adSnso s2dme) .s2 e S)a .os sSpm oiesemc iisleelps use spcteirecasit eesd with Monanchora
unsegeumifertao, pwrohdicuhc perboodtuhctehse 1c6rβa-mhybdesrcoixdyincrsaamnbdebscaitdzienl la(1d6i)n, ecsracmlasbseessciadsicis aiclliuds (t1ra5t)e adnwd ibthatMzeollnaadnicnheosr a
seems etosee mper mtoo d tpuor cpoerd bouodctuehc betho bteuho nct trhghau temih fceberr eaacs,mr cawibmdheibniscecshis da cpniidnrdosi n dbasuan atcdzne esdbl la 1abt6dzaβeitn-zlhleeaylsdl dacidnrlaoeinsxssy eecscls ra caaslmasse sibsss ee aissls cla uiidsss itiinrslal ui(tl1eslu6dtr)s a,wt trceairtdtahe m dwMb iwteohnsit caMhind cMoihcno oaarnnacac inhdco h(r1ao5 ra) and batzelladines
J–uLn g(3u6if–e3ra8,) w(Thaicbhleps r1o dauncde s2)1.6 Oβ-thhyerd rgoexnyecrraa msebeemsc itdoi npr(o1d6)u,ccera omnblye socnidei cTaGcAid f(a1m5)ialyn.d Fboart zeexlalamdpinlee,s tJo– L
unguuifneurganu,g iwfueirhfaei,rc awh, hwpirchohidc hpu rcpoeJrds–o uL1dc6 u(eβ3cs-6e h1–sy6 31dβ86r-)βh o(-yxThydaycrbdrolaerxmosy xc1byr eacasmrncadibmd ei2bns)ec. i(sOd1c6iitdn)h, i e(ncr1r 6(ag1)me,6 n)cb,er earcsamrca isbmdeeiebcsm ecais dcctiiioddc pia(c1rc o5aidd)c i uad(1nc 5e(d1 ) o 5ban)an latdyzn eodblnal abtedza eTitnzlGleeaAlsdl a indfaeimns eisly . For example, to
da(3te6,– B38at)z(eTllaab slpes. w1aasn don2l)y. sOhtohwerng teon perroadsueceem btaotzperlloadduinceeso Anl–yI o(2n6e–3T4G).A family. Forexample,todate,
J–L (J3–6LJ–– 3L(83 )6( 3–(T63–8a3)b 8l(e)T s(a T1ba laebnsl ed1sd 2aa1)tn .ea d,On Bd2tah) .t2e z)Ore. ltglOhae tesnhrpe e.rgr awe gnsaeeesnre oaem rnsa let yose e smphe rmotoow d tnpou rctpoeord oopudnrcolueydc oueon cnoleeyn b lToyaGn tozeAen lT elfa GaTdmAGini Alfeyas .mf AaFimo–lyrIi .l( ey2Fx.6o aF–rmo3 e4rpx )le.ae xm,a tpmol ep,l et,o to
BatzIneltlearseps.tiwngalsyo, nal ychsheomwontatxoopnroomdiucc estbuadtyze lsluagdgineessteAd– tIh(a2t6 –t3h4e) .biogenetically related guanidine
date,d Badatteaz,te eBll,a aBt szapetlz.l eawl lsaap ss. pow.n awlysa ossnh oloynwI lnsynth e sotrhoweo spnwtir ntonogd tlpuoyr c,po eard bo uadccthuezec ebmelal abotdzataeitnzxlleoealsndl aoAidnm–einIis c e(A 2ss6 –At–uI3 –d(4I2y )6(. 2 –s63u–4g3).g4 )e.s ted that the biogenetically related guanidine
alkaloiIdnst eisreoslatitnegdl yfr,oamc Chreammobtea cxroamnobme, iMcosntuandcyhosruag agrbeustsecudlat,h Pattiltohcaeubliiso sgpeicnueltiifcera,l layndre Hlaetmedimgyucaalne isdpi.n, e
