You will find below the list of publications of all the members of the Peptides, Glycoconjugates and Metals in Biology research pole. For individual or theme-specific publications, please consult the research or the personal pages via the members list using the sidebar navigation tool.
2016 |
Candida albicans β-1,2 mannosyl transferase Bmt3: Preparation and evaluation of a β (1,2), α (1,2)-tetramannosyl fluorescent substrate Article de journal L Cattiaux; A Mée; M Pourcelot; G Sfihi-Loualia; T Hurtaux; E Maes; C Fradin; B Sendid; D Poulain; E Fabre; F Delplace; Y Guérardel; J -M Mallet Bioorganic and Medicinal Chemistry, 24 (6), p. 1362–1368, 2016. @article{Cattiaux:2016, title = {Candida albicans β-1,2 mannosyl transferase Bmt3: Preparation and evaluation of a β (1,2), α (1,2)-tetramannosyl fluorescent substrate}, author = {L Cattiaux and A M\'{e}e and M Pourcelot and G Sfihi-Loualia and T Hurtaux and E Maes and C Fradin and B Sendid and D Poulain and E Fabre and F Delplace and Y Gu\'{e}rardel and J -M Mallet}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84959017817&doi=10.1016%2fj.bmc.2016.02.008&partnerID=40&md5=e3851c9bd6b9f1934462c8735a0de331}, doi = {10.1016/j.bmc.2016.02.008}, year = {2016}, date = {2016-01-01}, journal = {Bioorganic and Medicinal Chemistry}, volume = {24}, number = {6}, pages = {1362--1368}, abstract = {We describe for the first time the chemical synthesis of a tetramannoside, containing both α (1 → 2) and β (1 → 2) linkages. Dodecylthio (lauryl) glycosides were prepared from odorless dodecyl thiol and used as donors for the glycosylation steps. This tetramannoside, was coupled to a mantyl group, and revealed to be a perfect substrate of β-mannosyltransferase Bmt3, confirming the proposed specificity and allowing the preparation of a pentamannoside sequence (β Man (1,2) β Man (1,2) α Man (1,2) α Man (1,2) α Man) usable as a novel substrate for further elongation studies. © 2016 Elsevier Ltd. All rights reserved.}, keywords = {}, pubstate = {published}, tppubtype = {article} } We describe for the first time the chemical synthesis of a tetramannoside, containing both α (1 → 2) and β (1 → 2) linkages. Dodecylthio (lauryl) glycosides were prepared from odorless dodecyl thiol and used as donors for the glycosylation steps. This tetramannoside, was coupled to a mantyl group, and revealed to be a perfect substrate of β-mannosyltransferase Bmt3, confirming the proposed specificity and allowing the preparation of a pentamannoside sequence (β Man (1,2) β Man (1,2) α Man (1,2) α Man (1,2) α Man) usable as a novel substrate for further elongation studies. © 2016 Elsevier Ltd. All rights reserved. |
Formation and investigation of 6-cysteinyl amino methylated β-cyclodextrin self-assembled monolayers Article de journal V Kolivoška; R Sokolová; J Kocábová; C Loukou; J -M Mallet; M Hromadová Monatshefte fur Chemie, 147 (1), p. 45–51, 2016. @article{Kolivoska:2016, title = {Formation and investigation of 6-cysteinyl amino methylated β-cyclodextrin self-assembled monolayers}, author = {V Kolivo\v{s}ka and R Sokolov\'{a} and J Koc\'{a}bov\'{a} and C Loukou and J -M Mallet and M Hromadov\'{a}}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84952863776&doi=10.1007%2fs00706-015-1609-2&partnerID=40&md5=001daecf5d1e75e217cdba44d4cc9f35}, doi = {10.1007/s00706-015-1609-2}, year = {2016}, date = {2016-01-01}, journal = {Monatshefte fur Chemie}, volume = {147}, number = {1}, pages = {45--51}, abstract = {6 -Cysteinyl amino methylated β-cyclodextrin was adsorbed on Au(111) as well as on mercury electrode. Scanning probe microscopy and electrochemical techniques confirmed that a chemisorbed self-assembled monolayer (SAM) of the β-cyclodextrin is formed, proving that a single -SH moiety located in the cysteinyl group is sufficient to anchor the entire methylated β-cyclodextrin molecule to the electrode surface. Thus, formed SAM can potentially serve as sensor layer for various organic molecules such as pesticides, antibiotics, and optically active compounds. © 2015 Springer-Verlag Wien.}, keywords = {}, pubstate = {published}, tppubtype = {article} } 6 -Cysteinyl amino methylated β-cyclodextrin was adsorbed on Au(111) as well as on mercury electrode. Scanning probe microscopy and electrochemical techniques confirmed that a chemisorbed self-assembled monolayer (SAM) of the β-cyclodextrin is formed, proving that a single -SH moiety located in the cysteinyl group is sufficient to anchor the entire methylated β-cyclodextrin molecule to the electrode surface. Thus, formed SAM can potentially serve as sensor layer for various organic molecules such as pesticides, antibiotics, and optically active compounds. © 2015 Springer-Verlag Wien. |
Evaluation of monovalent and multivalent iminosugars to modulate Candida albicans β-1,2-mannosyltransferase activities Article de journal T Hurtaux; G Sfihi-Loualia; Y Brissonnet; J Bouckaert; J -M Mallet; B Sendid; F Delplace; E Fabre; S G Gouin; Y Guérardel Carbohydrate Research, 429 , p. 123–127, 2016. @article{Hurtaux:2016, title = {Evaluation of monovalent and multivalent iminosugars to modulate Candida albicans β-1,2-mannosyltransferase activities}, author = {T Hurtaux and G Sfihi-Loualia and Y Brissonnet and J Bouckaert and J -M Mallet and B Sendid and F Delplace and E Fabre and S G Gouin and Y Gu\'{e}rardel}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84956666590&doi=10.1016%2fj.carres.2016.01.004&partnerID=40&md5=aab3c88b7a14fba6bffa454a2ccea6d0}, doi = {10.1016/j.carres.2016.01.004}, year = {2016}, date = {2016-01-01}, journal = {Carbohydrate Research}, volume = {429}, pages = {123--127}, abstract = {β-1,2-Linked oligomannosides substitute the cell wall of numerous yeast species. Several of those including Candida albicans may cause severe infections associated with high rates of morbidity and mortality, especially in immunocompromised patients. β-1,2-Mannosides are known to be involved in the pathogenic process and to elicit an immune response from the host. In C. albicans, the synthesis of β-mannosides is under the control of a family of nine genes coding for putative β-mannosyltransferases. Two of them, CaBmt1 and CaBmt3, have been shown to initiate and prime the elongation of the β-mannosides on the cell-wall mannan core. In the present study, we have assessed the modulating activities of monovalent and multivalent iminosugar analogs on these enzymes in order to control the enzymatic bio-synthesis of β-mannosides. We have identified a monovalent deoxynojirimycin (DNJ) derivative that inhibits the CaBmt1-catalyzed initiating activity, and mono-, tetra- and polyvalent deoxymannojirimycin (DMJ) that modulate the CaBmt1 activity toward the formation of a single major product. Analysis of the aggregating properties of the multivalent iminosugars showed their ability to elicit clusterization of both CaBmt1 and CaBmt3, without affecting their activity. These results suggest promising roles for multivalent iminosugars as controlling agents for the biosynthesis of β-1,2 mannosides and for monovalent DNJ derivative as a first target for the design of future β-mannosyltransferase inhibitors. © 2016 Elsevier Ltd. All rights reserved.}, keywords = {}, pubstate = {published}, tppubtype = {article} } β-1,2-Linked oligomannosides substitute the cell wall of numerous yeast species. Several of those including Candida albicans may cause severe infections associated with high rates of morbidity and mortality, especially in immunocompromised patients. β-1,2-Mannosides are known to be involved in the pathogenic process and to elicit an immune response from the host. In C. albicans, the synthesis of β-mannosides is under the control of a family of nine genes coding for putative β-mannosyltransferases. Two of them, CaBmt1 and CaBmt3, have been shown to initiate and prime the elongation of the β-mannosides on the cell-wall mannan core. In the present study, we have assessed the modulating activities of monovalent and multivalent iminosugar analogs on these enzymes in order to control the enzymatic bio-synthesis of β-mannosides. We have identified a monovalent deoxynojirimycin (DNJ) derivative that inhibits the CaBmt1-catalyzed initiating activity, and mono-, tetra- and polyvalent deoxymannojirimycin (DMJ) that modulate the CaBmt1 activity toward the formation of a single major product. Analysis of the aggregating properties of the multivalent iminosugars showed their ability to elicit clusterization of both CaBmt1 and CaBmt3, without affecting their activity. These results suggest promising roles for multivalent iminosugars as controlling agents for the biosynthesis of β-1,2 mannosides and for monovalent DNJ derivative as a first target for the design of future β-mannosyltransferase inhibitors. © 2016 Elsevier Ltd. All rights reserved. |
Antagonistic Effect of Acetates in C–N Bond Formation with In Situ Generated Diazonium Salts: A Combined Theoretical and Experimental Study Article de journal I Fabre; L A Perego; J Bergès; I Ciofini; L Grimaud; M Taillefer European Journal of Organic Chemistry, 2016 (35), p. 5887–5896, 2016. @article{Fabre:2016, title = {Antagonistic Effect of Acetates in C\textendashN Bond Formation with In Situ Generated Diazonium Salts: A Combined Theoretical and Experimental Study}, author = {I Fabre and L A Perego and J Berg\`{e}s and I Ciofini and L Grimaud and M Taillefer}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85002657035&doi=10.1002%2fejoc.201600891&partnerID=40&md5=ee236c20eefb6f1f6ece9494a9cd139c}, doi = {10.1002/ejoc.201600891}, year = {2016}, date = {2016-01-01}, journal = {European Journal of Organic Chemistry}, volume = {2016}, number = {35}, pages = {5887--5896}, abstract = {The mechanism of the copper-catalyzed arylation of nitrogen heterocycles using anilines via diazonium salts has been studied by combining DFT and experimental data. A CuI/CuIII redox mechanism is proposed. Our study has revealed the multiple roles of the acid/base couple AcOH/AcO\textendash. An in situ formed triazene species maintains a low concentration of diazonium salts in the reaction medium, which ensures limited formation of decomposition products. The results of DFT calculations have explained the lower reactivity of imidazole nucleophiles as compared with pyrazole in the arylation reaction. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim}, keywords = {}, pubstate = {published}, tppubtype = {article} } The mechanism of the copper-catalyzed arylation of nitrogen heterocycles using anilines via diazonium salts has been studied by combining DFT and experimental data. A CuI/CuIII redox mechanism is proposed. Our study has revealed the multiple roles of the acid/base couple AcOH/AcO–. An in situ formed triazene species maintains a low concentration of diazonium salts in the reaction medium, which ensures limited formation of decomposition products. The results of DFT calculations have explained the lower reactivity of imidazole nucleophiles as compared with pyrazole in the arylation reaction. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim |
