guanidinas naturales

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Natural guanidine derivatives

Roberto G. S. Berlinck*

Instituto de Qumica de So Carlos, Universidade de So Paulo CP 780, CEP 13560-970,So Carlos, SP - Brasil. E-mail: [email protected]

Received (in Cambridge, UK) 21st May 2002First published as an Advance Article on the web 5th August 2002

Covering: 1998 to 2001. Previous review: Nat. Prod. Rep. , 1999, 339

The chemistry (isolation, biosynthesis and synthesis) and biological activities of natural products bearing a guanidinefunction are reviewed, including macrocyclic derivatives from terrestrial microbes, peptides from cyanobacteria andguanidine alkaloids from marine invertebrates. The review contains 258 references.

1 Introduction2 Natural guanidines from terrestrial microorganisms3 Natural guanidines from marine and freshwater

microorganisms4 Natural guanidines from marine invertebrates4.1 Marine sponges4.2 Other marine invertebrates5 Natural guanidines from higher plants6 Natural guanidines from terrestrial invertebrates7 References

Roberto G. S. Berlinck

Born in So Paulo city (Brazil), Roberto G. S. Berlinck graduated in chemistry at the Universidade Estadual de

Campinas in 1987. In 1988, he left Brazil to develop his PhD atthe Facult des Sciences of the Universit Libre de Bruxelles,under the supervision of Professor Jean-Claude Braekman. Back to Brazil in 1992, he moved to the Instituto de Qumica de SoCarlos, Universidade de So Paulo in 1993 as an invited lecturer.He was appointed assistant professor in 1995 and associate

professor in 2001. Between 1997 and 1998, he spent a six monthsabbatical with Professor Raymond J. Andersen at the Universityof British Columbia, Vancouver, Canada. Since 1994 ProfessorBerlincks research interests include the isolation and synthesis of biologically active marine natural products. More recently, hestarted a research program on marine microbiology, as a topic of his current multidisciplinary collaborative research programincluding chemistry, pharmacology and marine biology.Additionally, his interests include literature, oriental philosophyand music.

1 Introduction

This review updates the literature of natural products with aguanidine function. As in the previous reviews, 13 the topicscovered here include the isolation and structure determination,total synthesis, biosynthesis and the biological activities of guanidine compounds that have been reported during theperiod between 1998 and 2001. Previously uncovered literatureis also discussed.

New methods of guanidine synthesis, 451 guanidine physico-chemical and structural studies, 5254 and synthetic guanidinederivatives which present potent biological activities 5577 havebeen reported in the literature. Additionally, synthetic guani-dine are also of interest acting as catalysts, 7894 as selectiveoxoanion hosts, 95100 as superpotent sweeteners, 101 in nucleotidemimetics, 102107 in sugar mimetics, 108110 in lipid mimetics, 111 andin peptide mimetics. 112127

2 Natural guanidines from terrestrial microorganisms

Two new, A-53930A ( 1), A-53930B ( 2), and one known ( 3)streptothricin derivatives with unde ned stereochemistry havebeen isolated from Streptomyces vinaceusdrappus SANK62394. 128 All compounds inhibited [ 125 I] -conotoxin MVIIAbinding to N-type Ca 2 channels at the nanomolar range, and[3H]norepinephrine release from chick cerebral cortex synapto-somes at the micromolar range. The new 1 and 2 streptothricinderivatives also displayed marginal antibiotic activity againstGram-negative bacteria.

Neocopiamycin B ( 4) has been isolated from Streptomyceshygroscopicus var. crystallogenes , and displayed antifungalactivity and low toxicity in mice. 129 A related macrocycle,dihydroniphimycin ( 5) isolated from S. hygroscopicus 15, pre-sented broad antimicrobial activity against several strains of fungi, yeasts and Gram-positive bacteria. 130 Another strain of Streptomyces produced pyrronamycins A ( 6) and B ( 7), moder-ately antiviral and antimicrobial agents, which did not exhibitinhibition of mammalian topoisomerase I and II. Pyrrona-mycin B ( 6) binds to AT-rich sequences of the DNA minorgroove, and displays in vivo antitumor activity against sarcoma180 and human lung carcinoma. 131

A new chitinase inhibitor, argi n (8), has been obtained fromthe fungi Gliocladium sp. FTD-0668 using a complex isolationprocedure, including both cation and anion exchange, HP-20resin adsorption, reversed phase, and gel ltration chrom-atographies. 132,133 The authors suggested that the guanidine

function of di ff erent chitinase inhibitors may be a relevantstructural feature for this bioactivity.

