Insights into the Biosynthesis of Cyclic Guanidine Alkaloids from Crambeidae Marine Sponges

Article abstract of DOI:10.1002/anie.201809539

Among the outstanding chemical diversity found in marine sponges, cyclic guanidine alkaloids, present in species of the family Crambeidae, are particularly attractive, not only because of their unique chemical features, but also due to a broad range of bi

Full text of DOI:10.1002/anie.201809539

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Accepted Article
Title: Insights into the Biosynthesis of Cyclic Guanidine Alkaloids from
Crambeidae Marine Sponges
Authors: Siguara Silva, Francois Oberhansli, Marie-Aude Tribalat,
Gregory Genta-Jouve, Jean-Louis Teyssie, Marie-Yasmine
Dechraoui-Bottein, Jean-Francois Gallard, Laurent Evanno,
Erwan Poupon, and Olivier Paul Thomas
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201809539
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10.1002/anie.201809539
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Insights into the Biosynthesis of Cyclic Guanidine Alkaloids from
Crambeidae Marine Sponges
Siguara B. L. Silva,[a,b] François Oberhänsli,[c] Marie-Aude Tribalat,[a] Grégory Genta-Jouve,[d] Jean-
Louis Teyssié,[c] Marie-Yasmine Dechraoui-Bottein,[c] Jean-François Gallard,[e] Laurent Evanno,*[b]
Erwan Poupon*[b], and Olivier P. Thomas*[a,f]
Abstract: Among the outstanding chemical diversity found in marine
sponges, cyclic guanidine alkaloids present in species of the family
Crambeidae are particularly attractive, first because of unique
chemical features but also due to a broad range of biological activities.
Despite a growing interest for these natural products as therapeutic
agents, their metabolic pathway has not been experimentally
investigated, and a hypothesis based on the reactivity of free
guanidines is still largely accepted. The first ex situ feeding
experiments using radiolabelled precursors performed on the
Mediterranean sponge Crambe crambe suggests arginine and fatty
acids as precursors in the metabolic pathway of crambescins. A
subsequent bio-inspired approach supported the change of paradigm
in the metabolic pathway of cyclic guanidine alkaloids. A large part of
the chemical diversity of this family would therefore originate from a
tethered Biginelli-like reaction between C-2/C-3 activated fatty acids
and a central guanidinylated pyrrolinium.
trabectedin).[3] Of particular interest, cyclic guanidine alkaloids
(CGA) present in some groups of sponges have shown an
outstanding range of bioactivities.[4] More precisely, sponges of
the genera Batzella, Crambe and Monanchora (Family:
Crambeidae) are rich in CGA with unique chemical architectures
like the bicyclic crambescins (e.g. crambescin A2-448 (1)),
tricyclic batzelladines (e.g. batzelladine A (2)) or pentacyclic
crambescidins (e.g. crambescidin 800 (3)) endowed with a broad
range of antitumoral and antimicrobial activities (Figure 1).[5] The
therapeutic potential of this family of natural products has been
supported by some patents especially on crambescidin
analogues.[6]
The marine environment is now well recognized as a source of
unique metabolites produced through diverse and original
metabolic pathways. While some pathways of microbial origin
have been unravelled in the last decades mainly due to advances
in genomics,[1] the biosynthesis of entire families of natural
products found in marine invertebrates has not been addressed
experimentally yet.[2] Marine alkaloids have been identified as
metabolites with high pharmacological potential, as exemplified
by the marketing of the anticancer drug ecteinascidin 743 (aka
[a]
[b]
UMR Géoazur, Université Nice Sophia Antipolis, CNRS, IRD,
Observatoire de la Côte d’Azur, 250 rue Albert Einstein, 06560
Valbonne, France
Pharmacognosie et Chimie des Substances Naturelles
BioCIS, Université Paris-Sud, Université Paris-Saclay, CNRS
92290 Châtenay-Malabry, France
Figure 1. Illustrating the chemical complexity of key Cyclic Guanidine Alkaloids.
Yet, surprisingly, only hypotheses have been proposed for the
metabolic pathways of these highly complex and bioactive CGA
so far. The first hypothesis was put forward by the group of Snider
in the 1990ies where a simple condensation of a guanidine on a
polyketide chain might lead to the complex structures of
ptilomycalin and crambescins (Scheme 1).[7] The success of
efficient “biomimetic” total syntheses, especially from the groups
of Snider and Overman, left no doubt on a “full polyketide origin”
of these sponge alkaloids with a late condensation of a free
guanidine onto a well suited oxidized carbon backbone.[8] This
metabolic hypothesis has not been really questioned until recently,
when an alternate proposition emerged from the isolation of
unsaturated derivatives of crambescins from the sponge C.