Mechanistic Studies on the Palladium-Catalyzed Direct C-5 Arylation of Imidazoles: The Fundamental Role of the Azole as a Ligand for Palladium Article de journal L A Perego; L Grimaud; F Bellina Advanced Synthesis and Catalysis, 358 (4), p. 597–609, 2016. @article{Perego:2016, title = {Mechanistic Studies on the Palladium-Catalyzed Direct C-5 Arylation of Imidazoles: The Fundamental Role of the Azole as a Ligand for Palladium}, author = {L A Perego and L Grimaud and F Bellina}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84958765009&doi=10.1002%2fadsc.201500888&partnerID=40&md5=347f25ab343ee17c9163ff0face21def}, doi = {10.1002/adsc.201500888}, year = {2016}, date = {2016-01-01}, journal = {Advanced Synthesis and Catalysis}, volume = {358}, number = {4}, pages = {597--609}, abstract = {An in-depth mechanistic study on the palladium-catalyzed direct arylation of imidazoles at the C-5 position is presented. The interactions of triphenylphosphine (PPh3)-ligated aryl-Pd species with 1,2-dimethyl-1H-imidazole (dmim) have been studied in detail. In contrast with previous suggestions, phosphine-ligated organo-Pd species are not active and the reaction proceeds through imidazole-ligated organo-Pd intermediates. The kinetics of the oxidative addition of aryl halides with dmim-ligated Pd(0) species have been characterized in a Pd(dba)2/dmim model system. A thorough study of the equilibria involving novel [ArPd(dmim)2X] complexes (X=I, OAc) and the unexpected cationic [ArPd(dmim)3]+ is also reported. The ability of these species to effect the C-H arylation of dmim at room temperature in the presence of acetate is also demonstrated. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.}, keywords = {}, pubstate = {published}, tppubtype = {article} } An in-depth mechanistic study on the palladium-catalyzed direct arylation of imidazoles at the C-5 position is presented. The interactions of triphenylphosphine (PPh3)-ligated aryl-Pd species with 1,2-dimethyl-1H-imidazole (dmim) have been studied in detail. In contrast with previous suggestions, phosphine-ligated organo-Pd species are not active and the reaction proceeds through imidazole-ligated organo-Pd intermediates. The kinetics of the oxidative addition of aryl halides with dmim-ligated Pd(0) species have been characterized in a Pd(dba)2/dmim model system. A thorough study of the equilibria involving novel [ArPd(dmim)2X] complexes (X=I, OAc) and the unexpected cationic [ArPd(dmim)3]+ is also reported. The ability of these species to effect the C-H arylation of dmim at room temperature in the presence of acetate is also demonstrated. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. |
Multiple Roles of Isocyanides in Palladium-Catalyzed Imidoylative Couplings: A Mechanistic Study Article de journal L A Perego; P Fleurat-Lessard; L El Kaïm; I Ciofini; L Grimaud Chemistry - A European Journal, 22 (43), p. 15491–15500, 2016. @article{Perego:2016a, title = {Multiple Roles of Isocyanides in Palladium-Catalyzed Imidoylative Couplings: A Mechanistic Study}, author = {L A Perego and P Fleurat-Lessard and L El Ka\"{i}m and I Ciofini and L Grimaud}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84987936672&doi=10.1002%2fchem.201602913&partnerID=40&md5=9a9ece2d660e15f9e495bcca8fbe847e}, doi = {10.1002/chem.201602913}, year = {2016}, date = {2016-01-01}, journal = {Chemistry - A European Journal}, volume = {22}, number = {43}, pages = {15491--15500}, abstract = {Kinetic, spectroscopic and computational studies examining a palladium-catalyzed imidoylative coupling highlight the dual role of isocyanides as both substrates and ligands for this class of transformations. The synthesis of secondary amides from aryl halides and water is presented as a case study. The kinetics of the oxidative addition of ArI with RNC-ligated Pd0species have been studied and the resulting imidoyl complex [(ArC=NR)Pd(CNR)2I] (Ar=4-F-C6H4}, keywords = {}, pubstate = {published}, tppubtype = {article} } Kinetic, spectroscopic and computational studies examining a palladium-catalyzed imidoylative coupling highlight the dual role of isocyanides as both substrates and ligands for this class of transformations. The synthesis of secondary amides from aryl halides and water is presented as a case study. The kinetics of the oxidative addition of ArI with RNC-ligated Pd0species have been studied and the resulting imidoyl complex [(ArC=NR)Pd(CNR)2I] (Ar=4-F-C6H4 |
Optimized conditions for Passerini-Smiles reactions and applications to benzoxazinone syntheses Article de journal E Martinand-Lurin; A Dos Santos; E Robineau; P Retailleau; P Dauban; L Grimaud; L El Kaïm Molecules, 21 (9), 2016. @article{Martinand-Lurin:2016, title = {Optimized conditions for Passerini-Smiles reactions and applications to benzoxazinone syntheses}, author = {E Martinand-Lurin and A Dos Santos and E Robineau and P Retailleau and P Dauban and L Grimaud and L El Ka\"{i}m}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84988973862&doi=10.3390%2fmolecules21091257&partnerID=40&md5=ae9025719d60f467f4126f08addd11ab}, doi = {10.3390/molecules21091257}, year = {2016}, date = {2016-01-01}, journal = {Molecules}, volume = {21}, number = {9}, abstract = {Initial conditions disclosed for the Passerini-Smiles reaction are associated with a lack of efficiency that has prevented chemists from using it since its discovery. We wish to report herein our thorough study in the development of new experimental conditions for this coupling between electron-poor phenols, isocyanides, and carbonyl derivatives. These new conditions have been applied to several synthetic strategies towards benzoxazinones. © 2016 by the authors; licensee MDPI.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Initial conditions disclosed for the Passerini-Smiles reaction are associated with a lack of efficiency that has prevented chemists from using it since its discovery. We wish to report herein our thorough study in the development of new experimental conditions for this coupling between electron-poor phenols, isocyanides, and carbonyl derivatives. These new conditions have been applied to several synthetic strategies towards benzoxazinones. © 2016 by the authors; licensee MDPI. |
TiCl4-Mediated Preparation of Thiophthalide Derivatives via Formal Thio-Passerini Reactions Article de journal S Ponra; A Nyadanu; L E Kaïm; L Grimaud; M R Vitale Organic Letters, 18 (16), p. 4060–4063, 2016. @article{Ponra:2016, title = {TiCl4-Mediated Preparation of Thiophthalide Derivatives via Formal Thio-Passerini Reactions}, author = {S Ponra and A Nyadanu and L E Ka\"{i}m and L Grimaud and M R Vitale}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84983371914&doi=10.1021%2facs.orglett.6b01937&partnerID=40&md5=83eb6dc235b19ab27683ad9a40a59d52}, doi = {10.1021/acs.orglett.6b01937}, year = {2016}, date = {2016-01-01}, journal = {Organic Letters}, volume = {18}, number = {16}, pages = {4060--4063}, abstract = {By the formal extension of the Passerini reaction to thiocarbonyl derivatives, the straightforward preparation of thiophthalides is disclosed. This method involves the intermediate formation of a sulfanyl-phthalide and a titanium tetrachloride mediated isocyanide insertion reaction. When tert-butyl thiol is used, thanks to the deprotection of the tert-butyl group, a thiophthalide resulting from a 1,5-Mumm rearrangement is isolated. Owing to the multifaceted activity of TiCl4, all steps may conveniently be performed in one pot, starting directly from 2-formylbenzoic acids, tert-butyl thiol, and various isocyanides. © 2016 American Chemical Society.}, keywords = {}, pubstate = {published}, tppubtype = {article} } By the formal extension of the Passerini reaction to thiocarbonyl derivatives, the straightforward preparation of thiophthalides is disclosed. This method involves the intermediate formation of a sulfanyl-phthalide and a titanium tetrachloride mediated isocyanide insertion reaction. When tert-butyl thiol is used, thanks to the deprotection of the tert-butyl group, a thiophthalide resulting from a 1,5-Mumm rearrangement is isolated. Owing to the multifaceted activity of TiCl4, all steps may conveniently be performed in one pot, starting directly from 2-formylbenzoic acids, tert-butyl thiol, and various isocyanides. © 2016 American Chemical Society. |
Influence of the Oxazole Ring Connection on the Fluorescence of Oxazoyl-Triphenylamine Biphotonic DNA Probes Article de journal Blaise Dumat; Elodie Faurel-Paul; Pauline Fornarelli; Nicolas Saettel; Germain Metgé; Céline Fiorini-Debuisschert; Fabrice Charra; Florence Mahuteau-Betzer; Marie-Paule Teulade-Fichou Organic & Biomolecular Chemistry, 14 (1), p. 358-370, 2016. @article{Dumat:2016a, title = {Influence of the Oxazole Ring Connection on the Fluorescence of Oxazoyl-Triphenylamine Biphotonic DNA Probes}, author = {Blaise Dumat and Elodie {Faurel-Paul} and Pauline Fornarelli and Nicolas Saettel and Germain Metg\'{e} and C\'{e}line {Fiorini-Debuisschert} and Fabrice Charra and Florence {Mahuteau-Betzer} and Marie-Paule {Teulade-Fichou}}, doi = {10.1039/C5OB02225H}, year = {2016}, date = {2016-01-01}, journal = {Organic & Biomolecular Chemistry}, volume = {14}, number = {1}, pages = {358-370}, abstract = {The oxazole ring connection of these DNA minor-groove binders strongly impacts their on\textendashoff behavior.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The oxazole ring connection of these DNA minor-groove binders strongly impacts their on–off behavior. |
Mitochondria-Targeted Triphenylamine Derivatives Activatable by Two-Photon Excitation for Triggering and Imaging Cell Apoptosis Article de journal Rahima Chennoufi; Houcine Bougherara; Nathalie Gagey-Eilstein; Blaise Dumat; Etienne Henry; Frédéric Subra; Stéphanie Bury-Moné; Florence Mahuteau-Betzer; Patrick Tauc; Marie-Paule Teulade-Fichou; Eric Deprez Scientific Reports, 6 (January), p. 21458-21458, 2016. @article{Chennoufi:2016, title = {Mitochondria-Targeted Triphenylamine Derivatives Activatable by Two-Photon Excitation for Triggering and Imaging Cell Apoptosis}, author = {Rahima Chennoufi and Houcine Bougherara and Nathalie {Gagey-Eilstein} and Blaise Dumat and Etienne Henry and Fr\'{e}d\'{e}ric Subra and St\'{e}phanie {Bury-Mon\'{e}} and Florence {Mahuteau-Betzer} and Patrick Tauc and Marie-Paule {Teulade-Fichou} and Eric Deprez}, doi = {10.1038/srep21458}, year = {2016}, date = {2016-01-01}, journal = {Scientific Reports}, volume = {6}, number = {January}, pages = {21458-21458}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
