195 results on '"Alain Wagner"'
Search Results
2. A Novel Family of Acid-Cleavable Linker Based on Cyclic Acetal Motifs for the Production of Antibody-Drug Conjugates with High Potency and Selectivity
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Tony Rady, Lorenzo Turelli, Marc Nothisen, Elisabetta Tobaldi, Stéphane Erb, Fabien Thoreau, Oscar Hernandez-Alba, Sarah Cianferani, François Daubeuf, Alain Wagner, and Guilhem Chaubet
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Pharmacology ,Immunoconjugates ,Organic Chemistry ,Hydrazones ,Biomedical Engineering ,Pharmaceutical Science ,Antineoplastic Agents ,Bioengineering ,Ado-Trastuzumab Emtansine ,Mice ,Acetals ,Cell Line, Tumor ,Animals ,Humans ,Carrier Proteins ,Biotechnology - Abstract
Cleavable linkers have become the subject of intense study in the field of chemical biology, particularly because of their applications in the construction of antibody-drug conjugates (ADC), where they facilitate lysosomal cleavage and liberation of drugs from their carrier protein. Due to lysosomes' acidic nature, acid-labile motifs have attracted much attention, leading to the development of hydrazone and carbonate linkers among several other entities. Continuing our efforts in designing new moieties, we present here a family of cyclic acetals that exhibit excellent plasma stability and acid lability, notably in lysosomes. Incorporated in ADC, they led to potent constructs with picomolar potency in vitro and similar in vivo efficacy as the commercially available ADC Kadcyla in mouse xenograft models.
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- 2022
3. Bicyclo[6.1.0]nonyne carboxylic acid for the production of stable molecular probes
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Igor Dovgan, Marc Nothisen, Michel Mosser, Guilhem Chaubet, Alain Wagner, Stéphane Erb, Tony Rady, and Sarah Cianférani
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chemistry.chemical_classification ,chemistry.chemical_compound ,chemistry ,Bicyclic molecule ,General Chemical Engineering ,Carboxylic acid ,Chemical biology ,Surface modification ,Peptide bond ,Alcohol ,General Chemistry ,Molecular probe ,Combinatorial chemistry - Abstract
Bicyclo[6.1.0]non-4-yn-9-ylmethanol (BCN alcohol) is the most prominent strained-alkyne scaffold in chemical biology. Described herein is the synthesis of an oxidized analogue – BCN acid – whose facile functionalization via amide bond formation yields more stable derivatives than the classically encountered carbamates.
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- 2021
4. Investigating Ugi/Passerini Multicomponent Reactions for the Site‐Selective Conjugation of Native Trastuzumab**
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Alain Wagner, Steve Hessmann, Charlotte Sornay, Stéphane Erb, Guilhem Chaubet, Igor Dovgan, Thomas Botzanowski, Anthony Ehkirch, Sarah Cianférani, Conception et application de molécules bioactives (CAMB), Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Département Sciences Analytiques et Interactions Ioniques et Biomoléculaires (DSA-IPHC), Institut Pluridisciplinaire Hubert Curien (IPHC), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), and Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)
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Immunoconjugates ,multicomponent reaction ,Lysine ,antibody-drug conjugates ,Peptide ,010402 general chemistry ,01 natural sciences ,Catalysis ,law.invention ,Residue (chemistry) ,Antineoplastic Agents, Immunological ,law ,antibodies ,[CHIM]Chemical Sciences ,Amino Acid Sequence ,Amino Acids ,ComputingMilieux_MISCELLANEOUS ,chemistry.chemical_classification ,Bioconjugation ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,General Chemistry ,Trastuzumab ,Combinatorial chemistry ,0104 chemical sciences ,Drug delivery ,Recombinant DNA ,Amine gas treating ,Conjugate - Abstract
International audience; Site-selective modification of proteins has been the object of intense studies over the past decades, especially in the therapeutic field. Prominent results have been obtained with recombinant proteins, for which site-specific conjugation is made possible by the incorporation of particular amino acid residues or peptide sequences. In parallel, methods for the site-selective and site-specific conjugation of native and natural proteins are starting to thrive, allowing the controlled functionalization of various types of amino acid residues. Pursuing the efforts in this field, we planned to develop a new type of site-selective method, aiming at the simultaneous conjugation of two amino acid residues. We reasoned that this should give higher chances of developing a site-selective strategy compared to the large majority of existing methods that solely target a single residue. We opted for the Ugi four-center three-component reaction to implement this idea, with the aim of conjugating the side-chain amine and carboxylate groups of two neighbouring lysine and aspartate/glutamate. Herein, we show that this strategy can give access to valuable antibody conjugates bearing several different payloads, and limits the potential conjugation sites to only six on the model antibody trastuzumab. Posttranslational modifications of proteins is Nature's way of generating a rich and diverse proteome from a more limited genetic coding capability. First occurrences of intentional, man-made-artificial-proteins modifications using a defined chemical-thus excluding the food-related Maillard reaction for example-could be dated back to the use of formaldehyde in the tanning industry or for the production of toxoids, 1,2 which evolved later on to immunization studies using chemically-modified bovine serum albumin in the 1900s and eventually led to Landsteiner's synthetic haptenes studies. 3,4 The field of protein modification has since largely benefited from the understanding of proteins' and amino acids' structures coupled to the parallel appearance of more efficient and precise analytical tools. This finally resulted in the development of bioconjugation reagents with excellent chemoselectivity towards various amino acids' side chains groups (i.e. residue-selectivity) that translated into major applications, notably in the pharmaceutical field with the generation of protein-fluorophore adducts for trafficking studies, or the polyethyleneglycol chains functionalization (PEGylation) of proteins to give less-immunogenic and more plasma-stable conjugates. 5,6 However, site selectivity quickly emerged as the main limitation of chemoselective strategies, due to the presence of multiple copies of each type of amino acid residue at the surface of proteins. Statistic conjugation of surface-accessible lysine residues with amine-selective reagents typically results in highly heterogeneous mixtures, containing up to millions of different adducts when large proteins such as antibodies are utilised. 7,8 Each of these adducts possessing distinct physicochemical properties, such chemoselective conjugation necessarily leads to mixtures with different in-vivo pharmacokinetic properties along with virtually no reproducibility in batch-to-batch production. 9,10 Regioselective (i.e., site-specific) methods were thus developed and are currently dominated by the use of recombinant proteins, incorporating exogenous amino acid residues-natural or unnatural-or peptide sequences that can be specifically targeted by a tailored reagent or strategy. 11-13 In parallel, site-selective chemical strategies for the conjugation of native and natural proteins have also flourished over the past few years, giving rise to methods targeting various types of amino acids-e.g. lysine, cysteine, tryptophan, tyrosine-that proved to be effective on proteins of all sorts of sizes, including antibodies. 14-28 With the aim of pursuing the efforts in this field, we could not help but notice that the vast majority of previously reported strategies for the site-selective conjugation of native proteins were focused on the modification of a unique residue. We hypothesized that targeting two different amino acid side chains simultaneously would lower the enormous subset of possibilities given by single-residue bioconjugation techniques, thus increasing our chances of developing a site-selective method by minimising the number
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- 2020
5. Design and evaluation of ionizable peptide amphiphiles for siRNA delivery
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Patrick Neuberg, Jean-Serge Remy, Antoine Kichler, Alain Wagner, Conception et application de molécules bioactives (CAMB), Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and CCSD, Accord Elsevier
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siRNA delivery ,Small interfering RNA ,[SDV]Life Sciences [q-bio] ,Pharmaceutical Science ,Peptide ,02 engineering and technology ,030226 pharmacology & pharmacy ,03 medical and health sciences ,RNA interference ,0302 clinical medicine ,Genes, Reporter ,Cell Line, Tumor ,Amphiphile ,Cationic amphiphiles ,Humans ,Gene silencing ,Histidine ,Gene Silencing ,RNA, Small Interfering ,Luciferases ,chemistry.chemical_classification ,Kinase ,Gene Transfer Techniques ,Tryptophan ,[SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences ,Endosomal escape ,021001 nanoscience & nanotechnology ,Amino acid ,[SDV] Life Sciences [q-bio] ,[SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences ,chemistry ,Biochemistry ,Tyrosine ,Peptides ,0210 nano-technology - Abstract
International audience; Small interfering RNAs (siRNAs) can down-regulate the expression of a target mRNA molecule in a sequence-specific manner, making them an attractive new class of drugs with broad potential for the treatment of diverse human diseases. Here, we report the synthesis of a series of cationic amphiphiles which were obtained by the coupling of amino acids and dipeptides onto a lipidic double chain. The new amphiphiles presenting a peptidic motif on a short hydrophilic spacer group were evaluated for selective gene silencing through RNA interference. Our results show that tryptophan residues boost siRNA delivery in an unexpected manner. The silencing experiments performed with very low concentrations of siRNA showed that the best formulations could induce significant death of tumor cells after silencing of polo-like kinase 1 which is implicated in cell cycle progression. In addition, these Trp containing peptide amphiphiles were highly efficient siRNA delivery vectors even in presence of competing serum proteins.
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- 2019
6. Sydnone-based turn-on fluorogenic probes for no-wash protein labeling and in-cell imaging
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Antoine Sallustrau, Manas R. Pattanayak, Marc Nothisen, Sarah Bregant, Alain Wagner, Lucie Plougastel, Frédéric Taran, Davide Audisio, and Margaux Riomet
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010402 general chemistry ,Protein labeling ,Sydnones ,01 natural sciences ,Catalysis ,Turn (biochemistry) ,chemistry.chemical_compound ,Materials Chemistry ,Biological media ,Humans ,Reactivity (chemistry) ,Fluorescent Dyes ,Microscopy, Confocal ,Cycloaddition Reaction ,Strain (chemistry) ,010405 organic chemistry ,Chemistry ,Metals and Alloys ,Proteins ,General Chemistry ,Combinatorial chemistry ,Cycloaddition ,0104 chemical sciences ,Surfaces, Coatings and Films ,Electronic, Optical and Magnetic Materials ,Alkynes ,Ceramics and Composites ,Electrophoresis, Polyacrylamide Gel ,Sydnone ,HeLa Cells - Abstract
We report the synthesis and use of sydnone-based profluorophores as tools for imaging applications. These new probes display exquisite reactivity towards strain promoted cycloaddition reactions with cycloalkynes allowing fast, efficient and selective labeling in biological media. Styryl-pyridinium sydnone probes were found particularly interesting for click reactions to proceed selectively inside cells.