crambe.[9] Altogether, valuable clues led to reconsider the
biosynthetic origin of these alkaloids and they include: i- the
Dr L. Evanno, Prof. Dr. E. Poupon E-mail: laurent.evanno@u-
psud.fr, erwan.poupon@u-psud.fr
[c]
[d]
Radioecology Laboratory, International Atomic Energy Agency—
Environment Laboratories, MC 98012, Monaco
Laboratoire de Chimie-Toxicologie Analytique et Cellulaire (C-TAC)
UMR CNRS 8638 COMETE, Universitꢀ Paris-Descartes, 4, avenue
de l’Observatoire, 75006 Paris, France
Jean-François Gallard, Institut de Chimie des Substances
Naturelles, CNRS UPR 2301, Université Paris-Saclay, 1, avenue de
la Terrasse, 91198 Gif-sur-Yvette, France
Marine Biodiscovery, School of Chemistry and Ryan Institute
National University of Ireland Galway (NUI Galway)
University Road H91 TK33 Galway, Ireland
Prof. Dr. O. P. Thomas
E-mail: olivier.thomas@nuigalway.ie
[e]
[f]
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201809539
Angewandte Chemie International Edition
COMMUNICATION
recurrent presence of
a
central and α-substituted
total syntheses of batzelladines elaborated around key
pyrrole/pyrrolidine scaffolds,[10] these observations set the scene
for an alternative biosynthetic pathway closely related to the
ornithine pathway of some alkaloids (Mannich-type α-alkylations
of nitrogens).[11]
guanidinopyrrolidine in CGA, ii- the inconsistency to establish the
“Birch’ C2 patterning” of a classical polyketide origin in the Snider
hypothesis and iii- the existence of simple and closely related
guanidine alkaloids isolated from the plant Cimicifuga racemosa,
cimipronidine (4), cyclocimipronidine (5).[10] Together with elegant
Scheme 1. Biosynthetic hypotheses for cyclic guanidine alkaloids from marine sponges: building of a new hypothesis.
The change of paradigm would thus consist in a mixed
biosynthetic origin (Scheme 1): L-arginine as building block for a
C4-guanidine unit connected to putative exogenous activated
fatty acid precursors as depicted in scheme 1. In brief, L-arginine
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(6) may provide the central platform guanidinopyrrolinium 10
through a sequence of oxidative deamination decarboxylation
cyclization steps, involving agmatine (7) or 2-oxoarginine (8) and
4-guanidinobutanal (9). This latter pyrrolinium salt may then
represent a perfect electrophile for Mannich-type reactions
involving C-2 activated oxo-fatty acids of type 11 (explaining
thereby the observed diversity of side chains in the series).
containing CGA (Figure 2).[2a, 14] The encrusting sponge Crambe
crambe (Family: Crambeidae) was selected as an appropriate
model to this end as it is widespread in the Western
Mediterranean sea, and also well known to produce both
crambescins and crambescidins CGA.[2a, 14] Crambescin C1-480
(14) was chosen as the targeted CGA to track in the complex
alkaloid metabolome due to its high concentration and ease of
HPLC purification. Specimens of C. crambe were collected with
their substrate to avoid any stress and maintained healthy in open
system aquaria. Radiolabelled precursors were selected for
feeding experiments, as previous studies with sponge natural
products demonstrated their suitability due to a much higher
detection sensitivity compared to stable isotopes.[15] Inspired by
current hypotheses but also the availability of radiolabelled
precursors, the following 14C labelled precursors were selected:
Subsequent
cyclisation
through
a
tethered
Biginelli
condensation[12] would ensure the formation of the central 1-
amino-pyrrolo[1,2-c]pyrimidine (12) as a central biosynthetic
platform of CGA. Final esterification with diverse guanidinylated
alcohols that may also arise from L-arginine (6) or homoarginine
(13) would provide crambescins A and then crambescins C (e.g.
crambescin C1-480 (14)) after hydrolysis of the pyrrolinium. The
transformation of crambescin A into C could arise from an
oxidation of the nitrogen into an iminium followed by hydrolysis
into an aldehyde and a final reduction into a primary alcohol. This
transformation is supported by biotransformations of amino
derivatives.[13]
L-[guanidino-14C]arginine,
[guanidino-14C]agmatine,
L-[U-
14C]lysine, L-[5-14C]ornithine, [U-14C]acetic acid, and [1-14C]lauric
acid. Briefly, lysine and ornithine were chosen as they represent
the most common starting precursors of non-aromatic alkaloids.