Thrombospondin-1 Mimetic Agonist Peptides Induce Selective Death in Tumor Cells: Design, Synthesis, and Structure-Activity Relationship Studies Article de journal T Denèfle; H Boullet; L Herbi; C Newton; A -C Martinez-Torres; A Guez; E Pramil; C Quiney; M Pourcelot; M D Levasseur; E Lardé; R Moumné; F -X Ogi; P Grondin; H Merle-Beral; O Lequin; S A Susin; P Karoyan Journal of Medicinal Chemistry, 59 (18), p. 8412–8421, 2016. @article{Denefle:2016, title = {Thrombospondin-1 Mimetic Agonist Peptides Induce Selective Death in Tumor Cells: Design, Synthesis, and Structure-Activity Relationship Studies}, author = {T Den\`{e}fle and H Boullet and L Herbi and C Newton and A -C Martinez-Torres and A Guez and E Pramil and C Quiney and M Pourcelot and M D Levasseur and E Lard\'{e} and R Moumn\'{e} and F -X Ogi and P Grondin and H Merle-Beral and O Lequin and S A Susin and P Karoyan}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84988735397&doi=10.1021%2facs.jmedchem.6b00781&partnerID=40&md5=56822fdf1d99463527e7e00830952716}, doi = {10.1021/acs.jmedchem.6b00781}, year = {2016}, date = {2016-01-01}, journal = {Journal of Medicinal Chemistry}, volume = {59}, number = {18}, pages = {8412--8421}, abstract = {Thrombospondin-1 (TSP-1) is a glycoprotein considered as a key actor within the tumor microenvironment. Its binding to CD47, a cell surface receptor, triggers programmed cell death. Previous studies allowed the identification of 4N1K decapeptide derived from the TSP-1/CD47 binding epitope. Here, we demonstrate that this peptide is able to induce selective apoptosis of various cancer cell lines while sparing normal cells. A structure-activity relationship study led to the design of the first serum stable TSP-1 mimetic agonist peptide able to trigger selective programmed cell death (PCD) of at least lung, breast, and colorectal cancer cells. Altogether, these results will be of valuable interest for further investigation in the design of potent CD47 agonist peptides, opening new perspectives for the development of original anticancer therapies. © 2016 American Chemical Society.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Thrombospondin-1 (TSP-1) is a glycoprotein considered as a key actor within the tumor microenvironment. Its binding to CD47, a cell surface receptor, triggers programmed cell death. Previous studies allowed the identification of 4N1K decapeptide derived from the TSP-1/CD47 binding epitope. Here, we demonstrate that this peptide is able to induce selective apoptosis of various cancer cell lines while sparing normal cells. A structure-activity relationship study led to the design of the first serum stable TSP-1 mimetic agonist peptide able to trigger selective programmed cell death (PCD) of at least lung, breast, and colorectal cancer cells. Altogether, these results will be of valuable interest for further investigation in the design of potent CD47 agonist peptides, opening new perspectives for the development of original anticancer therapies. © 2016 American Chemical Society. |
Multi-Stage Mass Spectrometry Analysis of Sugar-Conjugated β-Turn Structures to be Used as Probes in Autoimmune Diseases Article de journal C Giangrande; N Auberger; C Rentier; A M Papini; J -M Mallet; S Lavielle; J Vinh Journal of the American Society for Mass Spectrometry, 27 (4), p. 735–747, 2016. @article{Giangrande:2016, title = {Multi-Stage Mass Spectrometry Analysis of Sugar-Conjugated β-Turn Structures to be Used as Probes in Autoimmune Diseases}, author = {C Giangrande and N Auberger and C Rentier and A M Papini and J -M Mallet and S Lavielle and J Vinh}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84962245067&doi=10.1007%2fs13361-015-1321-9&partnerID=40&md5=404714782b302b757b996434cc44a993}, doi = {10.1007/s13361-015-1321-9}, year = {2016}, date = {2016-01-01}, journal = {Journal of the American Society for Mass Spectrometry}, volume = {27}, number = {4}, pages = {735--747}, abstract = {Synthetic sugar-modified peptides were identified as antigenic probes in the context of autoimmune diseases. The aim of this work is to provide a mechanistic study on the fragmentation of different glycosylated analogs of a synthetic antigenic probe able to detect antibodies in a subpopulation of multiple sclerosis patients. In particular the N-glucosylated type I′ β-turn peptide structure called CSF114(Glc) was used as a model to find signature fragmentations exploring the potential of multi-stage mass spectrometry by MALDI-LTQ Orbitrap. Here we compare the fragmentation of the glucosylated form of the synthetic peptide CSF114(Glc), bearing a glucose moiety on an asparagine residue, with less or non- immunoreactive forms, bearing different sugar-modifications, such as CSF114(GlcNAc), modified with a residue of N-acetylglucosamine, and CSF114[Lys7(1-deoxyfructopyranosyl)], this last one modified with a 1-deoxyfructopyranosyl moiety on a lysine at position 7. The analysis was set up using a synthetic compound specifically deuterated on the C-1 to compare its fragmentation with the fragmentation of the undeuterated form, and thus ascertain with confidence the presence on an Asn(Glc) within a peptide sequence. At the end of the study, our analysis led to the identification of signature neutral losses inside the sugar moieties to characterize the different types of glycosylation/glycation. The interest of this study lies in the possibility of applyimg this approach to the discovery of biomarkers and in the diagnosis of autoimmune diseases. © American Society for Mass Spectrometry 2016.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Synthetic sugar-modified peptides were identified as antigenic probes in the context of autoimmune diseases. The aim of this work is to provide a mechanistic study on the fragmentation of different glycosylated analogs of a synthetic antigenic probe able to detect antibodies in a subpopulation of multiple sclerosis patients. In particular the N-glucosylated type I′ β-turn peptide structure called CSF114(Glc) was used as a model to find signature fragmentations exploring the potential of multi-stage mass spectrometry by MALDI-LTQ Orbitrap. Here we compare the fragmentation of the glucosylated form of the synthetic peptide CSF114(Glc), bearing a glucose moiety on an asparagine residue, with less or non- immunoreactive forms, bearing different sugar-modifications, such as CSF114(GlcNAc), modified with a residue of N-acetylglucosamine, and CSF114[Lys7(1-deoxyfructopyranosyl)], this last one modified with a 1-deoxyfructopyranosyl moiety on a lysine at position 7. The analysis was set up using a synthetic compound specifically deuterated on the C-1 to compare its fragmentation with the fragmentation of the undeuterated form, and thus ascertain with confidence the presence on an Asn(Glc) within a peptide sequence. At the end of the study, our analysis led to the identification of signature neutral losses inside the sugar moieties to characterize the different types of glycosylation/glycation. The interest of this study lies in the possibility of applyimg this approach to the discovery of biomarkers and in the diagnosis of autoimmune diseases. © American Society for Mass Spectrometry 2016. |
Identification of an anti-inflammatory protein from Faecalibacterium prausnitzii, a commensal bacterium deficient in Crohn's disease Article de journal E Quévrain; M A Maubert; C Michon; F Chain; R Marquant; J Tailhades; S Miquel; L Carlier; L G Bermúdez-Humarán; B Pigneur; O Lequin; P Kharrat; G Thomas; D Rainteau; C Aubry; N Breyner; C Afonso; S Lavielle; J -P Grill; G Chassaing; J M Chatel; G Trugnan; R Xavier; P Langella; H Sokol; P Seksik Gut, 65 (3), p. 415–425, 2016. @article{Quevrain:2016, title = {Identification of an anti-inflammatory protein from Faecalibacterium prausnitzii, a commensal bacterium deficient in Crohn's disease}, author = {E Qu\'{e}vrain and M A Maubert and C Michon and F Chain and R Marquant and J Tailhades and S Miquel and L Carlier and L G Berm\'{u}dez-Humar\'{a}n and B Pigneur and O Lequin and P Kharrat and G Thomas and D Rainteau and C Aubry and N Breyner and C Afonso and S Lavielle and J -P Grill and G Chassaing and J M Chatel and G Trugnan and R Xavier and P Langella and H Sokol and P Seksik}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84960373289&doi=10.1136%2fgutjnl-2014-307649&partnerID=40&md5=74f8eb656f288a29a96faffebf9c2ee5}, doi = {10.1136/gutjnl-2014-307649}, year = {2016}, date = {2016-01-01}, journal = {Gut}, volume = {65}, number = {3}, pages = {415--425}, abstract = {Background: Crohn's disease (CD)-associated dysbiosis is characterised by a loss of Faecalibacterium prausnitzii, whose culture supernatant exerts an anti-inflammatory effect both in vitro and in vivo. However, the chemical nature of the anti-inflammatory compounds has not yet been determined. Methods: Peptidomic analysis using mass spectrometry was applied to F. prausnitzii supernatant. Antiinflammatory effects of identified peptides were tested in vitro directly on intestinal epithelial cell lines and on cell lines transfected with a plasmid construction coding for the candidate protein encompassing these peptides. In vivo, the cDNA of the candidate protein was delivered to the gut by recombinant lactic acid bacteria to prevent dinitrobenzene sulfonic acid (DNBS)-colitis in mice. Results: The seven peptides, identified in the F. prausnitzii culture supernatants, derived from a single microbial anti-inflammatory molecule (MAM), a protein of 15 kDa, and comprising 53% of non-polar residues. This last feature prevented the direct characterisation of the putative anti-inflammatory activity of MAM-derived peptides. Transfection of MAM cDNA in epithelial cells led to a significant decrease in the activation of the nuclear factor (NF)-?B pathway with a dose-dependent effect. Finally, the use of a food-grade bacterium, Lactococcus lactis, delivering a plasmid encoding MAM was able to alleviate DNBS-induced colitis in mice. Conclusions: A 15 kDa protein with anti-inflammatory properties is produced by F. prausnitzii, a commensal bacterium involved in CD pathogenesis. This protein is able to inhibit the NF-κB pathway in intestinal epithelial cells and to prevent colitis in an animal model.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Background: Crohn's disease (CD)-associated dysbiosis is characterised by a loss of Faecalibacterium prausnitzii, whose culture supernatant exerts an anti-inflammatory effect both in vitro and in vivo. However, the chemical nature of the anti-inflammatory compounds has not yet been determined. Methods: Peptidomic analysis using mass spectrometry was applied to F. prausnitzii supernatant. Antiinflammatory effects of identified peptides were tested in vitro directly on intestinal epithelial cell lines and on cell lines transfected with a plasmid construction coding for the candidate protein encompassing these peptides. In vivo, the cDNA of the candidate protein was delivered to the gut by recombinant lactic acid bacteria to prevent dinitrobenzene sulfonic acid (DNBS)-colitis in mice. Results: The seven peptides, identified in the F. prausnitzii culture supernatants, derived from a single microbial anti-inflammatory molecule (MAM), a protein of 15 kDa, and comprising 53% of non-polar residues. This last feature prevented the direct characterisation of the putative anti-inflammatory activity of MAM-derived peptides. Transfection of MAM cDNA in epithelial cells led to a significant decrease in the activation of the nuclear factor (NF)-?B pathway with a dose-dependent effect. Finally, the use of a food-grade bacterium, Lactococcus lactis, delivering a plasmid encoding MAM was able to alleviate DNBS-induced colitis in mice. Conclusions: A 15 kDa protein with anti-inflammatory properties is produced by F. prausnitzii, a commensal bacterium involved in CD pathogenesis. This protein is able to inhibit the NF-κB pathway in intestinal epithelial cells and to prevent colitis in an animal model. |
