Natural guanidine derivatives

Roberto G. S. Berlinck*
Instituto de Química de São Carlos, Universidade de São Paulo CP 780, CEP 13560-970,
São 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
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 Introduction
2 Natural guanidines from terrestrial microorganisms
3 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
Roberto G. S. Berlinck
Born in São 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 Faculté des Sciences of the Université Libre de Bruxelles,
under the supervision of Professor Jean-Claude Braekman. Back
to Brazil in 1992, he moved to the Instituto de Química de São
Carlos, Universidade de São 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
Berlinck’s 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.
1 Introduction
This review updates the literature of natural products with a
guanidine function. As in the previous reviews,
1–3
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,
4–51
guanidine physico-
chemical and structural studies,
52–54
and synthetic guanidine
derivatives which present potent biological activities
55–77
have
been reported in the literature. Additionally, synthetic guani-
dine are also of interest acting as catalysts,
78–94
as selective
oxoanion hosts,
95–100
as superpotent sweeteners,
101
in nucleotide
mimetics,
102–107
in sugar mimetics,
108–110
in lipid mimetics,
111
and
in peptide mimetics.
112–127
2 Natural guanidines from terrestrial microorganisms
Two new, A-53930A (1), A-53930B (2), and one known (3)
streptothricin derivatives with undefined stereochemistry have
been isolated from Streptomyces vinaceusdrappus SANK
62394.
128
All compounds inhibited [
125
I]ω-conotoxin MVIIA
binding to N-type Ca

channels at the nanomolar range, and
[
3
H]norepinephrine release from chick cerebral cortex synapto-
somes 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, 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 exhibit
inhibition of mammalian topoisomerase I and II. Pyrrona-
mycin 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, argifin (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 filtration chrom-
atographies.
132,133
The authors suggested that the guanidine
function of different chitinase inhibitors may be a relevant
structural feature for this bioactivity.
DOI: 10.1039/a901981b Nat. Prod. Rep., 2002, 19, 617–649 617
This journal is © The Royal Society of Chemistry 2002
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The first total synthesis of the HIV-1 protease inhibitors
Mer-N5075A (9), α-MAPI (12) and β-MAPI (13) have been
achieved through a multi-step procedure (Scheme 1–3).
134
α-MAPI (12) and analogues have been synthesized using a new
solid-phase N to C direction approach, in 84% overall yield
(Scheme 4).
135
The racemic TAN-1057 A/B mixture (14) has
been obtained through a multistep convergent synthesis
(Scheme 5).
136
A different approach, previously developed
137
(and discussed in the precedent review
3
) has been employed for
the synthesis of TAN-1057A/B analogues.
138
618 Nat. Prod. Rep., 2002, 19, 617–649
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The final steps of the biosynthesis of the antibiotic blasti-
cidin S (15) in Streptomyces griseochromogenes have been
elucidated (Scheme 6).
139
During these investigations, N-acetyl-
blasticidin S (16) has been isolated from S. griseochromogenes,
suggesting that 16 has a self-protection role for 15 in the micro-
organism. 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 µg per disk, while leucyl-
blasticidin S (17) presented a 15 mm inhibition zone at 75 µg
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 significant production of 15 was observed
when S. griseochromogenes was incubated with 16 in the culture
Scheme 1
Nat. Prod. Rep., 2002, 19, 617–649 619
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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 final
biosynthetic steps for the biosynthesis of 15. Therefore, the
authors suggested a detoxification 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 α,γ-diaminobutyric acid
(Scheme 7).
140
The unusual guanidine amino acid (2S,3R)-capreomycidine
(19), a constituent of the tuberculostatic cyclic peptides capreo-
mycins 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 benzyl-
amine in 98% yield. The condensation of 20 with the aluminum
enolate of 21 afforded the Mannich product 22 as a 3.3 : 1
mixture of two inseparable diastereomers. The guanidinylation
of 22 was achieved after tentative experiments with different
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 cycliz-
ation after rapid purification using Whatman brand silica gel.