Arginine (6) was selected as a provider of the guanidine moieties
of CGA, and agmatine (7) as a more advanced precursor even if
two pathways are plausible to convert arginine into 4-
guanidinobutanal (9) (Scheme 1, pathways a and b). Finally,
acetic acid was tested according to the Snider route involving
polyketides. In parallel, labelled lauric acid was chosen as the
putative exogenous fatty acid precursor (12:0) of crambescin C1-
480 following the mixed origin hypothesis. The use of beta-imager
detection ensured the highest sensitivity for the detection of
radiolabelled derivatives deposited on a TLC plate. Using two
replicates for each precursor and two purification steps with
different HPLC columns, radiolabelled lauric acid and arginine
were unambiguously incorporated into the targeted crambescin
C1-480 with specific activities of 36 and 11 Bq.nmol‒1 respectively
after the second HPLC purification (Figures 2 and 3). None of the
other tested precursors disclosed a stable specific activity after
the second purification therefore suggesting a low or no
contribution to the metabolic pathway of CGA. The clear
incorporation of lauric acid labelled at C-1 into 14 supports the
mixed origin hypothesis in the biosynthesis of CGA as no
radioactivity was evidenced with [U-14C]acetic acid. Even if these
two metabolites are biosynthetically linked, this result reveals a
direct and exogenous incorporation of lauric acid into CGA and
therefore supports our new hypothesis. The incorporation of
arginine labelled at the guanidine part suggests a key role of this
amino-acid in the metabolic pathway of CGA. Guanidine is not
known to be produced directly from arginine as the hydrolysis of
arginine releases urea. Therefore, the positive result with arginine
i) rules out the Snider hypothesis where guanidine is proposed to
condense directly on a polyketide chain; ii) supports the new
hypothesis where arginine is the source of the guanidine moiety
in CGA but also supplies some additional carbons to their
structures. In addition, the diversity of fatty hydrocarbon chains of
CGA can now be explained as a result of the diversity of
surrounding fatty acids available.
Figure 2. Design of the radiolabeled feeding experiments on C. crambe.
These two distinct hypotheses prompted us to design the first
feeding experiments with labelled precursors on a sponge
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10.1002/anie.201809539
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exposure.[18] Finally, a subsequent reduction of the aromatic
analogue with a 5:1 TFA/Et3SiH mixture led quantitatively to
crambescin A2-448 (1, 60% after HPLC purification), gratifyingly
confirming a higher thermodynamic stability for this isomer. A
feedback from the experimental isomerization issue to
biosynthetic considerations may let us consider that the real fatty
acid precursor involved in the condensation would be a C2-C3
unsaturated fatty acid rather than the 3-oxo derivative (see
Supplementary Information for a final slight modification of the
scenario).
Based on this successful transformation, we propose to break
down the chemical structure of more complex CGA in a similar
manner. Indeed, the tricyclic baztelladines and pentacyclic
crambescidins congeners might originate from a subsequent
tethered Biginelli condensation on the other side of the pyrrolidine
nitrogen affording the observed 5,6,9-triazaacenaphthylene as
depicted on scheme 1 and as beautifully anticipated in Herzon
total synthesis of batzelladine B.[11] These results give valuable
insights into the metabolic pathway of an entire and bioactive
family of sponge natural products suggesting a new construction
of alkaloids through successive tethered Biginelli type reactions.
They pave the way for the elucidation of an alternate pathway in
non-aromatic alkaloids and will inspire biochemists and molecular
biologists to target the genes and enzymes responsible for the
key depicted transformations.
Figure 3. Beta-imager counting (36 h) of the radioactivity associated with
Crambescin C1-466 after the first purification (Ending by P1) and the second
purification (Ending by P2) for duplicate experiments using the 14C-radiolabelled
precursors: lysine (LY), agmatine (AG), lauric acid (LA), ornithine (OR), arginine
(AR) and acetic acid (AC).
The contribution of ornithine and lysine in the metabolic pathways
of CGA has not been evidenced even if the level of sensitivity can
be responsible for a lack of radiodetection in 14 but it highlights
the key role of arginine in the biochemical pathway of the
nitrogenated parts of CGA. The absence of radioactivity detected
with the more advanced precursor agmatine (7) also labelled at
the guanidine part was not consistent with the first pathway (a)
and would rather suggest the pathway (b) and the involvement of
2-oxoarginine (8) into the production of 4-guanidinobutanal (9)
(Scheme 1).
With strong experimental evidence of a mixed origin for the CGA
biosynthesis, we investigated the chemical feasibility of the
hypothesis through a bio-inspired synthesis of crambescins. The
appealing tethered Biginelli-type cascade reaction prompted us to
investigate this key reaction to build the heterocyclic core of CGA.
Crambescin A2-448 (1) was chosen as a convenient target with a
rather simple 1-amino-pyrrolo[1,2-c]pyrimidine core (Figure 1).
