Bidimensional lamellar assembly by coordination of peptidic homopolymers to platinum nanoparticles

A key challenge for designing hybrid materials is the development of chemical tools to control the organization of inorganic nanoobjects at low scales, from mesoscopic (~µm) to nanometric (~nm). So far, the most efficient strategy to align assemblies of nanoparticles consists in a bottom-up approach by decorating block copolymer lamellae with nanoobjects. This well accomplished procedure is nonetheless limited by the thermodynamic constraints that govern copolymer assembly, the entropy of mixing as described by the Flory–Huggins solution theory supplemented by the critical influence of the volume fraction of the block components. Here we show that a completely different approach can lead to tunable 2D lamellar organization of nanoparticles with homopolymers only, on condition that few elementary rules are respected: 1) the polymer spontaneously allows a structural preorganization, 2) the polymer owns functional groups that interact with the nanoparticle surface, 3) the nanoparticles show a surface accessible for coordination

Antitrypanosomatid Pharmacomodulation at Position 3 of the 8-Nitroquinolin-2(1H)-one Scaffold Using Palladium-Catalysed Cross-Coupling Reactions

International audienceAn antikinetoplastid pharmacomodulation study at position 3 of the recently described hit molecule 3-bromo-8-nitroquinolin-2(1H)-one was conducted. Twenty-four derivatives were synthesised using the Suzuki-Miyaura cross-coupling reaction and evaluated in vitro on both Leishmania infantum axenic amastigotes and Trypanosoma brucei brucei trypomastigotes. Introduction of a para-carboxyphenyl group at position 3 of the scaffold led to the selective antitrypanosomal hit molecule 3-(4-carboxyphenyl)-8-nitroquinolin-2(1H)-one (21) with a lower reduction potential (-0.56 V) than the initial hit (-0.45 V). Compound 21 displays micromolar antitrypanosomal activity (IC50 =1.5 μm) and low cytotoxicity on the human HepG2 cell line (CC50 =120 μm), having a higher selectivity index (SI=80) than the reference drug eflornithine. Contrary to results previously obtained in this series, hit compound 21 is inactive toward L. infantum and is not efficiently bioactivated by T. brucei brucei type I nitroreductase, which suggests the existence of an alternative mechanism of action

Cyclic Poly(α-peptoid)s by Lithium bis(trimethylsilyl)amide (LiHMDS)-Mediated Ring-Expansion Polymerization: Simple Access to Bioactive Backbones

Cyclic polymers display unique physicochemical and biological properties. However, their development is often limited by their challenging preparation. In this work, we present a simple route to cyclic poly(α-peptoids) from N-alkylated-N-carboxyanhydrides (NNCA) using LiHMDS promoted ring-expansion polymerization (REP) in DMF. This new method allows the unprecedented use of lysine-like monomers in REP to design bioactive macrocycles bearing pharmaceutical potential against Clostridioides difficile, a bacterium responsible for nosocomial infections

New 8-nitroquinolinone derivative displaying submicromolar in vitro activities against both Trypanosoma brucei and cruzi

International audienceAn antikinetoplastid pharmacomodulation study was conducted at position 6 of the 8-nitroquinolin-2(1H)-one pharmacophore. Fifteen new derivatives were synthesized and evaluated in vitro against L. infantum, T. brucei brucei, and T. cruzi, in parallel with a cytotoxicity assay on the human HepG2 cell line. A potent and selective 6-bromo-substituted antitrypanosomal derivative 12 was revealed, presenting EC50 values of 12 and 500 nM on T. b. brucei trypomastigotes and T. cruzi amastigotes respectively, in comparison with four reference drugs (30 nM ≤ EC50 ≤ 13 μM). Moreover, compound 12 was not genotoxic in the comet assay and showed high in vitro microsomal stability (half life >40 min) as well as favorable pharmacokinetic behavior in the mouse after oral administration. Finally, molecule 12 (E° = −0.37 V/NHE) was shown to be bioactivated by type 1 nitroreductases, in both Leishmania and Trypanosoma, and appears to be a good candidate to search for novel antitrypanosomal lead compounds