After removal of protecting groups, the product was subjected
to a series of purification steps, including cationic ion-exchange
chromatography, in order to obtain the natural amino acid (19)
in >99% ee (by chiral HPLC).
3 Natural guanidines from marine and freshwater
microorganisms
Different reviews have covered the status of the recent
research on cyanobacterial toxins, many of which are respon-
sible for severe human and animals intoxications.
142–147
Gupta
and co-workers reported a possible molecular mechanism to
explain the binding of different phosphatase inhibitors, includ-
ing microcystin-LR (26), with protein phosphatases PP1
and PP2A.
148
An electrospray ionization mass spectrometry
study of different microcystins concluded that microcystins
devoid of the arginine residue always present sodium adduct
ions [M ϩ Na]
ϩ
as the base peak, while arginine bearing micro-
cystins always gave [M ϩ H]
ϩ
and [M ϩ 2H]

ions, with the
relative intensity independent of the sample pH.
149
620 Nat. Prod. Rep., 2002, 19, 617–649
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Scheme 3
Scheme 4
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Scheme 5
Several structurally new cyanobacterial peptides containing
an arginine or a modified arginine moiety have been isolated.
These include aeruginosin 103-A (27) from Microcystis viridis,
which displayed thrombin, trypsin and plasmin inhibitory
activity at the µM range. The bulk 1-amidino-2-ethoxy-3-amido
substituted piperidine ring of aeruginosin 103-A appears to
have a negative effect towards the enzyme inhibitory activity of
27.
150
A closely related new peptidic derivative is microcin
SF608 (28), which has been obtained along with micro-
peptin SF909 (29) and micropeptin SF995 (30) from an
undescribed species of Microcystis cyanobacterium.
151
Micro-
peptin SF909 (29) inhibited chymotrypsin with IC
50
at 4.0 µg
mL
Ϫ1
, while micropeptin SF995 (30) and microcin SF608 (28)
inhibited trypsin with IC
50
at 0.2 and 0.5 µg mL
Ϫ1
, 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 struc-
ture of 31 has been established by MALDI-TOF mass spectro-
metry analysis only. The structure of compound 32 was
proposed after extensive analysis of NMR data and displayed
inhibitory activity against carboxypeptidase A with IC
50
at
3.8 µg mL
Ϫ1
. A Brazilian strain of Microcystis RST 9501 pro-
duced [-Leu
1
]microcystin-LR (33),
154
which presented the
same lethal dose of microcystin-LR (100 µg kg
Ϫ1
). The strain
Nodularia PCC 7804, originally isolated from a freshwater
thermal spring in France, produces [-Har
2
]nodularin (34), with
a lethal dose of 75 µg kg
Ϫ1
and inhibition of protein phos-
phatase 1 (PP1) with IC
50
of 4.5 nM.
155
The Namikoshi and
622 Nat. Prod. Rep., 2002, 19, 617–649
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Scheme 6
Nat. Prod. Rep., 2002, 19, 617–649 623
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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
scientific presentation in the 36
th
Symposium on the Chemistry
of Natural Products, held in Hiroshima.
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.
624 Nat. Prod. Rep., 2002, 19, 617–649
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The total synthesis of aeruginosin 298-A (38) has been
accomplished (Scheme 9), and the S configuration 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 result-
ing 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 sub-
sequent multi-step procedure first gave the unnatural -leucine
stereoisomer presenting different 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 confirmed through another
multi-step synthesis (Schemes 10 and 11).
159
Three new dehydrobutyrine-containing microcystin deriv-
atives, 42–44, have been isolated from the cyanobacterium
Nostoc sp. and identified 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 IC
50
at 8.0 and 4.0 µg mL
Ϫ1
,
respectively, but both compounds did not inhibit chymotrypsin
at 45 µg mL
Ϫ1
. Micropeptin SD979 and SD1002 inhibited
chymotrypsin at 2.4 and 3.2 µg mL
Ϫ1
, respectively, but not
trypsin at 18.0 µg mL
Ϫ1
.
