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5. ¿Click¿ Synthesis and Pharmacological Evaluation of sp2-Iminosugars S- and C-Glycosides

Author

García-Moreno, M. I., Sánchez-Fernández, E. M., Padrón, J. M., García-Hernández, R., Gamarro, Francisco, García Fernández, J. M., and Ortiz Mellet, C.

Abstract

sp2-Iminosugars are carbohydrate mimics with unique properties in terms of chemical and structural versatility. The presence of a pseudoamide nitrogen at the position of the ring oxygen in monosaccharides enables glycosidation reactions and strongly favors the ¿-orientation of glycosidic substituents by the convergence of the anomeric and steric effects. In the last years, several approaches have been explored to access sp2-iminosugar O-, N-, S-, and C-glycosides as mimetics of bioactive glycoconjugates. Thus, sp2-iminoglycolipid (sp2-IGLs) analogs of immunoregulatory glycolipids were synthesized and found to exhibit a variety of pharmacological activities against cancer,1 parasitic diseases2 and inflammatory disorders.3 In this context, we now present a molecular diversity-oriented strategy to access a-S or ¿-C sp2-IGLs in high yield and with total stereocontrol that exploit several ¿click¿ methodologies. A series of derivatives have been prepared in this manner and their glycosidase inhibitory, antiproliferative and antileishmanial activities were screened in parallel in the frame of structureactivity relationship studies.

Published
2020

6. sp2-Iminosugar glycolipid mimetics as immunoregulatory agents

Author

Sánchez-Fernández, E. M., García-Moreno, M. I., Arroba, A. I., Aguilar-Diosdado, Manuel, Padrón, J. M., García-Hernández, Raquel, Gamarro, Francisco, García Fernández, J. M., Sánchez-Aparicio, J.-E, Masgrau, L., and Ortiz Mellet, C.

Abstract

Monosaccharide analogs of the sp2-minosugar family offer unprecedented opportunities to access enzymatically and chemically stable glycoconjugate mimetics amenable to drug discovery programs. In this context, the 1-dodecylsulfonyl-5N,6O-oxomethylidenenojirimycin (DSO2-ONJ) (Figure 1), a sp2-iminoglycolipid (IGL) representative, has shown outstandinganti-inflammatory activity in microglia, reducing gliosis in diabetic db/db mice.1DSO2-ONJ further inhibited the activation of human monocyte-derived dendritic cells (DCs) by lipopolysaccharide (LPS) in vitro and in vivo in amouse model of acute inflammation.2Biochemical studies and computational docking experiments endorsed a mechanism of action that implies attachment to the allosteric lipid binding pocket of p38-mitogen-activated protein kinase (MAPK), a key protein in the regulation of the innate immuneresponse. This binding mode has also been demonstrated with sp2-IGLs incorporating at the pseudoanomeric position different polyfluoroalkyl segments of varied lengths that facilitate passage through cell membranes. This modification resulted in a 10-fold higher effectiveness at eliciting p38 (Figure 1).3 In this communication we will present the synthesis of differentfluorinated sp2-IGLs and their biological evaluation in the context of three pathologiesthat share common signaling pathways: cancer, Leishmania infection and inflammation.

Published
2020

9. scFv-1SM3 in complex with glycopeptide containing an sp2-imino sugar

Author

Bermejo, I.A., primary, Navo, C.D., additional, Castro-Lopez, J., additional, Samchez-Fernandez, E.M., additional, Guerreiro, A., additional, Avenoza, A., additional, Busto, J.H., additional, Garcia-Martin, F., additional, Nishimura, S.I., additional, Garcia-Fernandez, J.M., additional, Ortiz-Mellet, C., additional, Bernardes, G.J.L., additional, Hurtado-Guerrero, R., additional, Peregrina, J.M., additional, and Corzana, F., additional

Published
2020
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10. Trehalose-based siamese twin amphiphiles with tunable self-assembling, DNA nanocomplexing and gene delivery properties

Author

Carbajo-Gordillo, A.I. (Ana I.), Rodríguez-Lavado, J. (Julio), Jiménez-Blanco, J.L. (José Luis), Benito, J.M. (Juan M.), Di-Giorgio, C. (Christophe), Vélaz-Rivas, I. (Icíar), Tros-de-Ilarduya, C. (Conchita), Ortiz-Mellet, C. (Carmen), and García-Fernández, J.M. (José M.)