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- 2019
7. Non-specific interactions of antibody-oligonucleotide conjugates with living cells
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Marc Nothisen, Alain Wagner, Isabelle Kuhn, Sergii Kolodych, Sarah Cianférani, Victor Lehot, Stéphane Erb, Guilhem Chaubet, Conception et application de molécules bioactives (CAMB), Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Département Sciences Analytiques et Interactions Ioniques et Biomoléculaires (DSA-IPHC), Institut Pluridisciplinaire Hubert Curien (IPHC), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), and Syndivia SAS
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0301 basic medicine ,[SDV]Life Sciences [q-bio] ,Cell ,Oligonucleotides ,Medicinal chemistry ,02 engineering and technology ,Non specific ,Drug safety ,Multidisciplinary ,biology ,Drug discovery ,Chemistry ,021001 nanoscience & nanotechnology ,Chemical biology ,3. Good health ,Nucleic acids ,medicine.anatomical_structure ,Biochemistry ,Medicine ,Antibody ,0210 nano-technology ,hal-03200308 ,Cell Survival ,Science ,Biologics ,Sciences du Vivant [q-bio]/Biochimie, Biologie Moléculaire ,Article ,Antibodies ,03 medical and health sciences ,Cell Line, Tumor ,medicine ,Humans ,Nucleic-acid therapeutics ,Pharmacology ,Oligonucleotide ,Ligand binding assay ,Proteins ,DNA ,Trastuzumab ,Cell selectivity ,Kinetics ,030104 developmental biology ,Drug delivery ,Nucleic acid ,biology.protein ,Antibody therapy ,Chemical modification ,Conjugate - Abstract
Antibody-Oligonucleotide Conjugates (AOCs) represent an emerging class of functionalized antibodies that have already been used in a wide variety of applications. While the impact of dye and drug conjugation on antibodies’ ability to bind their target has been extensively studied, little is known about the effect caused by the conjugation of hydrophilic and charged payloads such as oligonucleotides on the functions of an antibody. Previous observations of non-specific interactions of nucleic acids with untargeted cells prompted us to further investigate their impact on AOC binding abilities and cell selectivity. We synthesized a series of single- and double-stranded AOCs, as well as a human serum albumin-oligonucleotide conjugate, and studied their interactions with both targeted and non-targeted living cells using a time-resolved analysis of ligand binding assay. Our results indicate that conjugation of single strand oligonucleotides to proteins induce consistent non-specific interactions with cell surfaces while double strand oligonucleotides have little or no effect, depending on the preparation method.
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- 2021
8. Frontispiece: Investigating Ugi/Passerini Multicomponent Reactions for the Site‐Selective Conjugation of Native Trastuzumab
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Stéphane Erb, Alain Wagner, Sarah Cianférani, Guilhem Chaubet, Igor Dovgan, Charlotte Sornay, Anthony Ehkirch, Thomas Botzanowski, and Steve Hessmann
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Bioconjugation ,Chemistry ,Trastuzumab ,Organic Chemistry ,Drug delivery ,Site selective ,medicine ,General Chemistry ,Combinatorial chemistry ,Catalysis ,medicine.drug - Published
- 2020
9. Manniindole, an indole derivative from the roots of
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Josette Linda, Toussi Matchi, Diderot, Tchamo Noungoue, Isabelle, Kuhn, Jérôme, Boissier, Jean Claude, Tchouankeu, Marc, Nothisen, Guilhem, Chaubet, Delphine, Garnier, Sylvain, Ursuegui, Silvère Augustin, Ngouela, and Alain, Wagner
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Indoles ,Animals ,Annonaceae ,Schistosoma mansoni ,Plant Roots - Abstract
A new alkaloid, manniindole
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- 2020
10. Frontispiz: Ethynylation of Cysteine Residues: From Peptides to Proteins in Vitro and in Living Cells
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Romain Tessier, Stéphane Erb, Alexander Adibekian, Charlotte Sornay, Jerome Waser, Guilhem Chaubet, Daniel Abegg, Sarah Cianférani, Brendan G. Dwyer, Raj Kumar Nandi, Alain Wagner, and Javier Ceballos
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Bioconjugation ,Biochemistry ,Chemistry ,General Medicine ,Proteomics ,In vitro ,Cysteine - Published
- 2020
11. Frontispiece: Ethynylation of Cysteine Residues: From Peptides to Proteins in Vitro and in Living Cells
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Romain Tessier, Raj Kumar Nandi, Brendan G. Dwyer, Daniel Abegg, Charlotte Sornay, Javier Ceballos, Stéphane Erb, Sarah Cianférani, Alain Wagner, Guilhem Chaubet, Alexander Adibekian, and Jerome Waser
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General Chemistry ,Catalysis - Published
- 2020
12. Inhibition of dengue virus infection by mannoside glycolipid conjugates
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Christopher G. Mueller, Patrick Neuberg, Evelyne Schaeffer, Astrid Hoste, Adrien Brulefert, Jean-Daniel Fauny, Alain Wagner, Vincent Flacher, Immunopathologie et chimie thérapeutique (ICT), Centre National de la Recherche Scientifique (CNRS)-Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Conception et application de molécules bioactives (CAMB), Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg - Faculté de Médecine [Strabourg] (FMTS), Immunologie et chimie thérapeutiques (ICT), Cancéropôle du Grand Est-Centre National de la Recherche Scientifique (CNRS), Institut de biologie moléculaire et cellulaire (IBMC), and Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)
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0301 basic medicine ,[SDV.BIO]Life Sciences [q-bio]/Biotechnology ,viruses ,030106 microbiology ,Dengue virus ,Serogroup ,Virus Replication ,medicine.disease_cause ,Antiviral Agents ,Endosome membrane ,Dengue fever ,Cell membrane ,Inhibitory Concentration 50 ,03 medical and health sciences ,Glycolipid ,Viral envelope ,Virology ,Chlorocebus aethiops ,Drug Discovery ,medicine ,Animals ,Humans ,Sciences du Vivant [q-bio]/Immunologie ,Vero Cells ,Pharmacology ,biology ,Dendritic Cells ,Hep G2 Cells ,Dengue Virus ,medicine.disease ,biology.organism_classification ,3. Good health ,Flavivirus ,030104 developmental biology ,medicine.anatomical_structure ,Mannosides ,[SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology ,Vero cell ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Glycolipids - Abstract
International audience; Dengue virus (DENV), a mosquito-borne flavivirus, causes severe and potentially fatal symptoms in millions of infected individuals each year. Although dengue fever represents a major global public health problem, the vaccines or antiviral drugs proposed so far have not shown sufficient efficacy and safety, calling for new antiviral developments. Here we have shown that a mannoside glycolipid conjugate (MGC) bearing a trimannose head with a saturated lipid chain inhibited DENV productive infection. It showed remarkable cell promiscuity, being active in human skin dendritic cells, hepatoma cell lines and Vero cells, and was active against all four DENV serotypes, with an IC 50 in the low micromolar range. Time-of-addition experiments and structure-activity analyses revealed the importance of the lipid chain to interfere with an early viral infection step. This, together with a correlation between antiviral activity and membrane polarization by the lipid moiety indicated that the in-hibitor functions by blocking viral envelope fusion with the endosome membrane. These finding establish MGCs as a novel class of antivirals against the DENV.
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- 2018
13. Arginine-selective bioconjugation with 4-azidophenyl glyoxal: application to the single and dual functionalisation of native antibodies
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Igor Dovgan, Christian D. Muller, Alain Wagner, Sylvain Ursuegui, Steve Hessmann, Chloé Michel, Stéphane Erb, Guilhem Chaubet, Sarah Cianférani, Conception et application de molécules bioactives (CAMB), Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut Pluridisciplinaire Hubert Curien (IPHC), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Syndivia SAS, Cooltech Applications, and Cooltech
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Azides ,Immunoconjugates ,medicine.drug_class ,Arginine ,010402 general chemistry ,Monoclonal antibody ,Phenylglyoxal ,01 natural sciences ,Biochemistry ,chemistry.chemical_compound ,medicine ,[CHIM]Chemical Sciences ,Physical and Theoretical Chemistry ,Guanidine ,Bioconjugation ,Cycloaddition Reaction ,010405 organic chemistry ,Lysine ,Organic Chemistry ,Antibodies, Monoclonal ,Trastuzumab ,Combinatorial chemistry ,Cycloaddition ,3. Good health ,0104 chemical sciences ,chemistry ,Alkynes ,Reagent ,Glyoxal ,Azide ,Conjugate - Abstract
International audience; Here, we introduce 4-azidophenyl glyoxal (APG) as an efficient plug-and-play reagent for the selective functionalisation of arginine residues in native antibodies. The selective reaction between APG and arginines’ guanidine groups allowed a facile introduction of azide groups on the monoclonal antibody trastuzumab (plug stage). These pre-functionalised antibody–azide conjugates were then derivatised during the “play stage” via a biorthogonal cycloaddition reaction with different strained alkynes. This afforded antibody-fluorophore and antibody–oligonucleotide conjugates, all showing preserved antigen selectivity and high stability in human plasma. Due to a lower content of arginines compared to lysines in native antibodies, this approach is thus attractive for the preparation of more homogeneous conjugates. This method proved to be orthogonal to classical lysine-based conjugation and allowed straightforward generation of dual-payload antibody.