How to unveil self-quenched fluorophores and subsequently map the subcellular distribution of exogenous peptides Article de journal J -M Swiecicki; F Thiebaut; M Di Pisa; S Gourdin -Bertin; J Tailhades; C Mansuy; F Burlina; S Chwetzoff; G Trugnan; G Chassaing; S Lavielle Scientific Reports, 6 , 2016. @article{Swiecicki:2016, title = {How to unveil self-quenched fluorophores and subsequently map the subcellular distribution of exogenous peptides}, author = {J -M Swiecicki and F Thiebaut and M Di Pisa and S Gourdin -Bertin and J Tailhades and C Mansuy and F Burlina and S Chwetzoff and G Trugnan and G Chassaing and S Lavielle}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84957837107&doi=10.1038%2fsrep20237&partnerID=40&md5=3b6ebb5cc1852323b58fc293948a9914}, doi = {10.1038/srep20237}, year = {2016}, date = {2016-01-01}, journal = {Scientific Reports}, volume = {6}, abstract = {Confocal laser scanning microscopy (CLSM) is the most popular technique for mapping the subcellular distribution of a fluorescent molecule and is widely used to investigate the penetration properties of exogenous macromolecules, such as cell-penetrating peptides (CPPs), within cells. Despite the membrane-association propensity of all these CPPs, the signal of the fluorescently labeled CPPs did not colocalize with the plasma membrane. We studied the origin of this fluorescence extinction and the overall consequence on the interpretation of intracellular localizations from CLSM pictures. We demonstrated that this discrepancy originated from fluorescence self-quenching. The fluorescence was unveiled by a "dilution" protocol, i.e. by varying the ratio fluorescent/non-fluorescent CPP. This strategy allowed us to rank with confidence the subcellular distribution of several CPPs, contributing to the elucidation of the penetration mechanism. More generally, this study proposes a broadly applicable and reliable method to study the subcellular distribution of any fluorescently labeled molecules.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Confocal laser scanning microscopy (CLSM) is the most popular technique for mapping the subcellular distribution of a fluorescent molecule and is widely used to investigate the penetration properties of exogenous macromolecules, such as cell-penetrating peptides (CPPs), within cells. Despite the membrane-association propensity of all these CPPs, the signal of the fluorescently labeled CPPs did not colocalize with the plasma membrane. We studied the origin of this fluorescence extinction and the overall consequence on the interpretation of intracellular localizations from CLSM pictures. We demonstrated that this discrepancy originated from fluorescence self-quenching. The fluorescence was unveiled by a "dilution" protocol, i.e. by varying the ratio fluorescent/non-fluorescent CPP. This strategy allowed us to rank with confidence the subcellular distribution of several CPPs, contributing to the elucidation of the penetration mechanism. More generally, this study proposes a broadly applicable and reliable method to study the subcellular distribution of any fluorescently labeled molecules. |
Isomerization and Oligomerization of Truncated and Mutated Tau Forms by FKBP52 are Independent Processes Article de journal A Kamah; F X Cantrelle; I Huvent; J Giustiniani; K Guillemeau; C Byrne; Y Jacquot; I Landrieu; E E Baulieu; C Smet; B Chambraud; G Lippens Journal of Molecular Biology, 428 (6), p. 1080–1090, 2016. @article{Kamah:2016, title = {Isomerization and Oligomerization of Truncated and Mutated Tau Forms by FKBP52 are Independent Processes}, author = {A Kamah and F X Cantrelle and I Huvent and J Giustiniani and K Guillemeau and C Byrne and Y Jacquot and I Landrieu and E E Baulieu and C Smet and B Chambraud and G Lippens}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84959261786&doi=10.1016%2fj.jmb.2016.02.015&partnerID=40&md5=fa8b175818d6093a38424aca150b0eb2}, doi = {10.1016/j.jmb.2016.02.015}, year = {2016}, date = {2016-01-01}, journal = {Journal of Molecular Biology}, volume = {428}, number = {6}, pages = {1080--1090}, abstract = {The aggregation of the neuronal Tau protein is one molecular hallmark of Alzheimer's disease and other related tauopathies, but the precise molecular mechanisms of the aggregation process remain unclear. The FK506 binding protein FKBP52 is able to induce oligomers in the pathogenic Tau P301L mutant and in a truncated form of the wild-type human Tau protein. Here, we investigate whether FKBP52's capacity to induce Tau oligomers depends on its prolyl cis/trans isomerase activity. We find that FKBP52 indeed can isomerize selected prolyl bonds in the different Tau proteins, and that this activity is carried solely by its first FK506 binding domain. Its capacity to oligomerize Tau is, however, not linked to this peptidyl-prolyl isomerase activity. In addition, we identified a novel molecular interaction implying the PHF6 peptide of Tau and the FK1/FK2 domains of FKBP52 independent of FK506 binding; these data point toward a non-catalytic molecular interaction that might govern the effect of FKBP52 on Tau. © 2016 Elsevier Ltd. All rights reserved.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The aggregation of the neuronal Tau protein is one molecular hallmark of Alzheimer's disease and other related tauopathies, but the precise molecular mechanisms of the aggregation process remain unclear. The FK506 binding protein FKBP52 is able to induce oligomers in the pathogenic Tau P301L mutant and in a truncated form of the wild-type human Tau protein. Here, we investigate whether FKBP52's capacity to induce Tau oligomers depends on its prolyl cis/trans isomerase activity. We find that FKBP52 indeed can isomerize selected prolyl bonds in the different Tau proteins, and that this activity is carried solely by its first FK506 binding domain. Its capacity to oligomerize Tau is, however, not linked to this peptidyl-prolyl isomerase activity. In addition, we identified a novel molecular interaction implying the PHF6 peptide of Tau and the FK1/FK2 domains of FKBP52 independent of FK506 binding; these data point toward a non-catalytic molecular interaction that might govern the effect of FKBP52 on Tau. © 2016 Elsevier Ltd. All rights reserved. |
A β-turn motif in the steroid hormone receptor's ligand-binding domains interacts with the peptidyl-prolyl isomerase (PPIase) catalytic site of the immunophilin FKBP52 Article de journal C Byrne; M A Henen; M Belnou; F -X Cantrelle; A Kamah; H Qi; J Giustiniani; B Chambraud; E -E Baulieu; G Lippens; I Landrieu; Y Jacquot Biochemistry, 55 (38), p. 5366–5376, 2016. @article{Byrne:2016, title = {A β-turn motif in the steroid hormone receptor's ligand-binding domains interacts with the peptidyl-prolyl isomerase (PPIase) catalytic site of the immunophilin FKBP52}, author = {C Byrne and M A Henen and M Belnou and F -X Cantrelle and A Kamah and H Qi and J Giustiniani and B Chambraud and E -E Baulieu and G Lippens and I Landrieu and Y Jacquot}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84989260723&doi=10.1021%2facs.biochem.6b00506&partnerID=40&md5=d6d3646263e00c9bd3049c235c894a13}, doi = {10.1021/acs.biochem.6b00506}, year = {2016}, date = {2016-01-01}, journal = {Biochemistry}, volume = {55}, number = {38}, pages = {5366--5376}, abstract = {The immunophilin FKBP52 interacts with nuclear steroid hormone receptors. Studying the crystal structure of human estrogen receptor α (hERα) and using nuclear magnetic resonance, we show here that the short V364PGF367 sequence, which is located within its ligand-binding domain and adopts a type II β-turn conformation in the protein, binds the peptidyl-prolyl isomerase (PPIase or rotamase) FK1 domain of FKBP52. Interestingly, this turn motif displays strong similarities with the FKBP52 FK1 domain-binding moiety of macrolide immunomodulators such as rapamycin and GPI-1046, an immunophilin ligand with neuroprotective characteristics. An increase in the hydrophobicity of the residue preceding the proline and cyclization of the VPGF peptide strengthen its recognition by the FK1 domain of FKBP52. Replacement of the Pro residue with a dimethylproline also enhances this interaction. Our study not only contributes to a better understanding of how the interaction between the FK1 domain of FKBP52 and steroid hormone receptors most likely works but also opens new avenues for the synthesis of FKBP52 FK1 peptide ligands appropriate for the control of hormone-dependent physiological mechanisms or of the functioning of the Tau protein. Indeed, it has been shown that FKBP52 is involved in the intraneuronal dynamics of the Tau protein. © 2016 American Chemical Society.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The immunophilin FKBP52 interacts with nuclear steroid hormone receptors. Studying the crystal structure of human estrogen receptor α (hERα) and using nuclear magnetic resonance, we show here that the short V364PGF367 sequence, which is located within its ligand-binding domain and adopts a type II β-turn conformation in the protein, binds the peptidyl-prolyl isomerase (PPIase or rotamase) FK1 domain of FKBP52. Interestingly, this turn motif displays strong similarities with the FKBP52 FK1 domain-binding moiety of macrolide immunomodulators such as rapamycin and GPI-1046, an immunophilin ligand with neuroprotective characteristics. An increase in the hydrophobicity of the residue preceding the proline and cyclization of the VPGF peptide strengthen its recognition by the FK1 domain of FKBP52. Replacement of the Pro residue with a dimethylproline also enhances this interaction. Our study not only contributes to a better understanding of how the interaction between the FK1 domain of FKBP52 and steroid hormone receptors most likely works but also opens new avenues for the synthesis of FKBP52 FK1 peptide ligands appropriate for the control of hormone-dependent physiological mechanisms or of the functioning of the Tau protein. Indeed, it has been shown that FKBP52 is involved in the intraneuronal dynamics of the Tau protein. © 2016 American Chemical Society. |