InterIensIttneinrtegesrlyetis,n tgian lygc,hl yea,m aaclok htaceahlmxoeoiomdntsaoo xitmsaooxincloao ntmseotduimc df irycso tmussutd uCgydgr yasemu sstgbeugedg ec grstatehemsadtbte edtt,h hMtaeht o abnttiha onteghc ehebno irobeatgi ioaecgrnabeleulntysie cctuarieclllalaya,l tlPyertde illr oaegctlaeuaudtael nidsgi dusgpianuinceaui dnliiifnderei,n aen d Hemimycale sp.,
Masr.h aDoMlrkuuaMaglrd.sl ao D2 re.i0r dDvu1g6sers,un 1ig2st4s0uo ,12 7a6l0a7,l1 l1t6ye4, , d1 b747e,f 7ruo7 nmiteCdr ainm bae sicnragmleb ge,enMuosn, apnrcehfeorreanatribaullsyc uClraa,mPbteil o[5c3au].l is spiculifer, and H1e0m oifm 214y0 c 1oa0fl 2oe4f 24
alkalaolikdaalskl oiasilodolsiad tises odisl afortloeadmte fd Cr ofrsrmahomo mCbue rlC adcmrr eaabmvmee bbcneer t,ac umMraablmoleny,b a Mebn, ecMo hnuooanrnnaiatc aenhrdcobhr uiaons ra caaru b alsuraib,sn ucPgustlcliealu o,gl caPea,tn uPiullotissicl ,aos pupcairlciuesufl sielsiprf eisecrpnu,i tcaliiuanfelldirlfy, e H arC,ne armdan miHdmb eyHemc e[ai5mmle3i y]ms.cp ya.lc,e a slep s.,p .,
sp.,shouldeventuallybeunitedinasinglegenus,preferentiallyCrambe[53].
shousldhs oehuvoledun letduv eaevlnleytun btauell auyl nlbyie tbe uedn uiintne iadt e sidinn igan l seai ngsgeinnlegu lgse,e gnpeurnesfu,e spr,er penfrteeiarfeellnryet niCatrlilaayml lCybe rC a[mr5a3bm]e. b [e5 3[5].3 ].
AnotAhenAro ntcholteahrs esicrf liaccsalastisifosiicnfa ictciaaotnnio nbc aecn am nba edb eem wamTdaiaetbdh le ew t3hiw.t ehGi t Ashtah cmtelha eses s aefsmsira. semt , efi srefsictr,os nts,d esc eoacnnoddn daf onaudnr tdfho ufcorlutahrst shec lsa,c slaasesnssd,e saa, n adn da a
Table 3. GA classes.
modimfieomddo itdfhiieifrdide td hc ltiarhsdisr cddl aecsslasc srdsibe dsinecrgsic bpriienbngint apgce ypncetlnaicct aytcrciyTlaiacczbl aitlcrae itca3rez.inaaGzaaAapcaehccnltaehasnypsaelhepstn.hhety hsleyknleeelne steko senklsee tllioeknteos nc lrsika lmeik cber eacsmrcaibmdeibnsecsis d(c1ii–dn2sin5 ()s1 –(12–52) 5)
TableT 3aT.b GalebA l3 ec. lG3a.s AGs eAcsl.a cslsaesss.e s.
No Class 1 Class 2 Class 3 Class 4 Ref.
(Tabl(eT (3aT)b.al eb l3e) .3 ) . No Class 1 Class 2 Class 3 Class 4 Ref.
WiNthoWo uWNiNtt hoiNottoah ukooti un Ctgta l ktaiainsnkCtsgiCon l 1 Clagiaa nlss catsiscnoso 11 tsuoa n1 cacCt ocalcuanonsuyCts n gal2CtaC ne alsnylaansu ss ygs2ss e 2gr2nee uvnsiu srisoe vnrei svmCiiosalniadoC senmlCs,a samls3Csado a3lsemads, s ees3s ,o o s3mbo seme roev baostbeiosrvCenCraslvlt aaiamosstCssniaNo 4sly4CHn a mslsb aseams y4soaR uy4be t elfb iR.noe Re eufoedRt.ulf.i e.nt lfei.nd e. d.