DOI: 10.1039/a901981b Nat. Prod. Rep. , 2002, 19 , 617649 617

This journal is The Royal Society of Chemistry 2002

Pubshedon05Augus2002onhppubsrscorgdo101039A901981B

View Online / Journal Homepage / Table of Contents for this issue
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The rst total synthesis of the HIV-1 protease inhibitorsMer-N5075A ( 9), -MAPI ( 12) and -MAPI ( 13) have beenachieved through a multi-step procedure (Scheme 1 3). 134

-MAPI ( 12) and analogues have been synthesized using a newsolid-phase N to C direction approach, in 84% overall yield

(Scheme 4). 135 The racemic TAN-1057 A/B mixture ( 14) hasbeen obtained through a multistep convergent synthesis(Scheme 5). 136 A di ff erent approach, previously developed 137

(and discussed in the precedent review3

) has been employed forthe synthesis of TAN-1057A/B analogues. 138

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Scheme 3

Scheme 4

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Scheme 6

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Scheme 7

Scheme 8

Rinehart review 145 reports the isolation of the cytotoxicaeruginoguanidines 98-A ( 35), 98-B ( 36) and 98-C ( 37) fromM. aeruginosa NIES-100, by Murakami and collaborators as a

scienti c presentation in the 36th

Symposium on the Chemistryof Natural Products, held in Hiroshima.

The crystal structure of aeruginosin 298-A ( 38) thrombincomplex 156 and of aeruginosin 98-B ( 39) trypsin complex 157

have been solved, and, in both cases, showed unparalleled

features which may be of interest for further drug developmentof thrombin and trypsin inhibitors.

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The total synthesis of aeruginosin 298-A ( 38) has beenaccomplished (Scheme 9), and the S con guration at the

-leucine residue was corrected to R in -leucine, present in thenatural product. 158 The 2-carboxy-6-hydroxyoctahydroindole(Choi) residue was synthesized starting with a Birch reaction onprotected tyrosine, followed with treatment of the result-ing dihydroanisole with HCl in MeOH to give a mixture of octahydroindol-6-ones. The products were benzylated andchromatographically separated. The excess exo isomer wasequilibrated into the corresponding endo isomer in acidicmethanol, in more than 90% extension. The change of theN -protecting group in the Choi residue was necessary to achievethe stereoselective reduction of the ketone group. The sub-sequent multi-step procedure rst gave the unnatural -leucinestereoisomer presenting di ff erent NMR data to that of thenatural product. The synthesis of natural aeruginosin 298-A(38) was completed after substitution of the -leucine residueby -leucine. The stereochemistry of the leucine residue of aeruginosin 298-A ( 38) was also con rmed through anothermulti-step synthesis (Schemes 10 and 11). 159

Three new dehydrobutyrine-containing microcystin deriv-atives, 42 44 , have been isolated from the cyanobacteriumNostoc sp. and identi ed by analysis of spectroscopic data. 160

Four new protease inhibitors, micropeptins SD944 ( 45),SD979 ( 46), SD999 ( 47) and SD1002 ( 48), have been isolated

from Microcystis aeruginosa .161

Micropeptins SD944 andSD999 inhibited trypsin with IC 50 at 8.0 and 4.0 g mL 1,

respectively, but both compounds did not inhibit chymotrypsinat 45 g mL 1. Micropeptin SD979 and SD1002 inhibitedchymotrypsin at 2.4 and 3.2 g mL 1, respectively, but nottrypsin at 18.0 g mL 1.

Another modi ed peptide, kasumigamide ( 49), has beenisolated from Microcystis aeruginosa NIES-87. 162 Kasumig-amide displayed antialgal activity against the green algaChlamydomonas neglecta (NIES-439) at 2 g mL 1. Additionalarginine-containing modi ed peptides are the protein phos-phatase inhibitors oscillamides B ( 50) and C ( 51), isolated fromthe cyanobacterium Planktothrix (Oscillatoria ) agardhii andPlanktothrix rubescens .163 Both 50 and 51 displayed inhibit-ory activity against protein serine/threonine phosphatase PP1and PP2A at 100 g mL 1. Both compounds did not inhibitprotein tyrosine phosphatase (PTP-S2) or dual-speci cityphosphatase (VHR and Cdc25B). Oscillamide C ( 51) presentedIC 50 values of 0.90 and 1.33 M against PP1 and PP2A,respectively.