Another modified peptide, kasumigamide (49), has been
isolated from Microcystis aeruginosa NIES-87.
162
Kasumig-
amide displayed antialgal activity against the green alga
Chlamydomonas neglecta (NIES-439) at 2 µg mL
Ϫ1
. Additional
arginine-containing modified peptides are the protein phos-
phatase inhibitors oscillamides B (50) and C (51), isolated from
the cyanobacterium Planktothrix (Oscillatoria) agardhii and
Planktothrix rubescens.
163
Both 50 and 51 displayed inhibit-
ory activity against protein serine/threonine phosphatase PP1
and PP2A at 100 µg mL
Ϫ1
. Both compounds did not inhibit
protein tyrosine phosphatase (PTP-S2) or dual-specificity
phosphatase (VHR and Cdc25B). Oscillamide C (51) presented
IC
50
values of 0.90 and 1.33 µM 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 ЊC during four weeks in the
dark at pH 7. Interestingly, the toxin present in the cyano-
bacterium crude extract is photosensitive, being rapidly
degraded under direct sunlight with a half-life of 4 hours;
however, its photostability increases after purification.
164
The complete biogenetic pathway of cylindrospermopsin
(52) has been established.
165
It is derived from five 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, 617–649 625
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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 by
molecular mechanics.
A new cyclindrospermopsin derivative, 7-epi-cylindro-
spermopsin (54), has been isolated from Aphanizomenon
626 Nat. Prod. Rep., 2002, 19, 617–649
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Scheme 10
ovalisporum, through a multi-step chromatographic procedure
employing ODS flash chromatography, chromatography on
Sephadex G-25 and C
18
reversed phase preparative HPLC.
166
Another related derivative is the non-toxic 7-deoxycylindro-
spermopsin (55), also isolated from C. raciborskii.
167
This latter
derivative differs not only by the absence of the 7-hydroxy func-
tion, 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 different approaches toward the synthesis of cylin-
drospermopsin (52) have been reported,
168–171
its total synthesis
was recently achieved in 3.5% overall yield (Schemes 13, 14).
172
A
series of stepwise interconversions yielded stereospecifically the
functionalized piperidine (56) from 3-picoline. Piperidine (56)
had the required stereochemistry of cylindrospermopsin tri-
cyclic 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 func-
tional group interconversions in order to obtain, after hydro-
genolysis and triple bond reduction, the diamino deprotected
form of 58. This intermediate was reacted with cyanogen
bromide in order to obtain the desired five 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 CuBr
2
, followed
by immediate hydrogenolysis of guanidine protecting groups, to
give a 3 : 2 mixture of stereoisomers at C-7 through an intra-
molecular S
N
2 reaction. The stereoisomers could be separated
by flash chromatography after removal of the acetyl group at
C-12. Monosulfation of 61 with 6 equivalents of SO
3
ؒDMF in
anhydrous pyridine gave 60–80% of cylindrospermopsin (52)
after purification by C
18
reversed-phase column chromato-
graphy. Not only spectroscopic data, but also the toxicity of
Nat. Prod. Rep., 2002, 19, 617–649 627
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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 Altero-
monas luteoviolaceum,
174
has been reported.
175
A [4 ϩ 3] con-
vergent strategy was envisaged (Schemes 15, 16 and 17), by
coupling two fragments and macrocyclization between Gly-Arg
and Gly-β-OH-Asp, since the formation of amide bonds at
Gly as a C-terminal avoids racemization and steric constraint.
Additionally, the β-turn conformation and the Gly-Arg-β-OH-
Asp-Gly sequence are structural features that facilitate the
macrocyclization of a linear precursor.
The ethiological origin of tetrodotoxin (TTX, 67) and bio-
genetically 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 estab-
lished.
177
The hydroxy groups at C-6 and C-11 presented a key
role to the binding to sodium channels, probably as hydrogen
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, 11-
nortetrodotoxin-6(S)-ol (68) from the puffer fish Arothron
nigropunctatus
178
and 5-deoxytetrodotoxin (69) from the puffer
fish 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 final
step of the biosynthesis of TTX.