The Use of Mn(II) Bound to His-tags as Genetically Encodable Spin-Label for Nanometric Distance Determination in Proteins Article de journal H Y V Ching; F C Mascali; H C Bertrand; E M Bruch; P Demay-Drouhard; R M Rasia; C Policar; L C Tabares; S Un Journal of Physical Chemistry Letters, 7 (6), p. 1072–1076, 2016. @article{Ching:2016, title = {The Use of Mn(II) Bound to His-tags as Genetically Encodable Spin-Label for Nanometric Distance Determination in Proteins}, author = {H Y V Ching and F C Mascali and H C Bertrand and E M Bruch and P Demay-Drouhard and R M Rasia and C Policar and L C Tabares and S Un}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84962539336&doi=10.1021%2facs.jpclett.6b00362&partnerID=40&md5=16161dac85830ffcae821a41e6480d4c}, doi = {10.1021/acs.jpclett.6b00362}, year = {2016}, date = {2016-01-01}, journal = {Journal of Physical Chemistry Letters}, volume = {7}, number = {6}, pages = {1072--1076}, abstract = {A genetically encodable paramagnetic spin-label capable of self-assembly from naturally available components would offer a means for studying the in-cell structure and interactions of a protein by electron paramagnetic resonance (EPR). Here, we demonstrate pulse electron-electron double resonance (DEER) measurements on spin-labels consisting of Mn(II) ions coordinated to a sequence of histidines, so-called His-tags, that are ubiquitously added by genetic engineering to facilitate protein purification. Although the affinity of His-tags for Mn(II) was low (800 μM), Mn(II)-bound His-tags yielded readily detectable DEER time traces even at concentrations expected in cells. We were able to determine accurately the distance between two His-tag Mn(II) spin-labels at the ends of a rigid helical polyproline peptide of known structure, as well as at the ends of a completely cell-synthesized 3-helix bundle. This approach not only greatly simplifies the labeling procedure but also represents a first step towards using self-assembling metal spin-labels for in-cell distance measurements. © 2016 American Chemical Society.}, keywords = {}, pubstate = {published}, tppubtype = {article} } A genetically encodable paramagnetic spin-label capable of self-assembly from naturally available components would offer a means for studying the in-cell structure and interactions of a protein by electron paramagnetic resonance (EPR). Here, we demonstrate pulse electron-electron double resonance (DEER) measurements on spin-labels consisting of Mn(II) ions coordinated to a sequence of histidines, so-called His-tags, that are ubiquitously added by genetic engineering to facilitate protein purification. Although the affinity of His-tags for Mn(II) was low (800 μM), Mn(II)-bound His-tags yielded readily detectable DEER time traces even at concentrations expected in cells. We were able to determine accurately the distance between two His-tag Mn(II) spin-labels at the ends of a rigid helical polyproline peptide of known structure, as well as at the ends of a completely cell-synthesized 3-helix bundle. This approach not only greatly simplifies the labeling procedure but also represents a first step towards using self-assembling metal spin-labels for in-cell distance measurements. © 2016 American Chemical Society. |
RIDME spectroscopy on high-spin Mn2+ centers Article de journal D Akhmetzyanov; H Y V Ching; V Denysenkov; P Demay-Drouhard; H C Bertrand; L C Tabares; C Policar; T F Prisner; S Un Physical Chemistry Chemical Physics, 18 (44), p. 30857–30866, 2016. @article{Akhmetzyanov:2016, title = {RIDME spectroscopy on high-spin Mn2+ centers}, author = {D Akhmetzyanov and H Y V Ching and V Denysenkov and P Demay-Drouhard and H C Bertrand and L C Tabares and C Policar and T F Prisner and S Un}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-85025823502&doi=10.1039%2fc6cp05239h&partnerID=40&md5=d3a6cd609c88b382cf0297ed361d4003}, doi = {10.1039/c6cp05239h}, year = {2016}, date = {2016-01-01}, journal = {Physical Chemistry Chemical Physics}, volume = {18}, number = {44}, pages = {30857--30866}, abstract = {Pulsed EPR dipolar spectroscopy is a powerful tool for determining the structure and conformational dynamics of biological macromolecules, as it allows precise measurements of distances in the range of 1.5-10 nm. Utilization of high-spin Mn2+ species as spin probes for distance measurements is of significant interest, because they are biologically compatible and endogenous in numerous biological systems. However, to date dipolar spectroscopy experiments with this kind of species have been underexplored. Here we present pulsed electron electron double resonance (PELDOR also called DEER) and relaxation-induced dipolar modulation enhancement (RIDME) experiments, which have been performed at W-band (94 GHz) and J-band frequencies (263 GHz) on a bis-MnDOTA (DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate) model system. The distances obtained from these experiments are in good agreement with predictions. RIDME experiments reveal a significantly higher modulation depth compared to PELDOR, which is an important consideration for biological samples. These experiments also feature higher harmonics of the dipolar coupling frequency due to effective multiple-quantum relaxation of high-spin Mn2+ as well as the multiple-component background function. Harmonics of the dipolar coupling frequency were taken into account by including additional terms in the kernel function of Tikhonov regularization analysis. © The Owner Societies 2016.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Pulsed EPR dipolar spectroscopy is a powerful tool for determining the structure and conformational dynamics of biological macromolecules, as it allows precise measurements of distances in the range of 1.5-10 nm. Utilization of high-spin Mn2+ species as spin probes for distance measurements is of significant interest, because they are biologically compatible and endogenous in numerous biological systems. However, to date dipolar spectroscopy experiments with this kind of species have been underexplored. Here we present pulsed electron electron double resonance (PELDOR also called DEER) and relaxation-induced dipolar modulation enhancement (RIDME) experiments, which have been performed at W-band (94 GHz) and J-band frequencies (263 GHz) on a bis-MnDOTA (DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate) model system. The distances obtained from these experiments are in good agreement with predictions. RIDME experiments reveal a significantly higher modulation depth compared to PELDOR, which is an important consideration for biological samples. These experiments also feature higher harmonics of the dipolar coupling frequency due to effective multiple-quantum relaxation of high-spin Mn2+ as well as the multiple-component background function. Harmonics of the dipolar coupling frequency were taken into account by including additional terms in the kernel function of Tikhonov regularization analysis. © The Owner Societies 2016. |
Photophysical properties of single core multimodal probe for imaging (SCoMPI) in a membrane model and in cells Article de journal S Hostachy; J -M Swiecicki; C Sandt; N Delsuc; C Policar Dalton Transactions, 45 (7), p. 2791–2795, 2016. @article{Hostachy:2016, title = {Photophysical properties of single core multimodal probe for imaging (SCoMPI) in a membrane model and in cells}, author = {S Hostachy and J -M Swiecicki and C Sandt and N Delsuc and C Policar}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84958064177&doi=10.1039%2fc5dt03819g&partnerID=40&md5=fb027086e6424b54b23cc2c11098e273}, doi = {10.1039/c5dt03819g}, year = {2016}, date = {2016-01-01}, journal = {Dalton Transactions}, volume = {45}, number = {7}, pages = {2791--2795}, abstract = {The spectroscopic properties of two luminescent Re(i) tricarbonyl complexes conjugated with two cell-penetrating peptides were examined. Fluorescence experiments and IR quantification in membrane models and in cells showed unexpectedly strong luminescence enhancement for one of the complexes in a lipid environment. © The Royal Society of Chemistry 2016.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The spectroscopic properties of two luminescent Re(i) tricarbonyl complexes conjugated with two cell-penetrating peptides were examined. Fluorescence experiments and IR quantification in membrane models and in cells showed unexpectedly strong luminescence enhancement for one of the complexes in a lipid environment. © The Royal Society of Chemistry 2016. |
New insight into the structural, electrochemical and biological aspects of macroacyclic Cu(II) complexes derived from S-substituted dithiocarbazate schiff bases Article de journal M L Low; L Maigre; M I M Tahir; E R T Tiekink; P Dorlet; R Guillot; T B Ravoof; R Rosli; J -M Pagès; C Policar; N Delsuc; K A Crouse European Journal of Medicinal Chemistry, 120 , p. 1–12, 2016. @article{Low:2016, title = {New insight into the structural, electrochemical and biological aspects of macroacyclic Cu(II) complexes derived from S-substituted dithiocarbazate schiff bases}, author = {M L Low and L Maigre and M I M Tahir and E R T Tiekink and P Dorlet and R Guillot and T B Ravoof and R Rosli and J -M Pag\`{e}s and C Policar and N Delsuc and K A Crouse}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84967102584&doi=10.1016%2fj.ejmech.2016.04.027&partnerID=40&md5=71cde180942655ac9c57205e82887fcf}, doi = {10.1016/j.ejmech.2016.04.027}, year = {2016}, date = {2016-01-01}, journal = {European Journal of Medicinal Chemistry}, volume = {120}, pages = {1--12}, abstract = {Copper (II) complexes synthesized from the products of condensation of S-methyl- and S-benzyldithiocarbazate with 2,5-hexanedione (SMHDH2 and SBHDH2 respectively) have been characterized using various physicochemical (elemental analysis, molar conductivity, magnetic susceptibility) and spectroscopic (infrared, electronic) methods. The structures of SMHDH2, its copper (II) complex, CuSMHD, and the related CuSBHD complex as well as a pyrrole byproduct, SBPY, have been determined by single crystal X-ray diffraction. In order to provide more insight into the behaviour of the complexes in solution, electron paramagnetic resonance (EPR) and electrochemical experiments were performed. Antibacterial activity and cytotoxicity were evaluated. The compounds, dissolved in 0.5% and 5% DMSO, showed a wide range of antibacterial activity against 10 strains of Gram-positive and Gram-negative bacteria. Investigations of the effects of efflux pumps and membrane penetration on antibacterial activity are reported herein. Antiproliferation activity was observed to be enhanced by complexation with copper. Preliminary screening showed Cu complexes are strongly active against human breast adenocarcinoma cancer cell lines MDA-MB-231 and MCF-7. © 2016 Published by Elsevier Masson SAS.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Copper (II) complexes synthesized from the products of condensation of S-methyl- and S-benzyldithiocarbazate with 2,5-hexanedione (SMHDH2 and SBHDH2 respectively) have been characterized using various physicochemical (elemental analysis, molar conductivity, magnetic susceptibility) and spectroscopic (infrared, electronic) methods. The structures of SMHDH2, its copper (II) complex, CuSMHD, and the related CuSBHD complex as well as a pyrrole byproduct, SBPY, have been determined by single crystal X-ray diffraction. In order to provide more insight into the behaviour of the complexes in solution, electron paramagnetic resonance (EPR) and electrochemical experiments were performed. Antibacterial activity and cytotoxicity were evaluated. The compounds, dissolved in 0.5% and 5% DMSO, showed a wide range of antibacterial activity against 10 strains of Gram-positive and Gram-negative bacteria. Investigations of the effects of efflux pumps and membrane penetration on antibacterial activity are reported herein. Antiproliferation activity was observed to be enhanced by complexation with copper. Preliminary screening showed Cu complexes are strongly active against human breast adenocarcinoma cancer cell lines MDA-MB-231 and MCF-7. © 2016 Published by Elsevier Masson SAS. |