Subjects
Química [Materias Investigacion], Farmacia [Materias Investigacion]
Abstract

An original family of multivalent vectors encompassing gemini and facial amphiphilicity, namely cationic Siamese twin surfactants, has been prepared fromthe disaccharide trehalose; molecular engineering lets us modulate the self-assembling properties and the topology of the nanocomplexes with plasmid DNA for efficient gene delivery in vitro and in vivo.

Published
2019

11. Biophysics and protein corona analysis of Janus cyclodextrin-DNA nanocomplexes. Efficient cellular transfection on cancer cells

Author

Martínez-Negro, M., primary, Caracciolo, G., additional, Palchetti, S., additional, Pozzi, D., additional, Capriotti, A.L., additional, Cavaliere, C., additional, Laganà, A., additional, Ortiz Mellet, C., additional, Benito, J.M., additional, García Fernández, J.M., additional, Aicart, E., additional, and Junquera, E., additional

Published
2017
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13. Trehalose-based Janus cyclooligosaccharides: the “Click” synthesis and DNA-directed assembly into pH-sensitive transfectious nanoparticles

Author

Jiménez Blanco, J. L., primary, Ortega-Caballero, F., additional, Blanco-Fernández, L., additional, Carmona, T., additional, Marcelo, G., additional, Martínez-Negro, M., additional, Aicart, E., additional, Junquera, E., additional, Mendicuti, F., additional, Tros de Ilarduya, C., additional, Ortiz Mellet, C., additional, and García Fernández, J. M., additional

Published
2016
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14. Conformationally-locked N -glycosides: Exploiting long-range non-glycone interactions in the design of pharmacological chaperones for Gaucher disease

Author

Química Analítica i Química Orgànica, Universitat Rovira i Virgili, Castillón S, García Fernández JM, Ortiz Mellet C, Díaz Y, Suzuki Y, Ohno K, Nanba E, Higaki K, Rísquez R, Castilla J, Química Analítica i Química Orgànica, Universitat Rovira i Virgili, Castillón S, García Fernández JM, Ortiz Mellet C, Díaz Y, Suzuki Y, Ohno K, Nanba E, Higaki K, Rísquez R, and Castilla J

Abstract

© 2014 Elsevier Masson SAS. Pyranoid-type glycomimetics having a cis-1,2-fused glucopyranose-2-alkylsulfanyl-1,3-oxazoline (Glc-PSO) structure exhibit an unprecedented specificity as inhibitors of mammalian β-glucosidase. Notably, their inhibitory potency against human β-glucocerebrosidase (GCase) was found to be strongly dependent on the nature of aglycone-type moieties attached at the sulfur atom. In the particular case of υ-substituted hexadecyl chains, an amazing influence of the terminal group was observed. A comparative study on a series of Glc-PSO derivatives suggests that hydrogen bond acceptor functionalities, e.g. fluoro or methyloxycarbonyl, significantly stabilize the Glc-PSO:GCase complex. The S-(16-fluorohexadecyl)-PSO glycomimetic turned out to be a more potent GCase competitive inhibitor than ambroxol, a non glycomimetic drug currently in pilot trials as a pharmacological chaperone for Gaucher disease. Moreover, the inhibition constant increased by one order of magnitude when shifting from neutral (pH 7) to acidic (pH 5) media, a favorable characteristic for a chaperone candidate. Indeed, the fluoro-PSO derivative also proved superior to ambroxol in mutant GCase activity enhancement assays in N370S/N370S Gaucher fibroblasts. The results presented here represent a proof of concept of the potential of exploiting long-range non-glycone interactions for the optimization of glycosidase inhibitors with chaperone activity.