H NH
AsececmoAsr etdcoAseice mnpocegcrr m to1doto or di tdn puotgihr cnp oeetgord d bo tutoaodhct tuteeahhH c dbreeNtNeaho HdpbtteN2ahaoo H ctt rrNNatrh2tehae H prNtedme2ho H,pc ber2Mrot eaec1rsodmrHNt cnae,i bdmadMHNne,i bnscNMoNHNechsniso oNadHNacrnnniiaadncN dHinhsis nNcNo bathrshanao Nat erdiHzna sNm e2 dbitlshlao abttesdzhat m eitesnzl tlomeeuHNaslsddlot aHNN ciissdnelttNadN euiHNsnss tdsgNN euHNeciesdelsn Nad ciausel Nasgsdse s e i(ssgsnT e eauaisnls sblau u li(sesssT sti(air sTl1bal Hu aitlalNeebslnusHdtldr eNHNNs 1aswt HH 2tr aNNH1Nea)inHHt .dta hNdNNeSN n dwHo HM2dNN m)iw HHt.o2 NhenS)i Ht .oas MhSnpm[ o7cMeohem0nc o]ioase ernnpas asce nphccoeiehrcaHsoi erNas H NH [70]
Ju–nLg u(Ju3i–f6neLJu–rg–a n31uL(,8g 3 i wf)u6(e 3i–r(hf1Ta63e1i,–r8ac a3w1h)b, 8 l(hwep)T isr(achH oTh1biNdac laehpbuns lrcH epode1NsNrds H o2 a1uN1d)n c.6a u deβONncs -d2e thN1h)s y.62 e 1dβ)Or.6 r- tgβhOoNhe-yxtehnydhryec errgdrorNaae rx gmonNyse xeecbnyrereaeamcs r+mrsca a1eit bmd oseoeei m brnspe ecm rmi(stod1oco d6ii trdnpou)e, i rc (npgocNe1r rud 6(aoo1Nau)mdn,6nc lu)cNeiby ,drc e acoNeios n mrn cnaoeilbemdyn m e +ilTbocys 1oG ecn aioisoeedAccnr tiii Ty dedcmf G aiTa(com1AcG r5aiei dA)clf ygi aHa d(.muf1 n aFa5H(dim1on)l y5ribHaid .)la ne yFiHatxdn . zo na eFerdbm[ lo m7al erapb0tx odza]lea[e ieitx7men[,zl0a 7tleety]apm0[olsd7 l]l aep 0ind,]l e eitn,os etos
date,d Badatteaz,te eBll,a aBt szapetlz.l eawl lsaap ss. pow.n awlysa os snh oloynw ls ynh s othowo pnwr tonod tpuo r cpoerd bo+uad 1ct uezo c erb+e lmal 1abt+ dzooa1erirt nzoe lmle erag l+sdomlu 1aAriadnoeon– erirgnIiesmd u e(gA2isaonu6 nr–Ae–eaIi 3d n–m(4I2iidn )o6(.e2ii –ne 63mte–4y 3)om .4i e)o.ti ye ty H
guanidinemoiety AcHanthHe llHa
InterIensIttneinrtegesrlyetis,n tgian lygc,hl yea,m aco htceahmxeoomntaooxtmaCoxinlcoao tnmshotruimicad iycs tussutdugydg yseu sstgeugdge gsttehesadtte dtth htaeht abttih otegh eebn iobetgiioecgnaelelntyie ctarieclllayal tlyerde lr aegtleuadtae ndgi dugianuneai dniindAeinc aen thella
Clathria Arenochalina
sahlkoaulsaoldhlikdsa oehalsuvklo oilaesduinlodo letdlsiuavd teaiesesvln odlieytsl unafo brttaloeuealdml taBCuye laf d nrlbCrytaBi ozefm traberem atulobedmzlae nme Cu lb iilneta rnCe a ciadmtrr eaa sbiCdmmiHnen l biabecgaCnemter l h ,raseca CiarmMir m nigmalsaCabgmCeiyoC btnelnncllhre,abeaga aau rMtet lmlnBihhg,esea r rc,eMbao i ighetnanpazoeo aurernnnelsalafuc, ae anhsp rrco,ebr hrpeunaofrs treaeicaarrfu ebealllunrraBCyeb,sta runicCPtaaustztmrliclielaaaluylbmol,ll elacaCPyb a,te r uCPi all[motir5sica3l bamos]eupc. b ail[cieu5su 3l[ sil5]sip.Af3 AeisA]crrpA.ru, eice cncalnaaiunoAnofBnelccAdttiarrhhhhAf,te eaca eHeAznarlrallliel,eilnonncea lnanaclmaadt aahnohn icaHedtmhllhi leayHenamll caileana imml ae i ymscpya.lc,e a slAep sr.,pBe n.a,ot zchelallai na