Hétérocycles oxygénés : Synthèse, Réactivité et Application à la préparation de polymères Biodégradables

Synthetic biodegradable polymers have attracted increasing interest over the last ten years. Polyesters occupy a leading position due to their additional bioassimilable character. : They can be of natural or synthetic origin. At any rate, they can be prepared by ring-opening polymerization (ROP) from lactons1. The use of these lactones is sometimes restricted because of their weak reactivity. This problem can be avoided by the use of very reactive catalytic systems based on strong metal reactivity which are not always compatible with an application in biology (pharmacology, environment)2. An approach to offset this problem consists in 'chemically 'speeding up these monomers to improve the process of polymerization. L-lacOCA is an analogue of L-lactide which has a function O-Carboxyanhydride (OCA). This monomer is much more reactive than the identical cyclical dilactone: it polymerizes in a controlled way and in a living manner in softer conditions3. This work begins with a theoretical study of ROP of L-lacOCA and L-lactide catalyzed by 4-diméthylaminopyridine (DMAP) in the presence of alcohol. The mechanism of polymerization revealed consists in a basic activation of the initiator by the DMAP. For this catalyst, it has been shown for the first time an unusual bifunctional mode of action, where a weak energy hydrogen bonding was involved4. The second part of the manuscript describes the development of ROP of L-lacOCA with an ecofriendly catalytic system: the enzymatic catalysis. Up to now, enzymes accomplished ROP of the lactide hardly. With lipases Novozyme 435 and PS, it was possible to obtain easelier polylactide of high molecular weight from the activated analogue of lactide. In the case of Novozyme 435, the polymerization was controlled and has a living character. In a last part, we tried to extend the principle of activation of the OCA moiety to other monomers. We studied ROP of β-OCAs, 6-rings O-carboxyanhydrides which could give access to natural polymers as polyhydroxybutyrate. Three monomers of this type, PivOCA, MepOCA and ButOCA were synthetized. The study of their reactivity put forward a problem of selectivity between the two carbonyls of the OCA moiety during the nucleophilic attack. Because of secondary reactions, experiments of ROP have shown that it was difficult to achieve properly the synthesis of these polyesters.Références1. Biopolymers, Wiley VCH, 2003, Vol. 3a-3b-4.2. O. Dechy-Cabaret, B. Martin-Vaca, D. Bourissou, Chem. Rev., 2004 (104) 6147.3. O. Thillaye du Boullay, E. Marchal, B. Martin-Vaca, F. P. Cossio and D. Bourissou., J. Am. Chem. Soc., 2006 (128) 16442.4. C. Bonduelle, B. Martin-Vaca, F.P. Cossio, D. Bourissou, Chem. Eur. J., 2008 , 14, 5304.L'utilisation de polymères biodégradables synthétiques connaît un grand essor depuis une dizaine d'années. Parmi ces polymères, les polyesters occupent une place privilégiée car ils sont biocompatibles : ils sont d'origine naturelle ou d'origine synthétique. Dans tous les cas, on peut les préparer par polymérisation par ouverture de cycle (ROP) à partir de lactones1. L'utilisation des lactones est parfois limitée à cause de leur faible polymérisabilité. Cette dernière est contournée par l'utilisation de systèmes catalytiques très réactifs souvent à base de métaux qui ne sont pas toujours compatibles avec une application en biologie (pharmacologie, environnement)2. Une approche pour pallier ce problème consiste à activer ‘chimiquement' ces monomères pour en tirer un avantage dans le processus de polymérisation. Le L-lacOCA est ainsi un analogue du L-lactide qui possède une fonction O-carboxyanhydride (OCA). Ce monomère est beaucoup plus réactif que la dilactone cyclique équivalente : il polymérise de façon contrôlée et vivante dans des conditions catalytiques plus douces3. Ce travail commence par une étude théorique de la ROP du L-lacOCA et du L-lactide catalysée par la 4-diméthylaminopyridine (DMAP) et en présence d'un alcool. Le mécanisme de la polymérisation ainsi révélé consiste en une activation basique de l'amorceur par la DMAP. Pour ce catalyseur, il y a mise en évidence pour la première fois d'un mode d'action bifonctionnel inusuel qui met en jeu une liaison hydrogène de faible énergie4. La deuxième partie du manuscrit décrit le développement de la ROP du L-lacOCA avec un systême catalytique alternatif écocompatible : la catalyse enzymatique. Jusqu'à maintenant, les enzymes réalisent difficilement la ROP du lactide. Avec deux lipases, la Novozyme 435 et la lipase PS, il a été possible d'obtenir du polylactide de haut poids moléculaire à partir du monomère activé. Dans le cas de la Novozyme 435, la polymérisation est contrôlée et possède un caractère vivant. Dans une dernière partie, nous avons essayé d'étendre le principe d'activation du motif OCA à d'autres monomères. Nous avons étudié la ROP des β-OCAs, les O-carboxyanhydrides à 6 chaînons qui pourraient donner accès aux polymères naturels comme le PHB. Trois monomères de ce type, le PivOCA, le MepOCA et le ButOCA ont été synthétisés. L'étude de leurs réactivités a mis en avant un problème de sélectivité entre les deux carbonyls du motif OCA lors d'une attaque nucléophile. A cause de réactions secondaires, les essais de ROP ont montré qu'il était difficile d'accéder proprement à des polyesters.Références1. Biopolymers, Wiley VCH, 2003, Vol. 3a-3b-4.2. O. Dechy-Cabaret, B. Martin-Vaca, D. Bourissou, Chem. Rev., 2004 (104) 6147.3. O. Thillaye du Boullay, E. Marchal, B. Martin-Vaca, F. P. Cossio and D. Bourissou., J. Am. Chem. Soc., 2006 (128) 16442.4. C. Bonduelle, B. Martin-Vaca, F.P. Cossio, D. Bourissou, Chem. Eur. J., 2008 , 14, 5304

