An Interlocked Figure-of-Eight Molecular Shuttle.

Here is reported the synthesis and characterization of an interlocked figure-of-eight rotaxane molecular shuttle from a dibenzo-24-crown-8 (DB24C8) derivative. This latter bears two molecular chains, whose extremities are able to react together by click chemistry. One of the two substituting chain holds an ammonium function aimed at driving the self-entanglement through the complexation of the DB24C8 moiety. In the targeted figure-of-eight rotaxane, shuttling of the DB24C8 along the threaded axle from the best ammonium station to the weaker binding site triazolium was performed through deprotonation or deprotonation-then-carbamoylation of the ammonium. This way, two discrete co-conformational states were obtained, in which the folding and size of the two loops could be changed.

Interplay between a Foldamer Helix and a Macrocycle in a Foldarotaxane Architecture.

The design and synthesis of a novel rotaxane/foldaxane hybrid architecture is reported. The winding of an aromatic oligoamide helix host around a dumbbell-shaped thread-like guest, or axle, already surrounded by a macrocycle was evidenced by NMR spectroscopy and X-ray crystallography. The process proved to depend on the position of the macrocycle along the axle and the associated steric hindrance. The macrocycle thus behaves as a switchable shield that modulates the affinity of the helix for the axle. Reciprocally, the foldamer helix acts as a supramolecular auxiliary that compartmentalizes the axle. In some cases, the macrocycle is forced to move along the axle to allow the foldamer to reach its best recognition site.

[Maternal and child protection services at home. Results from a national study.] / Les interventions à domicile en Protection maternelle et infantile. Résultats d'une étude nationale.

Maternal and child protection services ("PMI") are French universal services providing prevention and health promotion services to parents and their newborn children up to the age of 6. They specifically offer home visitation services in order to reach families that could not be seen otherwise. This paper presents the results of a national survey describing these home visitation services and their local implantation. Sixty French ?départements? (59%), constituting the territorial unit for the PMI answered the survey. The results point out that family reach remains a challenge for these services. Organizational issues represent the main barrier to implement and deliver home visitation with sufficient reach and quality. The services now provide home visitation based on risk factors, while the universality of services seems to be no longer guaranteed. The number of tasks that the nurses have been charged with can explain these difficulties, as well as the lack of financial and human resources.

[Effects of the homecare assistance program on maternal and child protection services.] / Effets du programme d'accompagnement du retour à domicile sur les pratiques des services de protection maternelle et infantile.

In 2010, the French Ministry of Health started the implementation of the "PRADO" process, which constitutes a way to finance two early post-partum home visits by midwives. These two visits occur between the third and twelfth day of the newborn child. However, this PRADO program has come as a supplementary service, while the Maternal and child protection services ("PMI") were already in charge of home visitation in early postpartum up to the child's sixth birthday. Through a qualitative survey, this study aimed at evaluating the effect of the implementation of the PRADO program over the PMI structure and home visitation intervention. The results suggest an important lack of coordination between these services that appear to be in competition with each other, while both financed by public funding. The PMI services expressed their feeling that families were less well served in early postpartum, with these two services.

The Importance of Length and Flexibility of Macrocycle-Containing Molecular Translocators for the Synthesis of Improbable [2]Rotaxanes.

This work reports on the use of molecular translocators to capture a dibenzo-24-crown-8 (DB24C8) and then release it onto targeted molecular axles to afford, after removal of the translocator, [2]rotaxanes that do not hold any template site. Various translocators were studied and successfully aided the synthesis, with more or less efficacy, of [2]rotaxanes of different lengths. During the releasing step, the DB24C8 macrocycle shuttles along the thread, and the localization of the macrocycle might be driven by steric repulsion on the translocator part and/or electronic attraction of the targeted part of the axle to be encircled, which depends on both the nature of the translocator and the targeted thread to be encircled.

How Secondary and Tertiary Amide Moieties are Molecular Stations for Dibenzo-24-crown-8 in [2]Rotaxane Molecular Shuttles?

Interlocked molecular machines like [2]rotaxanes are intriguing aesthetic molecules. The control of the localization of the macrocycle, which surrounds a molecular axle, along the thread leads to translational isomers of very different properties. Although many moieties have been used as sites of interactions for crown ethers, the very straightforwardly obtained amide motif has more rarely been envisaged as molecular station. In this article, we report the use of secondary and tertiary amide moieties as efficient secondary molecular station in pH-sensitive molecular shuttles. Depending on the N-substitution of the amide station, and on deprotonation or deprotonation-carbamoylation, the actuation of the molecular machinery differs accordingly to very distinct interactions between the axle and the DB24C8.