Lessons learnt from related works led us to envisage
straightforward biomimetic approaches respecting as closely as
possible the biosynthetic hypothesis.[16] Therefore, an oxidative
decarboxylation of arginine (6) was investigated to generate the
highly reactive pyrrolinium salt 10 in situ (Scheme 2). Silver(II)
picolinate[17] was chosen according to Lee’s procedure and
permitted to perform three biomimetic transformations in a single
pot: i- oxidative decarboxylation ii- deamination into aldehyde 9,
and iii- intramolecular dehydration into 10. To achieve a
convergent synthesis, the suitable fully functionalized β-keto ester
15 was concomitantly prepared. A bio-inspired homologation of
lauric acid (16) was successfully envisaged: monobenzylester
malonate 17 (as a surrogate of malonyl-CoA) was engaged in a
Knoevenagel-Claisen-type reaction/decarboxylation sequence
providing 18 in good yield. Hydrogenolysis of this latter provided
an unstable β-ketoacid 19 which was esterified with the protected
guanidino-alcohol 20 (prepared by guanidinylation of
aminobutanol 21). From the two entities 10 and 15, the key step
could be investigated. The projected cascade sequence
proceeded smoothly under optimized buffered conditions
(morpholine/acetic acid 1:1 mol/mol) in trifluoroethanol at reflux,
allowing for the construction of the bicyclic system of crambescins
in a single operation. Indeed, purification by preparative HPLC
provided the expected isocrambescin A2-448 (22) validating
thereby the entire cascade of reactions from L-Arg. The
apparently trivial final isomerization into 1 was largely investigated
using a set of diverse conditions (acidic, basic, ruthenium
catalysis…) and was proven to be difficult to mimic. Anyhow, a
slow oxidation process into didehydrocrambescin A2-448 (23)
was observed that could be accelerated under air and light
Acknowledgements
The scholarship of S. S. was funded by Brazilian Foundation
Capes (process: 99999.010184/2013-09) and M.-A. T. benefited
from a scholarship from the French Ministry of Higher Education
and Research. We are grateful to Fabrice Beau (CEA Saclay-
France) for performing the beta-imager counting. Camille Dejean
and Jean-Christophe Jullian (Université Paris-Sud-France) are
gratefully acknowledged for NMR assistance and Karine Leblanc
(Université Paris-Sud-France) for HPLC assistance. Part of this
work was funded by the CNRS initiative “Projets Exploratoires
Premier Soutien (PEPS ExoMod)” and another part (Grant-Aid
Agreement No. PBA/MB/16/01) is carried out with the support of
the Marine Institute and is funded under the Marine Research
Programme by the Irish Government. The International Atomic
Energy Agency is grateful to the Government of the Principality of
Monaco for the support provided to its Environment Laboratories.
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10.1002/anie.201809539
Angewandte Chemie International Edition
COMMUNICATION
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F. Gallard, R. Guillot, K. Leblanc, E. O. N'Nang, V. Turpin, C. Kouklovsky,
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Scheme 2. Bio-inspired synthesis of crambescin A2-448 following the mixed
biosynthetic origin chemical logic. Reaction conditions: a) CDI, iPrMgCl, THF,
0 °C then r.t., 63%; b) Pd/C, H2, MeOH, r.t., quantitative; c) DIPEA, formamide,
dioxane, r.t. 68%; d) DCC, DMAP, DCM, 0°C then r.t., 54%; e) Ag(pic)2, H2O,
70 °C, f) AcOH, morpholine, Na2SO4, TFE, reflux, 5 days, 16% (2 steps); g) aq.
HCl (1 M), h, 84 %; h) TFA : Et3SiH (5:1 v/v), r.t. 60%.
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R. Morley, B. Scanlon, J. Chem. Soc. C 1970, 815.
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structure of dehydro-crambescin A4 488 (see below): A. El-Demerdash,
C. Moriou, M.-T. Martin, A. de S. Rodrigues-Stien, S. Petek, M. Demoy-
Schneider, K. Hall, J. N. A. Hooper, C. Debitus, A. Al-Mourabit, J. Nat.
Prod. 2016, 79, 1929.
Keywords: Biosynthesis • Marine Sponges • Cyclic Guanidine
Alkaloids • Feeding experiments • Biomimetic synthesis
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Entry for the Table of Contents
COMMUNICATION
An unprecedented biosynthesis study
on the marine sponge Crambe
crambe permitted to suggest a mixed
origin (fatty acid/arginine) for
crambescins. The chemical logic of
the new scenario was ascertained by
a straightforward bio-inspired
Siguara B. L. Silva, François Oberhänsli,
Marie-Aude Tribalat, Grégory Genta-
Jouve, Jean-Louis Teyssié, Marie-
Yasmine Dechraoui-Bottein, Jean-
François Gallard, Laurent Evanno,*
Erwan Poupon* and Olivier P. Thomas*
Page No. – Page No.
synthesis of crambescin A2 and could
pave the way for a unified metabolic
pathway of cyclic guanidine alkaloids.
Changing the Paradigm in the
Biosynthesis of Cyclic Guanidine
Alkaloids from Crambeidae Marine
Sponges
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