Sponges * BatzeBllaaBt zaetlzleal la CramCberC amrabmCe brae mbe Hemimycale BaBtBzaietelzlmaelnlaa -
SponSSgppeSoospn n*go genesgs* e*s PC (*sPr eatPuimsldoeCCabucxerardC aaiuanmmrxleaiibsbSnlmel)eepa lb Hloean eMNgmeeoiHsmon f*eayHoMH mnlcieacetiomTmmPhlinesaoisai pymmbrenacaulcy yae hdTclc oea3aaar lT.xblea eGialn ebAe l3l elc.a lG3a .s AGsBMM eMAcasl.oota oB cznnsnlaesaaaBatlesznnnlasasecBcc.tle hhhlzasaoeoo.tr lrzralaaea l la MBBCBailioaeCetnmtmzlheaanBrnBlntilaaaahaicBeB tr hmziaioaeetnrl mzlaaea nl laa - -- - CBliaetmhnriaa -
PseudPa(sxPPeiutsniedleoualcldxaaaui nxlieisnMl)lealo lna aMncMohNnooaernona(facPo nhlticotilihrsoaopc raaau lis) MoNnaeMonfcMoohnliooatrninsaacp nhaco hrao ra Monanchora
No NNo o( PCtilloa(cPsaCs(tuPi ll1lCotia siclsl)aoa sucs a1lsiu s N1l)i C se)oP lfaotNilsliCosetNico Psl2Cafepaotu oiallslfliao oistscils as i2stpui las2ip s a CPlatislCosc l3aCau lslaisss 3s 3 MMPCCootnPinlllaaaoatMtcninshlaCccoCMsoruhhcn illlo4aCaoiCaoaars ur tnanllsahlaaacis rtsnhs ih 4acosr Rhr i4aaoe r fa. ReRfe. fM. Potinloacnacuhloirsa
PtilocPatuPillotisicl aoucaliusl is
NHN2HN2HN2H2 HN HNNHNNHN N N NH OHN HNHNHNNHNON N PHtONilHoHNNNNcPHHaHtNuNNPiHHllHotNiNNNNsicl HHHaoONNNucHHaHliNusHl is NH
1 2 21 1 HNHNNHHNN2HNNNHNN2HN22HN N NNHN HNN NNHNN N2 O nHN NONNONHNONHNN NNON O HnN HHNNHNHHNH HNHN[H70] - [-70[7] 0] HN H NH -
2 2 2 HN HNNH N N N N N N + 1 o r+ m1 + oo1rrn oe m rg omunrnNao=enn rn g1Nie=du o g1iNarn u no3eNair dnm 3 ii dn oeii n e mte y om ieotiye ty HHn H= 1HH oHHr 3 - - -
H
n = 1 no r=n 3 1= o1r o 3r 3 AAccAaanncHAttahhnceeAtalllhlncaaHea t lhnlHaet lhlea l la
ClathCrilaCa tlhartihar ia Crambe Arenochalina Acanthella
BaBtzaeBtlBzlaaaeBtt lzzlaaeetl lzllaeal la CramCberC Bamraatbzmeel blae HeCmriammybcea le AArAecBnaraCoAnetzcnAtrrehhAaoelcaelAmcnraallheiloncbnaancate lahohn i ncaethllhaila enall ailna a Arenochalina
Crambe Batzella Batzella Hemimycale BaBtzaeBtlzlaaeBt lzlaaet lzleal la
SpSopnSSogppneSoosgpn ne*gos gen e*sgs P* es*se PBC u*sar dePtCaPuaz(smxsrPdPeeeBCailuatbusnlmiaxaeerdldBeCot ua iaablzcnamlrdxxeaeateai auilz bSnlmnlxlleaeepiaeils l b nMllHlo)aelaean eloB lgmnaae aCitMHsmznl ea*ecMoByHlM mthlncahaeooBaaCitor mrmnlznnialeaaeaaitac yl mtznnhlhCceaccoyral hrhrillcaaoaeaoarm rlaeab e MHeoBCMmMnNarCaBoitaMeHomznnomnaleafecaMotBayHColbmthznnlnlchaaerieeocoBacCtait ar lmrhimnhlznliasmreaoaaeopaitca yr lmzrbanhmalcaeaecoya l bhrllcaeeaoa rlea ArMHBeBCBnaileioaoeAetBmnmtmzchriheaAienBrenBmlanmilnaraaalaicyBeioeB tn hnnmzccaiaoaaheoet nr llmzcaleaahela inl anlalaai -n a- -- - BBaietmzenllaa -
CramCberC amrabme be MonancPhosreau daxinella NPetoilfooclaituilsipsa MConlaCatnlhacCrhtilhoaCarr tailhaar tihar ia
