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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: rberlinck@iqsc.sc.usp.br Received (in Cambridge, UK) 21st May 2002 First published as an Advance Article on the web 5th August 2002
Covering: 1998 to 2001. Previous review: Nat. Prod. Rep., 1999, 339

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The chemistry (isolation, biosynthesis and synthesis) and biological activities of natural products bearing a guanidine function are reviewed, including macrocyclic derivatives from terrestrial microbes, peptides from cyanobacteria and guanidine alkaloids from marine invertebrates. The review contains 258 references. 1 2 3 Introduction Natural guanidines from terrestrial microorganisms Natural guanidines from marine and freshwater microorganisms 4 Natural guanidines from marine invertebrates 4.1 Marine sponges 4.2 Other marine invertebrates 5 Natural guanidines from higher plants 6 Natural guanidines from terrestrial invertebrates 7 References 1 Introduction

This review updates the literature of natural products with a guanidine function. As in the previous reviews,13 the topics covered here include the isolation and structure determination, total synthesis, biosynthesis and the biological activities of guanidine compounds that have been reported during the period between 1998 and 2001. Previously uncovered literature is also discussed. New methods of guanidine synthesis,451 guanidine physicochemical and structural studies,5254 and synthetic guanidine derivatives which present potent biological activities 5577 have been reported in the literature. Additionally, synthetic guanidine are also of interest acting as catalysts,7894 as selective oxoanion hosts,95100 as superpotent sweeteners,101 in nucleotide mimetics,102107 in sugar mimetics,108110 in lipid mimetics,111 and in peptide mimetics.112127 2 Natural guanidines from terrestrial microorganisms

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 at the 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 So Carlos, 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 month sabbatical with Professor Raymond J. Andersen at the University of British Columbia, Vancouver, Canada. Since 1994 Professor Berlincks research interests include the isolation and synthesis of biologically active marine natural products. More recently, he started a research program on marine microbiology, as a topic of his current multidisciplinary collaborative research program including chemistry, pharmacology and marine biology. Additionally, his interests include literature, oriental philosophy and music. DOI: 10.1039/a901981b

Two new, A-53930A (1), A-53930B (2), and one known (3) streptothricin derivatives with undened stereochemistry have been isolated from Streptomyces vinaceusdrappus SANK 62394.128 All compounds inhibited [125I]-conotoxin MVIIA binding to N-type Ca2 channels at the nanomolar range, and [3H]norepinephrine release from chick cerebral cortex synaptosomes at the micromolar range. The new 1 and 2 streptothricin derivatives also displayed marginal antibiotic activity against Gram-negative bacteria. Neocopiamycin B (4) has been isolated from Streptomyces hygroscopicus var. crystallogenes, and displayed antifungal activity and low toxicity in mice.129 A related macrocycle, dihydroniphimycin (5) isolated from S. hygroscopicus 15, presented 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), moderately antiviral and antimicrobial agents, which did not exhibit inhibition of mammalian topoisomerase I and II. Pyrronamycin B (6) binds to AT-rich sequences of the DNA minor groove, and displays in vivo antitumor activity against sarcoma 180 and human lung carcinoma.131 A new chitinase inhibitor, argin (8), has been obtained from the fungi Gliocladium sp. FTD-0668 using a complex isolation procedure, including both cation and anion exchange, HP-20 resin adsorption, reversed phase, and gel ltration chromatographies.132,133 The authors suggested that the guanidine function of dierent chitinase inhibitors may be a relevant structural feature for this bioactivity. Nat. Prod. Rep., 2002, 19, 617649 617

This journal is The Royal Society of Chemistry 2002

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The rst total synthesis of the HIV-1 protease inhibitors Mer-N5075A (9), -MAPI (12) and -MAPI (13) have been achieved through a multi-step procedure (Scheme 13).134 -MAPI (12) and analogues have been synthesized using a new solid-phase N to C direction approach, in 84% overall yield 618 Nat. Prod. Rep., 2002, 19, 617649

(Scheme 4).135 The racemic TAN-1057 A/B mixture (14) has been obtained through a multistep convergent synthesis (Scheme 5).136 A dierent approach, previously developed 137 (and discussed in the precedent review 3) has been employed for the synthesis of TAN-1057A/B analogues.138