Monitoring bicosomes containing antioxidants in normal and irradiated skin Article de journal E Fernández; S Hostachy; C Sandt; G Rodríguez; H C Bertrand; S Clède; M Cócera; A D L Maza; F Lambert; C Policar; O López RSC Advances, 6 (76), p. 72559–72567, 2016. @article{Fernandez:2016, title = {Monitoring bicosomes containing antioxidants in normal and irradiated skin}, author = {E Fern\'{a}ndez and S Hostachy and C Sandt and G Rodr\'{i}guez and H C Bertrand and S Cl\`{e}de and M C\'{o}cera and A D L Maza and F Lambert and C Policar and O L\'{o}pez}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84982684419&doi=10.1039%2fc6ra11170j&partnerID=40&md5=126bef944046a09450ae86ce5985c07f}, doi = {10.1039/c6ra11170j}, year = {2016}, date = {2016-01-01}, journal = {RSC Advances}, volume = {6}, number = {76}, pages = {72559--72567}, abstract = {This study evaluates the penetration of bicosome systems incorporating two different antioxidants into normal skin and skin exposed to ultraviolet-visible radiation (UV-VIS) by Fourier-transform infrared microspectroscopy (FT-IR) using synchrotron radiation. Bicosomes are phospholipid assemblies based on mixtures of discoidal lipid structures protected by spherical lipid vesicles able to incorporate different molecules. In the current work, the antioxidants incorporated in these systems were β-carotene and a Mn complex as a superoxide dismutase (SOD) mimic. Additionally, a rhenium tri-carbonyl derivative was incorporated in the bicosome systems in order to map their penetration following the tag specific carbonyl signal by FT-IR microspectroscopy. The characterization of bicosome systems using the dynamic light scattering technique (DLS) showed a modification in the size of the systems containing β-carotene (Bcβ) or MnII complex (BcMn). After skin permeation, FT-IR results indicated a higher and deeper penetration of the BcMn system than the Bcβ system into the skin. Likely, the different physicochemical properties of both antioxidants could be responsible for this effect. Moreover, the penetration of both bicosome systems in irradiated skin was lower in comparison with the normal skin. This fact could be a consequence of the alteration of water transport in the skin during the irradiation process. In conclusion, these results indicated the effectiveness of bicosome systems as skin carriers, and provide information to protect skin under radiation using antioxidants. © The Royal Society of Chemistry 2016.}, keywords = {}, pubstate = {published}, tppubtype = {article} } This study evaluates the penetration of bicosome systems incorporating two different antioxidants into normal skin and skin exposed to ultraviolet-visible radiation (UV-VIS) by Fourier-transform infrared microspectroscopy (FT-IR) using synchrotron radiation. Bicosomes are phospholipid assemblies based on mixtures of discoidal lipid structures protected by spherical lipid vesicles able to incorporate different molecules. In the current work, the antioxidants incorporated in these systems were β-carotene and a Mn complex as a superoxide dismutase (SOD) mimic. Additionally, a rhenium tri-carbonyl derivative was incorporated in the bicosome systems in order to map their penetration following the tag specific carbonyl signal by FT-IR microspectroscopy. The characterization of bicosome systems using the dynamic light scattering technique (DLS) showed a modification in the size of the systems containing β-carotene (Bcβ) or MnII complex (BcMn). After skin permeation, FT-IR results indicated a higher and deeper penetration of the BcMn system than the Bcβ system into the skin. Likely, the different physicochemical properties of both antioxidants could be responsible for this effect. Moreover, the penetration of both bicosome systems in irradiated skin was lower in comparison with the normal skin. This fact could be a consequence of the alteration of water transport in the skin during the irradiation process. In conclusion, these results indicated the effectiveness of bicosome systems as skin carriers, and provide information to protect skin under radiation using antioxidants. © The Royal Society of Chemistry 2016. |
Human TTR conformation altered by rhenium tris-carbonyl derivatives Article de journal L Ciccone; C Policar; E A Stura; W Shepard Journal of Structural Biology, 195 (3), p. 353–364, 2016. @article{Ciccone:2016, title = {Human TTR conformation altered by rhenium tris-carbonyl derivatives}, author = {L Ciccone and C Policar and E A Stura and W Shepard}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84991363542&doi=10.1016%2fj.jsb.2016.07.002&partnerID=40&md5=86e7e8d956bfdb39ae832e52b01a9dea}, doi = {10.1016/j.jsb.2016.07.002}, year = {2016}, date = {2016-01-01}, journal = {Journal of Structural Biology}, volume = {195}, number = {3}, pages = {353--364}, abstract = {Transthyretin (TTR) is a 54 kDa homotetrameric serum protein that transports thyroxine (T4) and retinol. TTR is potentially amyloidogenic due to homotetramer dissociation into monomeric intermediates that self-assemble as amyloid deposits and insoluble fibrils. Most crystallographic structures, including those of amyloidogenic variants show the same tetramer without major variations in the monomer-monomer interface nor in the volume of the interdimeric cavity. Soaking TTR crystals in a solution containing rhenium tris-carbonyl derivatives yields a TTR conformer never observed before. Only one of the two monomers of the crystallographic dimer is significantly altered, and the inner part of the T4 binding cavity is expanded at one end and shrunk at the other. The result redefines the mechanism of allosteric communication between the two sites, suggesting that negative cooperativity is a function of dimer asymmetry, which can be induced through internal or external binding. An aspect that remains unexplained is why the conformational changes are ubiquitous throughout the crystal although the heavy metal content of the derivatized crystals is relatively low. The conformational changes observed, which include Leu82, may represent a form of TTR better at scavenging β-Amyloid. At a resolution of 1.69 r{A}, with excellent refinement statistics and well defined electron density for all parts of the structure, it is possible to envisage answering important questions that range from protein cooperative behavior to heavy atom induced protein conformational modifications that can result in crystallographic non-isomorphism. © 2016 Elsevier Inc.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Transthyretin (TTR) is a 54 kDa homotetrameric serum protein that transports thyroxine (T4) and retinol. TTR is potentially amyloidogenic due to homotetramer dissociation into monomeric intermediates that self-assemble as amyloid deposits and insoluble fibrils. Most crystallographic structures, including those of amyloidogenic variants show the same tetramer without major variations in the monomer-monomer interface nor in the volume of the interdimeric cavity. Soaking TTR crystals in a solution containing rhenium tris-carbonyl derivatives yields a TTR conformer never observed before. Only one of the two monomers of the crystallographic dimer is significantly altered, and the inner part of the T4 binding cavity is expanded at one end and shrunk at the other. The result redefines the mechanism of allosteric communication between the two sites, suggesting that negative cooperativity is a function of dimer asymmetry, which can be induced through internal or external binding. An aspect that remains unexplained is why the conformational changes are ubiquitous throughout the crystal although the heavy metal content of the derivatized crystals is relatively low. The conformational changes observed, which include Leu82, may represent a form of TTR better at scavenging β-Amyloid. At a resolution of 1.69 Å, with excellent refinement statistics and well defined electron density for all parts of the structure, it is possible to envisage answering important questions that range from protein cooperative behavior to heavy atom induced protein conformational modifications that can result in crystallographic non-isomorphism. © 2016 Elsevier Inc. |