Published
2015

15. Conformationally-locked N -glycosides: Exploiting long-range non-glycone interactions in the design of pharmacological chaperones for Gaucher disease

Author

Enginyeria Química, Universitat Rovira i Virgili., Castillón, S., García Fernández, J.M., Ortiz Mellet, C., Díaz, Y., Suzuki, Y., Ohno, K., Nanba, E., Higaki, K., Rísquez, R., Castilla, J., Enginyeria Química, Universitat Rovira i Virgili., Castillón, S., García Fernández, J.M., Ortiz Mellet, C., Díaz, Y., Suzuki, Y., Ohno, K., Nanba, E., Higaki, K., Rísquez, R., and Castilla, J.

Abstract

10.1016/j.ejmech.2014.11.002, Pyranoid-type glycomimetics having a cis-1,2-fused glucopyranose-2-alkylsulfanyl-1,3-oxazoline (Glc-PSO) structure exhibit an unprecedented specificity as inhibitors of mammalian ß-glucosidase. Notably, their inhibitory potency against human ß-glucocerebrosidase (GCase) was found to be strongly dependent on the nature of aglycone-type moieties attached at the sulfur atom. In the particular case of ?-substituted hexadecyl chains, an amazing influence of the terminal group was observed. A comparative study on a series of Glc-PSO derivatives suggests that hydrogen bond acceptor functionalities, e.g. fluoro or methyloxycarbonyl, significantly stabilize the Glc-PSO:GCase complex. The S-(16-fluorohexadecyl)-PSO glycomimetic turned out to be a more potent GCase competitive inhibitor than ambroxol, a non glycomimetic drug currently in pilot trials as a pharmacological chaperone for Gaucher disease. Moreover, the inhibition constant increased by one order of magnitude when shifting from neutral (pH 7) to acidic (pH 5) media, a favorable characteristic for a chaperone candidate. Indeed, the fluoro-PSO derivative also proved superior to ambroxol in mutant GCase activity enhancement assays in N370S/N370S Gaucher fibroblasts. The results presented here represent a proof of concept of the potential of exploiting long-range non-glycone interactions for the optimization of glycosidase inhibitors with chaperone activity.

Published
2015

16. Probing the nature of the cluster effect observed with synthetic multivalent galactosides and PNA lectin

Author

Almant, M., Mastouri, A., Gallergo-Yerga, L., Garcia-Fernandez, J. M., Ortiz Mellet, C., Kovensky, J., Morandat, S., Karim EL KIRAT, Gouin, S. G., David, Chantal, Laboratoire des Glucides (LG), Université de Picardie Jules Verne (UPJV)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Génie Enzymatique et Cellulaire (GEC), Université de Technologie de Compiègne (UTC)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS), Biomécanique et Bioingénierie (BMBI), and Université de Technologie de Compiègne (UTC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
biological sciences
Abstract