SponSgpeSosp n*o gnegsP( es*Pse t (u*iPl dPot(acisPxlPaeo(tiuuscPnileldaeotiuuasilclld)xlaoa iaiuc snx)ale iiusnlNll)eai sCle l)oal fa oNtlhiCetrNioislafCeapo otallh(fai oPtrtilihtsiaitrpl iioasacp aau lis) MoMnPaotMninlcoaMohcnnaoocaurhnnaloaci rsnha co hrao ra MPoBNMtniileeaooMomcnnfaocaMonBuhlnnlaiioitoceBa sirnhmnsiaoepac nmrnahaa con hraao - r a - - Clathria
MPotinloaMcnPacMotuhPinlloootiarsincnla aoac ucnhalcoiuhrsla oi rsa NeofoNlietNiosfepooalfi otilsitpiasp a CPlatitlhoCrcialaCau tllhaisrt ihar ia Monanchora
(Ptilo(cPa(tuPillotisicl)ao ucaliusl)i s) *Spongeswithoutanygenusrevisionmade. PtiPlotciPlaotucPillaotiusicl laoiucs aliusl is
PtilocPatuPillotisicl aoucaliusl is MonaMncMohnooarnnaac nhcohrao ra Ptilocaulis
* Sponges without any genus revision made. PtiloNcPHatuPillotiNsicl HaoNucHaliusl is
O* SHpoOngOHesOH withOouOt any genus revision made.
2.3. AnalyticalToolsNfHor2TNGHNA2*H SS2ptroHNun* cgSt*epu sSorN pHNwnaolgiHNntAehgsnNo ewausNl itwyt ahsiniotshyuo tg uaetnn ayun sgy erN egnveuinssu iNroNsen vrN eimsviNaiosdniNoe m.n amdaed. e. HN HNNHHN NHNH
2.3. An2a lyti2c a2l TooHlNs forH NNT2H.G3N.A AN SntNarluycttiucNarla Tl AoNonlsaN lfyosri sT GA StnructunNranl ANnNalysis H H H - - -
TGAstructuraldeterminationshavebeenaccomplishedbasedonextensiveNMR(1Dand2D)
2.3. A2n.32aT.l. y3GAt. AniAcaa nlsly atTtrliyuoctocailtlcs uaT flroo aTrol lo Tsdo GlfesotA ref o rTSrmG tTriAuGnc aASttuti rSoruatnrcls utA uchnrtauaavlrl yaeAls bniAsea nleyansl iyass cics omplished base d on ex tensive NMR (1D and 2D)
andMSanalyses,andc hemT GicAa l sdtergurcatud raatilo dn e.t erminationn =s 1h nao vr=n e 3 1= b o1er eo 3nr a3c complished based on extensive NMR (1D and 2D)
anTdG MATST hsaGteTnrAuGaflc oAystlutsl roesrutsawrc,lu t iaduncntergduate lrsc raadehmlnce eddtitminee oMratinmectSiaroim lina sndnaisnetaa ihgaloytragniasvouseden isah ds,bt a eaiehvolneianenndv .e b eac e hcbfecoeenomre manitcc hpacaelocli csmdsohetpmergdluipr scablhtiduaseahsrdteeei dobdd na obse.n aet e sdere xmodtn eionn enasx itetviexoentn eNsHniovMsfeivR NceH r (MNa1HmDMR b aR (en1 sD d(c1 i D2daDni nad)n- 2doD r2)D )
The following section is a guideline for the structure determination of crambescidin- or
and bMaantSazd nea lMdnla aMSdl yiaSnsn eeaa-snll,iy akaslneyedssGe, cAsah,n deadmne rcdiihcv caeaThmlt heidvimecee agisfclro baadlyldle odagtwhetrigeaionidrnraga.cd thi asoatenricoa.t nci ot.e nr isitsi caf raggumideenlitnsev iafotrh ethues eAsotcfrauNncAtMthuceAaRlrlnceaaat hnndetdelhlteaMel lraSm ainnaaltyiosens .of crambescidin- or
batzelladine-like GA derivatives by their characteristic fragments via the use of NMR and MS
