5 research outputs found
Des glycodyn[n]arĂšnes aux polymĂšres dynamiques comme ligands multivalents de lectines
Pseudomonas aeruginosa has developed increased resistance to antibiotics. Alternatives are being developed, including the study of anti-adhesive agents. This strategy aims to the inhibition of bacterial adhesion to host cells. In our laboratory, anti-adhesive glycoclusters have been designed and validated in vivo. The combination of multivalence and dynamic combinatorial chemistry could allow us to identify new glycoclusters of biological interest. Glycosylated dithiophenol building blocks were studied for the recognition of bacterial lectins. These dithiophenols had showed the preferential formation of glycodyn[3]arenes and glycodyn[4]arenes macrocycles. Biological studies are underway to evaluate their binding properties and toxicity in vitro. An additional generation of building blocks has been designed using a double dynamic combinatorial chemistry to allow the polymerisation of glycodyn[n]arenes into glycodynamers. A dithiophenol building block incorporating a polymerisable function (aldehyde/hydrazide) will be required to reach the glycodynamers, as well as water-soluble spacer arms for polymerisation. This will allow the transition from the lectin scale (glycodyn[n]arenes) to the bacterial scale (glycodynamers). Two dynamic orthogonal combinatorial chemistries will then be involved based on dithiophenol and aldehyde/hydrazide building blocks.La bactĂ©rie Pseudomonas aeruginosa a dĂ©veloppĂ© une rĂ©sistance accrue aux antibiotiques. Des alternatives se dĂ©veloppent, notamment lâĂ©tude dâagents antiadhĂ©sifs. Cette stratĂ©gie vise Ă bloquer les protĂ©ines Ă la surface de la bactĂ©rie pour empĂȘcher son adhĂ©sion sur les cellules hĂŽtes. Au sein du laboratoire, des glycoclusters antiadhĂ©sifs ont dĂ©jĂ Ă©tĂ© synthĂ©tisĂ©s et ont fait leurs preuves in vivo. Lâalliance de la multivalence et de la chimie combinatoire dynamique pourrait nous permettre dâidentifier de nouveaux glycoclusters dâintĂ©rĂȘt biologique. Des briques molĂ©culaires dithiophĂ©nol glycosylĂ©es ont Ă©tĂ© Ă©tudiĂ©es pour la reconnaissance de lectines bactĂ©riennes. Celles-ci ont montrĂ© la formation prĂ©fĂ©rentielle de macrocycles de type glycodyn[3]arĂšnes et glycodyn[4]arĂšnes. Des Ă©tudes biologiques sont en cours pour Ă©valuer leur efficacitĂ© et leur toxicitĂ© in vitro. En parallĂšle de ces travaux, une nouvelle gĂ©nĂ©ration de briques molĂ©culaires a Ă©tĂ© imaginĂ©e. Elle devra rĂ©pondre Ă une problĂ©matique de double chimie combinatoire dynamique pour permettre la polymĂ©risation des glycodyn[n]arĂšnes en glycodynamĂšres. Une brique dithiophĂ©nol incorporant une fonction polymĂ©risable (aldĂ©hyde/hydrazide) sera nĂ©cessaire pour atteindre les glycodynamĂšres, ainsi que des bras espaceurs hydrosolubles pour la polymĂ©risation. Ceci permettra de passer de lâĂ©chelle de la lectine (glycodyn[n]arĂšnes) Ă celle de la bactĂ©rie (glycodynamĂšres). Deux chimies combinatoires dynamiques orthogonales seront alors mises en jeu sur la base de briques dithiophĂ©nol dâune part et aldĂ©hyde/hydrazide dâautre part
From glycodyn[n]arenes to dynamic polymers as multivalent ligand for lectins
La bactĂ©rie Pseudomonas aeruginosa a dĂ©veloppĂ© une rĂ©sistance accrue aux antibiotiques. Des alternatives se dĂ©veloppent, notamment lâĂ©tude dâagents antiadhĂ©sifs. Cette stratĂ©gie vise Ă bloquer les protĂ©ines Ă la surface de la bactĂ©rie pour empĂȘcher son adhĂ©sion sur les cellules hĂŽtes. Au sein du laboratoire, des glycoclusters antiadhĂ©sifs ont dĂ©jĂ Ă©tĂ© synthĂ©tisĂ©s et ont fait leurs preuves in vivo. Lâalliance de la multivalence et de la chimie combinatoire dynamique pourrait nous permettre dâidentifier de nouveaux glycoclusters dâintĂ©rĂȘt biologique. Des briques molĂ©culaires dithiophĂ©nol glycosylĂ©es ont Ă©tĂ© Ă©tudiĂ©es pour la reconnaissance de lectines bactĂ©riennes. Celles-ci ont montrĂ© la formation prĂ©fĂ©rentielle de macrocycles de type glycodyn[3]arĂšnes et glycodyn[4]arĂšnes. Des Ă©tudes biologiques sont en cours pour Ă©valuer leur efficacitĂ© et leur toxicitĂ© in vitro. En parallĂšle de ces travaux, une nouvelle gĂ©nĂ©ration de