Recent Developments in Phosphonium Chemistry

International audience2.1 Introduction 2.2 Synthesis of Phosphonium Salts 2.3 Phosphonium Salts as a Tool for Organic Synthesis 2.4 Phosphonium Salts for Biological and Medical Applications 2.5 Conclusio

Synthèse et organisations supramoléculaires de nouveaux bolaamphiphiles dissymétriques

Le travail présenté dans ce mémoire a été effectué dans le cadre de l étude des relations structure-organisation au sein des systèmes moléculaires organisés. Appliqué à une nouvelle famille de bolaamphiphiles, il concerne la synthèse et l évaluation des propriétés physico-chimiques de bolaamphiphiles dissymétriques comportant une tête polaire neutre de type saccharidique et une tête cationique dérivée de la glycine bétaïne. En dispersion aqueuse, ces molécules conduisent à la formation de vésicules, de systèmes de type tubulaires ou encore de filaments en fonction de la taille et/ou de la nature du squelette hydrophobe. Nous décrivons également, la synthèse d un bolaamphiphile dont la particularité est de comporter un marqueur de spin de type nitroxyde. Après avoir évalué les propriétés physico-chimiques de ce bolaamphiphle, son application à l étude de la dynamique des molécules au sein des agrégats formés en milieu aqueux par la spectroscopie de résonance paramagnétique électronique (RPE) a été envisagé.This thesis presents a study of the relationships between the chemical structure and the organisation of monomers in supramolecular assemblies. We evaluate the physicochemical properties of a new family of bolaamphiphiles by various methods (X-ray diffraction, DSC, transmission electron microscopy and optical microscopy). The dissymmetrical bolaamphiphiles, that we synthesize and investigate, bear a neutral saccharidic polar head and a cationic headgroup derived from glycine betaïne. In aqueous media, these molecules form of vesicles, tubule-like or filaments depending on the size and/or the nature of the hydrophobic skeleton. We also described the synthesis of a bolaamphiphile that contains a nitroxide moiety at the cationic headgroup. The physico-chemical properties of this spin labeled bolaamphiphile were evaluated either in aqueous media. We use this bolaamphiphile to study the dynamics of the molecules into the supramolecular aggregates which are formed by electron paramagnetic resonance spectroscopy (EPR).RENNES1-BU Sciences Philo (352382102) / SudocSudocFranceF

Small-Angle and Wide-Angle X-Ray Scattering Study of Slow Relaxation Following Phase Transitions of New Bolaamphiphiles Based on N-(12-Betainylamino-Dodecane)-octyl β-D-Glucofuranosiduronamide Chloride.

International audienceIn the present study, we investigated the polymorphism and its time-dependence of a new series of bolaamphiphile molecules based on N-(12-Betainylamino-dodecane)-octyl β-D-Glucofuranosiduronamide Chloride. To obtain six members of this series, the length of the main bridging chain and the lateral chain were varied in order to modify the hydrophilic-lipophilic balance. Another chemical modification was to introduce a diacetylenic unit in the middle of the bridging chain to study the influence of the π-π stacking on the supramolecular organization of these molecules. Dry bolaamphiphiles self-organize in supramolecular structures such as lamellar crystalline structure, Lc; lamellar gel structure, Lβ′; lamellar fluid structure, Lα; and lamellar isotropic structure, L. Thermal hysteresis of these structures, following phase transitions, are investigated by small-angle and wide-angle X-ray scattering. Once the thermal cycle is accomplished, the system remains in the kinetically stabilized undercooled high-temperature phase at the temperature of 20°C. Subsequently, the time-dependence of the relaxation to the thermodynamically stable phase is followed, and very slow relaxation for a period on the order of hours or days is observed. The study of the polymorphism and the stability of various phases of this new series of bolaamphiphiles--which are issued from natural primary resources (sugar beet and wheat) and thus interesting for potential application in pharmaceutical, cosmetics, or food industry--was undertaken in this work