179
A number of asym-
metric synthetic approaches to tetrodotoxin (67) have been
reported.
180–186
4 Natural guanidines from marine invertebrates
4.1 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
628 Nat. Prod. Rep., 2002, 19, 617–649
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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 been
reported.
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 the
same species of marine sponge and reported under the name
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Scheme 13
styloguanidines.
189
Acetylation of palau’amine (70) with acetic
anhydride in pyridine gave a mixture of acetylated compounds.
The acetamide derivative of 70 was obtained by treatment with
aqueous Ac
2
O and sodium acetate. Since the primary amine
Scheme 14
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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. Palau’amine
displayed low toxicity (LD
50
13 mg kg
Ϫ1
intraperitoneal
in mice), antibiotic activity against Penicillium notatum
(24 mm zone inhibition at 50 µg per disk), immunosuppressive
activity in mixed lymphocyte reaction (IC
50
< 18 ng mL
Ϫ1
),
and cytotoxicity against murine lymphocytes (1.5 µg mL
Ϫ1
),
P-388 (IC
50
0.1 µg mL
Ϫ1
) and A-549 (IC
50
0.2 µg mL
Ϫ1
) cell
lines. 4,5-Dibromopalau’amine (72) displayed cytotoxic
activity against human melanoma with IC
50
0.25 µg mL
Ϫ1
.
Palau’amine was the target of a new enantioselective synthesis
strategy.
190
Axinellamides A-D 76–79 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 purification by
HPLC. While axinellamide A (76) did not display antibiotic
activity, axinellamides B–D 77–79 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 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) 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
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Scheme 16
Scheme 17
632 Nat. Prod. Rep., 2002, 19, 617–649
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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 dibromo-
iphakellin (88) and molecular modelling. Taurodiscapamide
(87) displayed antihistaminic activity at 0.1 mM. A related
metabolite, the fish 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 flabellata
198
and
Stylissa carteri,
199
have been synthesized (Scheme 20).
200
A new
member of the pyrrole-imidazole alkaloids is 12-chloro-11-
hydroxydibromoisophakellin (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. brevi-
styla.
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 19
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 difficulty to observe carbons C-3
and C-6 in the
13
C NMR spectrum, since the compound can
present a pyrazine–pyrazinone tautomeric interconversion.
After the addition of DCl in DMSO-d
6
, a NOE effect observed
between H-4Ј 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
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 finding constitutes the
first 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 actino-
mycetes 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 1–3 (99–101),
new ptilomycalin A derivatives, from the Indian marine sponge
Neofolistipa dianchora.
207
Structure elucidation was accom-
plished by comparison of
13
C and MS data with data previously
reported for crambescidins. The authors suggest that 99–101
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 µg
mL
Ϫ1
. Related polycyclic compounds have been isolated from
two sponges belonging to the genus Monanchora.
208
Dehydro-
batzelladine 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, guanidine-
catalyzed transesterification of the ester function with CD
3
OD
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 anti-
microbial 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.
210–217
For instance,
the absolute stereochemistry of the bicyclic core of batzelladine
A (106), as well as the relative stereochemistry of the left-
hand tricyclic moiety of batzelladine F (107), have been
revised by synthesis of model compounds.
218–220
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. Overman’s group developed a method-
ology 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-iso-
crambescidin 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
synthesis of 14,15,16-isocrambescidin 800 is shown in Scheme
22–25, 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-TsOHؒH
2
O in CHCl
3
or
with PPTS in CHCl
3
, these reaction conditions gave poor yields
of the desired product 115 along with secondary products dif-
ficult 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-isocrambes-
cidin 657 (110) was achieved by exposure of the mixture 115 ϩ
116 to Et
3
N 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)-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 absolute
stereochemistry as S.
224
A complete account on the relative
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Scheme 21
636 Nat. Prod. Rep., 2002, 19, 617–649
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Scheme 22
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Scheme 23
energy of different 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 un-
precedented guanidinium alkaloids. The structure of stellett-
azole A (120), including the absolute configuration, was
established by analysis of spectroscopic data and chemical
degradation.