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- 2018
14. Reduction–rebridging strategy for the preparation of ADPN-based antibody–drug conjugates
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Alain Wagner, Oleksandr Koniev, Sergii Kolodych, Brigitte Renoux, Jitka Eberova, Sarah Cianférani, Igor Dovgan, Sébastien Papot, Anthony Ehkirch, Conception et application de molécules bioactives (CAMB), Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie des Milieux et Matériaux de Poitiers (IC2MP), Université de Poitiers-Institut national des sciences de l'Univers (INSU - CNRS)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut Pluridisciplinaire Hubert Curien (IPHC), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Spectrométrie de Masse BioOrganique [Strasbourg] (LSMBO), Département Sciences Analytiques et Interactions Ioniques et Biomoléculaires (DSA-IPHC), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut Pluridisciplinaire Hubert Curien (IPHC), and Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)
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0301 basic medicine ,Drug ,media_common.quotation_subject ,Pharmaceutical Science ,01 natural sciences ,Biochemistry ,03 medical and health sciences ,Drug Discovery ,ComputingMilieux_MISCELLANEOUS ,media_common ,Pharmacology ,biology ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,[CHIM.CATA]Chemical Sciences/Catalysis ,Combinatorial chemistry ,0104 chemical sciences ,3. Good health ,body regions ,030104 developmental biology ,Homogeneous ,biology.protein ,Molecular Medicine ,Antibody ,Disulphide bonds ,Conjugate - Abstract
The reduction–rebridging strategy is a powerful method for the preparation of stable and homogeneous antibody–drug conjugates (ADCs). In this communication, we describe the development of the arylene-dipropiolonitrile (ADPN) functional group for the rebridging of reduced disulphide bonds and its application in the preparation of potent and selective ADCs.
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- 2018
15. Bioorthogonal Click and Release Reaction of Iminosydnones with Cycloalkynes
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Sabrina Bernard, Alain Wagner, Davide Audisio, Oleksandr Koniev, Sarah Bregant, Lucie Plougastel, Jijy Elyian, Elodie Decuypere, Sandra Gabillet, Sergii Kolodych, Frédéric Taran, Antoine Sallustrau, Margaux Riomet, Minh Nguyet Trinh, and Ramar Arun Kumar
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010405 organic chemistry ,Chemistry ,Chemical biology ,General Medicine ,General Chemistry ,010402 general chemistry ,01 natural sciences ,Combinatorial chemistry ,Catalysis ,0104 chemical sciences ,Click chemistry ,Posttranslational modification ,Drug release ,Cleavable linker ,Bioorthogonal chemistry - Abstract
We report the discovery of a new bioorthogonal click-and-release reaction involving iminosydnones and strained alkynes. This transformation leads to two products resulting from the ligation and fragmentation of iminosydnones under physiological conditions. Optimized iminosydnones were successfully used to design innovative cleavable linkers for protein modification, thus opening up new areas in the fields of drug release and target-fishing applications. This click-and-release technology offers the possibility of exchanging tags on proteins for functionalized cyclooctynes under mild and bioorthogonal conditions.
- Published
- 2017
16. Abstract 691: Antibody conjugated to a bispecific RNA molecule targeting RIG-I and PLK1
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Alain Wagner, Dmitri Wiederschain, Renaud Morales, Hervé Bouchard, Nicolas Basse, Safia Deddouche-Grass, Tony Rady, Guilhem Chaubet, Sarah Cianférani, and Stéphane Erb
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Cancer Research ,Oncology ,Biochemistry ,biology ,RIG-I ,Chemistry ,biology.protein ,RNA molecule ,Conjugated system ,Antibody ,PLK1 - Abstract
Simultaneous access to several targets has become the subject of intense studies in immuno-oncology. In order to benefit from the synergies provided by the activation of different signaling pathways in immunology and the knockdown of proteins involved in cancer cell survival, we established a bispecific approach. The activation of the innate immune response by delivering agonists of pattern-recognition receptors (PRR) such as RIG-I (retinoic acid-inducible I) represents a promising strategy. RIG-I detects short double-stranded RNA molecules ended by a 5'-di/triphosphate moiety (5'ppp-dsRNA). RIG-I activation promotes type I IFN secretion and cancer-cell selective apoptosis. To obtain a bifunctional molecule, the 5'ppp-dsRNA sequence was designed to silence PLK1 (polo-like kinase 1). Suppressing PLK1 expression with small interfering RNAs (siRNA) leads to cell cycle arrest and retards cancer cell growth. This concept of bifunctional RNAs has been validated by using non-targeted systems.1 To enhance this synergy, we conjugated this 5'ppp-siPLK1 to an antibody for a specific delivery to cancerous cells that overexpress erythropoietin-producing hepatocellular receptor A2 (EphA2) at their surface. Upon binding to EphA2 receptor, the antibody is well internalized, thus making it a good vehicle to deliver the bispecific 5'ppp-siPLK1. After EphA2-positive cells treatment, we observed RIG-I specific activation as well as PLK1 depletion. Both effects were correlated with cellular apoptosis and the mode of action was further confirmed with mechanistic and kinetic studies. Finally, while non-modified unconjugated siRNA has a very short half-life in plasma, we observed an increase in stability for the antibody-5'ppp-siPLK1 conjugates. These data suggest that anti-EphA2 receptor antibody could be used to deliver a bispecific RNA molecule. References:1H. Poeck, R. Besch, C. Maihoefer, M. Renn, D. Tormo, S. S. Morskaya, S. Kirschnek, E. Gaffal, J. Landsberg, J. Hellmuth, A. Schmidt, D. Anz, M. Bscheider, T. Schwerd, C. Berking, C. Bourquin, U. Kalinke, E. Kremmer, H. Kato, S. Akira, R. Meyers, G. Häcker, M. Neuenhahn, D. Busch, J. Ruland, S. Rothenfusser, M. Prinz, V. Hornung, S. Endres, T. Tüting and G. Hartmann, 5′-triphosphate-siRNA: turning gene silencing and Rig-I activation against melanoma, Nat. Med., 2008, 14, 1256-1263. Citation Format: Tony Rady, Stéphane Erb, Safia Deddouche-Grass, Renaud Morales, Hervé Bouchard, Guilhem Chaubet, Sarah Cianférani, Dmitri Wiederschain, Nicolas Basse, Alain Wagner. Antibody conjugated to a bispecific RNA molecule targeting RIG-I and PLK1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 691.
- Published
- 2021
17. Structural investigation of cyclo-dioxo maleimide cross-linkers for acid and serum stability
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Alain Wagner, Jean-Michel Becht, Igor Dovgan, Elisabetta Tobaldi, and Michel Mosser
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Models, Molecular ,0301 basic medicine ,Protein Conformation ,Serum Albumin, Human ,Ring (chemistry) ,Biochemistry ,Adduct ,Maleimides ,03 medical and health sciences ,chemistry.chemical_compound ,Drug Stability ,Succinimide ,Humans ,Organic chemistry ,Sulfhydryl Compounds ,Physical and Theoretical Chemistry ,Methylene ,Solubility ,Maleimide ,Pyrans ,Chemistry ,Organic Chemistry ,Water ,Hydrogen-Ion Concentration ,Combinatorial chemistry ,030104 developmental biology ,Linker ,Conjugate - Abstract
The biochemical characteristics of hetero-bifunctional cross-linkers used in bioconjugates are of essential importance to the desired features of the final adduct (i.e. antibody-drug conjugates). These include stability in biological media, chemical and biological reactivities, cleavability under defined conditions, and solubility. In our previous work, we introduced a new amino-to-thiol linker, maleimidomethyl dioxane (MD), as an alternative to classical maleimide conjugation, with increased hydrophilicity and serum stability due to succinimidyl ring-opening. In this work, we investigate the generality of linkers containing a dioxo-ring with regard to their ability to self-hydrolyze and their surprising stability at a low pH. We synthesized four FRET probes which allowed us to address the stability of the dioxo-ring and to study the maleimide ring-opening and the thiol-exchange processes by means of detecting and measuring the generation of fluorescence. It was found that the ring expansion (from a 5- to a 6-membered ring) improved the stability of the probes in aqueous media, and the increase of the chain length between the dioxo-ring and the succinimide ring (from methylene to ethylene) decreased the rate of succinimidyl ring-opening.
- Published
- 2017
18. pH-Responsive Nanometric Polydiacetylenic Micelles Allow for Efficient Intracellular siRNA Delivery
- Author
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Alain Wagner, Manon Ripoll, Patrick Neuberg, Antoine Kichler, Nassera Tounsi, Jean-Serge Remy, Laboratoire de Chimie des Systèmes Fonctionnels, Centre National de la Recherche Scientifique (CNRS), Conception et application de molécules bioactives (CAMB), Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Bioimagerie et Pathologies (LBP), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), and Biophotonique et Pharmacologie (CNRS UMR 7213)
- Subjects
[SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT] ,Small interfering RNA ,Materials science ,Polymers ,education ,Nanotechnology ,Protonation ,Endosomes ,02 engineering and technology ,010402 general chemistry ,01 natural sciences ,Micelle ,imidazole ,Drug Delivery Systems ,Amphiphile ,Histidine ,General Materials Science ,proton sponge effect ,RNA, Small Interfering ,Cytotoxicity ,Micelles ,technology, industry, and agriculture ,Hydrogen-Ion Concentration ,021001 nanoscience & nanotechnology ,0104 chemical sciences ,Photopolymer ,siRNA ,photopolymerization ,Biophysics ,0210 nano-technology ,Intracellular - Abstract
International audience; A novel generation of pH-responsive photopolymerized diacetylenic amphiphile (PDA) micelles with a diameter of 10 nm was designed and optimized for the intracellular delivery of siRNAs. Dialysis and photopolymerization of the micelles allowed a strong reduction of the cytotoxicity of the nanovector, while the hydrophilic histidine headgroup permitted enhancing the siRNA delivery potential by improving the endosomal escape via imidazole protonation. These PDA-micellar systems were fully characterized by DLS, TEM, and DOSY-NMR experiments. The resulting bioactive complexes of PDA-micelles with siRNA were shown to have an optimal size below 100 nm.
