Publications by authors named "Bastien Nay"

38 Publications

Programmed Multiple C-H Bond Functionalization of the Privileged 4-hydroxyquinoline Template.

Chemistry 2021 Apr 13. Epub 2021 Apr 13.

Laboratoire de Synthèse Organique, Ecole Polytechnique, ENSTA, CNRS, Institut Polytechnique de Paris, 91128, Palaiseau Cedex, France.

The introduction of substituents on bare heterocyclic scaffolds can selectively be achieved by directed C-H functionalization. However, such methods have only occasionally been used, in an iterative manner, to decorate various positions of a medicinal scaffold to build chemical libraries. We herein report the multiple, site selective, metal-catalyzed C-H functionalization of a "programmed" 4-hydroxyquinoline. This medicinally privileged template indeed possesses multiple reactive sites for diversity-oriented functionalization, of which four were targeted. The C-2 and C-8 decorations were directed by an N-oxide, before taking benefit of an O-carbamoyl protection at C-4 to perform a Fries rearrangement and install a carboxamide at C-3. This also released the carbonyl group of 4-quinolones, the ultimate directing group to functionalize position 5. Our study highlights the power of multiple C-H functionalization to generate diversity in a biologically relevant library, after showing its strong antimalarial potential.
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http://dx.doi.org/10.1002/chem.202100929DOI Listing
April 2021

Diversity-oriented synthesis of 17-spirosteroids.

Beilstein J Org Chem 2020 28;16:880-887. Epub 2020 Apr 28.

Unité Molécules de Communication et Adaptations des Micro-organismes (MCAM), Muséum National d'Histoire Naturelle, CNRS, Paris, France.

A diversity-oriented synthesis (DOS) approach has been used to functionalize 17-ethynyl-17-hydroxysteroids through a one-pot procedure involving a ring-closing enyne metathesis (RCEYM) and a Diels-Alder reaction on the resulting diene, under microwave irradiations. Taking advantage of the propargyl alcohol moiety present on commercially available steroids, this classical strategy was applied to mestranol and lynestrenol, giving a collection of new complex 17-spirosteroids.
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http://dx.doi.org/10.3762/bjoc.16.79DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214869PMC
April 2020

Complex Polypropionates from a South China Sea Photosynthetic Mollusk: Isolation and Biomimetic Synthesis Highlighting Novel Rearrangements.

Angew Chem Int Ed Engl 2020 07 20;59(29):12105-12112. Epub 2020 May 20.

State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Zhangjiang Hi-Tech Park, Shanghai, 201203, China.

Placobranchus ocellatus is well known to produce diverse and complex γ-pyrone polypropionates. In this study, the chemical investigation of P. ocellatus from the South China Sea led to the discovery and identification of ocellatusones A-D, a series of racemic non-γ-pyrone polyketides with novel skeletons, characterized by a bicyclo[3.2.1]octane (1, 2), a bicyclo[3.3.1]nonane (3) or a mesitylene-substituted dimethylfuran-3(2H)-one core (4). Extensive spectroscopic analysis, quantum chemical computation, chemical synthesis, and/or X-ray diffraction analysis were used to determine the structure and absolute configuration of the new compounds, including each enantiomer of racemic compounds 1-4 after chiral HPLC resolution. An array of new and diversity-generating rearrangements is proposed to explain the biosynthesis of these unusual compounds based on careful structural analysis and comparison with six known co-occurring γ-pyrones (5-10). Furthermore, the successful biomimetic semisynthesis of ocellatusone A (1) confirmed the proposed rearrangement through an unprecedented acid induced cascade reaction.
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http://dx.doi.org/10.1002/anie.202003643DOI Listing
July 2020

Variation of chemical compounds in wild Heliconiini reveals ecological factors involved in the evolution of chemical defenses in mimetic butterflies.

Ecol Evol 2020 Mar 13;10(5):2677-2694. Epub 2020 Feb 13.

Institut de Systématique, Evolution, Biodiversité (ISYEB) Muséum National d'Histoire Naturelle CNRS Sorbonne-Université EPHE Université des Antilles Paris France.