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The nal steps of the biosynthesis of the antibiotic blasticidin S (15) in Streptomyces griseochromogenes have been elucidated (Scheme 6).139 During these investigations, N-acetylblasticidin S (16) has been isolated from S. griseochromogenes, suggesting that 16 has a self-protection role for 15 in the microorganism. However, the previous isolation of leucylblasticidin S (17) from the same microbial source raised the question about the true function of both 16 and 17. Additional biosynthetic and antimicrobial experiments were performed in order to clarify these points. N-Acetylblasticidin S (16) showed no antibacterial activity at 410 g per disk, while leucylblasticidin S (17) presented a 15 mm inhibition zone at 75 g per disk, a 20 fold lower activity of blasticidin S (15). The biosynthetic experiments demonstrated the formation of N-acetylblasticidin S (16) and leucylblasticidin S (17) from

their corresponding N-guanidine demethylated intermediates. Additionally, no signicant production of 15 was observed when S. griseochromogenes was incubated with 16 in the culture

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Scheme 1

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Scheme 2

medium, while the conversion of 17 to 15 was complete under the same conditions, pointing to Scheme 6 as the nal biosynthetic steps for the biosynthesis of 15. Therefore, the authors suggested a detoxication role for N-acetylblasticidin S (16) and a self-protecting role against 15 for leucylblasticidin S (17). The amino acid portion of blasticidin S, blastidic acid (18), was successfully synthesized from ,-diaminobutyric acid (Scheme 7).140 The unusual guanidine amino acid (2S,3R)-capreomycidine (19), a constituent of the tuberculostatic cyclic peptides capreomycins and tuberactinomycins, was the target of an improved asymmetric synthesis (Scheme 8), using the oxazinone (21) as a chiral template.141 The imine 20 was prepared from 3-(tert-butyldimethylsilyloxy)propionaldehyde and benzylamine in 98% yield. The condensation of 20 with the aluminum enolate of 21 aorded the Mannich product 22 as a 3.3 : 1 mixture of two inseparable diastereomers. The guanidinylation of 22 was achieved after tentative experiments with dierent guanidylating reagents. The carbinol deprotected guanidylated product (24) was shown to be unstable in both acidic and alkaline media, and was subjected to a Mitsunobu-type cyclization after rapid purication using Whatman brand silica gel. After removal of protecting groups, the product was subjected to a series of purication steps, including cationic ion-exchange chromatography, in order to obtain the natural amino acid (19) in >99% ee (by chiral HPLC). 620 Nat. Prod. Rep., 2002, 19, 617649

3 Natural guanidines from marine and freshwater microorganisms Dierent reviews have covered the status of the recent research on cyanobacterial toxins, many of which are responsible for severe human and animals intoxications.142147 Gupta and co-workers reported a possible molecular mechanism to explain the binding of dierent phosphatase inhibitors, including microcystin-LR (26), with protein phosphatases PP1 and PP2A.148 An electrospray ionization mass spectrometry study of dierent microcystins concluded that microcystins devoid of the arginine residue always present sodium adduct ions [M Na] as the base peak, while arginine bearing microcystins always gave [M H] and [M 2H]2 ions, with the relative intensity independent of the sample pH.149

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Scheme 4

Scheme 3

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Scheme 5

Several structurally new cyanobacterial peptides containing an arginine or a modied arginine moiety have been isolated. These include aeruginosin 103-A (27) from Microcystis viridis, which displayed thrombin, trypsin and plasmin inhibitory activity at the M range. The bulk 1-amidino-2-ethoxy-3-amido substituted piperidine ring of aeruginosin 103-A appears to have a negative eect towards the enzyme inhibitory activity of 27.150 A closely related new peptidic derivative is microcin SF608 (28), which has been obtained along with micropeptin SF909 (29) and micropeptin SF995 (30) from an undescribed species of Microcystis cyanobacterium.151 Micropeptin SF909 (29) inhibited chymotrypsin with IC50 at 4.0 g mL1, while micropeptin SF995 (30) and microcin SF608 (28) inhibited trypsin with IC50 at 0.2 and 0.5 g mL1, respectively. Anabaenopeptin G (31), isolated from Planktothrix agardhii HUB 011,152 is closely related to anabaenopeptin H (32) isolated from Oscillatoria agardhii NIES-595.153 The structure of 31 has been established by MALDI-TOF mass spectrometry analysis only. The structure of compound 32 was proposed after extensive analysis of NMR data and displayed inhibitory activity against carboxypeptidase A with IC50 at 3.8 g mL1. A Brazilian strain of Microcystis RST 9501 produced [-Leu1]microcystin-LR (33),154 which presented the same lethal dose of microcystin-LR (100 g kg1). The strain Nodularia PCC 7804, originally isolated from a freshwater 622 Nat. Prod. Rep., 2002, 19, 617649