The TfohTlelho ewfo ilfnlooglwl osiwnecgint igbos anetsc zetiiecsolt lniaao d niigs n uiesai- d laiegk lueigni dueGei dAlfieon lrdei n etefrho ievrf o asrtttih vrteuCeh csrest a utbmrsryuCtebr ce ruCtt adhucmreetrauebtimree r r ebdcme he ditaneerratametcirtoimennArai inrstoeitanoiftc noAi occ frhnrAroeaaa nrflmg oeionnmccfba hore aecacshlmnrciaantiblsmdai en ibvnsaeci -ai sd cotiirhdn e-in o-u rso er of NMR and MS
analyses. BatzeBllaaBt zaetlzleal la
batz2eb.l3ala.bt1dza.eitNnzlleeaMl-dllaiRikdneSein p-Gleei-kcAletirk odeGs ecAGraoi nAvpdaay eltdyirviesvereaissv tB. iabvatyteizv sete Blhlbsaae Byt ibza reyt tlzh cleahetl hilaarer iacrc htcaehrraaiscrHtatieeccmr tiefsirrHmtaiisecgyHtm cmiecfairm mleaefni grymatcmsgya lecmvean ileatesn ttvsh ieav iuaths Beteah toeuzf esB luelNaa sBt eoMza fet olRzlNfea l laMNan MRd RaM naSdn dM MS S
an alSyapsnoeaasnnl.STyg apGselSyoesApss n*oe. g Nsne.g sMP es*sRe C u*sr dPapasmxePeCicubsnt eerdreC uaaalmlrdxaahai bmnxaeei vbnleleea Cl alal ah tihgCrhilaCac tlohanrtihtaer inat ofinfMoromn aaMnticMoohnnooa.rnnaDac nhucoehraot roa therelaBtiievmenBsaiigeB mnieanmlan riac -h nes-s ,-t he
M onaMn cMohn ooarnnaac nhcohrao ra NeofoNlietNiosfepooalfi otilsitpiasp a ClathCrilaCa tlhartihar ia
1H–1HCOSY(ePxtpileo(crPiam(tuPilleotisincl)aot uciasliusal)pi sp) ropriateinhelpingtofindwhetheroneoranotherTGAclassispresent
PtilocPatuPillotisicl aoucaliusl is MonaMncMohnooarnnaac nhcohrao ra
PtilocPatuPillotisicl aoucaliusl is

* Spon* gS*ep sSo pwnogintehgso ewus itwt ahinothyuo tg uaetnn ayun sgy er egnveuinssu irosen vr eimsviaiosdnioe m.n amdaed. e.

2.3. A2n.32a.l. y3At. niAcaanlly aTtliyoctoaillcs aT floo Tro loTso GlfsoA rf o TSrG tTrAuGc AStut rSruatrcl utAucnrtuaalrl yaAls niAsa nlyasliyss is
TGAT sGtTrAuGc Astut rsrutarclut ducteruatelr radmle ditneeratmetiroimnnaisnt ihaotanivosen h sba ehveaenv beae cbecenoe manc paclocicsmohpmedlip sblhiasehsdee dbd a obsnae sdee xodtn eon ensx ietvexent eNsnivMseivR Ne (MN1DMR aR(n1 Dd(1 D2aDn ad)n 2dD 2)D )
and ManSad na Mdn aMSl yaSsn eaasnl,y aaslnyedsse, csah,n eadmn cdihc caehml edimceagiclr aadlde dagetrigaodrnaa.d ti aotnio. n .
The TfohTlelho ewfo ilfnlooglwl osiwnecgint igos nesc etiicsot niao nigs uisai d aeg luignidueei dlfieonlrei n tefho erf o srtth rteuh cest utrsruterc utducetruete rredm editneeratmetiroimnnai ntoiaoft nioc nroa fm ocfb reacsmrcaibmdeibnsec-i sdcoiirdn -in o- ro r
batzeblalabtdzaeitnzlleeal-dllaiikdneein -Glei-kAleik deG eAGri Avda etdirvieveraisv tiabvtyeiv ste hbse yib ry th chethiarer iacrc htcaehrraaiscrtatieccr tiefsrrtaiiscgt micfr eafngratmsg emvnieatsn ttvsh ieav iuaths eteh oeuf s ueN seoM f oRNf aMNnMRd RaM naSdn dM MS S
analyasneaasnl.y aslyesse. s.