Evolutionary convergence of color pattern in mimetic species is tightly linked with the evolution of chemical defenses. Yet, the evolutionary forces involved in natural variations of chemical defenses in aposematic species are still understudied. Herein, we focus on the evolution of chemical defenses in the butterfly tribe Heliconiini. These neotropical butterflies contain large concentrations of cyanogenic glucosides, cyanide-releasing compounds acting as predator deterrent. These compounds are either de novo synthesized or sequestered from their host plant, so that their concentrations may depend on host plant specialization and host plant availability. We sampled 375 wild Heliconiini butterflies across Central and South America, covering 43% species of this clade, and quantify individual variations in the different CGs using liquid chromatography coupled with tandem mass spectrometry. We detected new compounds and important variations in chemical defenses both within and among species. Based on the most recent and well-studied phylogeny of Heliconiini, we show that ecological factors such as mimetic interactions and host plant specialization have a significant association with chemical profiles, but these effects are largely explained by phylogenetic relationships. Our results therefore suggest that shared ancestries largely contribute to chemical defense variation, pointing out at the interaction between historical and ecological factors in the evolution of Müllerian mimicry.
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http://dx.doi.org/10.1002/ece3.6044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069300PMC
March 2020

Time resolved transient circular dichroism spectroscopy using synchrotron natural polarization.

Struct Dyn 2019 Sep 31;6(5):054307. Epub 2019 Oct 31.

Synchrotron SOLEIL, L'Orme des Merisiers, Gif-sur-Yvette 91192, France.

Ultraviolet (UV) synchrotron radiation circular dichroism (SRCD) spectroscopy has made an important contribution to the determination and understanding of the structure of bio-molecules. In this paper, we report an innovative approach that we term time-resolved SRCD (tr-SRCD), which overcomes the limitations of current broadband UV SRCD setups. This technique allows accessing ultrafast time scales (down to nanoseconds), previously measurable only by other methods, such as infrared (IR), nuclear magnetic resonance (NMR), fluorescence and absorbance spectroscopies, and small angle X-ray scattering (SAXS). The tr-SRCD setup takes advantage of the natural polarization of the synchrotron radiation emitted by a bending magnet to record broadband UV CD faster than any current SRCD setup, improving the acquisition speed from 10 mHz to 130 Hz and the accessible temporal resolution by several orders of magnitude. We illustrate the new approach by following the isomer concentration changes of an azopeptide after a photoisomerization. This breakthrough in SRCD spectroscopy opens up a wide range of potential applications to the detailed characterization of biological processes, such as protein folding and protein-ligand binding.
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http://dx.doi.org/10.1063/1.5120346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823104PMC
September 2019

One-Pot Synthesis of Metastable 2,5-Dihydrooxepines through Retro-Claisen Rearrangements: Method and Applications.

Chemistry 2019 Jun 27;25(36):8643-8648. Epub 2019 May 27.

Laboratoire de Synthèse Organique, Ecole Polytechnique, CNRS, ENSTA, Institut Polytechnique de Paris, 91128, Palaiseau, France.

A one-pot methodology to synthesize metastable bicyclic 2,5-dihydrooxepines from cyclic 1,3-diketones and 1,4-dibromo-2-butenes through the retro-Claisen rearrangement of syn-2-vinylcyclopropyl diketone intermediates is reported. DFT calculations were performed to understand the reaction selectivity and mechanisms towards [1,3]- or [3,3]-sigmatropic rearrangements, highlighting the crucial influence of the temperature. The reaction was successfully applied to a short protecting group-free total synthesis of radulanin A, a natural 2,5-dihydrobenzoxepine. Moreover, the strong herbicidal potential of this natural product is demonstrated for the first time.
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http://dx.doi.org/10.1002/chem.201901675DOI Listing
June 2019

Why has transparency evolved in aposematic butterflies? Insights from the largest radiation of aposematic butterflies, the Ithomiini.

Proc Biol Sci 2019 04;286(1901):20182769

1 Institut Systématique Évolution Biodiversité (ISYEB), CNRS, MNHN, Sorbonne Université , EPHE, Université des Antilles, CP50 75005 Paris , France.

Defended species are often conspicuous and this is thought to be an honest signal of defences, i.e. more toxic prey are more conspicuous. Neotropical butterflies of the large Ithomiini tribe numerically dominate communities of chemically defended butterflies and may thus drive the evolution of mimetic warning patterns. Although many species are brightly coloured, most are transparent to some degree. The evolution of transparency from a warning-coloured ancestor is puzzling as it is generally assumed to be involved in concealment. Here, we show that transparent Ithomiini species are indeed less detectable by avian predators (i.e. concealment). Surprisingly, transparent species are not any less unpalatable, and may in fact be more unpalatable than opaque species, the latter spanning a larger range of unpalatability. We put forth various hypotheses to explain the evolution of weak aposematic signals in these butterflies and other cryptic defended prey. Our study is an important step in determining the selective pressures and constraints that regulate the interaction between conspicuousness and unpalatability.
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http://dx.doi.org/10.1098/rspb.2018.2769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6501930PMC
April 2019

Marine sponges of the genus as promising drug sources: chemical and biological aspects.