briques molĂ©culaires a Ă©tĂ© imaginĂ©e. Elle devra rĂ©pondre Ă une problĂ©matique de double chimie combinatoire dynamique pour permettre la polymĂ©risation des glycodyn[n]arĂšnes en glycodynamĂšres. Une brique dithiophĂ©nol incorporant une fonction polymĂ©risable (aldĂ©hyde/hydrazide) sera nĂ©cessaire pour atteindre les glycodynamĂšres, ainsi que des bras espaceurs hydrosolubles pour la polymĂ©risation. Ceci permettra de passer de lâĂ©chelle de la lectine (glycodyn[n]arĂšnes) Ă celle de la bactĂ©rie (glycodynamĂšres). Deux chimies combinatoires dynamiques orthogonales seront alors mises en jeu sur la base de briques dithiophĂ©nol dâune part et aldĂ©hyde/hydrazide dâautre part.Pseudomonas aeruginosa has developed increased resistance to antibiotics. Alternatives are being developed, including the study of anti-adhesive agents. This strategy aims to the inhibition of bacterial adhesion to host cells. In our laboratory, anti-adhesive glycoclusters have been designed and validated in vivo. The combination of multivalence and dynamic combinatorial chemistry could allow us to identify new glycoclusters of biological interest. Glycosylated dithiophenol building blocks were studied for the recognition of bacterial lectins. These dithiophenols had showed the preferential formation of glycodyn[3]arenes and glycodyn[4]arenes macrocycles. Biological studies are underway to evaluate their binding properties and toxicity in vitro. An additional generation of building blocks has been designed using a double dynamic combinatorial chemistry to allow the polymerisation of glycodyn[n]arenes into glycodynamers. A dithiophenol building block incorporating a polymerisable function (aldehyde/hydrazide) will be required to reach the glycodynamers, as well as water-soluble spacer arms for polymerisation. This will allow the transition from the lectin scale (glycodyn[n]arenes) to the bacterial scale (glycodynamers). Two dynamic orthogonal combinatorial chemistries will then be involved based on dithiophenol and aldehyde/hydrazide building blocks
Des glycodyn[n]arĂšnes aux polymĂšres dynamiques comme ligands multivalents de lectines
Pseudomonas aeruginosa has developed increased resistance to antibiotics. Alternatives are being developed, including the study of anti-adhesive agents. This strategy aims to the inhibition of bacterial adhesion to host cells. In our laboratory, anti-adhesive glycoclusters have been designed and validated in vivo. The combination of multivalence and dynamic combinatorial chemistry could allow us to identify new glycoclusters of biological interest. Glycosylated dithiophenol building blocks were studied for the recognition of bacterial lectins. These dithiophenols had showed the preferential formation of glycodyn[3]arenes and glycodyn[4]arenes macrocycles. Biological studies are underway to evaluate their binding properties and toxicity in vitro. An additional generation of building blocks has been designed using a double dynamic combinatorial chemistry to allow the polymerisation of glycodyn[n]arenes into glycodynamers. A dithiophenol building block incorporating a polymerisable function (aldehyde/hydrazide) will be required to reach the glycodynamers, as well as water-soluble spacer arms for polymerisation. This will allow the transition from the lectin scale (glycodyn[n]arenes) to the bacterial scale (glycodynamers). Two dynamic orthogonal combinatorial chemistries will then be involved based on dithiophenol and aldehyde/hydrazide building blocks.La bactĂ©rie Pseudomonas aeruginosa a dĂ©veloppĂ© une rĂ©sistance accrue aux antibiotiques. Des alternatives se dĂ©veloppent, notamment lâĂ©tude dâagents antiadhĂ©sifs. Cette stratĂ©gie vise Ă bloquer les protĂ©ines Ă la surface de la bactĂ©rie pour empĂȘcher son adhĂ©sion sur les cellules hĂŽtes. Au sein du laboratoire, des glycoclusters antiadhĂ©sifs ont dĂ©jĂ Ă©tĂ© synthĂ©tisĂ©s et ont fait leurs preuves in vivo. Lâalliance de la multivalence et de la chimie combinatoire dynamique pourrait nous permettre dâidentifier de nouveaux glycoclusters dâintĂ©rĂȘt biologique. Des briques molĂ©culaires dithiophĂ©nol glycosylĂ©es ont Ă©tĂ© Ă©tudiĂ©es pour la reconnaissance de