International audience; We designed a set of multi-galactosides with valencies ranging from one to seven and different spacer-arm lengths. The compounds display a high structural homology for a strict assessment of multivalent phenomena. The multimers were first evaluated by an enzyme-linked lectin assay (ELLA) toward the peanut agglutinin (PNA). The binding affinity was shown to be dependent on the spacer-arm length, and cluster effects were observed for the galactosides bearing the shortest and the longest linkers. The latter compounds were shown to be much more potent PNA cross-linkers in a "sandwich assay". Dynamic light scattering (DLS) experiments also revealed the formation of soluble aggregates between heptavalent derivatives with medium or long linkers and the labeled PNA. ELLA experiments performed with valency-controlled clusters and labeled lectins are therefore not always devoid from aggregative processes. The precise nature of the multivalent interaction observed by ELLA for the compounds bearing the shortest linkers, which are unable to form PNA aggregates, was further investigated by atomic force microscopy (AFM). The galactosides were grafted onto the tip of a cantilever and the PNA lectin onto a gold surface. Similar unbinding forces were registered when the valency of the ligands was increased, thus showing that the multimers cannot interact more strongly with PNA. Multiple binding events to the PNA were also never observed, thus confirming that a chelate binding mode does not operate with the multivalent galactosides, probably because the linkers are too short. Altogether, these results suggest that the cluster effect that operates in ELLA with the multimers is not related to additional PNA stabilizations and can be ascribed to local concentration effects that favor a dynamic turnover of the tethered galactosides in the PNA binding sites.

Published
2013

19. Trehalose- and glucose-derived glycoamphiphiles: Small-molecule and nanoparticle toll-like receptor 4 (TLR4) modulators

Author

Rodriguez Lavado, J, Sestito, S, Cighetti, R, Aguilar Moncayo, E, Oblak, A, Lainšček, D, Jiménez Blanco, J, García Fernández, J, Ortiz Mellet, C, Jerala, R, Calabrese, V, Peri, F, SESTITO, STEFANIA ENZA, CIGHETTI, ROBERTO, CALABRESE, VALENTINA, PERI, FRANCESCO, Rodriguez Lavado, J, Sestito, S, Cighetti, R, Aguilar Moncayo, E, Oblak, A, Lainšček, D, Jiménez Blanco, J, García Fernández, J, Ortiz Mellet, C, Jerala, R, Calabrese, V, Peri, F, SESTITO, STEFANIA ENZA, CIGHETTI, ROBERTO, CALABRESE, VALENTINA, and PERI, FRANCESCO

Abstract

An increasing number of pathologies have been linked to Toll-like receptor 4 (TLR4) activation and signaling, therefore new hit and lead compounds targeting this receptor activation process are urgently needed. We report on the synthesis and biological properties of glycolipids based on glucose and trehalose scaffolds which potently inhibit TLR4 activation and signaling in vitro and in vivo. Structure-activity relationship studies on these compounds indicate that the presence of fatty ester chains in the molecule is a primary prerequisite for biological activity and point to facial amphiphilicity as a preferred architecture for TLR4 antagonism. The cationic glycolipids here presented can be considered as new lead compounds for the development of drugs targeting TLR4 activation and signaling in infectious, inflammatory, and autoimmune diseases. Interestingly, the biological activity of the best drug candidate was retained after adsorption at the surface of colloidal gold nanoparticles, broadening the options for clinical development

Published
2014

20. Regioselective synthesis and biological evaluation of spirosulfamidates gycosides from exoglycals

Author

Benltifa, M., Kiss, M. De, Garcia-Moreno, M.I., Ortiz-Mellet, C., Gueyrard, D., Waddouachi, A., Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (ICBMS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-École Supérieure Chimie Physique Électronique de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and Depierre, Frédérique

Subjects
[CHIM.ORGA]Chemical Sciences/Organic chemistry, [CHIM.ORGA] Chemical Sciences/Organic chemistry, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2009

23. Preparation of nanosphere amphiphilic cyclodextrin derivatives as biological transporters

Author

Defaye, J., Balbuena, P., Benito, J.-M., Diaz-Moscoso, A., Di Giorgio, C., Garcia Fernandez, J.-M., Ortiz-Mellet, C., Vierling, P., Wouessidjewe, D., Département de pharmacochimie moléculaire (DPM), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Departamento de Química Orgánica, Facultad de Química, Instituto de Investigaciones Químicas, Laboratoire de Chimie des Molécules Bioactives et des Arômes (LCMBA), Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Institut de Chimie du CNRS (INC)

Subjects
[SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences
Published
2008