Construction modulaire de lipophospholipides

The present invention relates to fluorescent and/or targeting lipophilic compounds having the general formula (R1O) (R2O) P (O) - R3 - R4 - R5 wherein R1 and R2 are each independently a linear or branched, saturated or unsaturated C2-C24 alkyl, or a linear or branched, saturated or unsaturated C2-C24 monoalkenyl or polyalkenyl, the polyalkenyl having from 2 to 4 double bonds, or a linear or branched, saturated or unsaturated C2-C24 monoalkinyl or polyalkinyl, the polyalkinyl having from 2 to 4 triple bonds; R3 is selected from 0, S, -C(R6)2-, -CH(R7)-, -C(S) -N(R6) -, - CH ( SR7 ) - S - S - or -N(R6)- wherein R6 is a hydrogen atom or a C1 - C4 alkyl, and R7 is a C1 - C4 alkyl; R4 comprises at least one junction function and at least one linker; and R5 is at least one chemical fluorescent group or at least one targeting group. Methods for preparing said lipophilic compounds are also disclosed

High Deborah numbers in membrane-mimetic bolaamphiphile assemblies

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Aerosol Delivery to the Airways Using Cationic Lipid Nanocomplexes in a Perspective of Cystic Fibrosis Treatment

International audienceDiseases affecting the respiratory tract are numerous and many are disabling or deadly. Nucleic acids are emerging as a new tool and a new therapeutic class of compounds that could be used to address some lung diseases. However, considering the different anatomical barriers and the physicochemical behavior of nucleic acids in the blood stream, lungs are not easy to treat following a general administration. In this context, aerosol delivery is largely considered as an adapted and noninvasive approach avoiding the hepatic metabolism. This local delivery leads to a lung concentration and limits eventual side effects associated with a systemic injection. However, aerosol administration of active molecules is a real challenge due to the physical, chemical, and biological obstacles, such as respiratory movement, surfactant, or bacterial strains. Nanocomplexes have the potential to increase bioavailability and favor intracellular penetration of specific drugs into the pulmonary tissue. In this chapter, we will present our strategy to develop efficient gene carriers that, from a synthesis point of view, can be prepared on a large scale. We will discuss their use in preparing various formulations and their progressive adaptation to the airway constraints. In particular, we will focus our attention on cationic amphiphilic complexes used for aerosol gene delivery and we will present promising formulations in preclinical studies in a cystic fibrosis context.Les maladies touchant les voies respiratoires sont nombreuses et parfois mortelles. Les acides nucléiques apparaissent comme de nouveaux outils et une nouvelle classe thérapeutique qui pourraient être utilisés vis-à-vis de certaines maladies pulmonaires. Cependant, considérant les différentes barrières anatomiques et les caractéristiques physico-chimiques des acides nucléiques placés dans le flux sanguin, les poumons ne sont pas facile à traiter par une approche systémique. Dans ce contexte, l’aérosolisation, qui est une administration non invasive, est une approche pertinente. Ainsi, cette délivrance locale peut aussi contribuer à éviter des effet secondaires associés à une délivrance systémique. Néanmoins, la délivrance par aérosol est un véritable défi du fait des obstacles physiques, chimiques et biologiques tel que le mouvement respiratoire, la présence de surfactants ou de bactéries. Les nano-complexes ont le potentiel d’augmenter la biodisponibilité et de favoriser la pénétration intracellulaire. Dans ce chapitre, nous présentons nos stratégies pour développer des transporteurs de gènes efficaces. Cela inclut la conception des nano-vecteurs et leurs évaluations. Un focus est fait sur les amphiphiles cationiques qui sont utilisés pour une administration de plasmide par aérosols. Nous montrons que certaines formulations produisent des résultats précliniques intéressants et cela dans le contexte de la mucoviscidose

Construction modulaire de lipophospholipides

The present invention relates to fluorescent and/or targeting lipophilic compounds having the general formula (R1O) (R2O) P (O) - R3 - R4 - R5 wherein R1 and R2 are each independently a linear or branched, saturated or unsaturated C2-C24 alkyl, or a linear or branched, saturated or unsaturated C2-C24 monoalkenyl or polyalkenyl, the polyalkenyl having from 2 to 4 double bonds, or a linear or branched, saturated or unsaturated C2-C24 monoalkinyl or polyalkinyl, the polyalkinyl having from 2 to 4 triple bonds; R3 is selected from 0, S, -C(R6)2-, -CH(R7)-, -C(S) -N(R6) -, - CH ( SR7 ) - S - S - or -N(R6)- wherein R6 is a hydrogen atom or a C1 - C4 alkyl, and R7 is a C1 - C4 alkyl; R4 comprises at least one junction function and at least one linker; and R5 is at least one chemical fluorescent group or at least one targeting group. Methods for preparing said lipophilic compounds are also disclosed