Acta Pharm Sin B 2019 Mar 16;9(2):237-257. Epub 2018 Oct 16.

State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China.

Marine sponges of the genus are well known as rich sources of diverse and complex biologically relevant natural products, including alkaloids, terpenoids, peptides, lipids, and steroids. Some of these metabolites, with novel structures and promising biological activities, have attracted a lot of attention from chemists seeking to perform their total synthesis in parallel to intensive biological studies towards new drug leads. In this review, we summarized the distribution of the chemically investigated sponges, the isolation, synthesis and biological activities of their secondary metabolites, covering the literature from 1982 to early 2018.
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http://dx.doi.org/10.1016/j.apsb.2018.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6437601PMC
March 2019

Multifaceted Study on a Cytochalasin Scaffold: Lessons on Reactivity, Multidentate Catalysis, and Anticancer Properties.

Chemistry 2018 Nov 21;24(62):16686-16691. Epub 2018 Oct 21.

Muséum National d'Histoire Naturelle, Unité Molécules de Communication et Adaptation des Micro-organismes, CNRS, 57 rue Cuvier, 75005, Paris, France.

An intramolecular Diels-Alder (IMDA) reaction efficiently accelerated by Schreiner's thiourea is reported, to build a functionalized cytochalasin scaffold (periconiasin series) for biological purposes. DFT calculation highlighted a unique multidentate cooperative hydrogen bonding in this catalysis. The deprotection end game afforded a collection of diverse structures and showed the peculiar reactivity of the Diels-Alder cycloadducts upon functionalization. Biological studies revealed strong cytotoxicity of a few compounds on breast cancer cell lines while actin polymerization is preserved.
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http://dx.doi.org/10.1002/chem.201804023DOI Listing
November 2018

An Integrative Approach to Decipher the Chemical Antagonism between the Competing Endophytes Paraconiothyrium variabile and Bacillus subtilis.

J Nat Prod 2017 11 15;80(11):2863-2873. Epub 2017 Nov 15.

Unité Molécules de Communication et Adaptation des Micro-organismes (UMR 7245), Sorbonne Université, Muséum National d'Histoire Naturelle, CNRS , CP 54, 57 rue Cuvier, 75005 Paris, France.

An integrative approach combining traditional natural products chemistry, molecular networking, and mass spectrometry imaging has been undertaken to decipher the molecular dialogue between the fungus Paraconiothyrium variabile and the bacterium Bacillus subtilis, which were isolated as endophytes from the conifer Cephalotaxus harringtonia and are characterized by a strong and mutual antibiosis. From this study, we highlight that bacterial surfactins and a fungal tetronic acid are involved in such competition and that the fungus is able to hydrolyze surfactins to fight against the bacterial partner.
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http://dx.doi.org/10.1021/acs.jnatprod.6b01185DOI Listing
November 2017

Inhibition of Phytophthora species, agents of cocoa black pod disease, by secondary metabolites of Trichoderma species.

Environ Sci Pollut Res Int 2018 Oct 30;25(30):29901-29909. Epub 2017 Sep 30.

Sorbonne Universités, Muséum National d'Histoire Naturelle, Centre National de la Recherche Scientifique (CNRS UMR 7245), 57 rue Buffon, CP54, 75005, Paris, France.

Cocoa production is affected by the black pod disease caused by several Phytophthora species that bring, about each year, an estimated loss of 44% of world production. Chemical control remains expensive and poses an enormous risk of poisoning for the users and the environment. Biocontrol by using antagonistic microorganisms has become an alternative to the integrated control strategy against this disease. Trichoderma viride T7, T. harzanium T40, and T. asperellum T54, which showed in vivo and in vitro antagonistic activity against P. palmivora, were cultured and mycelia extracted. Inhibition activity of crude extracts was determined, and then organic compounds were isolated and characterized. The in vitro effect of each compound on the conidia germination and mycelia growth of four P. palmivora, two P. megakaria, and one P. capsici was evaluated. T. viride that displayed best activities produced two active metabolites, viridin and gliovirin, against P. palmivora and P. megakaria strains. However, no activity against P. capsici was observed. Besides being active separately, these two compounds have a synergistic effect for both inhibitions, mycelia growth and conidia germination. These results provide the basis for the development of a low-impact pesticide based on a mixture of viridin and gliovirine.
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http://dx.doi.org/10.1007/s11356-017-0283-9DOI Listing
October 2018

A Reactive Eremophilane and Its Antibacterial 2(1H)-Naphthalenone Rearrangement Product, Witnesses of a Microbial Chemical Warfare.