24. Glycochimie et thérapeutique: Les cyclodextrines en Pharmacie, perpectives pour le ciblage d'actifs thérapeutiques et le contrôle d'interactions membranaires

Author

Defaye, J., Garcia Fernandez, J.-M., Ortiz Mellet, C., Département de pharmacochimie moléculaire (DPM), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Instituto de Investigaciones Químicas, and Departamento de Química Orgánica, Facultad de Química

Subjects
[SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2007

26. Carbohydrate-derived spiroketals. Stereoselective synthesis of di-D-fructose dianhydrides by boron trifluoride promoted glycosylation-spiroketalization of acetal precursors

Author

Ortiz Mellet C, García Fernández Jm, Jacques Defaye, Marta Gómez-García, and Juan M. Benito

Subjects
Anomer, Glycosylation, Stereochemistry, Molecular Conformation, Fructose, 010402 general chemistry, Cleavage (embryo), Disaccharides, 01 natural sciences, Biochemistry, chemistry.chemical_compound, Structure-Activity Relationship, Organic chemistry, Spiro Compounds, Physical and Theoretical Chemistry, Boranes, Boron trifluoride, 010405 organic chemistry, Chemistry, Organic Chemistry, D fructose, Acetal, Stereoisomerism, Carbohydrate, 0104 chemical sciences, Stereoselectivity
Abstract

[reaction: see text] Di-D-fructose 1,2':2,1'-dianhydrides, dispiro-tricyclic disaccharides widely found in food materials, have been stereoselectively prepared in one-pot reaction from O-protected D-fructose 1,2-acetonide precursors by treatment with boron trifluoride diethyl etherate. The dimerization sequence involves (i) cleavage of the anomeric acetal linkage, (ii) autoglycosylation, and (iii) final spiroketalization, the stereochemical outcome being strongly dependent on the nature of the hydroxyl protecting groups.

Published
2001

27. Carbohydrate-derived spiroketals. Stereoselective synthesis of di-D-fructose dianhydrides by boron trifluoride promoted glycosylation-spiroketalization of acetal precursors

Author

Defaye, J., Benito, J.-M., Gomez-Garcia, M., Ortiz-Mellet, C., Garcia Fernandez, J.-M., Département de pharmacochimie moléculaire (DPM), and Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)

Subjects
[CHIM.OTHE]Chemical Sciences/Other
Published
2001

28. Cyclodextrin neoglycoconjugates (Revue)

Author

Defaye, J., Garcia-Fernandez, J.-M., Ortiz-Mellet, C., Département de pharmacochimie moléculaire (DPM), and Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)

Subjects
[CHIM.OTHE]Chemical Sciences/Other
Published
2001

29. Neuronopathic Gaucher's disease: induced pluripotent stem cells for disease modelling and testing chaperone activity of small compounds

Author

Tiscornia, G., primary, Lorenzo Vivas, E., additional, Matalonga, L., additional, Berniakovich, I., additional, Barragan Monasterio, M., additional, Eguizabal, C., additional, Gort, L., additional, Gonzalez, F., additional, Ortiz Mellet, C., additional, Garcia Fernandez, J. M., additional, Ribes, A., additional, Veiga, A., additional, and Izpisua Belmonte, J. C., additional

Published
2013
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33. Tuning glycosidase inhibition through aglycone interactions: pharmacological chaperones for Fabry disease and GM1 gangliosidosis

Author

Aguilar-Moncayo, M., primary, Takai, T., additional, Higaki, K., additional, Mena-Barragán, T., additional, Hirano, Y., additional, Yura, K., additional, Li, L., additional, Yu, Y., additional, Ninomiya, H., additional, García-Moreno, M. I., additional, Ishii, S., additional, Sakakibara, Y., additional, Ohno, K., additional, Nanba, E., additional, Ortiz Mellet, C., additional, García Fernández, J. M., additional, and Suzuki, Y., additional

Published
2012
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