Cylindrospermopsin ( 52), a hepatotoxin isolated from thecyanobacteria Cylindrospermopsis raciborskii , Aphanizomenonovalisporum and Umezakia natans , has been the subject of various investigations. 164 The toxin stability was tested, and itwas shown that the toxin degraded slowly in both acidic andalkaline media, and it is stable at 50 C during four weeks in thedark at pH 7. Interestingly, the toxin present in the cyano-bacterium crude extract is photosensitive, being rapidlydegraded under direct sunlight with a half-life of 4 hours;however, its photostability increases after puri cation. 164

The complete biogenetic pathway of cylindrospermopsin(52) has been established. 165 It is derived from ve acetate unitshaving guanidinoacetic acid as the starter unit of the polyketidechain. Moreover, it was shown that the guanidine moietyarises from the incorporation of guanidinoacetic acid, the latter

originates from glycine. Glycine is also the direct precursor of the methyl group. Additionally, the authors observed that the

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Scheme 9

biosynthesis of the guanidine moiety does not arise from trans-amidination, as usual, and its origin remains unknown. The

overall proposed biosynthetic pathway is shown in Scheme 12,in which the minimum energy conformation of the putative

cylindrospermopsin intermediate ( 53) has been calculated bymolecular mechanics.

A new cyclindrospermopsin derivative, 7- epi -cylindro-spermopsin ( 54), has been isolated from Aphanizomenon

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Scheme 11

synthetic ()-cylindrospermopsin was assessed. The racemicmixture was shown to be less potent than natural 52 , butthe non-sulfated racemic diol form of 52 presents a similartoxicity to that of the natural product. The chemistry, biologyand biological activities of cylindrospermopsin and its naturalderivatives have been recently reviewed. 173

The total synthesis of the marine siderophore alterobactin A(62), previously isolated from the marine bacterium Altero-monas luteoviolaceum ,174 has been reported. 175 A [4 3] con-vergent strategy was envisaged (Schemes 15, 16 and 17), bycoupling two fragments and macrocyclization between Gly-Argand Gly- -OH-Asp, since the formation of amide bonds atGly as a C-terminal avoids racemization and steric constraint.Additionally, the -turn conformation and the Gly-Arg- -OH-Asp-Gly sequence are structural features that facilitate themacrocyclization of a linear precursor.

The ethiological origin of tetrodotoxin (TTX, 67) and bio-genetically related compounds have been reviewed. 176 Chemicalstructure versus activity as sodium channel blockers of 67 andof thirteen natural and synthetic derivatives have been estab-

lished.177

The hydroxy groups at C-6 and C-11 presented a keyrole to the binding to sodium channels, probably as hydrogen

donors. The C-11 hydroxy group appears to form a hydrogenbond with a carboxylic acid residue of a sodium channelprotein.

Two new tetrodotoxin derivatives have been isolated, 11-nortetrodotoxin-6( S )-ol ( 68) from the pu ff er sh Arothronnigropunctatus 178 and 5-deoxytetrodotoxin ( 69) from the pu ff er sh Fugu poecilonotus .179 The deoxygenated tetrodotoxinderivatives appear to be biosynthetic precursors ratherthan metabolic products of 67 . The occurrence of both 68and 69 suggests that the C-5 and/or C-11 oxidation is the nalstep of the biosynthesis of TTX. 179 A number of asym-metric synthetic approaches to tetrodotoxin ( 67) have beenreported. 180 186

4 Natural guanidines from marine invertebrates

4.1 Marine sponges

An interesting and insightful review discusses the biogenesisof bromopyrrole-imidazole alkaloids isolated from marinesponges belonging to the Order Agelasidae, Hymeniacidonidae

and Axinellidae based on the tautomerism and ambivalentreactivity of the 2-aminoimidazole group. 187

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Scheme 12

A full account of the isolation of palau amine ( 70) and

related congeners 71 75 from Stylotella aurantium has beenreported. 188 4-Bromopalau amine ( 71) and 4,5-dibromopalau -

amine ( 72) have been isolated as new congeners, while iso-

palau amines 73 75 have been previously isolated from thesame species of marine sponge and reported under the name

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Scheme 13

styloguanidines. 189 Acetylation of palau amine ( 70) with aceticanhydride in pyridine gave a mixture of acetylated compounds.