225
While compound 120 exhibited potent anti-
bacterial activity against Eschericha coli and inhibitory activity
against Ca

/calmodulin-dependent phosphodiesterase, stellett-
azole 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 Ca

/calmodulin-dependent phosphodiesterase
and potent antibacterial agents against E. coli (10 µg per
disk).
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 chemical
degradation but have drawn the structure with the correct R
configuration.
230
Another linear guanidine metabolite, aplysill-
amide 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 A
1
(128), A
2
(129), B
2
(130), C (131) and D (132), as well as dihydrocyclotheonamide
A (133).
235
All peptides inhibited thrombin with IC
50
at 1.0, 3.0,
1.3, 0.19, 1.4 and 0.33 µM, respectively, and inhibited trypsin
with IC
50
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 α-keto group
in the k-arginine residue. This fact may explain the low activity
of peptides 128–133 when compared with the activity of
cyclotheonamide A.
235
Tokaramide A (134) is a new cathepsin B inhibitor isolated
from the marine sponge Theonella aff. mirabilis. Its structure
has been determined by analysis of spectroscopic data and
chemical degradation.
236
Interestingly, all three cathepsin B
638 Nat. Prod. Rep., 2002, 19, 617–649
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Scheme 24
inhibitors known, tokaramide A (134), leupeptin (135)
from different 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 aff. 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 IC
50
at 1.4 µg mL
Ϫ1
.
The polypeptide discodermin A (138) isolated from the
marine sponge Discodermia kiiensis
240
promotes permeabiliz-
ation of the plasma membrane of A10 cells to the non-
permeable fluorescent probes ethidium homodimer-1 (MW =
857), calcein (MW = 623), as well as permeabilization of
vascular tissue cells to Ca

and ATP.
241
Eurypamide A (139) was isolated from the sponge
Microciona eurypa and identified by analysis of spectroscopic
data 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 the
desired product, the Boc protected (140), was obtained in 58%
Nat. Prod. Rep., 2002, 19, 617–649 639
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Scheme 25
yield. The [2 ϩ 2] cycloaddition of 140 was tentatively per-
formed in CD
3
OD, but only the trans to cis isomerization of the
double bonds was observed. The same reaction in D
2
O was
rationalized as favourable, since the hydrophobic effect was
expected to keep the hydroxystyrylamido groups close together.
Indeed, cycloanchinopeptolide (141) was obtained in 48% yield
after irradiation of 140 in D
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640 Nat. Prod. Rep., 2002, 19, 617–649
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Scheme 26
Scheme 27
Nat. Prod. Rep., 2002, 19, 617–649 641
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4.2 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 struc-
ture of 143 was secured by interpretation of spectroscopic data
and by X-ray diffraction analysis of the derivative 144 obtained
by 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 yielded
N-(methoxybenzoyl)-NЈ-methylguanidine (148) along with
related derivatives.
247
Minalemines A–F (149–154) 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
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 estab-
lished by analysis of spectroscopic data and confirmed by syn-
thesis, 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 officinalis. The mixed
shikimate-mevalonate agmatine derivative fontaineine (161) has
Scheme 28 HOBt = hydroxybenzotriazole.
642 Nat. Prod. Rep., 2002, 19, 617–649
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Nat. Prod. Rep., 2002, 19, 617–649 643
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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 A–C
(162–164) have been isolated from Celosia argentea (Amaran-
thaceae), together with moroidin (165), previously isolated
from Laportea moroides (Labiatae).
252
Celogentins A–C
inhibited the polymerization of tubulin at concentrations of
IC
50
20 µM, 30 µM and 0.8 µM, respectively.
While martinelline (166) and martinellic acid (167), previ-
ously isolated from Martinella iquitosensis, have been the target
of 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 wasps
polyamine toxins have been published.
255–257
A new synthesis of
hirudonine (168), an anti-coagulant agent isolated from the
leech Hirudo officinalis, has been reported (Scheme 32).
258
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