Org Lett 2017 08 24;19(15):4038-4041. Epub 2017 Jul 24.

Muséum National d'Histoire Naturelle , CNRS (UMR 7245 MCAM), Sorbonne Universités, 57 rue Cuvier (CP 54), 75005 Paris, France.

Two sesquiterpenes, 4-epi-microsphaeropsisin (1) and a dihydrofurano-2(1H)-naphthalenone (variabilone, 2) which represents a new skeleton, were isolated from endophytic fungus Paraconiothyrium variabile. Reactivity studies showed that eremophilane 1 is a precursor of 2 through acid-promoted methyl 1,2-migration and aromatization. An electrophilic intermediate of this transformation was intercepted by N-acetylcysteamine, a biomimetic nucleophile. Only compound 2 was antibacterial against endophytic bacterium Bacillus subtilis (coisolated with P. variabile), suggesting a role in the microbial competition in plants.
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http://dx.doi.org/10.1021/acs.orglett.7b01788DOI Listing
August 2017

Asymmetric Total Synthesis of Distaminolyne A and Revision of Its Absolute Configuration.

Org Lett 2017 02 23;19(3):714-717. Epub 2017 Jan 23.

State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , No. 555, Zu Chong Zhi Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China.

The first total synthesis of a marine derived polyacetylene, distaminolyne A, and its enantiomer were achieved from the commercially available undec-10-en-1-ol. A key proline-catalyzed asymmetric α-aminooxylation of an aldehyde intermediate was used to introduce the chiral center en route to the enantiomerically pure 1,2-amino alcohols. The absolute configuration of both synthesized enantiomers of distaminolyne A was confirmed by using chiral derivatizing agents, leading to revision of the natural product absolute configuration from 2S to 2R. Antibacterial, pancreatic lipase (PL) inhibitory, and protein-tyrosine phosphatase 1B (PTP1B) inhibitory activities were evaluated.
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http://dx.doi.org/10.1021/acs.orglett.6b03892DOI Listing
February 2017

Variation in cyanogenic compounds concentration within a Heliconius butterfly community: does mimicry explain everything?

BMC Evol Biol 2016 12 15;16(1):272. Epub 2016 Dec 15.

Institut Systématique, Evolution, Biodiversité, UMR 7205 MNHN-CNRS-EPHE-UPMC- Sorbonne Universités, Muséum National d'Histoire Naturelle, Bâtiment d'entomologie, CP050, 57 rue Cuvier, 75005, Paris, France.

Background: Aposematic species advertise their unpalatability using warning signals such as striking coloration. Given that predators need to sample aposematic prey to learn that they are unprofitable, prey with similar warning signals share the cost of predator learning. This reduction in predation risk drives evolutionary convergence of warning signals among chemically defended prey (Müllerian mimicry). Whether such warning signal convergence is associated to similar defence levels among co-mimics is still an open question that has rarely been tested in wild populations. We quantified variation in cyanide-based (CN) chemical protection in wild caught individuals of eight aposematic Heliconius butterfly species belonging to four sympatric mimicry rings. We then tested for correlations between chemical protection and ecological species-specific traits.

Results: We report significant differences in CN concentrations both within and between sympatric species, even when accounting for the phylogeny, and within and between mimicry rings, even after considering inter-specific variation. We found significant correlations between CN concentration and both hostplant specialization and gregarious behaviour in adults and larvae. However, differences in CN concentrations were not significantly linked to mimicry ring abundance, although the two most toxic species did belong to the rarest mimicry ring.

Conclusions: Our results suggest that mimicry can explain the variation in the levels of chemical defence to a certain extent, although other ecological factors are also relevant to the evolution of such variability.
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http://dx.doi.org/10.1186/s12862-016-0843-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5160018PMC
December 2016

Antimicrobial Oligophenalenone Dimers from the Soil Fungus Talaromyces stipitatus.

J Nat Prod 2016 Dec 14;79(12):2991-2996. Epub 2016 Dec 14.

Unité Molécules de Communication et Adaptation des Micro-organismes (UMR 7245), Sorbonne Université, Muséum National d'Histoire Naturelle , CNRS, CP 54, 57 Rue Cuvier, 75005 Paris, France.

New polyketide-derived oligophenalenone dimers, 9a-epi-bacillisporin E (1) and bacillisporins F-H (2-5), along with the known bacillisporin A (6), were isolated from the fungus Talaromyces stipitatus. Their structures and absolute configurations were determined on the basis of spectroscopic analyses, electronic circular dichroism, and GIAO NMR shift calculation followed by DP4 analysis. The antimicrobial activity of these compounds was evaluated against a panel of human pathogenic bacteria. Among them, bacillisporin H (5) exhibited antimicrobial activity together with modest cytotoxicity against HeLa cells.
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http://dx.doi.org/10.1021/acs.jnatprod.6b00458DOI Listing
December 2016

First Total Synthesis, Structure Revision, and Natural History of the Smallest Cytochalasin: (+)-Periconiasin G.