thermal spring in France, produces [-Har2]nodularin (34), with a lethal dose of 75 g kg1 and inhibition of protein phosphatase 1 (PP1) with IC50 of 4.5 nM.155 The Namikoshi and

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Scheme 6

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Scheme 7

Scheme 8

Rinehart review 145 reports the isolation of the cytotoxic aeruginoguanidines 98-A (35), 98-B (36) and 98-C (37) from M. aeruginosa NIES-100, by Murakami and collaborators as a scientic presentation in the 36th Symposium on the Chemistry of Natural Products, held in Hiroshima. 624 Nat. Prod. Rep., 2002, 19, 617649

The crystal structure of aeruginosin 298-A (38) thrombin complex 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 development of thrombin and trypsin inhibitors.

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The total synthesis of aeruginosin 298-A (38) has been accomplished (Scheme 9), and the S conguration at the -leucine residue was corrected to R in -leucine, present in the natural product.158 The 2-carboxy-6-hydroxyoctahydroindole (Choi) residue was synthesized starting with a Birch reaction on protected tyrosine, followed with treatment of the resulting dihydroanisole with HCl in MeOH to give a mixture of octahydroindol-6-ones. The products were benzylated and chromatographically separated. The excess exo isomer was equilibrated into the corresponding endo isomer in acidic methanol, in more than 90% extension. The change of the N-protecting group in the Choi residue was necessary to achieve the stereoselective reduction of the ketone group. The subsequent multi-step procedure rst gave the unnatural -leucine stereoisomer presenting dierent NMR data to that of the natural product. The synthesis of natural aeruginosin 298-A (38) was completed after substitution of the -leucine residue by -leucine. The stereochemistry of the leucine residue of aeruginosin 298-A (38) was also conrmed through another multi-step synthesis (Schemes 10 and 11).159 Three new dehydrobutyrine-containing microcystin derivatives, 4244, have been isolated from the cyanobacterium Nostoc sp. and identied 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 and SD999 inhibited trypsin with IC50 at 8.0 and 4.0 g mL1,

respectively, but both compounds did not inhibit chymotrypsin at 45 g mL1. Micropeptin SD979 and SD1002 inhibited chymotrypsin at 2.4 and 3.2 g mL1, respectively, but not trypsin at 18.0 g mL1. Another modied peptide, kasumigamide (49), has been isolated from Microcystis aeruginosa NIES-87.162 Kasumigamide displayed antialgal activity against the green alga Chlamydomonas neglecta (NIES-439) at 2 g mL1. Additional arginine-containing modied peptides are the protein phosphatase inhibitors oscillamides B (50) and C (51), isolated from the cyanobacterium Planktothrix (Oscillatoria) agardhii and Planktothrix rubescens.163 Both 50 and 51 displayed inhibitory activity against protein serine/threonine phosphatase PP1 and PP2A at 100 g mL1. Both compounds did not inhibit protein tyrosine phosphatase (PTP-S2) or dual-specicity phosphatase (VHR and Cdc25B). Oscillamide C (51) presented IC50 values of 0.90 and 1.33 M against PP1 and PP2A, respectively. Cylindrospermopsin (52), a hepatotoxin isolated from the cyanobacteria Cylindrospermopsis raciborskii, Aphanizomenon ovalisporum and Umezakia natans, has been the subject of various investigations.164 The toxin stability was tested, and it was shown that the toxin degraded slowly in both acidic and alkaline media, and it is stable at 50 C during four weeks in the dark at pH 7. Interestingly, the toxin present in the cyanobacterium crude extract is photosensitive, being rapidly degraded under direct sunlight with a half-life of 4 hours; however, its photostability increases after purication.164 The complete biogenetic pathway of cylindrospermopsin (52) has been established.165 It is derived from ve acetate units having guanidinoacetic acid as the starter unit of the polyketide chain. Moreover, it was shown that the guanidine moiety arises 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 Nat. Prod. Rep., 2002, 19, 617649 625