Active Esters as Pseudostoppers for Slippage Synthesis of [2]Pseudorotaxane Building Blocks: A Straightforward Route to Multi-Interlocked Molecular Machines.

The efficient synthesis and very easy isolation of dibenzo[24]crown-8-based [2]pseudorotaxane building blocks that contain an active ester motif at the extremity of the encircled molecular axle and an ammonium moiety as a template for the dibenzo[24]crown-8 is reported. The active ester acts both as a semistopper for the [2]pseudorotaxane species and as an extensible extremity. Among the various investigated active ester moieties, those that allow for the slippage process are given particular focus because this strategy produces fewer side products. Extension of the selected N-hydroxysuccinimide ester based pseudorotaxane building block by using either a mono- or a diamino compound, both containing a triazolium moiety, is also described. These provide a pH-dependent two-station [2]rotaxane molecular machine and a palindromic [3]rotaxane molecular machine, respectively. Molecular machinery on both interlocked compounds through variation of pH was studied and characterized by means of NMR spectroscopy.

A strategy utilizing a recyclable macrocycle transporter for the efficient synthesis of a triazolium-based [2]rotaxane.

A general synthesis of triazolium-containing [2]rotaxanes, which could not be accessed by other methods, is reported. It is based on a sequential strategy starting from a well-designed macrocycle transporter which contains a template for dibenzo-24-crown-8 and a N-hydroxysuccinimide (NHS) moiety. The sequence is: 1) synthesis by slippage of a [2]rotaxane building-block; 2) its elongation at its NHS end; 3) the delivery of the macrocycle to the elongated part of the axle by an induced translational motion; 4) the contraction process to yield the targeted [2]rotaxane and recycle the initial transporter.

A pH-sensitive peptide-containing lasso molecular switch.

The synthesis of a peptide-containing lasso molecular switch by a self-entanglement strategy is described. The interlocked rotaxane molecular machine consists of a benzometaphenylene[25]crown-8 (BMP25C8) macrocycle surrounding a molecular axle. This molecular axle contains a tripeptidic sequence and two molecular stations: a N-benzyltriazolium and a pH-sensitive anilinium station. The tripeptide is located between the macrocycle and the triazolium station, so that its conformation can be tailored depending on the shuttling of the macrocycle from one station to the other. At acidic pH, the macrocycle resides around the anilinium moiety, whereas it shuttles around the triazolium station after deprotonation. This molecular machinery thus forces the lasso to adopt a tightened or a loosened conformation.

A pH-sensitive lasso-based rotaxane molecular switch.

The synthesis of a pH-sensitive two-station [1]rotaxane molecular switch by self-entanglement of a non-interlocked hermaphrodite molecule, containing an anilinium and triazole moieties, is reported. The anilinium was chosen as the best template for the macrocycle benzometaphenylene[25]crown-8 (BMP25C8) and allowed the self-entanglement of the molecule. The equilibrium between the hermaphrodite molecule and the pseudo[1]rotaxane was studied by (1)H NMR spectroscopy: the best conditions of self-entanglement were found in the less polar solvent CD(2)Cl(2) and at high dilution. The triazole moiety was then benzylated to afford a benzyltriazolium moiety, which then played a dual role. On one hand, it acts as a bulky gate to trap the BMP25C8, thus to avoid any self-disentanglement of the molecular architecture. On another hand, it acts as a second molecular station for the macrocycle. At acidic pH, the BMP25C8 resides around the best anilinium molecular station, displaying the lasso [1]rotaxane in a loosened conformation. The deprotonation of the anilinium molecular station triggers the shuttling of the BMP25C8 around the triazolium moiety, therefore tightening the lasso.

Gold manno-glyconanoparticles: multivalent systems to block HIV-1 gp120 binding to the lectin DC-SIGN.