The acetamide derivative of 70 was obtained by treatment withaqueous Ac 2O and sodium acetate. Since the primary amine

Scheme 14

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Scheme 15

group was more reactive upon the acetylation reaction, theauthors suggested that it has a more pronounced basicity thanthe guanidine group belonging to the spiro-ring. The relativestereochemistry of 70 was completely deduced by analysis of NOE data, while the absolute stereochemistry (as shown) wassuggested as the same of monobromophakellin hydrochlorideby analysis of the circular dichroism spectrum. Palau aminedisplayed low toxicity (LD 50 13 mg kg 1 intraperitonealin mice), antibiotic activity against Penicillium notatum(24 mm zone inhibition at 50 g per disk), immunosuppressiveactivity in mixed lymphocyte reaction (IC 50 < 18 ng mL 1),and cytotoxicity against murine lymphocytes (1.5 g mL 1),P-388 (IC 50 0.1 g mL 1) and A-549 (IC 50 0.2 g mL 1) celllines. 4,5-Dibromopalau amine ( 72) displayed cytotoxicactivity against human melanoma with IC 50 0.25 g mL 1.Palau amine was the target of a new enantioselective synthesisstrategy. 190

Axinellamides A-D 76 79 have been isolated from Axinellasp. originally from Australia. 191 The crude methanol extractdisplayed antibacterial activity against Helicobacter pylori , andwas subjected to a C-18 reversed-phase LC/ECI MS analysis(gradient of acetonitrile in 0.1% TFA solution). The antibioticaxinellamides eluted in retention times between 14.0 and15.0 minutes, and were isolated after chromatography of thecrude extract on Sephadex LH-20, followed by puri cation byHPLC. While axinellamide A ( 76) did not display antibiotic

activity, axinellamides B D 77 79 were active with a minimuminhibitory concentration of 1 mM.

4-Bromopyrrolyl-2-carboxyhomoarginine ( 80) was isolatedfrom Agelas wiedenmayeri originally from Florida. 192 Although80 does not appear to correlate with the biogenetic pathwaysproposed earlier 193 and also recently, 187 such a structuralvariation is rather expected. For instance, biosynthetic experi-ments 194 proved that the biogenetically related alkaloid steven-sine ( 81) from Teichaxinella morchella incorporate proline ( 82)and ornithine ( 83) as the biosynthetic precursors of the 4,5-dibromopyrrole-2-carboxylic acid moiety and histidine ( 84) asthe precursor of the 3-amino-1-(2-aminoimidazolyl)prop-1-enemoiety. Therefore, it is possible that such alkaloids may

incorporate other amino acid precursors, such as homoargininein 80 . Curiously, however, stevensine did not incorporate

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Scheme 16

Scheme 17

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labeled arginine ( 85).194 Two syntheses established the absolutestereochemistry of 80 , one starting from -homoarginine(Scheme 18, 72% overall yield), the other starting from -lysine(Scheme 19, 60% overall yield). 195

New pyrrole-imidazole alkaloids are cyclooroidin ( 86) andtaurodiscapamide ( 87), isolated from Agelas oroides .196 Theabsolute stereochemistry of 86 at C-9 ( S ) was established bycomparison with the circular dichroism spectrum of dibromo-iphakellin ( 88) and molecular modelling. Taurodiscapamide(87) displayed antihistaminic activity at 0.1 mM. A relatedmetabolite, the sh antifeedant N -methyldibromoisophakellin(89), has been isolated from Stylissa caribica .197 The Z isomer

of debromohymenialdisine ( 90) as well as debromohymenialdi-sine ( 91), respectively isolated from Phakellia abellata 198 andStylissa carteri ,199 have been synthesized (Scheme 20). 200 A newmember of the pyrrole-imidazole alkaloids is 12-chloro-11-hydroxydibromoisophakellin ( 92) from Axinella brevistyla ,which seems to be biogenetically derived from the previouslyreported girolline ( 93) and 4,5-dibromopyrrole-2-carboxylicacid, both of which have also been isolated from A. brevi-styla .201 While ugibohlin ( 94) has been isolated from Axinellacarteri ,202 sventrin ( 95) was obtained from Agelas sventres .203