Chemistry 2016 Oct 9;22(43):15257-15260. Epub 2016 Sep 9.

Muséum National d'Histoire Naturelle, CNRS (UMR 7245), Sorbonne Universités, 57 rue Cuvier (CP 54), 75005, Paris, France.

The total synthesis of the smallest cytochalasin isolated so far, periconiasin G, which bears a seven-membered ring in lieu of the usual macrocycle, has been performed from both enantiomers of citronellal, relying on an intramolecular Diels-Alder reaction in favor of the natural endo stereochemistry. We show that, among the four synthesized stereoisomers, including the exo isomers, the one matching the NMR data of the natural product was not that assigned in the original report, imposing structure revision. The natural product, previously isolated from a plant-mutualistic fungus, was biologically investigated taking into account its natural history, showing significant effects against the phytopathogenic fungus Botrytis cinerea and thus opening new opportunities in combating this pest.
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http://dx.doi.org/10.1002/chem.201603734DOI Listing
October 2016

3-Acylated tetramic and tetronic acids as natural metal binders: myth or reality?

Nat Prod Rep 2016 Apr 16;33(4):540-8. Epub 2016 Feb 16.

Muséum National d'Histoire Naturelle, CNRS, UMR 7245 Molécules de Communication et Adaptation des Micro-organismes, 57 rue Cuvier (CP 54), 75005 Paris, France.

Covering: up to 20153-Acylated tetramic and tetronic acids are characterized by a low pKa and are likely to be deprotonated under physiological conditions. In addition, their structure makes them excellent chelators of metallic cations. We will discuss the significance of these chemical properties with regard to the biological properties and mechanisms of action of these compounds, highlighting the importance of considering them as salts or chelates for biological purposes, rather than acids.
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http://dx.doi.org/10.1039/c5np00144gDOI Listing
April 2016

Talaroketals A and B, unusual bis(oxaphenalenone) spiro and fused ketals from the soil fungus Talaromyces stipitatus ATCC 10500.

Org Biomol Chem 2016 Mar;14(9):2691-7

Sorbonne Universités, Muséum national d'Histoire naturelle, CNRS, Laboratoire Molécules de Communication et Adaptation des Microorganismes (MCAM), UMR 7245 CNRS-MNHN, CP 54, 57 rue Cuvier, 75005 Paris, France.

Two novel oxaphenalenone dimers, talaroketals A () and B (), were isolated from the soil fungus Talaromyces stipitatus. Their structures and absolute configurations were determined on the basis of spectroscopic analyses, X-ray diffraction experiments and electronic circular dichroism. Compound () features a rare benzannulated 5,6-spiroketal ring system within the dimeric bis(oxaphenalenone) skeleton while the parent compound () harbors a fused bicyclic furano-pyran moiety. These two compounds may biogenetically result from the reaction of duclauxin with a dihydrofuran derivative of botryodiplodin. Additionally, talaroketals A () and B () display modest antimicrobial activity against Staphylococcus aureus.
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http://dx.doi.org/10.1039/c5ob02657aDOI Listing
March 2016

Unexpected talaroenamine derivatives and an undescribed polyester from the fungus Talaromyces stipitatus ATCC10500.

Phytochemistry 2015 Nov 18;119:70-5. Epub 2015 Sep 18.

Molécules de Communication et Adaptation des Micro-organismes, UMR 7245 CNRS/MNHN, Muséum National d'Histoire Naturelle, 57 rue Cuvier (CP54), 75231 Paris Cedex 05, France. Electronic address:

Chemical investigation of the fungus Talaromyces stipitatus ATCC 10500, whose genome has been sequenced, led to the isolation of four undescribed talaroenamines B-E along with the known talaroenamine A. Their structures were elucidated on the basis of spectroscopic studies including mass spectrometry, extensive 2D NMR and electronic circular dichroism (ECD). Interestingly, talaroenamine A had previously been isolated from the strain of T. stipitatus Δtrop C, a strain knocked out for the gene encoding a non-heme Fe(II)-dependent dioxygenase catalyzing the oxidative ring expansion leading to the tropolone, but never from a wild-type strain. All talaroenamines were evaluated for their antiplasmodial activity and Talaroenamine D exhibited the best inhibition against the chloroquine-resistant Plasmodium falciparum (FcB1 strain) without noticeable toxicity on HeLa and preadipose cell lines. In the course of the chemical investigation of T. stipitatus, an undescribed polyester was also isolated and its absolute configuration was determined by hydrolysis and transesterification followed by gas chromatography on chiral column.
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http://dx.doi.org/10.1016/j.phytochem.2015.09.002DOI Listing
November 2015

Ring-closing enyne metathesis of terminal alkynes with propargylic hindrance.