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Scheme 9

biosynthesis of the guanidine moiety does not arise from transamidination, 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 626 Nat. Prod. Rep., 2002, 19, 617649

cylindrospermopsin intermediate (53) has been calculated by molecular mechanics. A new cyclindrospermopsin derivative, 7-epi-cylindrospermopsin (54), has been isolated from Aphanizomenon

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Scheme 10

ovalisporum, through a multi-step chromatographic procedure employing ODS ash chromatography, chromatography on Sephadex G-25 and C18 reversed phase preparative HPLC.166 Another related derivative is the non-toxic 7-deoxycylindrospermopsin (55), also isolated from C. raciborskii.167 This latter derivative diers not only by the absence of the 7-hydroxy function, but also in the uracil nucleus which appears to present two tautomeric forms. The changes in the structure of (55) may explain its lack of toxicity. While dierent approaches toward the synthesis of cylindrospermopsin (52) have been reported,168171 its total synthesis was recently achieved in 3.5% overall yield (Schemes 13, 14).172 A

series of stepwise interconversions yielded stereospecically the functionalized piperidine (56) from 3-picoline. Piperidine (56) had the required stereochemistry of cylindrospermopsin tricyclic fused system, and was protected before condensation with the protected form of the pyrimidine moiety of 52. The fully protected product (57) was subjected to a series of functional group interconversions in order to obtain, after hydrogenolysis and triple bond reduction, the diamino deprotected form of 58. This intermediate was reacted with cyanogen bromide in order to obtain the desired ve membered guanidine ring, followed by protection of the basic guanidine group, to give 59 in 45% yield. The protecting groups of guanidine and of secondary alcohols in 59 were then removed, before oxidation of the carbinol of position 7 and re-protection of the C-12 alcohol. The product 60 was brominated with CuBr2, followed by immediate hydrogenolysis of guanidine protecting groups, to give a 3 : 2 mixture of stereoisomers at C-7 through an intramolecular SN2 reaction. The stereoisomers could be separated by ash chromatography after removal of the acetyl group at C-12. Monosulfation of 61 with 6 equivalents of SO3DMF in anhydrous pyridine gave 6080% of cylindrospermopsin (52) after purication by C18 reversed-phase column chromatography. Not only spectroscopic data, but also the toxicity of Nat. Prod. Rep., 2002, 19, 617649 627

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Scheme 11

synthetic ()-cylindrospermopsin was assessed. The racemic mixture was shown to be less potent than natural 52, but the non-sulfated racemic diol form of 52 presents a similar toxicity to that of the natural product. The chemistry, biology and biological activities of cylindrospermopsin and its natural derivatives have been recently reviewed.173 The total synthesis of the marine siderophore alterobactin A (62), previously isolated from the marine bacterium Alteromonas luteoviolaceum,174 has been reported.175 A [4 3] convergent strategy was envisaged (Schemes 15, 16 and 17), by coupling two fragments and macrocyclization between Gly-Arg and Gly--OH-Asp, since the formation of amide bonds at Gly as a C-terminal avoids racemization and steric constraint. Additionally, the -turn conformation and the Gly-Arg--OHAsp-Gly sequence are structural features that facilitate the macrocyclization of a linear precursor. The ethiological origin of tetrodotoxin (TTX, 67) and biogenetically related compounds have been reviewed.176 Chemical structure versus activity as sodium channel blockers of 67 and of thirteen natural and synthetic derivatives have been established.177 The hydroxy groups at C-6 and C-11 presented a key role to the binding to sodium channels, probably as hydrogen 628 Nat. Prod. Rep., 2002, 19, 617649