Scheme 18

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Scheme 19

Scheme 20

The known dragmacidin D ( 96) and the new dragmacidinE ( 97) have both been isolated from the marine spongeSpongosorites sp. 204 The structure determination of 97 wasrather challenging, due to the di ffi culty to observe carbons C-3and C-6 in the 13 C NMR spectrum, since the compound canpresent a pyrazine pyrazinone tautomeric interconversion.After the addition of DCl in DMSO- d 6, a NOE e ff ect observedbetween H-4 and an exchangeable proton accounted for thepyrazine tautomer in solution. Since the guanidinium carbon

chemical shift did not vary after the addition of acid, it wassuggested that 97 was isolated as the guanidinium salt rather

than the free base. Both 96 and 97 displayed inhibitory activityof serine-threonine protein phosphatases. 204

Quite unexpectedly, two bromotyrosine-derived alkaloids,of which 98 (unnamed) is a guanidine derivative, have beenisolated from Oceanapia sp. 205 This nding constitutes the rst report of bromotyrosine-derived alkaloids from anon-Verongid sponge, since the occurrence of this family of compounds was restricted to sponges belonging to theOrder Verongida. Compound 98 inhibited mycothiolS-conjugate amidase, an enzyme which, in conjunction withmycothiol, plays a key function in protecting actino-

mycetes against alkylating agents and inactivation by othertoxins. 205

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The chemistry of polycyclic guanidine alkaloids isolatedfrom marine sponges of the genus Ptilocaulis , Crambe ,Monanchora and Batzella has been reviewed. 206 A very brief report presented the isolation of neofolitispates 1 3 (99 101 ),new ptilomycalin A derivatives, from the Indian marine spongeNeofolistipa dianchora .207 Structure elucidation was accom-plished by comparison of 13 C and MS data with data previouslyreported for crambescidins. The authors suggest that 99 101may be artifacts of isolation, since the sponge was stored inmethanol. Compound 100 and the mixture of 99 , 100 and 101displayed antiviral activity against Hepatitis-B virus at 5 gmL 1. Related polycyclic compounds have been isolated fromtwo sponges belonging to the genus Monanchora .208 Dehydro-batzelladine C ( 102 ) was isolated from M. arbuscula , whilecrambescidin 359 ( 103 ) and crambescidin 431 ( 104 ) have beenobtained from M. unguiculata . Analysis of NMR data of 102 indeuterated methanol indicated that several signals exchanged

with deuterium after a few hours. Additionally, guanidine-catalyzed transesteri cation of the ester function with CD 3ODyielded the deuterated methyl ester artifact. Compound 104was also considered as an artifact of isolation, since thesponge was stored in ethanol. Mirabilin G ( 105 ) has beenisolated from the sponge Clathria sp., and displayed anti-microbial activity against E. coli , Serratia marcescens andS. cerevisiae .209

Due to their unusual structural features and potent biologicalactivities, these biogenetically related guanidine alkaloids,which include ptilomycalin A, the crambescins, crambescidins,ptilocaulins, mirabilines and the batzelladines, have been thesubject of several new synthetic approaches. 210 217 For instance,the absolute stereochemistry of the bicyclic core of batzelladineA ( 106 ), as well as the relative stereochemistry of the left-hand tricyclic moiety of batzelladine F ( 107 ), have beenrevised by synthesis of model compounds. 218 220 The totalsynthesis of batzelladine E ( 108 ) has been completed in 3%overall yield (Scheme 21), 221 and enabled the correct geometryof the side chain double bond to be established as Z insteadof E .

Professor Larry E. Overman s group developed a method-ology for the enantioselective total synthesis of the same classof alkaloids, and they have been able to prepare the opticallypure 14,15,16-isocrambescidin 800 ( 109 ),222,223 13,14,15-iso-crambescidin 657 ( 110 ),222 ptilomycalin A ( 111 ), crambescidin657 ( 112 ), neofolitispates 2 ( 100 ) and crambescidin 800 ( 113 ).224