- Published
- 2016
19. Antibody-Oligonucleotide Conjugates as Therapeutic, Imaging, and Detection Agents
- Author
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Igor Dovgan, Alain Wagner, Sergii Kolodych, and Oleksandr Koniev
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Immunoconjugates ,medicine.medical_treatment ,Biomedical Engineering ,Oligonucleotides ,Pharmaceutical Science ,Bioengineering ,02 engineering and technology ,01 natural sciences ,Antibodies ,medicine ,Animals ,Humans ,Pharmacology ,biology ,010405 organic chemistry ,Oligonucleotide ,Chemistry ,Organic Chemistry ,Traction (orthopedics) ,021001 nanoscience & nanotechnology ,0104 chemical sciences ,Molecular Imaging ,Biochemistry ,biology.protein ,Antibody ,0210 nano-technology ,Biotechnology ,Conjugate - Abstract
Antibody-oligonucleotide conjugates (AOCs) are a novel class of synthetic chimeric biomolecules that has been continually gaining traction in different fields of modern biotechnology. This is mainly due to the unique combination of the properties of their two constituents, exceptional targeting abilities and antibody biodistribution profiles, in addition to an extensive scope of oligonucleotide functional and structural roles. Combining these two classes of biomolecules in one chimeric construct has therefore become an important milestone in the development of numerous biotechnological applications, including imaging (DNA-PAINT), detection (PLA, PEA), and therapeutics (targeted siRNA/antisense delivery). Numerous synthetic approaches have been developed to access AOCs ranging from stochastic chemical bioconjugation to site-specific conjugation with reactive handles, introduced into antibody sequences through protein engineering. This Review gives a general overview of the current status of AOC applications with a specific emphasis on the synthetic methods used for their preparation. The reported synthetic techniques are discussed in terms of their practical aspects and limitations. The importance of the development of novel methods for the facile generation of AOCs possessing a defined constitution is highlighted as a priority in AOC research to ensure the advance of their new applications.
- Published
- 2019
20. Palladium-Catalyzed Chemoselective and Biocompatible Functionalization of Cysteine-Containing Molecules at Room Temperature
- Author
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Alain Wagner, Sébastien Delacroix, Stéphane Erb, Samir Messaoudi, Stéphanie Nicolaÿ, Mouâd Alami, Riyadh Ahmed Atto AL-Shuaeeb, Sergii Kolodych, Jean-Daniel Brion, Sarah Cianférani, Jean-Christophe Cintrat, and Oleksandr Koniev
- Subjects
chemistry.chemical_classification ,Bioconjugation ,Phosphines ,010405 organic chemistry ,Organic Chemistry ,Temperature ,Proteins ,chemistry.chemical_element ,General Chemistry ,010402 general chemistry ,Biocompatible material ,01 natural sciences ,Combinatorial chemistry ,Catalysis ,0104 chemical sciences ,Amino acid ,Xanthenes ,chemistry ,Surface modification ,Molecule ,Cysteine ,Palladium - Abstract
The third generation of aminobiphenyl palladacycle pre-catalyst "G3-Xantphos" enables functionalization of peptides containing cysteine in high yields. The conjugation (bioconjugation) occurs chemoselectively at room temperature under biocompatible conditions. Extension of the method to protein functionalization allows selective bioconjugation of the trastuzumab antibody.
- Published
- 2016
21. Copper-free click chemistry for microdroplet's W/O interface engineering
- Author
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Alain Wagner, Sylvain Ursuegui, and Michel Mosser
- Subjects
Analyte ,010405 organic chemistry ,General Chemical Engineering ,Microfluidics ,Cycloalkyne ,Nanotechnology ,General Chemistry ,010402 general chemistry ,01 natural sciences ,0104 chemical sciences ,chemistry.chemical_compound ,chemistry ,Click chemistry ,Surface modification ,Azide ,Fluorosurfactant ,Copper-free click chemistry - Abstract
In droplet-based microfluidic, fluorosurfactants are essential to ensure the stability of the emulsion. Beyond this primary role, fluorosurfactants can be engineered to provide droplet inner surface specific interaction characteristics with analyte present in droplet content. Despite the high potency of such capture system in terms of micro-compartmentalisation and surface/analyte ratio, only few studies have reported the use of the water/fluorinated oil interphase to immobilize target molecules. The difficult synthesis of the required functionalized fluorosurfactants needed for each application may account for this relative desertion. To make microdroplet capture approaches more straightforward, we have investigated a ready-to-use click chemistry-based approach that enables intra-droplet chemical modification. This strategy, which avoids tedious synthesis of complex fluorosurfactant, opens access to a wide variety of functional heads via copper-free click chemistry using a pre-functionalized fluorosurfactant which can be easily obtained in large scale. To demonstrate the efficiency of the click chemistry-based microdroplet surface functionalization, we have synthesized an azide fluorosurfactant capable of stabilizing microdroplets and performed a series of intra-droplet surface functionalizations by introducing fluorescent-labeled cycloalkyne derivatives in the aqueous phase. By doing so, we were able to demonstrate via polarization fluorescence that molecules from the aqueous phase could be efficiently captured at the inner droplet surface. Furthermore, we also showed that the density of azide functions at the inner surface could be adjusted by diluting the functionalized surfactant with a non-functionalized one. Fluorescence polarization analysis revealed that these dilutions result in the production of microdroplets with controlled azide surface density.
- Published
- 2016
22. Expedient synthesis of trifunctional oligoethyleneglycol-amine linkers and their use in the preparation of PEG-based branched platforms
- Author
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Claire Imbs, Marta Dudek, Sylvain Ursuegui, Alain Wagner, Michel Mosser, Jérémy P. Schneider, and Florian Lauvoisard
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Nitrile ,010405 organic chemistry ,Organic Chemistry ,Imine ,Convergent synthesis ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Combinatorial chemistry ,Coupling reaction ,0104 chemical sciences ,chemistry.chemical_compound ,chemistry ,PEG ratio ,Amine gas treating ,Azide ,Physical and Theoretical Chemistry ,Bifunctional - Abstract
We designed a convergent synthesis pathway that provides access to trifunctional oligoethyleneglycol-amine (OEG-amine) linkers. By applying the reductive coupling of a primary azide to bifunctional OEG-azide precursors, the corresponding symmetrical dialkylamine bearing two homo-functional end chain groups and a central nitrogen was obtained. These building blocks bear minimal structural perturbation compared to the native OEG backbone which makes them attractive for biomedical applications. The NMR investigations of the mechanism process reveal the formation of nitrile and imine intermediates which can react with the reduced free amine form. Additionally, these trifunctional OEG-amine linkers were employed in a coupling reaction to afford branched multifunctional PEG dendrons which are molecularly defined. These discrete PEG-based dendrons (n = 16, 18 and 36) could be useful for numerous applications where multivalency is required.
- Published
- 2018
23. Co-delivery of anti-PLK-1 siRNA and camptothecin by nanometric polydiacetylenic micelles results in a synergistic cell killing
- Author
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Jean-Serge Remy, Patrick Neuberg, Manon Ripoll, Dominique Bagnard, Alain Wagner, Antoine Kichler, Marie Pierdant, Laboratoire de Chimie des Systèmes Fonctionnels, Centre National de la Recherche Scientifique (CNRS), Conception et application de molécules bioactives (CAMB), Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), U682 INSERM, and univOAK, Archive ouverte
- Subjects
Small interfering RNA ,Co delivery ,[SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT] ,[SDV.OT] Life Sciences [q-bio]/Other [q-bio.OT] ,Chemistry ,General Chemical Engineering ,02 engineering and technology ,General Chemistry ,010402 general chemistry ,021001 nanoscience & nanotechnology ,01 natural sciences ,Micelle ,In vitro ,0104 chemical sciences ,3. Good health ,Cell killing ,Sciences du Vivant [q-bio]/Autre [q-bio.OT] ,In vivo ,medicine ,Biophysics ,0210 nano-technology ,Camptothecin ,Drug metabolism ,medicine.drug - Abstract
International audience; Recently, it has been shown that the efficiency of antitumoral drugs can be enhanced when combined with therapeutic siRNAs. In the present study, an original platform based on polydiacetylenic micelles containing a cationic head group able to efficiently deliver a small interfering RNA (siRNA) targeting the PLK-1 gene while offering a hydrophobic environment for encapsulation of lipophilic drugs such as camptothecin is developed. We demonstrate that the co-delivery of these two agents with our micellar system results in a synergistic tumor cell killing of cervical and breast cancer cell lines in vitro. The combined drugs are active in a subcutaneous in vivo cancer model. Altogether, the results show that our nanometric micellar delivery system can be used for the development of new drug–siRNA combo-therapies.
- Published
- 2018
24. Polydiacetylenic nanofibers as new siRNA vehicles for in vitro and in vivo delivery
- Author
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V. Lindner, Antoine Kichler, Patrick Neuberg, Marc Nothisen, Alain Wagner, Imène Hamaidi, Thierry Massfelder, Sabrina Danilin, Manon Ripoll, Jean-Serge Remy, Institut de Chimie de Strasbourg, and Centre National de la Recherche Scientifique (CNRS)-Université Louis Pasteur - Strasbourg I-Institut de Chimie du CNRS (INC)
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,Small interfering RNA ,health care facilities, manpower, and services ,education ,LIM-Homeodomain Proteins ,Nanofibers ,Mice, Nude ,[CHIM.THER]Chemical Sciences/Medicinal Chemistry ,02 engineering and technology ,010402 general chemistry ,01 natural sciences ,Mice ,In vivo ,health services administration ,Cell Line, Tumor ,[CHIM]Chemical Sciences ,Gene silencing ,Animals ,General Materials Science ,Gene Silencing ,RNA, Small Interfering ,ComputingMilieux_MISCELLANEOUS ,Oncogene ,Chemistry ,021001 nanoscience & nanotechnology ,Xenograft Model Antitumor Assays ,In vitro ,Kidney Neoplasms ,Polyacetylene Polymer ,0104 chemical sciences ,Cell biology ,Cell culture ,Nanofiber ,Cancer cell ,Chimie/Chimie thérapeutique ,0210 nano-technology ,Injections, Intraperitoneal ,Transcription Factors - Abstract
Polydiacetylenic nanofibers (PDA-Nfs) obtained by photopolymerization of surfactant 1 were optimized for intracellular delivery of small interfering RNAs (siRNAs). PDA-Nfs/siRNA complexes efficiently silenced the oncogene Lim-1 in the renal cancer cells 786-O in vitro. Intraperitoneal injection of PDA-Nfs/siLim1 downregulated Lim-1 in subcutaneous tumor xenografts obtained with 786-O cells in nude mice. Thus, PDA-Nfs represent an innovative system for in vivo delivery of siRNAs.