donors. The C-11 hydroxy group appears to form a hydrogen bond with a carboxylic acid residue of a sodium channel protein. Two new tetrodotoxin derivatives have been isolated, 11nortetrodotoxin-6(S)-ol (68) from the puer sh Arothron nigropunctatus 178 and 5-deoxytetrodotoxin (69) from the puer sh Fugu poecilonotus.179 The deoxygenated tetrodotoxin derivatives appear to be biosynthetic precursors rather than metabolic products of 67. The occurrence of both 68 and 69 suggests that the C-5 and/or C-11 oxidation is the nal step of the biosynthesis of TTX.179 A number of asymmetric synthetic approaches to tetrodotoxin (67) have been reported.180186 4 4.1 Natural guanidines from marine invertebrates Marine sponges

An interesting and insightful review discusses the biogenesis of bromopyrrole-imidazole alkaloids isolated from marine sponges belonging to the Order Agelasidae, Hymeniacidonidae and Axinellidae based on the tautomerism and ambivalent reactivity of the 2-aminoimidazole group.187

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Scheme 12

A full account of the isolation of palauamine (70) and related congeners 7175 from Stylotella aurantium has been reported.188 4-Bromopalauamine (71) and 4,5-dibromopalau-

amine (72) have been isolated as new congeners, while isopalauamines 7375 have been previously isolated from the same species of marine sponge and reported under the name Nat. Prod. Rep., 2002, 19, 617649 629

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Scheme 13

Scheme 14

styloguanidines.189 Acetylation of palauamine (70) with acetic anhydride in pyridine gave a mixture of acetylated compounds. The acetamide derivative of 70 was obtained by treatment with aqueous Ac2O and sodium acetate. Since the primary amine 630 Nat. Prod. Rep., 2002, 19, 617649

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Scheme 15

group was more reactive upon the acetylation reaction, the authors suggested that it has a more pronounced basicity than the guanidine group belonging to the spiro-ring. The relative stereochemistry of 70 was completely deduced by analysis of NOE data, while the absolute stereochemistry (as shown) was suggested as the same of monobromophakellin hydrochloride by analysis of the circular dichroism spectrum. Palauamine displayed low toxicity (LD50 13 mg kg1 intraperitoneal in mice), antibiotic activity against Penicillium notatum (24 mm zone inhibition at 50 g per disk), immunosuppressive activity in mixed lymphocyte reaction (IC50 < 18 ng mL1), and cytotoxicity against murine lymphocytes (1.5 g mL1), P-388 (IC50 0.1 g mL1) and A-549 (IC50 0.2 g mL1) cell lines. 4,5-Dibromopalauamine (72) displayed cytotoxic activity against human melanoma with IC50 0.25 g mL1. Palauamine was the target of a new enantioselective synthesis strategy.190 Axinellamides A-D 7679 have been isolated from Axinella sp. originally from Australia.191 The crude methanol extract displayed antibacterial activity against Helicobacter pylori, and was subjected to a C-18 reversed-phase LC/ECI MS analysis (gradient of acetonitrile in 0.1% TFA solution). The antibiotic axinellamides eluted in retention times between 14.0 and 15.0 minutes, and were isolated after chromatography of the crude extract on Sephadex LH-20, followed by purication by HPLC. While axinellamide A (76) did not display antibiotic activity, axinellamides BD 7779 were active with a minimum inhibitory concentration of 1 mM.

4-Bromopyrrolyl-2-carboxyhomoarginine (80) was isolated from Agelas wiedenmayeri originally from Florida.192 Although 80 does not appear to correlate with the biogenetic pathways proposed earlier 193 and also recently,187 such a structural variation is rather expected. For instance, biosynthetic experiments 194 proved that the biogenetically related alkaloid stevensine (81) from Teichaxinella morchella incorporate proline (82) and ornithine (83) as the biosynthetic precursors of the 4,5dibromopyrrole-2-carboxylic acid moiety and histidine (84) as the precursor of the 3-amino-1-(2-aminoimidazolyl)prop-1-ene moiety. Therefore, it is possible that such alkaloids may incorporate other amino acid precursors, such as homoarginine in 80. Curiously, however, stevensine did not incorporate Nat. Prod. Rep., 2002, 19, 617649 631

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632
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Scheme 17