J Org Chem 2015 May 28;80(10):5359-63. Epub 2015 Apr 28.

†Unité Molécules de Communication et Adaptation des Micro-organismes, Sorbonne Universités, Muséum National d'Histoire Naturelle, Centre National de la Recherche Scientifique (CNRS UMR 7245), 57 rue Cuvier (CP 54), 75005 Paris, France.

The ring closing enyne metathesis of substrates with propargylic hindrance was investigated, revealing the successful combination of the Stewart-Grubbs catalysts and microwave heating sometimes up to 170 °C for oxacycles. Medium-sized rings were obtained from terminal alkynes previously reputed as reluctant substrates. This unmatched combination was applied to the synthesis of carbocycles and oxacycles. In addition, this is the first report on the use of the Stewart Grubbs catalyst in ring closing enyne metatheses.
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http://dx.doi.org/10.1021/acs.joc.5b00659DOI Listing
May 2015

Direct biosynthetic cyclization of a distorted paracyclophane highlighted by double isotopic labelling of L-tyrosine.

Org Biomol Chem 2015 Mar;13(12):3662-6

Muséum National d'Histoire Naturelle and Centre National de la Recherche Scientifique (joint unit UMR 7245 CNRS-MNHN), 57 rue Cuvier (CP 54), 75005 Paris, France.

The biosynthesis of pyrrocidines, fungal PK-NRP compounds featuring a strained [9]paracyclophane, was investigated in Acremonium zeae. We used a synthetic L-tyrosine probe, labelled with oxygen 18 as a reporter of phenol reactivity and carbon 13 as a tracer of incorporation of this exogenous precursor. The ((18)O)phenolic oxygen was incorporated, suggesting that phenol behaves as a nucleophile during the formation of the bent aryl ether.
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http://dx.doi.org/10.1039/c5ob00114eDOI Listing
March 2015

The fungal leaf endophyte Paraconiothyrium variabile specifically metabolizes the host-plant metabolome for its own benefit.

Phytochemistry 2014 Dec 21;108:95-101. Epub 2014 Oct 21.

Molécules de Communication et Adaptation des Microorganismes (MCAM), UMR 7245 CNRS/Muséum National d'Histoire Naturelle, Paris, France. Electronic address:

Fungal endophytes live inside plant tissues and some have been found to provide benefits to their host. Nevertheless, their ecological impact is not adequately understood. Considering the fact that endophytes are continuously interacting with their hosts, it is conceivable that both partners have substantial influence on each other's metabolic processes. In this context, we have investigated the action of the endophytic fungus Paraconiothyrium variabile, isolated from the leaves of Cephalotaxus harringtonia, on the secondary metabolome of the host-plant. The alteration of the leaf compounds by the fungus was monitored through metabolomic approaches followed by structural characterization of the altered products. Out of more than a thousand molecules present in the crude extract of the plant leaf, we have observed a specific biotransformation of glycosylated flavonoids by the endophyte. In all cases it led to the production of the corresponding aglycone via deglycosylation. The deglycosylated flavonoids turned out to display significant beneficial effects on the hyphal growth of germinated spores. Our finding, along with the known allelopathic role of flavonoids, illustrates the chemical cooperation underlying the mutualistic relationship between the plant and the endophyte.
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http://dx.doi.org/10.1016/j.phytochem.2014.09.021DOI Listing
December 2014

Chemically unprecedented biocatalytic (AuaG) retro-[2,3]-Wittig rearrangement: a new insight into aurachin B biosynthesis.

Chembiochem 2014 Nov 10;15(16):2349-52. Epub 2014 Sep 10.

Department of Biotechnology, Graduate School of Agricultural and Life Sciences, University of Tokyo, Tokyo (Japan).

