Design, synthesis and structural evaluation of peptidomimetics with a defined secondary structure

The synthesis of new delta-amino acids based on a gamma-butyrolactone ring was performed and they were inserted into various peptidomimetics for conformational studies. Some non-substituted and substituted butyrolactone building blocks were prepared by various methods. Then, homopeptides as well as mixed peptides were prepared and their secondary structures analysed by various techniques including 2d-NMR, CD spectroscopy and IR in solution. In the second part of this project, some building blocks based on a diketopiperazine scaffold were prepared and inserted into homopolymers and cyclic peptidomimetics for secondary structure evaluation. In addition to these peptides, some potential organocatalysts containing the diketopiperazine scaffold were also prepared

Improved racemate resolution of pentan-2-ol and trans-(Z)-cyclooct-5-ene-1,2-diol by lipase catalysis

International audienceLipases are important catalysts in chiral synthesis due to their wide substrate recognition combined witha high stereoselectivity. We demonstrate here that the state, free or immobilized, of Candida antarcticalipase B (CaLB) affects enantioselectivity and also alters the temperature dependancy of the enzyme. Thisindicates that CaLB undergoes various conformations induced by its interaction with the different immo-bilization supports studied. Molecular imprinting experiments, using immobilized enzyme co-dried withmimic substrate molecules, enhanced the enantiomeric ratio two-fold or three-fold, depending on theimmobilization support. The structure of the acyl donor has a pronounced effect on CaLB catalyzed res-olution, due to the proximity of the acyl and alcohol moieties during catalysis. When the acylation ofpentan-2-ol was examined, we found that the 3C methyl propanoate donor afforded the highest resolu-tion. Trans-(Z)-cyclooct-5-en-1,2-diol was used as a model racemic substrate to study the ability of lipaseto catalyze the resolution of difunctionalized compounds. There was a clear enhancement in the enan-tiomer selectivity of the biotransformation of the diol when vinyl butanoate is used as the acyl donor. Theconversion and enantiomeric excess of (1R,2R)-monoacetates were enhanced, using immobilized CaLB,when the chain length of the donors increased from C2 to C4

Synthesis of 2-Mercapto-(2-Oxoindolin-3-Ylidene)Acetonitriles from 3-(4-Chloro-5H-1,2,3-Dithiazol-5-Ylidene)Indolin-2-ones

International audienceAlkylidene oxindoles are important functional moieties and building blocks in pharmaceutical and synthetic chemistry. Our interest in biologically active compounds focused our studies on the synthesis of novel oxindoles, bearing on the exocyclic double bond at the C8, CN, and S groups. Extending the potential applications of Appel’s salt, we developed a new synthetic approach by investigating the reactions of C5-substituted 2-oxindoles with 4,5-dichloro-1,2,3-dithiazolium chloride (Appel’s salt) to give original (Z)-3-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)indolin-2-one derivatives, and new 2-mercapto-(2-oxoindolin-3-ylidene)acetonitriles via a dithiazole ring-opening reaction. The work described in this article represents further applications of Appel’s salt in the conception of novel heterocyclic rings, in an effort to access original bioactive compounds. Fifteen new compounds were prepared and fully characterized

Nanoparticles Produced by Ring-Opening Metathesis Polymerization Using Norbornenyl-poly(ethylene oxide) as a Ligand-Free Generic Platform for Highly Selective In Vivo Tumor Targeting

We described a norbornenyl-poly(ethylene oxide) nanoparticles ligand-free generic platform, made fluorescent with straightforward preparation by ring-opening metathesis polymerization (ROMP). Our method allowed to easily obtain a drug delivery system (DDS) with facilitated functionalization by means of azide-alkyne click chemistry and with a high selectivity for the tumor in vivo, while cellular internalization is obtained without cell targeting strategy. We demonstrated that our nanoparticles are internalized by endocytosis and colocalized with acidic intracellular compartments in two models of aggressive tumoral cell lines with low prognostic and limited therapeutic treatments. Our nanoparticles could be of real interest to limit the toxicity and to increase the clinical benefit of drugs suffering rapid clearance and side effects and an alternative for cancers with poorly efficient therapeutic solutions by associating the drug delivery in the tumor tissue with an acid-sensitive release system

Complexes de lanthanides à base de dendrimères

The present invention relates to a complex comprising at least one dendrimer and at least one lanthanide, in which the dendrimer comprises a unit of formula (I), wherein: C1 is a group with a valency of 4 of formula >N-CH2-CH2-NN-CH2-CH2-N<; - A1, A2 et A3 sont des groupes de formule -(CH2)2-C(O)-NH-(CH2)2-; ledit motif de formule (I) étant relié de façon covalente à au moins une antenne qui absorbe à une longueur d'onde allant de 500 nm à 900 nm

Cathepsin D activity and selectivity in the acidic conditions of a tumor microenvironment: Utilization in the development of a novel Cathepsin D substrate for simultaneous cancer diagnosis and therapy

International audienc

Histone Deacetylase Inhibitors Delivery using Nanoparticles with Intrinsic Passive Tumor Targeting Properties for Tumor Therapy

Fast clearance, metabolism and systemic toxicity are major limits for the clinical use of anti-cancer drugs. Histone deacetylase inhibitors (HDACi) present these defects despite displaying promising anti-tumor properties on tumor cells in vitro and in in vivo model of cancers. Specific delivery of anti-cancer drugs into the tumor should improve their clinical benefit by limiting systemic toxicity and by increasing the anti-tumor effect. In this work, we describe a simple and flexible polymeric nanoparticle platform highly targeting the tumor in vivo and triggering impressive tumor weight reduction when functionalized with HDACi. Our nanoparticles were produced by Ring Opening Metathesis Polymerization of azido-polyethylene oxide-norbornene macromonomers and functionalized using click chemistry. Using an orthotopic model of peritoneal invasive cancer, a highly selective accumulation of the particles in the tumor was obtained. A combination of epigenetic drugs involving a pH-responsive histone deacetylase inhibitor (HDACi) polymer conjugated to these particles gave 80% reduction of tumor weight without toxicity whereas the free HDACi has no effect. Our work demonstrates that the use of a nanovector with theranostic properties leads to an optimized delivery of potent HDACi in tumor and then, to an improvement of their anti-tumor properties in vivo

Histone deacetylase inhibitor-polymer conjugate nanoparticles for acid-responsive drug delivery

We report the synthesis of acid responsive polymeric nanoparticles (NPs) consisting of a polymerhistone deacetylase inhibitor conjugate. An innovative aspect of this drug delivery particle lies in the NP conjugation of a histone deacetylase (HDAC) inhibitor, CI-994 (Tacedinaline), introduced with a clickable acid-responsive prodrug during monomer synthesis, prior to polymerization. Another novelty lies in the selected norbornene (NB)-polyethylene oxide (PEO) macromonomer allowing standardization of the polymerization process by Ring-Opening Metathesis Polymerization (ROMP) and functionalization through azide-allcyne click chemistry. Herein we demonstrate that the synthesized polymer gave 300 nm core-shell spherical nanoparticles with low dispersity (0.04), high water dispersability thanks to the PEO shell and well controlled HDAC inhibitor prodrug loading. Bioluminescence Resonance Energy Transfer (BRET) assay in living cells and viability experiments demonstrated efficient cellular internalization without additional chemistry, drug release inside cells with restoration of the HDAC inhibition and induction of apoptosis. Such NPs should minimize drug release in vivo during blood circulation and trigger intracellular delivery after endocytosis, holding promises for improved efficacy of this class of epigenetic inhibitors. This standardized synthesis paves the way for multifunctional nanoparticles synthesis