The key step involves a tethered Biginelli condensation, whichprovides the central polycyclic core of the alkaloids. The

synthesis of 14,15,16-isocrambescidin 800 is shown in Scheme22 25, and established the absolute stereochemistry of C-43 asS .223 The formation of the pentacyclic core from 114 was ratherchallenging. Initially performed with p-TsOH H 2O in CHCl 3 orwith PPTS in CHCl 3 , these reaction conditions gave poor yieldsof the desired product 115 along with secondary products dif- cult to separate. The cyclization condition with 3 equivalentsHCl in EtOAc at room temperature yielded a 8 : 1 to 9 : 1mixture of two epimers, 115 and 116 , of which 115 wasobtained in 78% yield. The synthesis of 13,14,15-isocrambes-cidin 657 ( 110 ) was achieved by exposure of the mixture 115 116 to Et 3N in MeOH after removal of the carboxylic acidprotecting group. A mixture of the desired 117 together withthe diastereomer 118 and the cleaved 119 products wasobtained. Condensation of 117 with the readily available ( S )-7-hydroxyspermidine yielded 13,14,15-isocrambescidin 800 ( 109 )after removal of the Boc protecting groups. The synthesis of crambescidin 800 ( 113 ) also established the C-43 absolutestereochemistry as S .224 A complete account on the relative

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Scheme 21

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Scheme 22

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Scheme 23

energy of di ff erent stereoisomers of the pentacyclic guanidinecore is thoroughly discussed, and explains the reasons why the13,14,15- epi -crambescidin 800 polycyclic core is more stablethan the 13-epi and the 13,15- epi pentacyclic systems. 223

A Stelleta sp. marine sponge has yielded several un-precedented guanidinium alkaloids. The structure of stellett-azole A ( 120 ), including the absolute con guration, wasestablished by analysis of spectroscopic data and chemicaldegradation. 225 While compound 120 exhibited potent anti-bacterial activity against Eschericha coli and inhibitory activityagainst Ca 2 /calmodulin-dependent phosphodiesterase, stellett-azole B ( 121 ), isolated from the same sponge species, displayedonly marginal antibacterial activity against E. coli .226 Twodimeric stellettadines, namely bistellettadines A ( 122 ) and B(123 ) were also isolated from the same sponge, as moderateinhibitors of Ca 2 /calmodulin-dependent phosphodiesteraseand potent antibacterial agents against E. coli (10 g perdisk). 227

The absolute stereochemistry of the single stereogenic car-bon of stelledatine A ( 124 ) was established as R by total syn-thesis (Scheme 26), 228,229 although in the isolation report the

authors proposed the S absolute stereochemistry by chemicaldegradation but have drawn the structure with the correct R

con guration. 230 Another linear guanidine metabolite, aplysill-amide B ( 125 ),231 has been synthesized (Scheme 27). 232

Marine sponges belonging to the order Lithistida are aremarkable source of complex and potent bioactive naturalproducts, including polypeptides and polyketide macrolides. 233

The serine protease inhibitors cyclotheonamides E2 ( 126 ) andE3 ( 127 ) have been isolated from the Lithistid sponge Theonellasp. 234 Both peptides are thrombin and trypsin inhibitors at thenanomolar level. Six new peptides have been isolated fromTheonella swinhoei : pseudotheonamides A 1 ( 128 ), A 2 ( 129 ), B 2(130 ), C ( 131 ) and D ( 132 ), as well as dihydrocyclotheonamideA ( 133 ).235 All peptides inhibited thrombin with IC 50 at 1.0, 3.0,1.3, 0.19, 1.4 and 0.33 M, respectively, and inhibited trypsinwith IC 50 at 4.5, >10, 6.2, 3.8, >10, and 6.7 mM, respectively. Aspreviously observed, the inhibition of serine proteases by thecyclotheonamides is due to the presence of the -keto groupin the k-arginine residue. This fact may explain the low activityof peptides 128 133 when compared with the activity of cyclotheonamide A. 235

Tokaramide A ( 134 ) is a new cathepsin B inhibitor isolatedfrom the marine sponge Theonella aff . mirabilis . Its structure

has been determined by analysis of spectroscopic data andchemical degradation. 236 Interestingly, all three cathepsin B

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Scheme 24

inhibitors known, tokaramide A ( 134 ), leupeptin ( 135 )

from di ff erent Streptomyces species237

and E-64 ( 136 ) fromAspergillus japonicus 238 have an argininal residue. Cathepsins

are lysosomal cysteine proteases, important as physiologicalregulators. 236

Miraziridine ( 137 ) is a cysteine protease inhibitor peptideisolated from Theonella aff . mirabilis .239 The structure of 137 ,including its absolute stereochemistry, was established byanalysis of spectroscopic data and chemical degradation. Itincludes two very unusual residues: aziridine-2,3-dicarboxylicacid and the novel vinylogous arginine moiety. Miraziridine Ainhibited cathepsin B with IC 50 at 1.4 g mL 1.