AuaG is flavin-dependent monooxygenase responsible for the conversion of aurachin C to aurachin B, a reaction thought to resemble semipinacol migration of the farnesyl substituent. A study of the substrate tolerance of AuaG reveals that it has the peculiar ability to oxidise short-chain analogues of aurachin D. Unexpectedly, a novel retro-[2,3]-Wittig rearrangement was observed with an isoprenyl substrate analogue, thus leading to the 1,1-dimethylallyl ether. Additionally, we found that saturated-chain analogues of N-oxidised aurachin C were not transformed by the C3→C4 semipinacol reaction, as might have been expected for such substrates. Based on this and the unique retro-[2,3]-Wittig rearrangement, we discuss an alternative biosynthetic route for the conversion of aurachin C to aurachin B.
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http://dx.doi.org/10.1002/cbic.201402373DOI Listing
November 2014

Transition metal-promoted biomimetic steps in total syntheses.

Nat Prod Rep 2014 Apr 31;31(4):533-49. Epub 2014 Jan 31.

Muséum National d'Histoire Naturelle and Centre National de la Recherche Scientifique, Unité"Molécules de Communication et Adaptation des Micro-organismes" (UMR 7245 CNRS-MNHN), 57 rue Cuvier (CP 54), 75005 Paris, France.

This review summarizes the state-of-the-art on the use of transition metals in synthetic steps inspired by biosynthesis. After an introduction showing the importance of metals in life processes, with special emphasis on biosynthetic processes, their place in biomimetic synthesis will be described. Topics include oxidative cyclizations for polyether synthesis, electrophilic and radical cyclizations of polyprenoids, the role of palladium in electrocyclizations, oxidative biaryl couplings and other rearrangement steps.
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http://dx.doi.org/10.1039/c3np70077aDOI Listing
April 2014

Bio-inspired formal synthesis of hirsutellones A-C featuring an electrophilic cyclization triggered by remote Lewis acid-activation.

Chemistry 2013 Nov 18;19(48):16389-93. Epub 2013 Oct 18.

Muséum National d'Histoire Naturelle, 57 rue Cuvier (CP 54), 75005 Paris (France); CNRS, UMR 7245, Unité Molécules de Communication et Adaptation des Micro-organismes, Paris (France).

A bio-inspired strategy was used to complete the formal synthesis of the antitubercular hirsutellone B and congeners A and C, through construction of its decahydrofluorene core from a linear polyene strand activated at both ends by a silyl enol ether and an allyl acetate. Our synthesis features a key electrophilic cyclization, starting with the remote activation (by [Yb(OTf)3] or BF3·OEt2) of the allyl acetate and stereoselectively affording the C ring. This was followed by an intramolecular Diels-Alder reaction to get the tricyclic core of the natural product. The stereoselective reduction of the resulting ketone towards the formal intermediate was critical to the success of this strategy.
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http://dx.doi.org/10.1002/chem.201303570DOI Listing
November 2013

Synthesis and biological activities of the respiratory chain inhibitor aurachin D and new ring versus chain analogues.

Beilstein J Org Chem 2013 31;9:1551-8. Epub 2013 Jul 31.

Muséum National d'Histoire Naturelle, Unité Molécules de Communication et Adaptation des Micro-organismes (UMR 7245 CNRS-MNHN), 57 rue Cuvier (CP 54), 75005 Paris, France.

Aurachins are myxobacterial 3-farnesyl-4(1H)-quinolone derived compounds initially described as respiratory chain inhibitors, more specifically as inhibitors of various cytochrome complexes. They are also known as potent antibiotic compounds. We describe herein the first synthesis of aurachin D through a key Conrad-Limpach reaction. The same strategy was used to reach some ring as opposed to chain analogues, allowing for the description of structure-activity relationships. Biological screening of the analogues showed antiparasitic, cytotoxic, antibacterial and antifungal activities, and depletion of the mitochondrial membrane potential. The strongest activity was found on Plasmodium falciparum with a selectivity index of 345, compared to Vero cells, for the natural product and its geranyl analogue. The loss of mitochondrial membrane potential induced by aurachins in human U-2 OS osteosarcoma cells was studied, showing the best activity for aurachin D and a naphthalene analogue, yet without totally explaining the observed cytotoxic activity of the compounds. Finally, a synthetic entry is given to the complete carboheterocyclic core of aurachin H through the N-oxidation/epoxidation of aurachin D and a shorter chain analogue, followed by subsequent biomimetic cyclization.
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http://dx.doi.org/10.3762/bjoc.9.176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3740496PMC
August 2013

Hirsutellones and beyond: figuring out the biological and synthetic logics toward chemical complexity in fungal PKS-NRPS compounds.

Nat Prod Rep 2013 Jun;30(6):765-82

Muséum National d'Histoire Naturelle, Molécules de Communication et Adaptation des Micro-organismes (UMR 7245 CNRS-MNHN), 57 rue Cuvier (CP 54), 75005 Paris, France.