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labeled arginine (85).194 Two syntheses established the absolute stereochemistry 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) and taurodiscapamide (87), isolated from Agelas oroides.196 The absolute stereochemistry of 86 at C-9 (S) was established by comparison with the circular dichroism spectrum of dibromoiphakellin (88) and molecular modelling. Taurodiscapamide (87) displayed antihistaminic activity at 0.1 mM. A related metabolite, the sh antifeedant N-methyldibromoisophakellin (89), has been isolated from Stylissa caribica.197 The Z isomer of debromohymenialdisine (90) as well as debromohymenialdisine (91), respectively isolated from Phakellia abellata 198 and Stylissa carteri,199 have been synthesized (Scheme 20).200 A new member of the pyrrole-imidazole alkaloids is 12-chloro-11hydroxydibromoisophakellin (92) from Axinella brevistyla, which seems to be biogenetically derived from the previously reported girolline (93) and 4,5-dibromopyrrole-2-carboxylic acid, both of which have also been isolated from A. brevistyla.201 While ugibohlin (94) has been isolated from Axinella carteri,202 sventrin (95) was obtained from Agelas sventres.203

Scheme 18

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Scheme 20

The known dragmacidin D (96) and the new dragmacidin E (97) have both been isolated from the marine sponge Spongosorites sp.204 The structure determination of 97 was rather challenging, due to the diculty to observe carbons C-3 and C-6 in the 13C NMR spectrum, since the compound can present a pyrazinepyrazinone tautomeric interconversion. After the addition of DCl in DMSO-d6, a NOE eect observed between H-4 and an exchangeable proton accounted for the pyrazine tautomer in solution. Since the guanidinium carbon chemical shift did not vary after the addition of acid, it was suggested that 97 was isolated as the guanidinium salt rather 634 Nat. Prod. Rep., 2002, 19, 617649

than the free base. Both 96 and 97 displayed inhibitory activity of serine-threonine protein phosphatases.204 Quite unexpectedly, two bromotyrosine-derived alkaloids, of which 98 (unnamed) is a guanidine derivative, have been isolated from Oceanapia sp.205 This nding constitutes the rst report of bromotyrosine-derived alkaloids from a non-Verongid sponge, since the occurrence of this family of compounds was restricted to sponges belonging to the Order Verongida. Compound 98 inhibited mycothiol S-conjugate amidase, an enzyme which, in conjunction with mycothiol, plays a key function in protecting actinomycetes against alkylating agents and inactivation by other toxins.205

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The chemistry of polycyclic guanidine alkaloids isolated from marine sponges of the genus Ptilocaulis, Crambe, Monanchora and Batzella has been reviewed.206 A very brief report presented the isolation of neofolitispates 13 (99101), new ptilomycalin A derivatives, from the Indian marine sponge Neofolistipa dianchora.207 Structure elucidation was accomplished by comparison of 13C and MS data with data previously reported for crambescidins. The authors suggest that 99101 may be artifacts of isolation, since the sponge was stored in methanol. Compound 100 and the mixture of 99, 100 and 101 displayed antiviral activity against Hepatitis-B virus at 5 g mL1. Related polycyclic compounds have been isolated from two sponges belonging to the genus Monanchora.208 Dehydrobatzelladine C (102) was isolated from M. arbuscula, while crambescidin 359 (103) and crambescidin 431 (104) have been obtained from M. unguiculata. Analysis of NMR data of 102 in deuterated methanol indicated that several signals exchanged with deuterium after a few hours. Additionally, guanidinecatalyzed transesterication of the ester function with CD3OD yielded the deuterated methyl ester artifact. Compound 104 was also considered as an artifact of isolation, since the sponge was stored in ethanol. Mirabilin G (105) has been isolated from the sponge Clathria sp., and displayed antimicrobial activity against E. coli, Serratia marcescens and S. cerevisiae.209 Due to their unusual structural features and potent biological activities, these biogenetically related guanidine alkaloids, which include ptilomycalin A, the crambescins, crambescidins, ptilocaulins, mirabilines and the batzelladines, have been the subject of several new synthetic approaches.210217 For instance, the absolute stereochemistry of the bicyclic core of batzelladine A (106), as well as the relative stereochemistry of the lefthand tricyclic moiety of batzelladine F (107), have been revised by synthesis of model compounds.218220 The total synthesis of batzelladine E (108) has been completed in 3% overall yield (Scheme 21),221 and enabled the correct geometry of the side chain double bond to be established as Z instead of E. Professor Larry E. Overmans group developed a methodology for the enantioselective total synthesis of the same class of alkaloids, and they have been able to prepare the optically pure 14,15,16-isocrambescidin 800 (109),222,223 13,14,15-isocrambescidin 657 (110),222 ptilomycalin A (111), crambescidin 657 (112), neofolitispates 2 (100) and crambescidin 800 (113).224 The key step involves a tethered Biginelli condensation, which provides the central polycyclic core of the alkaloids. The