Bioinspired superoxide-dismutase mimics: The effects of functionalization with cationic polyarginine peptides Article de journal H Y V Ching; I Kenkel; N Delsuc; E Mathieu; I Ivanović-Burmazović; C Policar Journal of Inorganic Biochemistry, 160 , p. 172–179, 2016. @article{Ching:2016a, title = {Bioinspired superoxide-dismutase mimics: The effects of functionalization with cationic polyarginine peptides}, author = {H Y V Ching and I Kenkel and N Delsuc and E Mathieu and I Ivanovi\'{c}-Burmazovi\'{c} and C Policar}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84964372716&doi=10.1016%2fj.jinorgbio.2016.01.025&partnerID=40&md5=035d0c2b5ffd4ee0b6fb74df285838da}, doi = {10.1016/j.jinorgbio.2016.01.025}, year = {2016}, date = {2016-01-01}, journal = {Journal of Inorganic Biochemistry}, volume = {160}, pages = {172--179}, abstract = {Continuing a bio-mimetic approach, we have prepared peptide conjugates of a superoxide dismutase (SOD) mimic [MnL]+ (where HL = N-(2-hydroxybenzyl)-N,N'-bis[2-(N-methylimidazolyl)methyl]ethane-1,2-diamine), namely [MnL'-Arg(n-1)]n+ (where n = 2, 4, 7 and 10) and [MnL'-Gly1]+. [MnL'-Arg(n-1)]n+ contained cationic residue(s) that emulate the electrostatic channel of the enzyme. Physicochemical methods showed that functionalization at the secondary amine of HL did not impair coordination to MnII with association constants (Kassoc) between 1.6 and 3.3 × 106 M- 1. The MnIII/MnII redox potential of the conjugates was between 0.27 and 0.30 V vs SCE, slightly higher than [MnL]+ under the same conditions, but remain at a value that facilitates O2•- dismutation. The catalytic rate constant (kcat) of the dismutation for the series was studied using a direct stopped-flow method, which showed that for compounds with the same overall charge, the alkylation of the secondary amine of [MnL]+ (kcat = 5.0 ± 0.1 × 106 M- 1 s- 1) led to a lower value (i.e. for [MnL'Gly]+}, keywords = {}, pubstate = {published}, tppubtype = {article} } Continuing a bio-mimetic approach, we have prepared peptide conjugates of a superoxide dismutase (SOD) mimic [MnL]+ (where HL = N-(2-hydroxybenzyl)-N,N'-bis[2-(N-methylimidazolyl)methyl]ethane-1,2-diamine), namely [MnL'-Arg(n-1)]n+ (where n = 2, 4, 7 and 10) and [MnL'-Gly1]+. [MnL'-Arg(n-1)]n+ contained cationic residue(s) that emulate the electrostatic channel of the enzyme. Physicochemical methods showed that functionalization at the secondary amine of HL did not impair coordination to MnII with association constants (Kassoc) between 1.6 and 3.3 × 106 M- 1. The MnIII/MnII redox potential of the conjugates was between 0.27 and 0.30 V vs SCE, slightly higher than [MnL]+ under the same conditions, but remain at a value that facilitates O2•- dismutation. The catalytic rate constant (kcat) of the dismutation for the series was studied using a direct stopped-flow method, which showed that for compounds with the same overall charge, the alkylation of the secondary amine of [MnL]+ (kcat = 5.0 ± 0.1 × 106 M- 1 s- 1) led to a lower value (i.e. for [MnL'Gly]+ |
Bimodal X-ray and Infrared Imaging of an Organometallic Derivative of Praziquantel in Schistosoma mansoni Article de journal S Clède; N Cowan; F Lambert; H C Bertrand; R Rubbiani; M Patra; J Hess; C Sandt; N Trcera; G Gasser; J Keiser; C Policar ChemBioChem, 17 (11), p. 1004–1007, 2016. @article{Clede:2016, title = {Bimodal X-ray and Infrared Imaging of an Organometallic Derivative of Praziquantel in Schistosoma mansoni}, author = {S Cl\`{e}de and N Cowan and F Lambert and H C Bertrand and R Rubbiani and M Patra and J Hess and C Sandt and N Trcera and G Gasser and J Keiser and C Policar}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84973124415&doi=10.1002%2fcbic.201500688&partnerID=40&md5=608b1bb28a5237e0717a29ee815e73bc}, doi = {10.1002/cbic.201500688}, year = {2016}, date = {2016-01-01}, journal = {ChemBioChem}, volume = {17}, number = {11}, pages = {1004--1007}, abstract = {An organometallic derivative of praziquantel was studied directly in worms by using inductively coupled plasma-mass spectrometry (ICP-MS) for quantification and synchrotron-based imaging. X-ray fluorescence (XRF) and IR absorption spectromicroscopy were used for the first time in combination to directly locate this organometallic drug candidate in schistosomes. The detection of both CO (IR) and Cr (XRF) signatures proved that the Cr(CO)3 core remained intact in the worms. Images showed a preferential accumulation at the worm's tegument, consistent with a possible targeting of the calcium channel but not excluding other biological targets inside the worm. Imaginative imaging: Two synchrotron-based techniques - X-ray fluorescence and IR absorption spectroscopy - were used in combination for the first time to directly locate an organometallic drug candidate in schistosomes. This represents a novel approach to examine mechanisms of actions for organometallic compounds and might lead to the discovery of new drug candidates. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.}, keywords = {}, pubstate = {published}, tppubtype = {article} } An organometallic derivative of praziquantel was studied directly in worms by using inductively coupled plasma-mass spectrometry (ICP-MS) for quantification and synchrotron-based imaging. X-ray fluorescence (XRF) and IR absorption spectromicroscopy were used for the first time in combination to directly locate this organometallic drug candidate in schistosomes. The detection of both CO (IR) and Cr (XRF) signatures proved that the Cr(CO)3 core remained intact in the worms. Images showed a preferential accumulation at the worm's tegument, consistent with a possible targeting of the calcium channel but not excluding other biological targets inside the worm. Imaginative imaging: Two synchrotron-based techniques - X-ray fluorescence and IR absorption spectroscopy - were used in combination for the first time to directly locate an organometallic drug candidate in schistosomes. This represents a novel approach to examine mechanisms of actions for organometallic compounds and might lead to the discovery of new drug candidates. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. |
A Bis-Manganese(II)–DOTA Complex for Pulsed Dipolar Spectroscopy Article de journal P Demay-Drouhard; H Y V Ching; D Akhmetzyanov; R Guillot; L C Tabares; H C Bertrand; C Policar ChemPhysChem, p. 2066–2078, 2016. @article{Demay-Drouhard:2016, title = {A Bis-Manganese(II)\textendashDOTA Complex for Pulsed Dipolar Spectroscopy}, author = {P Demay-Drouhard and H Y V Ching and D Akhmetzyanov and R Guillot and L C Tabares and H C Bertrand and C Policar}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84977597209&doi=10.1002%2fcphc.201600234&partnerID=40&md5=38a2466ad0f00d0edb158d200429986c}, doi = {10.1002/cphc.201600234}, year = {2016}, date = {2016-01-01}, journal = {ChemPhysChem}, pages = {2066--2078}, abstract = {High-spin gadolinium(III) and manganese(II) complexes have emerged as alternatives to standard nitroxide radical spin labels for measuring nanometric distances by using pulsed electron\textendashelectron double resonance (PELDOR or DEER) at high fields/frequencies. For certain complexes, particularly those with relatively small zero-field splitting (ZFS) and short distances between the two metal centers, the pseudosecular term of the dipolar coupling Hamiltonian is non-negligible. However, in general, the contribution from this term during conventional data analysis is masked by the flexibility of the molecule of interest and/or the long tethers connecting them to the spin labels. The efficient synthesis of a model system consisting of two [Mn(dota)]2− (MnDOTA; DOTA4−=1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate) directly connected to the ends of a central rodlike oligo(phenylene\textendashethynylene) (OPE) spacer is reported. The rigidity of the OPE is confirmed by Q-band PELDOR measurements on a bis-nitroxide analogue. The MnII−MnII distance distribution profile determined by W-band PELDOR is in reasonable agreement with one simulated by using a simple rotamer analysis. The small degree of flexibility arising from the linking MnDOTA arm appears to outweigh the contribution from the pseudosecular term at this interspin distance. This study illustrates the potential of MnDOTA-based spin labels for measuring fairly short nanometer distances, and also presents an interesting candidate for in-depth studies of pulsed dipolar spectroscopy methods on MnII−MnII systems. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim}, keywords = {}, pubstate = {published}, tppubtype = {article} } High-spin gadolinium(III) and manganese(II) complexes have emerged as alternatives to standard nitroxide radical spin labels for measuring nanometric distances by using pulsed electron–electron double resonance (PELDOR or DEER) at high fields/frequencies. For certain complexes, particularly those with relatively small zero-field splitting (ZFS) and short distances between the two metal centers, the pseudosecular term of the dipolar coupling Hamiltonian is non-negligible. However, in general, the contribution from this term during conventional data analysis is masked by the flexibility of the molecule of interest and/or the long tethers connecting them to the spin labels. The efficient synthesis of a model system consisting of two [Mn(dota)]2− (MnDOTA; DOTA4−=1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate) directly connected to the ends of a central rodlike oligo(phenylene–ethynylene) (OPE) spacer is reported. The rigidity of the OPE is confirmed by Q-band PELDOR measurements on a bis-nitroxide analogue. The MnII−MnII distance distribution profile determined by W-band PELDOR is in reasonable agreement with one simulated by using a simple rotamer analysis. The small degree of flexibility arising from the linking MnDOTA arm appears to outweigh the contribution from the pseudosecular term at this interspin distance. This study illustrates the potential of MnDOTA-based spin labels for measuring fairly short nanometer distances, and also presents an interesting candidate for in-depth studies of pulsed dipolar spectroscopy methods on MnII−MnII systems. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim |
Indolin-2-one compounds targeting thioredoxin reductase as potential anticancer drug leads Article de journal K K Kaminska; H C Bertrand; H Tajima; W C Stafford; Q Cheng; W Chen; G Wells; E S J Arner; E -H Chew Oncotarget, 7 (26), p. 40233–40251, 2016. @article{Kaminska:2016, title = {Indolin-2-one compounds targeting thioredoxin reductase as potential anticancer drug leads}, author = {K K Kaminska and H C Bertrand and H Tajima and W C Stafford and Q Cheng and W Chen and G Wells and E S J Arner and E -H Chew}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84983002228&doi=10.18632%2foncotarget.9579&partnerID=40&md5=21b5120cc53147d2dce47cf9545ab207}, doi = {10.18632/oncotarget.9579}, year = {2016}, date = {2016-01-01}, journal = {Oncotarget}, volume = {7}, number = {26}, pages = {40233--40251}, abstract = {Several compounds bearing the indolinone chemical scaffold are known to possess anticancer properties. For example, the tyrosine kinase inhibitor sunitinib is an arylideneindolin-2-one compound. The chemical versatility associated with structural modifications of indolinone compounds underlies the potential to discover additional derivatives possessing anticancer properties. Previously synthesized 3-(2-oxoethylidene)indolin-2-one compounds, also known as supercinnamaldehyde (SCA) compounds in reference to the parent compound 1 [1-methyl-3(2- oxopropylidene)indolin-2-one], bear a nitrogen-linked α,β-unsaturated carbonyl (Michael acceptor) moiety. Here we found that analogs bearing N-substituents, in particular compound 4 and 5 carrying an N-butyl and N-benzyl substituent, respectively, were strongly cytotoxic towards human HCT 116 colorectal and MCF-7 breast carcinoma cells. These compounds also displayed strong thioredoxin reductase (TrxR) inhibitory activity that was likely attributed to the electrophilicity of the Michael acceptor moiety. Their selectivity towards cellular TrxR inhibition over related antioxidant enzymes glutathione reductase (GR), thioredoxin (Trx) and glutathione peroxidase (GPx) was mediated through targeting of the selenocysteine (Sec) residue in the highly accessible C-terminal active site of TrxR. TrxR inhibition mediated by indolin-2-one compounds led to cellular Trx oxidation, increased oxidative stress and activation of apoptosis signal-regulating kinase 1 (ASK1). These events also led to activation of p38 and JNK mitogen-activated protein kinase (MAPK) signaling pathways, and cell death with apoptotic features of PARP cleavage and caspase 3 activation. In conclusion, these results suggest that indolin-2-one-based compounds specifically targeting TrxR may serve as novel drug leads for anticancer therapy.