lectines bactĂ©riennes. Celles-ci ont montrĂ© la formation prĂ©fĂ©rentielle de macrocycles de type glycodyn[3]arĂšnes et glycodyn[4]arĂšnes. Des Ă©tudes biologiques sont en cours pour Ă©valuer leur efficacitĂ© et leur toxicitĂ© in vitro. En parallĂšle de ces travaux, une nouvelle gĂ©nĂ©ration de briques molĂ©culaires a Ă©tĂ© imaginĂ©e. Elle devra rĂ©pondre Ă une problĂ©matique de double chimie combinatoire dynamique pour permettre la polymĂ©risation des glycodyn[n]arĂšnes en glycodynamĂšres. Une brique dithiophĂ©nol incorporant une fonction polymĂ©risable (aldĂ©hyde/hydrazide) sera nĂ©cessaire pour atteindre les glycodynamĂšres, ainsi que des bras espaceurs hydrosolubles pour la polymĂ©risation. Ceci permettra de passer de lâĂ©chelle de la lectine (glycodyn[n]arĂšnes) Ă celle de la bactĂ©rie (glycodynamĂšres). Deux chimies combinatoires dynamiques orthogonales seront alors mises en jeu sur la base de briques dithiophĂ©nol dâune part et aldĂ©hyde/hydrazide dâautre part
Rim-differentiation vs. mixture of constitutional isomers: A binding study between pillar[5]arene-based glycoclusters and lectins from pathogenic bacteria
Macrocycle-based glycoclusters, on account of their promising anti-adhesive properties against bacteria, are potential therapeutic alternatives to classic antibiotics through the much less explored anti-adhesive strategy. In this study, a series of constitutionally-pure pentavalent glycoclusters was prepared by conjugating assorted azido-carbohydrates onto a penta-propargyl rim-differentiated pillar[5]arene (RD-P[5]) scaffold through Cu(I)-catalyzed azide-alkyne cycloaddition "click" reactions. Their binding towards therapeutically relevant bacterial lectins, such as LecA and LecB from Pseudomonas aeruginosa and concanavalin A (ConA), were evaluated subsequently by isothermal titration calorimetric studies. Most of these isomer-free RD-P[5] pentavalent glycoclusters, except the fucosylated ones, display good affinities to lectins. Nonetheless, the dissociation constants observed are similar to those displayed by an analogous pentavalent glycocluster consisting of four P[5] constitutional isomers, in which the RD-P[5] component merely accounts for 7% in the mixture. Our results revealed that high constitutional purity is not essential for achieving effective multivalent interactions between P[5]-based glycoclusters and lectins, presumably as a result of the conformationally labile nature of the P[5] scaffold. This information provides valuable design principles for low-cost and facile syntheses of glycosylated P[5]s for biomedical applications
Glucose-based spiro-oxathiazoles as in vivo anti-hyperglycemic agents through glycogen phosphorylase inhibition
International audienceThe design of glycogen phosphorylase (GP) inhibitors targeting the catalytic site of the enzyme is a promising strategy for a better control of hyperglycaemia in the context of type 2 diabetes. Glucopyranosylidene-spiro-heterocycles have been demonstrated as potent GP inhibitors, and more specifically spiro-oxathiazoles. A new synthetic route has now been elaborated through 1,3-dipolar cycloaddition of an aryl nitrile oxide to a glucono-thionolactone affording in one step the spiro-oxathiazole moiety. The thionolactone was obtained from the thermal rearrangement of a thiosulfinate precursor according to Fairbanksâ protocols, although with a revisited outcome and also rationalised with DFT calculations. The 2-naphthyl substituted glucose-based spiro-oxathiazole 5h, identified as one of the most potent GP inhibitors (Ki = 160 nM against RMGPb) could be produced on the gram-scale from this strategy. Further evaluation in vitro using rat and human hepatocytes demonstrated that compound 5h is a anti-hyperglycaemic drug candidates performing slightly better than DAB used as a positive control. Investigation in Zucker fa/fa rat model in acute and subchronic assays further confirmed the potency of compound 5h since it lowered blood glucose levels by âŒ36% at 30 mg kgâ1 and âŒ43% at 60 mg kgâ1. The present study is one of the few in vivo investigations for glucose-based GP inhibitors and provides data in animal models for such drug candidates