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synthesis of 14,15,16-isocrambescidin 800 is shown in Scheme 2225, and established the absolute stereochemistry of C-43 as S.223 The formation of the pentacyclic core from 114 was rather challenging. Initially performed with p-TsOHH2O in CHCl3 or with PPTS in CHCl3, these reaction conditions gave poor yields of the desired product 115 along with secondary products difcult to separate. The cyclization condition with 3 equivalents HCl in EtOAc at room temperature yielded a 8 : 1 to 9 : 1 mixture of two epimers, 115 and 116, of which 115 was obtained in 78% yield. The synthesis of 13,14,15-isocrambescidin 657 (110) was achieved by exposure of the mixture 115 116 to Et3N in MeOH after removal of the carboxylic acid protecting group. A mixture of the desired 117 together with the diastereomer 118 and the cleaved 119 products was obtained. Condensation of 117 with the readily available (S)-7hydroxyspermidine 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 absolute stereochemistry as S.224 A complete account on the relative

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636
Scheme 21 View Online

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Scheme 22

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Scheme 23

energy of dierent stereoisomers of the pentacyclic guanidine core is thoroughly discussed, and explains the reasons why the 13,14,15-epi-crambescidin 800 polycyclic core is more stable than the 13-epi and the 13,15-epi pentacyclic systems.223 A Stelleta sp. marine sponge has yielded several unprecedented guanidinium alkaloids. The structure of stellettazole A (120), including the absolute conguration, was established by analysis of spectroscopic data and chemical degradation.225 While compound 120 exhibited potent antibacterial activity against Eschericha coli and inhibitory activity against Ca2/calmodulin-dependent phosphodiesterase, stellettazole B (121), isolated from the same sponge species, displayed only marginal antibacterial activity against E. coli.226 Two dimeric stellettadines, namely bistellettadines A (122) and B (123) were also isolated from the same sponge, as moderate inhibitors of Ca2/calmodulin-dependent phosphodiesterase and potent antibacterial agents against E. coli (10 g per disk).227 The absolute stereochemistry of the single stereogenic carbon of stelledatine A (124) was established as R by total synthesis (Scheme 26),228,229 although in the isolation report the authors proposed the S absolute stereochemistry by chemical degradation but have drawn the structure with the correct R 638 Nat. Prod. Rep., 2002, 19, 617649

conguration.230 Another linear guanidine metabolite, aplysillamide B (125),231 has been synthesized (Scheme 27).232 Marine sponges belonging to the order Lithistida are a remarkable source of complex and potent bioactive natural products, including polypeptides and polyketide macrolides.233 The serine protease inhibitors cyclotheonamides E2 (126) and E3 (127) have been isolated from the Lithistid sponge Theonella sp.234 Both peptides are thrombin and trypsin inhibitors at the nanomolar level. Six new peptides have been isolated from Theonella swinhoei: pseudotheonamides A1 (128), A2 (129), B2 (130), C (131) and D (132), as well as dihydrocyclotheonamide A (133).235 All peptides inhibited thrombin with IC50 at 1.0, 3.0, 1.3, 0.19, 1.4 and 0.33 M, respectively, and inhibited trypsin with IC50 at 4.5, >10, 6.2, 3.8, >10, and 6.7 mM, respectively. As previously observed, the inhibition of serine proteases by the cyclotheonamides is due to the presence of the -keto group in the k-arginine residue. This fact may explain the low activity of peptides 128133 when compared with the activity of cyclotheonamide A.235 Tokaramide A (134) is a new cathepsin B inhibitor isolated from the marine sponge Theonella a. mirabilis. Its structure has been determined by analysis of spectroscopic data and chemical degradation.236 Interestingly, all three cathepsin B

