Synthesis and biomedical applications of supramolecular hydrogels derived from carbohydrates

Motivation: The low cytotoxicity, physical-chemical properties, structure made by nanofibers scaffolding and their ability to constitute drug nanocontainers, makes supramolecular hydrogels essential biomaterials to regenerative medicine, tissue engineering and new drugs development. Those structures thanks to the ability to emulate the conditions carried out in vivo and to constitute drugs diffusion models allow migration, growth and cell differentiation. [1],[2]By It, our research was directed to synthesis of light-curing neoglycolipids derivatives of azobenzene with capacity to form hydrogels or micelles. The E/Z isomerism of the double link N=N of the Azobenzene glycosides allows the united carbohydrates distribution to change, which will determine the effect of isomerism change in the capacity to form hydrogels or micelles by these structures.[3]Methods and Results: During this project a Azobenzene derived glycolipid was synthesized through different synthetic routes given the high degradability of the compounds and low yield reactions. The monomers structure used, as well as the glycolipid formed, has been determined by 1 H NMR and high resolution mass spectroscopy.Conclusions: To date we are trying to improve the synthesis methods and adjust the reaction condition to get better performance and stability of the compounds

Design and synthesis of supramolecular hydrogels for biomedical applications

Motivation: Only a few cells in the human organism keep their ability to regenerate. Hence, modern medical research intends to develop new ways to cultivate these cells with high regenerative capacity with the aim to reconstruct damaged organs and tissues. This is a challenging process currently carried out in 2D cultures, which do not reflect the in vivo conditions for cell growth and differentiation. Thus, recent studies are trying to get 3D cultures in order to reproduce the conditions that take place during development [1]. Moreover, 3D culture is applied for investigating cellular physiology, stem cell differentiation, and tumor models for studying interaction mechanisms between the extracellular matrix and cells [2]. This project aims to design and synthesize different biocompatible supramolecular hydrogels which emulate the extracellular matrix, and their use as scaffold for 3D cell growth. Moreover, the prepared supramolecular hydrogels could act as nanocontainers for the encapsulation of biomolecules and drugs, promoting growth, adhesion and cell differentiation. Methods and results: Within this project, four diacetylenic based glycolipids [3] have been designed and synthesized as responsive and self-organizing monomers by different synthetic routes. Self-association studies show that two of the four monomers generated 1D-tubular microstructures that hierarchically aggregate in water affording novel hydrogels, that expose a dense layer of carbohydrates to the water phase much like the glycocalyx at the cell membrane. The structure of the monomers has been determined by 1H NMR, 13C NMR, and high resolution mass spectroscopy, while aggregation and self- assembly of the formed nanomaterials have been investigated by transmission electron microscopy (TEM), scanning electron microscopy (SEM), and atomic force microscopy (AFM). Conclusions: From the work carried out in this project, the following conclusions can be drawn: Firstly, the synthetic design of the amphiphiles, based on the use of copper catalyzed azide alkyne cycloaddition [3] in order to enhance the stacking between the monomer in the supramolecular state in order to induce the gelation has been validated. And secondly, photo- polymerization of obtained nanomaterials leads to the formation of conjugated poly(diacetylene) backbones of alternating enyne groups which rigidify the glyconanomaterials, thus enhancing their physical stability, a critical issue for their future medical uses

New sulfur-phosphine ligands derived from sugars: synthesis and application in palladium-catalyzed allylic alkylation and in rhodium asymmetric hydrogenation

An efficient route to mixed phosphine / thioglycoside ligands type IV starting from glucose pentaacetate is reported. In only five steps the key epoxide 6 has been obtained in high yield and its structure determined by X-ray analysis. The ring opening of the tert-butyl 4,6-O-benzylidene- 2,3-anhydro-1-thio-β-D-allopyranoside 6 with diphenylphosphinyl lithium afforded the desired ligand as a single diastereoisomer. The prepared compounds act as a bidentate ligands as shown by X-ray analysis of the Rh(I)-complex 12. Preliminary results on the behaviour of these ligands in Pd(0)-catalyzed allylic alkylation, and in Rh(I)-catalyzed enamide hydrogenation are also reported.Dirección General de Investigaciones Científicas y Técnicas CTQ2006- 15515-CO2-01 y CTQ2007-61185Junta de Andalucía P06-FQM-01852 y P07- FQM-2774Fundación Ramón Arece