- Published
- 2018
25. MAPN: First-in-Class Reagent for Kinetically Resolved Thiol-to-Thiol Conjugation
- Author
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Alain Van Dorsselaer, Sergii Kolodych, J.-Y. Bonnefoy, Sarah Cianférani, Alain Wagner, Jitka Eberova, Zoljargal Baatarkhuu, Johann Stojko, and Oleksandr Koniev
- Subjects
Immunoconjugates ,Biomedical Engineering ,Pharmaceutical Science ,Bioengineering ,Conjugated system ,Mertansine ,Maleimides ,chemistry.chemical_compound ,Cell Line, Tumor ,Humans ,Organic chemistry ,Sulfhydryl Compounds ,Maleimide ,Pharmacology ,chemistry.chemical_classification ,Bioconjugation ,Organic Chemistry ,Kinetics ,chemistry ,Alkynes ,Reagent ,Thiol ,Indicators and Reagents ,Biotechnology ,Cysteine ,Conjugate - Abstract
Thiols are among the most frequently used functional groups in the field of bioconjugation. While there exists a variety of heterobifunctional reagents that allow for coupling thiols to other functions (e.g., amines, carboxylic acids), there is no specific reagent for creating heteroconjugates using two different thiols. In response to the ever-increasing demand for bioconjugation tools, we have developed p-(maleimide)-phenylpropionitrile (MAPN)-an efficient reagent for kinetically resolved thiol-to-thiol coupling. In a comparative study with its closest commercially available analogue, p-phenylenedimaleimide, MAPN has shown substantial advantages for the preparation of thiol-thiol heteroconjugates. Namely, an antibody-drug conjugate (ADC) with mertansine (DM1), conjugated to the cysteine residues of Trastuzumab, was prepared for the first time.
- Published
- 2015
26. Photopolymerized micelles of diacetylene amphiphile: physical characterization and cell delivery properties
- Author
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Andrey S. Klymchenko, Alain Wagner, Aurélia Perino, Jean-Serge Remy, Emmanuelle Morin-Picardat, Yves Mély, D. Weltin, Patrick Neuberg, Zeinab Darwich, Nicolas Anton, Laboratoire de Biophotonique et Pharmacologie - UMR 7213 (LBP), Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA)), Conception et application de molécules bioactives (CAMB), and Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
Cell Survival ,Polymers ,Ultraviolet Rays ,[SDV]Life Sciences [q-bio] ,Polyethylene glycol ,Micelle ,Catalysis ,Cell Line ,Polyethylene Glycols ,Polymerization ,Surface-Active Agents ,chemistry.chemical_compound ,Drug Delivery Systems ,Pulmonary surfactant ,Oxazines ,Polymer chemistry ,Amphiphile ,Materials Chemistry ,Humans ,Micelles ,ComputingMilieux_MISCELLANEOUS ,Fluorescent Dyes ,Diacetylene ,Metals and Alloys ,Polyynes ,General Chemistry ,Fluorescence ,Polyacetylene Polymer ,Surfaces, Coatings and Films ,Electronic, Optical and Magnetic Materials ,Characterization (materials science) ,chemistry ,Chemical engineering ,Ceramics and Composites ,HeLa Cells - Abstract
A series of polydiacetylene (PDA) - based micelles were prepared from diacetylenic surfactant bearing polyethylene glycol, by increasing UV-irradiation times. These polymeric lipid micelles were analyzed by physicochemical methods, electron microscopy and NMR analysis. Cellular delivery of fluorescent dye suggests that adjusting the polymerization state is vital to reach the full in vitro potential of PDA-based delivery systems.
- Published
- 2015
27. Developments and recent advancements in the field of endogenous amino acid selective bond forming reactions for bioconjugation
- Author
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Alain Wagner and Oleksandr Koniev
- Subjects
Models, Molecular ,chemistry.chemical_classification ,Immunoconjugates ,Bioconjugation ,Chemical biology ,Proteins ,Oxidation reduction ,Nanotechnology ,General Chemistry ,Biochemistry ,Amino acid ,chemistry ,Proteins metabolism ,Animals ,Insulin ,Organic chemistry ,Cattle ,Amino Acids ,Oxidation-Reduction ,Cyanates ,Biotechnology - Abstract
Bioconjugation methodologies have proven to play a central enabling role in the recent development of biotherapeutics and chemical biology approaches. Recent endeavours in these fields shed light on unprecedented chemical challenges to attain bioselectivity, biocompatibility, and biostability required by modern applications. In this review the current developments in various techniques of selective bond forming reactions of proteins and peptides were highlighted. The utility of each endogenous amino acid-selective conjugation methodology in the fields of biology and protein science has been surveyed with emphasis on the most relevant among reported transformations; selectivity and practical use have been discussed.
- Published
- 2015
28. Acyl Fluorides: Fast, Efficient, and Versatile Lysine-Based Protein Conjugation via Plug-and-Play Strategy
- Author
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Sergii Kolodych, Igor Dovgan, Stéphane Erb, Sylvain Ursuegui, Alain Wagner, Sarah Cianférani, and Chloé Michel
- Subjects
Azides ,Fluorophore ,Immunoconjugates ,Stereochemistry ,Receptor, ErbB-2 ,Acylation ,Lysine ,Biomedical Engineering ,Oligonucleotides ,Pharmaceutical Science ,Succinimides ,Bioengineering ,010402 general chemistry ,01 natural sciences ,chemistry.chemical_compound ,Fluorides ,Benzyl Compounds ,Humans ,Fluorescent Dyes ,Toxins, Biological ,Pharmacology ,chemistry.chemical_classification ,Cycloaddition Reaction ,Molecular Structure ,010405 organic chemistry ,Oligonucleotide ,Biomolecule ,Organic Chemistry ,Antibodies, Monoclonal ,Cycloaddition ,0104 chemical sciences ,chemistry ,Alkynes ,Surface modification ,Click Chemistry ,Azide ,Biotechnology - Abstract
We report a plug-and-play strategy for the preparation of functionally enhanced antibodies with a defined average degree of conjugation (DoC). The first stage (plug) allows the controllable and efficient installation of azide groups on lysine residues of a native antibody using 4-azidobenzoyl fluoride. The second step (play) allows for versatile antibody functionalization with a single payload or combination of payloads, such as a toxin, a fluorophore, or an oligonucleotide, via copper-free strain-promoted azide–alkyne cycloaddition (SPAAC). It is notable that in comparison to a classical N-hydroxysuccinimide ester (NHS) strategy, benzoyl fluorides show faster and more efficient acylation of lysine residues in a PBS buffer. This translates into better control of the DoC and enables the efficient and fast functionalization of delicate biomolecules at low temperature.
- Published
- 2017
29. Identification of autoreactive B cells with labeled nucleosomes
- Author
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Cécile Seifert, A. Guffroy, Thierry Martin, Anne-M Knapp, Anne-S Korganow, Jean-L Pasquali, Jean-D Fauny, Pauline Soulas-Sprauel, Vincent Gies, Alain Wagner, Hélène Dumortier, Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Conception et application de molécules bioactives (CAMB), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Chimie des Systèmes Fonctionnels, Centre National de la Recherche Scientifique (CNRS), Immunopathologie et chimie thérapeutique (ICT), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), and Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
0301 basic medicine ,Science ,Transgene ,Autoimmunity ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,medicine.disease_cause ,Autoantigens ,Article ,Cell Line ,Flow cytometry ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Sciences du Vivant [q-bio]/Biologie cellulaire ,medicine ,Animals ,Humans ,Lupus Erythematosus, Systemic ,B cell ,Autoantibodies ,B-Lymphocytes ,Multidisciplinary ,Lupus erythematosus ,Staining and Labeling ,biology ,medicine.diagnostic_test ,Autoantibody ,Flow Cytometry ,medicine.disease ,Molecular biology ,Nucleosomes ,3. Good health ,Cell biology ,030104 developmental biology ,Histone ,medicine.anatomical_structure ,Cell culture ,biology.protein ,Medicine ,Female ,Biomarkers ,030215 immunology - Abstract
The pathogenesis of autoimmune diseases has not been completely elucidated yet, and only a few specific treatments have been developed so far. In autoimmune diseases mediated by pathogenic autoantibodies, such as systemic lupus erythematosus, the specific detection and analysis of autoreactive B cells is crucial for a better understanding of the physiopathology. Biological characterization of these cells may help to define new therapeutic targets. Very few techniques allowing the precise detection of autoreactive B cells have been described so far. Herein we propose a new flow cytometry technique for specific detection of anti-nucleosome B cells, which secrete autoantibodies in systemic lupus erythematosus, using labeled nucleosomes. We produced different fluorochrome-labeled nucleosomes, characterized them, and finally tested them in flow cytometry. Nucleosomes labeled via the cysteines present in H3 histone specifically bind to autoreactive B cells in the anti-DNA transgenic B6.56R mice model. The present work validates the use of fluorochrome-labeled nucleosomes via cysteines to identify anti-nucleosome B cells and offers new opportunities for the description of autoreactive B cell phenotype.
- Published
- 2017
30. Copper-Chelating Azides for Efficient Click Conjugation Reactions in Complex Media
- Author
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Valentina Bevilacqua, Alain Wagner, Marc Nothisen, David Buisson, Manon Chaumontet, Frédéric Taran, Céline Puente, Mathias King, and Sandra Gabillet
- Subjects
Azides ,Biocompatibility ,Cycloaddition Reaction ,Chemistry ,chemistry.chemical_element ,General Chemistry ,General Medicine ,Copper ,Cycloaddition ,Catalysis ,chemistry.chemical_compound ,Polymer chemistry ,Click chemistry ,Reactivity (chemistry) ,Chelation ,Click Chemistry ,Azide ,Reactive Oxygen Species - Abstract
The concept of chelation-assisted copper catalysis was employed for the development of new azides that display unprecedented reactivity in the copper(I)-catalyzed azide-alkyne [3+2] cycloaddition (CuAAC) reaction. Azides that bear strong copper-chelating moieties were synthesized; these functional groups allow the formation of azide copper complexes that react almost instantaneously with alkynes under diluted conditions. Efficient ligation occurred at low concentration and in complex media with only one equivalent of copper, which improves the biocompatibility of the CuAAC reaction. Furthermore, such a click reaction allowed the localization of a bioactive compound inside living cells by fluorescence measurements.