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Several compounds bearing the indolinone chemical scaffold are known to possess anticancer properties. For example, the tyrosine kinase inhibitor sunitinib is an arylideneindolin-2-one compound. The chemical versatility associated with structural modifications of indolinone compounds underlies the potential to discover additional derivatives possessing anticancer properties. Previously synthesized 3-(2-oxoethylidene)indolin-2-one compounds, also known as supercinnamaldehyde (SCA) compounds in reference to the parent compound 1 [1-methyl-3(2- oxopropylidene)indolin-2-one], bear a nitrogen-linked α,β-unsaturated carbonyl (Michael acceptor) moiety. Here we found that analogs bearing N-substituents, in particular compound 4 and 5 carrying an N-butyl and N-benzyl substituent, respectively, were strongly cytotoxic towards human HCT 116 colorectal and MCF-7 breast carcinoma cells. These compounds also displayed strong thioredoxin reductase (TrxR) inhibitory activity that was likely attributed to the electrophilicity of the Michael acceptor moiety. Their selectivity towards cellular TrxR inhibition over related antioxidant enzymes glutathione reductase (GR), thioredoxin (Trx) and glutathione peroxidase (GPx) was mediated through targeting of the selenocysteine (Sec) residue in the highly accessible C-terminal active site of TrxR. TrxR inhibition mediated by indolin-2-one compounds led to cellular Trx oxidation, increased oxidative stress and activation of apoptosis signal-regulating kinase 1 (ASK1). These events also led to activation of p38 and JNK mitogen-activated protein kinase (MAPK) signaling pathways, and cell death with apoptotic features of PARP cleavage and caspase 3 activation. In conclusion, these results suggest that indolin-2-one-based compounds specifically targeting TrxR may serve as novel drug leads for anticancer therapy. |
Hexagonal-shaped chondroitin sulfate self-assemblies have exalted anti-HSV-2 activity Article de journal A Galus; J -M Mallet; D Lembo; V Cagno; M Djabourov; H Lortat-Jacob; K Bouchemal Carbohydrate Polymers, 136 , p. 113–120, 2016. @article{Galus:2016, title = {Hexagonal-shaped chondroitin sulfate self-assemblies have exalted anti-HSV-2 activity}, author = {A Galus and J -M Mallet and D Lembo and V Cagno and M Djabourov and H Lortat-Jacob and K Bouchemal}, url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-84941910307&doi=10.1016%2fj.carbpol.2015.08.054&partnerID=40&md5=cea3ce4315cf160b6b8b3c19d4ab3c9a}, doi = {10.1016/j.carbpol.2015.08.054}, year = {2016}, date = {2016-01-01}, journal = {Carbohydrate Polymers}, volume = {136}, pages = {113--120}, abstract = {The initial step in mucosal infection by the herpes simplex virus type 2 (HSV-2) requires its binding to certain glycosaminoglycans naturally present on host cell membranes. We took advantage of this interaction to design biomimetic supramolecular hexagonal-shaped nanoassemblies composed of chondroitin sulfate having exalted anti-HSV-2 activity in comparison with native chondroitin sulfate. Nanoassemblies were formed by mixing hydrophobically-modified chondroitin sulfate with α-cyclodextrin in water. Optimization of alkyl chain length grafted on chondroitin sulfate and the ratio between hydrophobically-modified chondroitin sulfate and α-cyclodextrin showed that more cohesive and well-structured nanoassemblies were obtained using higher α-cyclodextrin concentration and longer alkyl chain lengths. A structure-activity relationship was found between anti-HSV-2 activity and the amphiphilic nature of hydrophobically-modified chondroitin sulfate. Also, antiviral activity of hexagonal nanoassemblies against HSV-2 was further improved in comparison with hydrophobically-modified chondroitin sulfate. This work suggests a new biomimetic formulation approach that can be extended to other heparan-sulfate-dependent viruses. © 2015 Elsevier Ltd. All rights reserved.}, keywords = {}, pubstate = {published}, tppubtype = {article} } The initial step in mucosal infection by the herpes simplex virus type 2 (HSV-2) requires its binding to certain glycosaminoglycans naturally present on host cell membranes. We took advantage of this interaction to design biomimetic supramolecular hexagonal-shaped nanoassemblies composed of chondroitin sulfate having exalted anti-HSV-2 activity in comparison with native chondroitin sulfate. Nanoassemblies were formed by mixing hydrophobically-modified chondroitin sulfate with α-cyclodextrin in water. Optimization of alkyl chain length grafted on chondroitin sulfate and the ratio between hydrophobically-modified chondroitin sulfate and α-cyclodextrin showed that more cohesive and well-structured nanoassemblies were obtained using higher α-cyclodextrin concentration and longer alkyl chain lengths. A structure-activity relationship was found between anti-HSV-2 activity and the amphiphilic nature of hydrophobically-modified chondroitin sulfate. Also, antiviral activity of hexagonal nanoassemblies against HSV-2 was further improved in comparison with hydrophobically-modified chondroitin sulfate. This work suggests a new biomimetic formulation approach that can be extended to other heparan-sulfate-dependent viruses. © 2015 Elsevier Ltd. All rights reserved. |
2015 |
Development of Bright Fluorescent Quadracyclic Adenine Analogues: TDDFT-Calculation Supported Rational Design Article de journal Anders Foller Larsen; Blaise Dumat; Moa S Wranne; Christopher P Lawson; Søren Preus; Mattias Bood; Henrik Gradén; L Marcus Wilhelmsson; Morten Grøtli Scientific Reports, 5 , p. 12653-12653, 2015. @article{FollerLarsen:2015, title = {Development of Bright Fluorescent Quadracyclic Adenine Analogues: TDDFT-Calculation Supported Rational Design}, author = {Anders Foller Larsen and Blaise Dumat and Moa S Wranne and Christopher P Lawson and S\oren Preus and Mattias Bood and Henrik Grad\'{e}n and L Marcus Wilhelmsson and Morten Gr\otli}, doi = {10.1038/srep12653}, year = {2015}, date = {2015-07-01}, journal = {Scientific Reports}, volume = {5}, pages = {12653-12653}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
Feliciana Real Fernández; Margherita Di Pisa; Giada Rossi; Nicolas Auberger; Olivier Lequin; Maud Larregola; Amina Benchohra; Christelle Mansuy; Gerard Chassaing; Francesco Lolli; Joussef Hayek; Solange Lavielle; Paolo Rovero; Jean-Maurice Mallet; Anna Maria Papini Biopolymers, 104 (5), p. 560-576, 2015. @article{RealFernandez:2015, title = {Antibody Recognition in Multiple Sclerosis and Rett Syndrome Using a Collection of Linear and Cyclic N -Glucosylated Antigenic Probes: Antibody Recognition in Multiple Sclerosis and Rett Syndrome}, author = {Feliciana Real Fern\'{a}ndez and Margherita Di Pisa and Giada Rossi and Nicolas Auberger and Olivier Lequin and Maud Larregola and Amina Benchohra and Christelle Mansuy and Gerard Chassaing and Francesco Lolli and Joussef Hayek and Solange Lavielle and Paolo Rovero and Jean-Maurice Mallet and Anna Maria Papini}, doi = {10.1002/bip.22677}, year = {2015}, date = {2015-04-01}, journal = {Biopolymers}, volume = {104}, number = {5}, pages = {560-576}, keywords = {}, pubstate = {published}, tppubtype = {article} } |
Second-Generation Fluorescent Quadracyclic Adenine Analogues: Environment-Responsive Probes with Enhanced Brightness Article de journal Blaise Dumat; Mattias Bood; Moa S Wranne; Christopher P Lawson; Anders Foller Larsen; Søren Preus; Jens Streling; Henrik Gradén; Eric Wellner; Morten Grøtli; Marcus L Wilhelmsson Chemistry - A European Journal, 21 (10), p. 4039-4048, 2015. @article{Dumat:2015, title = {Second-Generation Fluorescent Quadracyclic Adenine Analogues: Environment-Responsive Probes with Enhanced Brightness}, author = {Blaise Dumat and Mattias Bood and Moa S Wranne and Christopher P Lawson and Anders Foller Larsen and S\oren Preus and Jens Streling and Henrik Grad\'{e}n and Eric Wellner and Morten Gr\otli and Marcus L Wilhelmsson}, doi = {10.1002/chem.201405759}, year = {2015}, date = {2015-03-01}, journal = {Chemistry - A European Journal}, volume = {21}, number = {10}, pages = {4039-4048}, abstract = {Fluorescent base analogues comprise a group of increasingly important molecules for the investigation of nucleic acid structure, dynamics, and interactions with other molecules. Herein, we report on the quantum chemical calculation aided design, synthesis, and characterization of four new putative quadracyclic adenine analogues. The compounds were efficiently synthesized from a common intermediate through a two-step pathway with the Suzuki-Miyaura coupling as the key step. Two of the compounds, qAN1 and qAN4, display brightnesses ($epsilonPhi$F ) of 1700 and 2300, respectively, in water and behave as wavelength-ratiometric pH probes under acidic conditions. The other two, qAN2 and qAN3, display lower brightnesses but exhibit polarity-sensitive dual-band emissions that could prove useful to investigate DNA structural changes induced by DNA-protein or -drug interactions. The four qANs are very promising microenvironment-sensitive fluorescent adenine analogues that display considerable brightness for such compounds.}, keywords = {}, pubstate = {published}, tppubtype = {article} } Fluorescent base analogues comprise a group of increasingly important molecules for the investigation of nucleic acid structure, dynamics, and interactions with other molecules. Herein, we report on the quantum chemical calculation aided design, synthesis, and characterization of four new putative quadracyclic adenine analogues. The compounds were efficiently synthesized from a common intermediate through a two-step pathway with the Suzuki-Miyaura coupling as the key step. Two of the compounds, qAN1 and qAN4, display brightnesses ($epsilonPhi$F ) of 1700 and 2300, respectively, in water and behave as wavelength-ratiometric pH probes under acidic conditions. The other two, qAN2 and qAN3, display lower brightnesses but exhibit polarity-sensitive dual-band emissions that could prove useful to investigate DNA structural changes induced by DNA-protein or -drug interactions. The four qANs are very promising microenvironment-sensitive fluorescent adenine analogues that display considerable brightness for such compounds. |