New sulfur-phosphine ligands derived from sugars: synthesis and application in palladium-catalyzed allylic alkilation and in rhodium asymmetric hydrogenation

14 páginas, 4 figuras, 5 esquemas, 2 tablas.An efficient route to mixed phosphine / thioglycoside ligands type IV starting from glucose pentaacetate is reported. In only five steps the key epoxide 6 has been obtained in high yield and its structure determined by X-ray analysis. The ring opening of the tert-butyl 4,6-O-benzylidene-2,3-anhydro-1-thio-β-D-allopyranoside 6 with diphenylphosphinyl lithium afforded the desired ligand as a single diastereoisomer. The prepared compounds act as a bidentate ligands as shown by X-ray analysis of the Rh(I)-complex 12. Preliminary results on the behaviour of these ligands in Pd(0)-catalyzed allylic alkylation, and in Rh(I)-catalyzed enamide hydrogenation are also reported.We thank the Dirección General de Investigación Científica y Técnica (grant No. CTQ2006-15515-CO2-01 and CTQ2007-61185), the Junta de Andalucía (grant P06-FQM-01852 and P07-FQM-2774), la Fundación Ramón Areces for financial support, and Mr M. Rudkowski for performing preliminary experimental work.Peer reviewe

Proline-coated gold nanoparticles as a highly efficient nanocatalyst for the enantioselective direct aldol reaction in water

Reported is an efficient approach to the synthesis of water-soluble proline-coated gold nanoparticles through a place exchange reaction between pentanethiolate stabilized gold nanoparticles and a proline-tethered amphiphilic thiol. Preliminary studies show that the nanocatalyst is highly active in an enamine type aldolisation leading to the desired product with nearly perfect diastereoselectivity and enantioselectivity using water as an innocuous solventMinisterio de Economía y Competitividad CTQ2010-21755-CO2-00Junta de Andalucía P07-FQM-277

NMR study on the stabilization and chiral discrimination of sulforaphane enantiomers and analogues by cyclodextrins

Sulforaphane (SFN), a phytochemical isolated from broccoli, is an important antitumoral compound with additional beneficial effect on other important diseases. However, the chemical instability of SFN has hampered its clinical use. In order to circumvent this problem, we report the first comparative study on the inclusion complexes of SFN and SFN homologues with different cyclodextrins by NMR spectroscopy. From this study it has been shown that α-CD is the most indicated cyclodextrin for the stabilization of SFN and SFN homologues, and that the highest affinity constant is that of the isothiocyanate obtained from the wasabi. Furthermore, the study of the inclusion complexes of α-CD and the non-natural SFN and analogues with S absolute configuration at sulfur shows for the first time that α-CD is able to discriminate between the two enantiomers, with the natural R enantiomers forming the inclusion complexes with higher affinity.Ministerio de Economía yCompetitividad (grants No. CTQ2016-78580-C2-1-R, and CTQ2016-78580-C2-2-R)Junta de Andalucía (P11-FQM-8046)EvgenPharm

Síntesis estereoselectiva de una nueva familia de beta -aminoésteres de interés farmacológico como inhibidores potenciales de la agregación plaquetaria.

Motivación: La utilización de compuestos estereoquímicamente puros presenta numerosas ventajas frente al uso de racematos en la industria farmacéutica, debido principalmente a la estrecha e importante relación existente entre quiralidad y actividad biológica. En este sentido, el trabajo que se presenta en esta comunicación se enmarca dentro de un proyecto más amplio encaminado al desarrollo de nuevas estrategias para el diseño y la síntesis estereoselectiva de compuestos quirales con actividad biológica de interés. En concreto, nos centramos en la síntesis enantioselectiva de compuestros derivados de hidroxi-ésteres y de sus correspondientes lactonas, con estructura de 4-aminocroman-2-ona, asi como sus análogos fosoforados. Estos compuestos conctituyen la estrcutura básica de una familia de inhibidores de la agregación plaquetaria, modulador de la formación de trombos (1), cuya síntesis hasta la fecha, no ha podido ser realizada en forma ópticamente pura. Métodos: La metodología aplicada se basa en la capacidad que presenta el grupo sulfinilo como inductor quiral en las adiciones nucleofílicas a N-sulfiniliminas quirales (2). Por una parte, la adición del anión de acetato de etilo permite obtener las correspondientes 2-aminocromanonas ópticamente puras. Y por otra parte, la adición del metil carbanión del fenilfosfinato de metilo da lugar a los correspondientes bioisósteros derivados de fósforo. Resultados: Las adiciones de ambos aniones resultan ser estereoselectivas y nos permiten acceder a una amplia quimioteca de derivados quirales cuya síntesis se ha llevado a cabo por vez primera en forma ópticamente pura, lo que permite el estudio de la actividad de ambos enantiómeros por separado. Conclusiones: Se ha desarrollado una nueva metodología general, fácil, eficaz y modulable para la síntesis estereoselectiva de ambos enantiómeros de una amplia gama de ésteres de diferente naturaleza, que constituyen una nueva familia de compuestos de interés para su posterior apliación en farmacología