Covering: up to early 2013. Fungal polyketides and their hybrid non ribosomal peptide derivatives are characterized by often striking structural features and biological activities. Their diversity and their complexity arise from highly organized and programmable biosynthetic pathways and have been challenged by many synthetic chemists. This review will conceptually illustrate how complexity can be generated, starting from a general biosynthetic purpose (the fundaments of PKS-NRPS assembly lines) and finally showing how the particular class of hirsutellone compounds has emerged from such processes in relation to post-elongation and secondary tailoring events. Synthetic efforts to produce these natural products will be described with a special emphasis on complexity-generating strategies and steps. Thus, the biosynthetic and synthetic works will be analyzed in a continuous flow, focusing on both the logic of Nature and organic chemists.
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http://dx.doi.org/10.1039/c3np70016jDOI Listing
June 2013

Geographic locality greatly influences fungal endophyte communities in Cephalotaxus harringtonia.

Fungal Biol 2013 Feb 8;117(2):124-36. Epub 2013 Jan 8.

Origine, Structure et Evolution de la Biodiversité, UMR 7205 CNRS/MNHN, Muséum National d'Histoire Naturelle, Paris, France.

Although endophytes of conifers have been extensively studied, few data are available on Cephalotaxaceae. We examined foliar and stem endophytes of Cephalotaxus harringtonia, within its natural range in Japan and outside its natural range in France to study the effect of geography on endophyte community composition. In Japan, rapidly growing endophytes were dominant and may have masked the real diversity, in comparison to France where most endophytes were growing slowly. Analyses of ITS rDNA revealed 104 different Blast Groups among 554 isolates. Almost no overlap between endophyte assemblages of C. harringtonia from the two countries was observed. It seems that Japanese C. harringtonia trees, which should be well adapted to their native site, would host a specific, endemic endophyte community, while trees that have been introduced recently to a foreign site, in France, should have captured existing cosmopolitan and more generalist taxa. In Japan the majority of xylariaceous taxa, which dominated the communities, were unknown and, although closely related to Asian taxa, may be new to science. Dothideomycetes were more prevalent in France. Locally, urban environment, particularly in Japan, may have introduced some perturbations in the native endophyte community of C. harringtonia, with an abundance of generalist fungi such as Nigrospora and Colletotrichum.
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http://dx.doi.org/10.1016/j.funbio.2012.12.005DOI Listing
February 2013

Chemical communication between the endophytic fungus Paraconiothyrium variabile and the phytopathogen Fusarium oxysporum.

PLoS One 2012 15;7(10):e47313. Epub 2012 Oct 15.

UMR 7245, MCAM, MNHN CNRS, Muséum National d'Histoire Naturelle, Paris, France.

Paraconiothyrium variabile, one of the specific endophytic fungi isolated from the host plant Cephalotaxus harringtonia, possesses the faculty to inhibit the growth of common phytopathogens, thus suggesting a role in its host protection. A strong antagonism between the endophyte P. variabile and Fusarium oxysporum was observed and studied using optic and electronic microscopies. A disorganization of the mycelium of F. oxysporum was thus noticed. Interestingly, the biological effect of the main secondary metabolites isolated from P. variabile against F. oxysporum did not account for this strong antagonism. However, a metabolomic approach of pure fungal strains and confrontation zones using the data analysis tool XCMS were analyzed and pointed out a competition-induced metabolite production by the endophyte in the presence of the phytopathogen. Subsequent MS/MS fragmentations permitted to identify one of the induced metabolites as 13-oxo-9,11-octadecadienoic acid and highlighted a negative modulation of the biosynthesis of beauvericin, one of the most potent mycotoxin of F. oxysporum, during the competition with the endophyte.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0047313PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3471838PMC
July 2013

Natural products from Cephalotaxus sp.: chemical diversity and synthetic aspects.

Nat Prod Rep 2012 Aug 20;29(8):845-69. Epub 2012 Jun 20.

Muséum National d'Histoire Naturelle, Molécules de Communication et Adaptation des Micro-organismes (UMR 7245 CNRS-MNHN), 57 rue Cuvier (CP 54), 75005 Paris, France.

The Cephalotaxus genus belongs to the Cephalotaxaceae family of conifers. Over the past decades it has proved to be a fruitful source of interesting natural products, especially alkaloids (cephalotaxine esters) and terpenoids (abietanes, troponoids), which often display medicinal properties, especially in the anticancer area. Homoharringtonine is active against some orphan leukaemia and is nowadays approaching marketability. A phytochemical update will be provided and the total synthesis of alkaloids and terpenoids will be discussed in detail.
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http://dx.doi.org/10.1039/c2np20037fDOI Listing
August 2012