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Scheme 24

inhibitors known, tokaramide A (134), leupeptin (135) from dierent Streptomyces species 237 and E-64 (136) from Aspergillus japonicus 238 have an argininal residue. Cathepsins

are lysosomal cysteine proteases, important as physiological regulators.236 Miraziridine (137) is a cysteine protease inhibitor peptide isolated from Theonella a. mirabilis.239 The structure of 137, including its absolute stereochemistry, was established by analysis of spectroscopic data and chemical degradation. It includes two very unusual residues: aziridine-2,3-dicarboxylic acid and the novel vinylogous arginine moiety. Miraziridine A inhibited cathepsin B with IC50 at 1.4 g mL1. The polypeptide discodermin A (138) isolated from the marine sponge Discodermia kiiensis 240 promotes permeabilization of the plasma membrane of A10 cells to the nonpermeable uorescent probes ethidium homodimer-1 (MW = 857), calcein (MW = 623), as well as permeabilization of vascular tissue cells to Ca2 and ATP.241 Eurypamide A (139) was isolated from the sponge Microciona eurypa and identied by analysis of spectroscopic data and chemical interconversions.242 ()-Anchinopeptolide D (140) and ()-cycloanchinopeptolide D (141), previously isolated from the sponge Anchinoe tenacior, have been synthesized (Scheme 28).243 The aldol condensation reaction yielded three stereoisomers, of which the desired product, the Boc protected (140), was obtained in 58% Nat. Prod. Rep., 2002, 19, 617649 639

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Scheme 25

yield. The [2 2] cycloaddition of 140 was tentatively performed in CD3OD, but only the trans to cis isomerization of the double bonds was observed. The same reaction in D2O was rationalized as favourable, since the hydrophobic eect was expected to keep the hydroxystyrylamido groups close together. Indeed, cycloanchinopeptolide (141) was obtained in 48% yield after irradiation of 140 in D2O. 640 Nat. Prod. Rep., 2002, 19, 617649

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Scheme 27

Scheme 26

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641

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ascidian Eudistoma sp. yielded the known trypargine (145), as well as the new trypargimine (146) and 1-carboxytrypargine (147).246 The ascidian Polycarpa aurata yielded N-(methoxybenzoyl)-N -methylguanidine (148) along with related derivatives.247 Minalemines AF (149154) have been isolated from the ascidian Didemnum rodriguesi.248 The absolute stereochemistry of minalemine A (149), was established by a convergent total synthesis via the condensation of 155 and 156 (Scheme 29 and 30).249 5 Natural guanidines from higher plants

4.2
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Other marine invertebrates

Limacianine (142) was isolated from the North Sea nudibranch Limacia clavigera.244 A new indole alkaloid (143, unnamed) was isolated from the ascidian Dendrodoa grossularia.245 The structure of 143 was secured by interpretation of spectroscopic data and by X-ray diraction analysis of the derivative 144 obtained by treatment of 143 with acetic anhydride in pyridine. The

Two agmatine hemiterpenes, smirvonine, also known as sphaerophysine (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 established by analysis of spectroscopic data and conrmed by synthesis, while the structure of 158 was secured by analysis of NMR and MS data. Interestingly, both 157 and 158 were found to be much less toxic than galegine (159) and 4-hydroxygalegine (160), previously isolated from Galega ocinalis. The mixed shikimate-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) from New Caledonia.251 The antimitotic peptides celogentins AC (162164) have been isolated from Celosia argentea (Amaranthaceae), together with moroidin (165), previously isolated from Laportea moroides (Labiatae).252 Celogentins AC inhibited the polymerization of tubulin at concentrations of IC50 20 M, 30 M and 0.8 M, respectively.

While martinelline (166) and martinellic acid (167), previously isolated from Martinella iquitosensis, have been the target of a new synthetic approach,253 martinellic acid was successfully synthesized (Scheme 31).254

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Scheme 31

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Scheme 32

7
1 2 3 4 5 6 7 8 9 10 11 12 13 14

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