Surface modulation of single-walled carbon nanotubes for selective bacterial cell agglutination

Background: Bacterial resistance to antibiotics is one of the biggest challenges facing medicine today. Anti-adhesive therapy, using inhibitors of bacterial adhesion to epithelial cells, one of the first stages of infection, is a promising approximation in this area. The size, shape, number of sugar and their placement are variables that have to be taken into account in order to develop multivalent systems able to inhibit the bacterial adhesion based on sugar-lectin interaction. Materials and methods: In the present work we report a modular approach for the synthesis of water-soluble 1D-carbon nanotube-sugar nanoconstructs, with the necessary flexibility to allow an efficient sugar-lectin interaction. The method is based on the reaction of aryl diazonium salts generated in situ from aniline-substituted mannose and lactose derivatives with single wall carbon nanotubes (SWCNTs) sidewalls. Results: Two hybrid nanosystems, I-II, exposing mannose or lactose and having a tetraethylene glycol spacer between the sugar and the nanotube sidewall were rapidly assembled and adequately characterized. The sweet nano-objects were then tested for their ability to agglutinate and selectively inhibit the growth of uropathogenic Escherichia coli. These studies have shown that nanosystem I, exposing mannose on the nanotube surface is able to agglutinate and to inhibit the bacterial growth unlike nano-objects II exposing lactose. Conclusion: The results reported constitute a proof of principle in using mannose-coated 1D-carbon nanotubes as antiadhesive drugs that compete for FimH binding and prevent the uropathogenic bacteria from adhering to the urothelial surface.Andalusian Government (FQM-313 to NK, BIO-026 to REW)Spanish Ministry of Economy and Competitiveness (CTQ2016-78580-C2-1-R to NK)University of Seville (V PLAN PROPIO to REW)European Regional Development Fund (FEDER

Steric Tuning of Sulfinamide/Sulfoxides as Chiral Ligands with C1, Pseudo-meso, and Pseudo‑C2 Symmetries: Application in Rhodium(I)-Mediated Arylation

A new family of sulfinamide/sulfoxide derivatives was synthesized as chiral bidentate ligands by stereoselective additions of methylsulfinyl carbanions to N-tert-butylsulfinylimines. The new ligands, with C1, pseudo-meso, and pseudo-C2 symmetries, were successfully assayed in Rh-catalyzed additions of arylboronic acids to activated ketones. The sterically dissymmetric C1 ligand (RS,SC,RS)-N-[1-(phenylsulfinyl)-3-methylbut-2-yl] tert-butylsulfinamide turned out to be the optimal one, allowing the 1,4-additions of diverse arylboronic acids, on different α,β-unsaturated cyclic ketones with high chemical yields and enantioselectivities up to >99% ee.Ministerio de Economía y Competitividad (Grant CTQ2016-78580-C2-2R

N -Isopropylsulfinylimines vs. N-tert -butylsulfinylimines in the stereoselective synthesis of sterically hindered amines: An improved synthesis of enantiopure (R)- And (S)-rimantadine and the trifluoromethylated analogues

An improved fully stereoselective synthesis of both enantiomers of rimantadine and its trifluoromethylated analogues has been developed, using N-isopropylsulfinylimines as a starting chiral material, proving the superiority of the isopropyl group as a chiral inducer over the tert-butyl group in the case of hindered N-sulfinylimines.Ministerio de Economía y Competitividad de España (MEC) - CTQ2016-78580-C2-2