Hétérocycles oxygénés (synthèse, réactivité et application à la préparation de polymères biodégradables)

TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF

Synthetic Glycopolypeptides as Biomimetic Analogues of Natural Glycoproteins

Glycoproteins are naturally produced by protein glycosylation and are involved in a wide range of cellular functions. This Review aims to summarize the preparation of well-defined synthetic glycoproteins by using chemical routes as well as to highlight the preparation of ideal polymeric analogues of natural glycoproteins: glycopolypeptides. These macromolecules are simplified models of glycoproteins and are designed with the purpose of both mimicking the properties of natural glycoproteins as well as bringing innovative polymeric structures for materials science applications

Multicompartmentalized polymeric systems: towards biomimetic cellular structure and function

The cell is certainly one of the most complex and exciting systems in Nature that scientists are still trying to fully understand. Such a challenge pushes material scientists to seek to reproduce its perfection by building biomimetic materials with high-added value and previously unmatched properties. Thanks to their versatility, their robustness and the current state of polymer chemistry science, we believe polymer-based materials to constitute or represent ideal candidates when addressing the challenge of biomimicry, which defines the focus of this review. The first step consists in mimicking the structure of the cell: its inner compartments, the organelles, with a multicompartmentalized structure, and the rest, i.e. the cytoplasm minus the organelles (mainly cytoskeleton/ cytosol) with gels or particular solutions (highly concentrated for example) in one compartment, and finally the combination of both. Achieving this first structural step enables us to considerably widen the gap of possibilities in drug delivery systems. Another powerful property of the cell lies in its metabolic function. The second step is therefore to achieve enzymatic reactions in a compartment, as occurs in the organelles, in a highly controlled, selective and efficient manner. We classify the most exciting polymersome nanoreactors reported in our opinion into two different subsections, depending on their very final concept or purpose of design. We also highlight in a thorough table the experimental sections crucial to such work. Finally, after achieving control over these prerequisites, scientists are able to combine them and push the frontiers of biomimicry further: from cell structure mimics towards a controlled biofunctionality. Such a biomimetic approach in material design and the future research it will stimulate, are believed to bring considerable enrichments to the fields of drug delivery, (bio)sensors, (bio)catalysis and (bio)technology