The HIV envelope glycoprotein gp120 takes advantage of the high-mannose clusters on its surface to target the C-type lectin dendritic cell-specific intracellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) on dendritic cells. Mimicking the cluster presentation of oligomannosides on the virus surface is a strategy for designing carbohydrate-based antiviral agents. Bio-inspired by the cluster presentation of gp120, we have designed and prepared a small library of multivalent water-soluble gold glyconanoparticles (manno-GNPs) presenting truncated (oligo)mannosides of the high-mannose undecasaccharide Man(9)GlcNAc(2) and have tested them as inhibitors of DC-SIGN binding to gp120. These glyconanoparticles are ligands for DC-SIGN, which also interacts in the early steps of infection with a large number of pathogens through specific recognition of associated glycans. (Oligo)mannosides endowed with different spacers ending in thiol groups, which enable attachment of the glycoconjugates to the gold surface, have been prepared. manno-GNPs with different spacers and variable density of mannose (oligo)saccharides have been obtained and characterized. Surface plasmon resonance (SPR) experiments with selected manno-GNPs have been performed to study their inhibition potency towards DC-SIGN binding to gp120. The tested manno-GNPs completely inhibit the binding from the micro- to the nanomolar range, while the corresponding monovalent mannosides require millimolar concentrations. manno-GNPs containing the disaccharide Manalpha1-2Manalpha are the best inhibitors, showing more than 20 000-fold increased activity (100 % inhibition at 115 nM) compared to the corresponding monomeric disaccharide (100 % inhibition at 2.2 mM). Furthermore, increasing the density of dimannoside on the gold platform from 50 to 100 % does not improve the level of inhibition.

NMR studies on the conformation of oligomannosides and their interaction with banana lectin.

The conformational and dynamic behaviour of three mannose containing oligosaccharides, a tetrasaccharide with alpha1-->2, and alpha1-->3, and a penta and a heptasaccharide with alpha1-->2, alpha1-->3, and alpha1-->6 linkages has been evaluated by molecular mechanics and dynamics simulations and NMR spectroscopical methods. It is found that they display a fair amount of conformational freedom, with one major and one minor conformation per glycosidic linkage. The evaluation of their recognition by banana lectin has also been performed by STD NMR methods and a preliminary view of their putative interaction mode has been carried out by means of docking procedures.

Glyconanoparticle-DNA interactions: an atomic force microscopy study.

Glyconanoparticles which present carbohydrate and amino groups motifs at their surface were produced. These particles were highly stable and soluble in aqueous solutions. The presence of the carbohydrate groups also allowed the inclusion of more strongly binding groups, without affecting solubility. The binding of a model DNA, plasmid by these nanoparticles was studied by atomic force microscopy, transmission electron microscopy, and gel electrophoresis. Significant differences between the nanoparticles based on their affinities for the DNA were found, with implications for their potential use as nonviral gene delivery agents.

Synthesis and biological activity of M6-P and M6-P analogs on fibroblast and keratinocyte proliferation.

A new synthetic route to obtain the carboxylate analog of mannose 6-phosphate (M6-P) is presented. The effects of the M6-P, the carboxylate and two other analogs (the phosphonate and the alpha,beta ethylenic carboxylate) on the proliferation of human keratinocytes and dermal fibroblasts as well as on the proliferation of a murine fibroblast cell line, 3T3-J2 are tested. We observed that M6-P is a potent inhibitor of proliferation of both fibroblasts and keratinocytes. Among its analogs, the phosphonate showed a similar effect on human dermal fibroblasts but not on keratinocytes.

Synthesis and properties of isocannabinoid and cholesterol derivatized rhamnosurfactants: application to liposomal targeting of keratinocytes and skin.

The usefulness of vesicles to cargo material depends on the design of new ligands able to incorporate easily inside the bilayer and also to direct the vesicles to the targeted site. Therefore, the synthesis of two new rhamnose-bearing surfactants is described. The hydrophobic part consists of cholesterol (in compound 3) and citrylidene phloroglucinol (in compound 6). The ability of these two rhamnolipids to incorporate into a DPPC membrane and to form aggregates is investigated, respectively, by differential scanning calorimetry and by surface tension measurements. Those two new surfactants were incorporated in fluorescent liposomes to study their interactions with keratinocytes and skin sections. Intraliposomal delivery to keratinocytes was observed in both cases, even if the kinetics of delivery were different according to the rhamnosurfactant used. Skin sections were stained by both liposomal formulations, and different interactions between the liposomes and skin cells according to the surfactant used were noted.