The polypeptide discodermin A ( 138 ) isolated from themarine sponge Discodermia kiiensis 240 promotes permeabiliz-ation of the plasma membrane of A10 cells to the non-permeable uorescent probes ethidium homodimer-1 (MW =857), calcein (MW = 623), as well as permeabilization of vascular tissue cells to Ca 2 and ATP. 241

Eurypamide A ( 139 ) was isolated from the spongeMicrociona eurypa and identi ed by analysis of spectroscopicdata and chemical interconversions. 242

()-Anchinopeptolide D ( 140 ) and ()-cycloanchino-peptolide D ( 141 ), previously isolated from the sponge Anchi-noe tenacior , have been synthesized (Scheme 28). 243 The aldol

condensation reaction yielded three stereoisomers, of which thedesired product, the Boc protected ( 140 ), was obtained in 58%

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Scheme 25

yield. The [2 2] cycloaddition of 140 was tentatively per-formed in CD 3OD, but only the trans to cis isomerization of thedouble bonds was observed. The same reaction in D 2O wasrationalized as favourable, since the hydrophobic e ff ect wasexpected to keep the hydroxystyrylamido groups close together.

Indeed, cycloanchinopeptolide ( 141 ) was obtained in 48% yieldafter irradiation of 140 in D 2O.

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4.2 Other marine invertebrates

Limacianine ( 142 ) was isolated from the North Sea nudibranchLimacia clavigera .244 A new indole alkaloid ( 143 , unnamed) wasisolated from the ascidian Dendrodoa grossularia .245 The struc-ture of 143 was secured by interpretation of spectroscopic dataand by X-ray di ff raction analysis of the derivative 144 obtainedby treatment of 143 with acetic anhydride in pyridine. The

ascidian Eudistoma sp. yielded the known trypargine ( 145 ),as well as the new trypargimine ( 146 ) and 1-carboxy-trypargine ( 147 ).246 The ascidian Polycarpa aurata yieldedN -(methoxybenzoyl)- N -methylguanidine ( 148 ) along withrelated derivatives. 247

Minalemines A F ( 149 154 ) have been isolated from theascidian Didemnum rodriguesi .248 The absolute stereochemistryof minalemine A ( 149 ), was established by a convergent totalsynthesis via the condensation of 155 and 156 (Scheme 29 and30). 249

5 Natural guanidines from higher plants

Two agmatine hemiterpenes, smirvonine, also known assphaerophysine ( 157 ), as well as its Z -4-hydroxy derivative(158 ), have been inadvertently omitted in the previous review.Both compounds were isolated from Galega orientalis(Fabaceae, Leguminosae). 250 The structure of 157 was estab-lished by analysis of spectroscopic data and con rmed by syn-thesis, while the structure of 158 was secured by analysis of NMR and MS data. Interestingly, both 157 and 158 were foundto be much less toxic than galegine ( 159 ) and 4-hydroxygalegine(160 ), previously isolated from Galega o fficinalis . The mixedshikimate-mevalonate agmatine derivative fontaineine ( 161 ) has

Scheme 28 HOBt = hydroxybenzotriazole.

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Scheme 29 DPPA = diphenylphosphoryl azide; HOBt = hydroxybenzotriazole.

Scheme 30

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been isolated from Fontainea pancheri (Euphorbiaceae) fromNew Caledonia. 251 The antimitotic peptides celogentins A C(162 164 ) have been isolated from Celosia argentea (Amaran-thaceae), together with moroidin ( 165 ), previously isolatedfrom Laportea moroides (Labiatae). 252 Celogentins A Cinhibited the polymerization of tubulin at concentrations of IC 50 20 M, 30 M and 0.8 M, respectively.

While martinelline ( 166 ) and martinellic acid ( 167 ), previ-ously isolated from Martinella iquitosensis , have been the targetof a new synthetic approach, 253 martinellic acid was success-fully synthesized (Scheme 31). 254

Scheme 31

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Scheme 32

6 Natural guanidines from terrestrial invertebrates

Several reviews on the biological activities of spider and waspspolyamine toxins have been published. 255 257 A new synthesis of

hirudonine ( 168 ), an anti-coagulant agent isolated from theleech Hirudo o fficinalis , has been reported (Scheme 32). 258

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