In vivo EPR extracellular pH-metry in tumors using a triphosphonated trityl radical.

Purpose: The ability to assess the extracellular pH (pHe) is an important issue in oncology, because extracellular acidification is associated with tumor aggressiveness and resistance to cytotoxic therapies. In this study, a stable triphosphonated triarylmethyl (TPTAM) radical was qualified as a pHe electron paramagnetic resonance (EPR) molecular reporter.

Methods: Calibration of hyperfine splitting as a function of pH was performed using a 1.

Delivery of siRNA targeting tumor metabolism using non-covalent PEGylated chitosan nanoparticles: Identification of an optimal combination of ligand structure, linker and grafting method.

PEGylated chitosan-based nanoparticles offer attractive platforms for siRNA cocktail delivery into tumors. Still, therapeutic efficacy requires us to select a rational combination of siRNAs and an efficient tumor delivery after systemic administration. Here, we showed that non-covalent PEGylation of chitosan-based nanoparticles loaded with siRNA targeting two key transporters of energy fuels for cancer cells, namely the lactate transporter MCT1 and the glutamine transporter ASCT2, could lead to significant antitumor effects.

Intracellular siRNA delivery dynamics of integrin-targeted, PEGylated chitosan-poly(ethylene imine) hybrid nanoparticles: A mechanistic insight.

Integrin-targeted nanoparticles are promising for the delivery of small interfering RNA (siRNA) to tumor cells or tumor endothelium in cancer therapy aiming at silencing genes essential for tumor growth. However, during the process of optimizing and realizing their full potential, it is pertinent to gain a basic mechanistic understanding of the bottlenecks existing for nanoparticle-mediated intracellular delivery. We designed αvβ3 integrin-targeted nanoparticles by coupling arginine-glycine-aspartate (RGD) or RGD peptidomimetic (RGDp) ligands to the surface of poly(ethylene glycol) (PEG) grafted chitosan-poly(ethylene imine) hybrid nanoparticles.

Functionalization of the PEG Corona of Nanoparticles by Clip Photochemistry in Water: Application to the Grafting of RGD Ligands on PEGylated USPIO Imaging Agent.

The fast development of nanomedicines requires more and more reliable chemical tools in order to accurately design materials and control the surface properties of the nano-objects used in biomedical applications. In this study we describe a smooth and simple photografting technique, i.e.

Self-assembling doxorubicin-tocopherol succinate prodrug as a new drug delivery system: synthesis, characterization, and in vitro and in vivo anticancer activity.

Self-assembled prodrugs forming nanoaggregates are a promising approach to enhance the antitumor efficacy and to reduce the toxicity of anticancer drugs. To achieve this goal, doxorubicin was chemically conjugated to d-α-tocopherol succinate through an amide bond to form N-doxorubicin-α-d-tocopherol succinate (N-DOX-TOS). The prodrug self-assembled in water into 250 nm nanostructures when stabilized with d-α-tocopherol poly(ethylene glycol) 2000 succinate.

(S)-1-(Pent-4'-enoyl)-4-(hydroxymethyl)-azetidin-2-one derivatives as inhibitors of human fatty acid amide hydrolase (hFAAH): synthesis, biological evaluation and molecular modelling.

A series of lipophilic ester derivatives (2a-g) of (S)-1-(pent-4'-enoyl)-4-(hydroxymethyl)-azetidin-2-one has been synthesised in three steps from (S)-4-(benzyloxycarbonyl)-azetidin-2-one and evaluated as novel, reversible, β-lactamic inhibitors of endocannabinoid-degrading enzymes (human fatty acid amide hydrolase (hFAAH) and monoacylglycerol lipase (hMAGL)). The compounds showed IC50 values in the micromolar range and selectivity for hFAAH versus hMAGL. The unexpected 1000-fold decrease in activity of 2a comparatively to the known regioisomeric structure 1a (i.

Macrocycle-embedded β-lactams as novel inhibitors of the Penicillin Binding Protein PBP2a from MRSA.