- Published
- 2014
31. Selective Irreversible Chemical Tagging of Cysteine with 3-Arylpropiolonitriles
- Author
-
Alain Van Dorsselaer, Geoffray Leriche, Marc Nothisen, Rachid Baati, Jean-Marc Strub, Christine Schaeffer-Reiss, Alain Wagner, Jean-Serge Remy, Oleksandr Koniev, Conception et application de molécules bioactives (CAMB), Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Spectrométrie de Masse BioOrganique [Strasbourg] (LSMBO), Département Sciences Analytiques et Interactions Ioniques et Biomoléculaires (DSA-IPHC), Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UNISTRA), Laboratoire de Chimie des Systèmes Fonctionnels, Centre National de la Recherche Scientifique (CNRS), Institut Gilbert-Laustriat : Biomolécules, Biotechnologie, Innovation Thérapeutique, and Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS)
- Subjects
animal structures ,Molecular Sequence Data ,Biomedical Engineering ,Pharmaceutical Science ,Bioengineering ,Peptide ,[CHIM.THER]Chemical Sciences/Medicinal Chemistry ,chemistry.chemical_compound ,Tandem Mass Spectrometry ,Nitriles ,Humans ,Organic chemistry ,Amino Acid Sequence ,Cysteine ,Chemoselectivity ,ComputingMilieux_MISCELLANEOUS ,Pharmacology ,chemistry.chemical_classification ,Bioconjugation ,[CHIM.ORGA]Chemical Sciences/Organic chemistry ,Organic Chemistry ,Combinatorial chemistry ,Amino acid ,Models, Chemical ,chemistry ,Reagent ,Muramidase ,Lysozyme ,Selectivity ,hormones, hormone substitutes, and hormone antagonists ,Chromatography, Liquid ,Biotechnology - Abstract
Exquisite chemoselectivity for cysteine has been found for a novel class of remarkably hydrolytically stable reagents, 3-arylpropiolonitriles (APN). The efficacy of the APN-mediated tagging was benchmarked against other cysteine-selective methodologies in a model study on a series of traceable amino acid derivatives. The selectivity of the methodology was further explored on peptide mixtures obtained by trypsin digestion of lysozyme. Additionally, the superior stability of APN-cysteine conjugates in aqueous media, human plasma, and living cells makes this new thiol-click reaction a promising methodology for applications in bioconjugation.
- Published
- 2014
32. A new series of Cs+, K+ and Na+ chelators: Synthesis, kinetics, thermodynamics and modeling
- Author
-
Alain Wagner, Nguyêt-Thanh Ha-Duong, Florent Barbault, Miryana Hémadi, Claude Lion, Antoine Le Roux, Alexandre Korovitch, and Jean-Michel El Hage Chahine
- Subjects
chemistry.chemical_classification ,Kinetics ,Ether ,Alkali metal ,Inorganic Chemistry ,chemistry.chemical_compound ,Reaction rate constant ,chemistry ,Materials Chemistry ,Molecule ,Organic chemistry ,Physical chemistry ,Qualitative inorganic analysis ,Chelation ,Physical and Theoretical Chemistry ,Crown ether - Abstract
The synthesis of two molecules, B1 and B2, based on elements of norbadione A, the natural Cs + chelator in mushrooms, associated, in the case of B2, with an 18-crown-6 ether is reported. Thermodynamic and kinetic analyses performed in water, ethanol and ethanol/water 9/1 v/v (M1) show in M1 and ethanol that B1 and B2 form stable complexes with Na + , K + and Cs + . Affinity constants, measured spectrophotometrically in ethanol and M1, by the use of the S pecfit program, are in the 10 5 and 10 6 range for B1 and B2, respectively. The second-order rate constants are in the 10 6 –10 7 M −1 s −1 range and the first-order rate constants about unity. The ratios of the second-order/first-order rate constants confirm the thermodynamic results in EtOH. The kinetic processes become much too fast to allow runs in M1. Molecular simulations in EtOH imply the existence of two isomers for each of the Cs + /B1 and Cs + /B2 complexes. With B1, the more stable one is that in which the two enolates are parallel and mimic the alkali-metal inclusion cavity already envisaged for norbadione A. With B2, two similar structures are extracted, in both of which Cs + is included in the crown ether and capped by the enolate. The affinity of B1 for Cs + is comparable to that of norbadione A, whereas that of B2 is higher. These results are encouraging as they introduce a new series of alkali chelators which can lead to molecules capable of complexing 137 Cs + for radioactive decontamination.
- Published
- 2013
33. 2-(Maleimidomethyl)-1,3-Dioxanes (MD): a Serum-Stable Self-hydrolysable Hydrophilic Alternative to Classical Maleimide Conjugation
- Author
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Igor Dovgan, Alain Wagner, Sergii Kolodych, and Oleksandr Koniev
- Subjects
0301 basic medicine ,Multidisciplinary ,Aqueous solution ,010405 organic chemistry ,Chemistry ,Ring (chemistry) ,01 natural sciences ,Combinatorial chemistry ,Article ,0104 chemical sciences ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,Förster resonance energy transfer ,Biochemistry ,Succinimide ,Reagent ,Maleimide ,Linker ,Conjugate - Abstract
The vast majority of antibody-drug conjugates (ADC) are prepared through amine-to-thiol conjugation. To date, N-Succinimidyl-4-(maleimidomethyl) cyclohexanecarboxylate (SMCC) has been one of the most frequently applied reagents for the preparation of ADC and other functional conjugates. However, SMCC-based conjugates suffer from limited stability in blood circulation and from a hydrophobic character of the linker, which may give rise to major pharmacokinetic implications. To address this issue, we have developed a heterobifunctional analogue of a SMCC reagent, i.e., sodium 4-(maleimidomethyl)-1,3-dioxane-5-carbonyl)oxy)-2,3,5,6- tetrafluorobenzenesulfonate (MDTF) for amine-to-thiol conjugation. By replacing the cyclohexyl ring in the SMCC structure with the 1,3-dioxane, we increased the hydrophilicity of the linker. A FRET probe based on MD linker was prepared and showed superior stability compared to the MCC linker in human plasma, as well as in a variety of aqueous buffers. A detailed investigation demonstrated an accelerated succinimide ring opening for MD linker, resulting in stabilized conjugates. Finally, the MDTF reagent was applied for the preparation of serum stable antibody-dye conjugate.
- Published
- 2016
34. Towards a KCC2 blocker pharmacophore model
- Author
-
Ledecq Marie, Stéphane Meunier, Benoit Mathieu, Laurent Provins, Christian Wolff, Sébastien Lengelé, Alain Wagner, Anne Frycia, Florence Lebon, Nathalie Bosman, Cecile Pegurier, Kashinath Dhurke, and Ananda Kumar Kanduluru
- Subjects
Models, Molecular ,Magnetic Resonance Spectroscopy ,Proline ,Stereochemistry ,Clinical Biochemistry ,Molecular Conformation ,Pharmaceutical Science ,Biochemistry ,Structure-Activity Relationship ,X-Ray Diffraction ,Furosemide ,Cell Line, Tumor ,Drug Discovery ,Potassium Channel Blockers ,Animals ,Humans ,Molecular Biology ,Ion Transport ,Symporters ,Chemistry ,Organic Chemistry ,High-Throughput Screening Assays ,Rats ,Molecular Medicine ,Anticonvulsants ,Pharmacophore - Abstract
A multi-disciplinary approach was used to identify the first pharmacophore model for KCC2 blockers: several physico-chemical studies such as XRD and NMR were combined to molecular modelling techniques, SAR analysis and synthesis of constrained analogues in order to determine a minimal conformational space regrouping few potential bioactive conformations. These conformations were further compared to the conformational space of a different series of KCC2 blockers in order to identify the common pharmacophoric features. The synthesis of more potent analogues in this second series confirmed the usefulness of this KCC2 blocker pharmacophore model.
- Published
- 2012
35. Capillary electrophoresis–inductively coupled plasma-mass spectrometry hyphenation for the determination at the nanogram scale of metal affinities and binding constants of phosphorylated ligands
- Author
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Mélanie Bourdillon, Michel Meyer, Yi Lin, Alain Wagner, Frédéric Taran, Rachid Baati, Marie Brellier, Agnès Hagège, Eric Doris, Fanny Varenne, and Loïc J. Charbonnière
- Subjects
Formates ,chemistry.chemical_element ,Ligands ,Lanthanoid Series Elements ,Biochemistry ,Mass Spectrometry ,Analytical Chemistry ,Metal ,chemistry.chemical_compound ,Capillary electrophoresis ,Europium ,Limit of Detection ,Inductively coupled plasma mass spectrometry ,Principal Component Analysis ,Chromatography ,Sodium formate ,Methanol ,Organic Chemistry ,Electrophoresis, Capillary ,Reproducibility of Results ,General Medicine ,Phosphorus Compounds ,chemistry ,visual_art ,Linear Models ,visual_art.visual_art_medium ,Thermodynamics ,Spectrophotometry, Ultraviolet ,Titration ,Absorption (chemistry) ,Phosphine - Abstract
A screening strategy based on hyphenated capillary electrophoresis and inductively coupled plasma mass spectrometry (CE–ICP-MS) was developed to classify phosphorylated ligands according to their europium(III) binding affinity in a hydro-organic medium (sodium formate, pH 3.7, H2O/MeOH 90:10, v/v). Taking advantage of the high sensibility of ICP-MS for detecting phosphorus, this method enabled to assess the affinity of a variety of phosphorylated compounds, including phosphine oxides, thiophosphines, phosphonates, and phosphinates, in less than 1 h and using less than 5 ng of substance. By varying the total europium concentration, complexation constants could be determined according to a sequential multiple run strategy, which proved to be in excellent agreement with the values obtained by UV–Vis absorption spectrophotometric titrations.