Phosphonic acid: preparation and applications

International audienceThe phosphonic acid functional group, which is characterized by a phosphorus atom bonded to three oxygen atoms (two hydroxy groups and one P=O double bond) and one carbon atom, is employed for many applications due to its structural analogy with the phosphate moiety or to its coordination or supramolecular properties. Phosphonic acids were used for their bioactive properties (drug, pro-drug), for bone targeting, for the design of supramolecular or hybrid materials, for the functionalization of surfaces, for analytical purposes, for medical imaging or as phosphoantigen. These applications are covering a large panel of research fields including chemistry, biology and physics thus making the synthesis of phosphonic acids a determinant question for numerous research projects. This review gives, first, an overview of the different fields of application of phosphonic acids that are illustrated with studies mainly selected over the last 20 years. Further, this review reports the different methods that can be used for the synthesis of phosphonic acids from dialkyl or diaryl phosphonate, from dichlorophosphine or dichlorophosphine oxide, from phosphonodiamide, or by oxidation of phosphinic acid. Direct methods that make use of phosphorous acid (H 3 PO 3 ) and that produce a phosphonic acid functional group simultaneously to the formation of the P-C bond, are also surveyed. Among all these methods, the dealkylation of dialkyl phosphonates under either acidic conditions (HCl) or using the McKenna procedure (a two-step reaction that makes use of bromotrimethylsilane followed by methanolysis) constitute the best methods to prepare phosphonic acids.</div

Phosphonodithioester–Amine Coupling as a Key Reaction Step for the Design of Cationic Amphiphiles Used for Gene Delivery

International audienceA convergent synthesis of cationic amphiphilic compounds is reported here with the use of the phosphonodithioester–amine coupling (PAC) reaction. This versatile reaction occurs at room temperature without any catalyst, allowing binding of the lipid moiety to a polar head group. This strategy is illustrated with the use of two lipid units featuring either two oleyl chains or two-branched saturated lipid chains. The final cationic amphiphiles were evaluated as carriers for plasmid DNA delivery in four cell lines (A549, Calu3, CFBE and 16HBE) and were compared to standards (BSV36 and KLN47). These new amphiphilic derivatives, which were formulated with DOPE or DOPE-cholesterol as helper lipids, feature high transfection efficacies when associated with DOPE. The highest transfection efficacies were observed in the four cell lines at low charge ratios (CR = 0.7, 1 or 2). At these CRs, no toxic effects were detected. Altogether, this new synthesis scheme using the PAC reaction opens up new possibilities for investigating the effects of lipid or polar head groups on transfection efficacies

mRNA Lipoplexes with Cationic and Ionizable α-Amino-lipophosphonates: Membrane Fusion, Transfection, mRNA Translation and Conformation

International audienceCationic liposomes are attractive carriers for mRNA delivery. Here, mRNA lipoplexes (LX) were prepared with the cationic lipids α-aminolipophosphonate (3b) or imidazolium lipophosphoramidate (2) associated with various α-aminolipophosphonates co-lipids comprising protonable groups (imidazole or pyridine) and DOPE. Physicochemical parameters of liposomes and their membrane fusion activity were measured. LXs comprising either 3b- or 2- allowed transfection of ~25% and 40% of dendritic cells with low cytotoxicity, respectively; the efficiency increased up to 80% when 2 was combined with the imidazole-based co-lipid 1. The transfections were high with 3b/1, 3b/DOPE, 2/1 and 2/DOPE LXs. We observed that the transfection level was not well correlated with the acid-mediated membrane fusion activity of liposomes supposed to destabilize endosomes. The mRNA release from LXs and its translation capacity after release were studied for the most efficient LXs. The results showed that the more mRNA was condensed, the poorer the translation efficiency after release was. In contrast to DNA, circular dichroism performed on mRNA complexed with 2/DOPE revealed the presence of denatured mRNA in LXs explaining this lack of translation efficiency. This is an important parameter that should be stressed for the preparation of mRNA LXs with a conserved mRNA translation activity