- Published
- 2012
36. Cleavable linkers in chemical biology
- Author
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Geoffray Leriche, Alain Wagner, and Louise Chisholm
- Subjects
Proteomics ,Reducing agent ,Clinical Biochemistry ,Chemical biology ,Pharmaceutical Science ,Biochemistry ,Nucleophile ,Drug Discovery ,Oxidizing agent ,Organic chemistry ,Molecular Biology ,Chemistry ,Organic Chemistry ,Oxidants ,Photochemical Processes ,Biocompatible material ,Combinatorial chemistry ,Enzymes ,Cross-Linking Reagents ,Pharmaceutical Preparations ,Metals ,Reducing Agents ,Reagent ,Electrophile ,Molecular Medicine ,Cleavable linker - Abstract
Interest in cleavable linkers is growing due to the rapid development and expansion of chemical biology. The chemical constrains imposed by the biological conditions cause significant challenges for organic chemists. In this review we will present an overview of the cleavable linkers used in chemical biology classified according to their cleavage conditions by enzymes, nucleophilic/basic reagents, reducing agents, photo-irradiation, electrophilic/acidic reagents, organometallic and metal reagents, oxidizing reagents.
- Published
- 2012
37. Design and Synthesis of New Antioxidants Predicted by the Model Developed on a Set of Pulvinic Acid Derivatives
- Author
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Alain Wagner, Thierry Le Gall, Stéphane Meunier, Pierre Bischoff, Damien Habrant, Igor Kuzmanovski, Sophie A.-L. Thetiot-Laurent, Antoine Le Roux, Marjana Novič, and Brice Nadal
- Subjects
Quantitative structure–activity relationship ,Antioxidant ,Ultraviolet Rays ,Iron ,General Chemical Engineering ,medicine.medical_treatment ,In silico ,Carboxylic Acids ,Quantitative Structure-Activity Relationship ,Library and Information Sciences ,Antioxidants ,Cell Line ,Lactones ,chemistry.chemical_compound ,medicine ,Humans ,Hydrogen Peroxide ,General Chemistry ,In vitro ,Pulvinic acid ,Computer Science Applications ,Initial training ,chemistry ,Biochemistry ,Drug Design ,Neural Networks, Computer ,Thymidine ,Oxidation-Reduction ,Primary screening - Abstract
Antioxidative activity expressed as protection of thymidine has been investigated for a set of 30 pulvinic acid derivatives. A combination of in vitro testing and in silico modeling was used for synthesis of new potential antioxidants. Experimental data obtained from a primary screening test based on oxidation under Fenton conditions and by an UV exposure followed by back-titration of the amount of thymidine remaining intact have been used to develop a computer model for prediction of antioxidant activity. Structural descriptors of 30 compounds tested for their thymidine protection activity were calculated in order to define the structure-property relationship and to construct predictive models. Due to the potential nonlinearity, the counter-propagation artificial neural networks were assessed for modeling of the antioxidant activity of these compounds. The optimized model was challenged with 80 new molecules not present in the initial training set. The compounds with the highest predicted antioxidant activity were considered for synthesis. Among the predicted structures, some coumarine derivatives appeared to be especially interesting. One of them was synthesized and tested on in vitro assays and showed some antioxidant and radioprotective activities, which turned out as a promising lead toward more potent antioxidants.
- Published
- 2011
38. Stereoselective Addition of Grignard Reagents to New P-Chirogenic N-Phosphinoylbenzaldimines: Effect of the Phosphorus Substituents on the Stereoselectivity
- Author
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Alain Wagner, Irene Notar Francesco, Françoise Colobert, and Coraline Egloff
- Subjects
chemistry.chemical_compound ,chemistry ,Bromide ,Reagent ,Organic Chemistry ,Diastereomer ,Grignard reaction ,Organic chemistry ,Stereoselectivity ,Physical and Theoretical Chemistry ,Chirality (chemistry) ,Adduct ,Stereocenter - Abstract
Several phosphinoylimines have been synthesized in five steps by starting from the appropriate phosphane oxide and were then treated with methylmagnesium bromide to give both diastereoisomers in high yields and with promising diastereomeric ratios. Then N-[(tert-butyl)(phenyl)phosphinoyl]benzaldimine, which displayed the best results, was subjected to the 1,2-addition of various Grignard reagents to evaluate the best chiral induction due to the stereogenic phosphorus atom. The corresponding adducts were obtained in excellent yields and with moderate to excellent diastereoisomeric ratios.
- Published
- 2011
39. Cationic Cyclization of 2-Alkenyl-1,3-dithiolanes: Diastereoselective Synthesis of trans-Decalins
- Author
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Fahmi Himo, Sylvie Goncalves, Rachid Baati, Stefano Santoro, Marc Nicolas, Alain Wagner, and Philippe Maillos
- Subjects
Models, Molecular ,Thioketal ,chemistry.chemical_classification ,Biological Products ,Reaction mechanism ,Ketone ,Stereochemistry ,Organic Chemistry ,Molecular Conformation ,Cationic polymerization ,Total synthesis ,Stereoisomerism ,Protonation ,Alkenes ,Naphthalenes ,Chemical synthesis ,Substrate Specificity ,chemistry.chemical_compound ,chemistry ,Nucleophile ,Cyclization ,Heterocyclic Compounds ,Quantum Theory - Abstract
An unprecedented and highly diastereoselective 6-endo-trig cyclization of 2-alkenyl-1,3-dithiolanes has been developed yielding trans-decalins, an important scaffold present in numerous di- and triterpenes. The novelty of this 6-endo-trig cyclization stands in the stepwise mechanism involving 2-alkenyl-1,3-dithiolane, acting as a novel latent initiator. It is suggested that the thioketal opens temporarily under the influence of TMSOTf, triggering the cationic 6-endo-trig cyclization, and closes after C-C bond formation and diastereoselective protonation to terminate the process. DFT calculations confirm this mechanistic proposal and provide a rationale for the observed diastereoselectivity. The reaction tolerates a wide range of functionalities and nucleophilic partners within the substrate. We have also shown that the one-pot 6-endo-trig cyclization followed by in situ 1,3-dithiolane deprotection afford directly the corresponding ketone. This improvement allowed the achievement of the shortest total synthesis of triptophenolide and the shortest formal synthesis of triptolide.
- Published
- 2011
40. A REPRESENTATION TO APPLY USUAL DATA MINING TECHNIQUES TO CHEMICAL REACTIONS — ILLUSTRATION ON THE RATE CONSTANT OF <font>S</font><font>N</font>2 REACTIONS IN WATER
- Author
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Alain Wagner, Frank Hoonakker, Nicolas Lachiche, and Alexandre Varnek
- Subjects
Molecule mining ,Quantitative structure–activity relationship ,Computer science ,Relational data mining ,computer.software_genre ,Support vector machine ,chemistry.chemical_compound ,chemistry ,Artificial Intelligence ,Cheminformatics ,Linear regression ,Graph (abstract data type) ,Molecular graph ,Data mining ,computer - Abstract
Chemical reactions always involve several molecules of two types, reactants and products. Existing data mining techniques, eg. Quantitative Structure Activity Relationship (QSAR) methods, deal with individual molecules only. In this article, we propose to use a Condensed Graph of Reaction (CGR) to merge all molecules involved in a reaction into one molecular graph. This allows one to consider reactions as pseudo-molecules and to develop QSAR models based on fragment descriptors. Then ISIDA (In SIlico Design and Analysis) fragment descriptors built from CGRs are used to generate models for the rate constant of S N 2 reactions in water, using three usual attribute-value regression algorithms (linear regression, support vector machine, and regression trees). This approach is compared favorably to two state-of-the-art relational data mining techniques.
- Published
- 2011
41. Programmed Dispersions of MWNTs in Aqueous Media by Coating with Photopolymerizable Synthetic Amphiphiles
- Author
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Stéphane Meunier, Emmanuel Contal, Cédric Thauvin, Emmanuelle Morin, Alain Wagner, Aurélia Perino, and Patrick Schultz
- Subjects
Materials science ,Cationic polymerization ,Supramolecular chemistry ,Nanotechnology ,Carbon nanotube ,engineering.material ,Micelle ,Surfaces, Coatings and Films ,Electronic, Optical and Magnetic Materials ,law.invention ,General Energy ,Photopolymer ,Chemical engineering ,Coating ,law ,Amphiphile ,engineering ,Physical and Theoretical Chemistry ,Dispersion (chemistry) - Abstract
Amphiphiles are known to be suitable molecules to disperse carbon nanotubes (CNTs) in water by shielding their highly hydrophobic surfaces. Herein, we describe tailored anionic, nonionic, and cationic photopolymerizable synthetic amphiphiles that are designed to achieve programmed pH-dependent dispersions of CNTs. The reported process involves (1) the assessment of the amphiphiles’ ability to form micelles in given buffer solutions, (2) the equilibrated self-assembly of the amphiphiles into hemimicellar structures on the hydrophobic surface of the CNTs, (3) the stabilization of these labile supramolecular assemblies by photopolymerization, (4) the purification of the obtained CNTs/photopolymerized lipidic assemblies (PLA) constructs, and (5) the characterization of the CNTs/PLA constructs pH dependant dispersion. In conclusion, we demonstrate that CNTs/PLA constructs with specific pH-dependent dispersion properties can easily be prepared. The constructs appear quite robust because they can withstand sever...
- Published
- 2011
42. 4-Halogeno-sydnones for fast strain promoted cycloaddition with bicyclo-[6.1.0]-nonyne
- Author
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Oleksandr Koniev, Lucie Plougastel, Christophe Créminon, Elodie Decuypere, Frédéric Taran, Alain Wagner, Sergii Kolodych, Simon Specklin, and David-Alexandre Buisson
- Subjects
Cycloaddition Reaction ,Strain (chemistry) ,Bicyclic molecule ,Stereochemistry ,Proton Magnetic Resonance Spectroscopy ,Metals and Alloys ,General Chemistry ,Medicinal chemistry ,Catalysis ,Cycloaddition ,Surfaces, Coatings and Films ,Electronic, Optical and Magnetic Materials ,Bridged Bicyclo Compounds ,chemistry.chemical_compound ,Halogens ,chemistry ,Materials Chemistry ,Ceramics and Composites ,Sydnone - Abstract
New sydnone derivatives have been synthesized and screened for their capacity to undergo fast copper-free cycloaddition reaction with bicyclo-[6.1.0]-nonyne. The influences of substitution in positions N-3 and C-4 of sydnones have been particularly studied leading to the identification of highly reactive partners for bio-orthogonal ligation reactions.
- Published
- 2014
43. Structure and Behavior of Polydiacetylene-Based Micelles
- Author
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Alain Wagner, Alain Rameau, Andrey S. Klymchenko, Emmanuel Contal, Alexandre Morere, Aurélia Perino, Jean-Michel Guenet, and Yves Mély
- Subjects
education.field_of_study ,Polymers and Plastics ,Chemistry ,Organic Chemistry ,Population ,Dispersity ,technology, industry, and agriculture ,macromolecular substances ,Condensed Matter Physics ,Micelle ,Photopolymer ,Membrane ,Polymerization ,Amphiphile ,Polymer chemistry ,Materials Chemistry ,Self-assembly ,Physical and Theoretical Chemistry ,education - Abstract
The effect of photopolymerization on the structure, stability and encapsulation properties of polydiacetylene micelles containing nitrilotriacetic acid head groups are investigated. Micellar nanostructures of 7-10 nm diameter are identified that are invariant after polymerization. In the micelles, the polymerized ene-yne chains are much shorter than in planar lipid membranes. SANS confirmed the presence of a monodisperse population of small particles before and after polymerization. It is shown that the CMC decreases manifold after micelle photopolymerization, indicating that it stabilizes the micellar structure. After photopolymerization, these micelles preserved their strong ability to solubilize a hydrophobic pigment, which makes them potentially interesting as drug delivery vehicles.
- Published
- 2010
44. An efficient one-pot four-step domino reaction for the synthesis of C2-substituted 3-methylcyclohex-2-enones
- Author
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Sylvie Goncalves, Rachid Baati, Marc Nicolas, Philippe Maillos, and Alain Wagner
- Subjects
chemistry.chemical_compound ,Cascade reaction ,Chemistry ,One pot reaction ,Organic Chemistry ,Drug Discovery ,Cationic polymerization ,Organic chemistry ,Biochemistry ,Chemical synthesis ,Enone - Abstract
An efficient one-pot four-step domino reaction of substituted β-ketoesters has been optimized giving rise to a large panel of C2-substituted 3-methylcyclohex-2-enones, an important scaffold for the preparation of various initiators for cationic or radical cyclizations. The developed methodology is quite general and applicable to a wide range of β-ketoester substrates, allowing the introduction of various functionalities at the C2 position of the 3-methylcyclohex-2-enones, in good to excellent yields.
- Published
- 2010
45. Structure-Reactivity Relationship Studies for Guanidine-Organocatalyzed Direct Intramolecular Aldolization of Ketoaldehydes
- Author
-
Peter Hammar, Cynthia Ghobril, Sanjeevarao Kodepelly, Fahmi Himo, Bernard Spiess, Alain Wagner, and Rachid Baati
- Subjects
Reaction mechanism ,organic chemicals ,Organic Chemistry ,Regioselectivity ,Structure reactivity ,Catalysis ,Inorganic Chemistry ,chemistry.chemical_compound ,chemistry ,Aldol reaction ,Organocatalysis ,Intramolecular force ,polycyclic compounds ,Organic chemistry ,Physical and Theoretical Chemistry ,Guanidine - Abstract
Structure-reactivity studies are performed to explore the reaction mechanism of the guanidine-catalyzed intramolecular aldol reaction of ketoaldehydes. A large number of guanidine and guanidine-lik ...
- Published
- 2010
46. A Practical and Efficient Total Synthesis of Potent Insulinotropic (2S,3R,4S)-4-Hydroxyisoleucine through a Chiral N-Protected γ-Keto-α-aminoester
- Author
-
Sandra De Lamo Marin, Alain Wagner, Charles Mioskowski, Cedric Catala, Sreekantha Ratna Kumar, and Alain Valleix
- Subjects
Enantiopure drug ,Stereochemistry ,Chemistry ,Organic Chemistry ,Enantioselective synthesis ,Total synthesis ,Physical and Theoretical Chemistry ,Condensation reaction ,Enantiomeric excess ,Chemical synthesis ,Mannich reaction ,Chiral resolution - Abstract
(2S,3R,4S)-4-Hydroxyisoleucine, which exhibits remarkable insulinotropic activity, is expected to be a potent drug to treat type II diabetes. We propose herein a four-step synthesis of the enantiopure natural product on the basis of successive Mannich condensation, catalytic epimerization, N-para-methoxyphenyl deprotection, and diastereoselective reduction. This compact economical and scalable sequence enables to perfectly control three contiguous chiral centers. It does not involve any chromatographic purification, and the desired compound is obtained in >99 % de, >99 % ee, and 22 % overall yield under our optimized conditions.
- Published
- 2010
47. Highly chemo- and stereoselective glycosidation of permethacrylated O-glycosyl trichloroacetimidate reagents promoted by TMSNTf2
- Author
-
Laure Dehuyser, Alain Wagner, Christelle Zandanel, and Rachid Baati
- Subjects
chemistry.chemical_classification ,Glycosylation ,Double bond ,Organic Chemistry ,Glycoside ,Biochemistry ,Combinatorial chemistry ,Chemical synthesis ,chemistry.chemical_compound ,chemistry ,Reagent ,Drug Discovery ,Stereoselectivity ,Glycosyl ,Chemoselectivity - Abstract
TMSNTf 2 has been used efficiently as a promoter in glycosidation reaction involving permethacrylated Schmidt reagents. While TMSNTf 2 is known to be a powerful activator for C O double bonds, we have discovered that this reagent can activate C N double bond selectively, even in the presence of excess C O groups of permethacrylated O -glycosyl trichloroacetimidate substrates. Glycosides are synthesized in moderate to reasonable yields with an excellent overall β-stereoselectivity.
- Published
- 2010
48. Photopolymerized Lipids Self-Assembly for the Solubilization of Carbon Nanotubes
- Author
-
Charles Mioskowski, Stéphane Meunier, Emmanuel Contal, Cédric Thauvin, Alain Wagner, Aurélia Perino, and Alexandre Morere
- Subjects
Nanotube ,Materials science ,Nanotubes, Carbon ,Surface Properties ,Water ,Nanotechnology ,Carbon nanotube ,engineering.material ,Lipids ,Micelle ,Surfaces, Coatings and Films ,law.invention ,Adsorption ,Photopolymer ,Solubility ,Coating ,law ,Materials Chemistry ,engineering ,lipids (amino acids, peptides, and proteins) ,Self-assembly ,Physical and Theoretical Chemistry ,Micelles - Abstract
Because they have a great propensity to aggregation in water, solubilization of carbon nanotubes (CNTs) in aqueous media remains an important challenge. Our laboratory has reported the self-organization of synthetic lipids into hemi-micellar structures at the carbon nanotubes surface. Subsequent stabilization of these carbon nanotube/lipid assembly (CNT/LA) constructs is achieved through photopolymerization of the diyne motif of the pentacosa-10,12-diynoic lipids. Herein we investigate the scope of this coating procedure for CNT solubilization. A panel of CNTs was selected according to the method of production and the characteristics of CNTs. The study revealed that it is possible to reach a complete lipid adsorption. The TEM analyses demonstrate that lipid hemi-micellar self-assemblies can be formed around SWNTs as well as around DWNTs and MWNTs, particularly for carbon nanotubes produced by the arc-discharged method. The nanotube suspensions show a very good stability and are homogeneous for months even at a high nanotubes concentration.
- Published
- 2010
49. Benzyl prolinate derivatives as novel selective KCC2 blockers
- Author
-
Stéphane Meunier, Laurent Provins, Philippe Collart, Ananda Kumar Kanduluru, Christian Wolff, Marie-Laure Delporte, Alain Wagner, Nathalie Pacico, Sébastien Lengelé, Cecile Pegurier, Lakshmana Rao Vadali, Nathalie Bosman, and Karine Leclercq
- Subjects
Proline ,Symporters ,Chemistry ,Stereochemistry ,Organic Chemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Stereoisomerism ,Biochemistry ,Rats ,Structure-Activity Relationship ,chemistry.chemical_compound ,Residue (chemistry) ,Drug Discovery ,Animals ,Molecular Medicine ,Structure–activity relationship ,Phenyl group ,Molecular Biology ,ADME - Abstract
The discovery and optimization of a novel class of selective submicromolar KCC2 blockers is described. Details of synthesis and SAR are given together with ADME properties of selected compounds. A methylsulfone residue on the R(1) phenyl group improved the overall general profile of these prolinate derivatives.
- Published
- 2010
50. A Chemometric Approach to Map Reaction Media Chemoselectivity: Example of Selective Debenzylation
- Author
-
Frank Hoonakker, Daniel Klär, Nicolas Bensel, Patrick Schneckenburger, Sylvie Goncalves, Alain Wagner, and Cedric Catala
- Subjects
chemistry.chemical_compound ,chemistry ,Hydrogenolysis ,Organic Chemistry ,Benzyl group ,Organic chemistry ,Ether ,Reactivity (chemistry) ,Physical and Theoretical Chemistry ,Chemoselectivity ,Selectivity ,Triethylamine ,Catalysis - Abstract
A chemometric process consisting in measuring the reactivity of a set of substrates under standardized and complementary reaction conditions was run to evaluate the possibility of building a coherent database that would give a general overview of the selectivity of a variety of catalysts. This systematic experimental approach was applied to the hydrogenolysis of O-benzyl ether compounds. Analysis of collected data revealed reaction conditions with precise chemoselectivity. For instance, Pd/C in EtOH or PdOH in THF enabled the specific cleavage of the benzyl group in the presence of p-CF 3 Bn groups, and addition of triethylamine in EtOH suppressed the cleavage of the phenoxybenzyl bond. The latter selectivity was exemplified on several polyfunctional substrates.
- Published
- 2010
Catalog
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