Assuming that bicyclic β-lactams endowed with high conformational adaptability should more easily form acyl-enzyme complexes with PBP2a than the traditional antibiotics, we have prepared a series of bis-2-oxo-azetidinyl macrocycles as potential inhibitors. The compounds are formally "head-head" (HH) cyclodimers of 1-(ω-alkenoyl)-3-(S)-(ω'-alkenoylamino)-2-azetidinones, with various lengths of the alkene chains, obtained by two successive metathesis reactions using the Grubbs catalyst. All compounds behave as acylating inhibitors of PBP2a and one β-lactam (5c), embedded into the largest ring (32 atoms), features an activity close to that of Ceftobiprole.

Polyethylene terephthalate membrane grafted with peptidomimetics: endothelial cell compatibility and retention under shear stress.

The present work aimed to treat a polyethylene terephthalate (PET) surface to make the biomaterial more 'attractive' in terms of attachment and shear stress response to endothelial cells with a view to possible applications in vascular grafting. A surface wet-chemistry protocol was applied to graft track-etched PET membranes with RGD peptidomimetics based on the tyrosine template and active at the nano-level vs. isolated human αvβ3 receptor, which was monitored by X-ray photoelectron spectroscopy, contact angle measurement and atomic force microscopy for characterization.

Targeted nanoparticles with novel non-peptidic ligands for oral delivery.

Orally administered targeted nanoparticles have a large number of potential biomedical applications and display several putative advantages for oral drug delivery, such as the protection of fragile drugs or modification of drug pharmacokinetics. These advantages notwithstanding, oral drug delivery by nanoparticles remains challenging. The optimization of particle size and surface properties and targeting by ligand grafting have been shown to enhance nanoparticle transport across the intestinal epithelium.

A pyrene- and phosphonate-containing fluorescent probe as guest molecule in a host polymer matrix.

New host-guest materials have been prepared by incorporation of a home-made organic probe displaying a pyrene motif and a phosphonate function into a regular amphiphilic copolymer. Using powder X-Ray diffraction, photoluminescence and FT-IR spectroscopy, we have been able to study the non-covalent interactions between the host matrix and the guest molecule in the solid state. Interestingly, we have shown that the matrix directs the guest spatial localization and alters its properties.

An unprecedented reversible mode of action of β-lactams for the inhibition of human fatty acid amide hydrolase (hFAAH).

A series of compound was prepared to clarify the reversible mechanism of β-lactamic hFAAH inhibitors on the one hand, and to modulate some of their physicochemical parameters on the other hand. In particular, two compounds (4b and 4e) were designed to display a potential good leaving group on the crucial carbonyl with a view to possibly acylating the active serine of the hFAAH catalytic triad. Reversibility studies showed that these two compounds retain the reversible mode of inhibition, suggesting a noncovalent interaction between our β-lactams and hFAAH.

Surface modification of polypropylene nonwovens with LDV peptidomimetics and their application in the leukodepletion of blood products.

For clinical indications and according to European standards, a depletion of the leukocytes from whole blood has to be realized before transfusion to a patient. In this study, the surface of a layer of meltblown oxygen-plasma treated polypropylene nonwoven (O(2)-PP), making part of the composition of leukodepletion filters, was modified with bioactive molecules to enhance the adhesion of leukocytes. These synthetic small molecules (called peptidomimetics) mimic the "Leu-Asp-Val" (LDV) tripeptide sequence recognized by the α(4)β(1) integrin, a receptor expressed on leukocytes.

Vibrational circular dichroism versus optical rotation dispersion and electronic circular dichroism for diastereomers: the stereochemistry of 3-(1'-hydroxyethyl)-1-(3'-phenylpropanoyl)-azetidin-2-one.

The absolute configuration of a relatively large and conformationally flexible chiral compound, 3-(1'-hydroxyethyl)-1-(3'-phenylpropanoyl)-azetidin-2-one, is determined using Vibrational Circular Dichroism (VCD) spectroscopy, Optical Rotation Dispersion (ORD) and Electronic Circular Dichroism (ECD). To that end a state of the art experimental VCD spectrum is compared to a theoretical spectrum and the absolute configuration is assigned. ORD and ECD are also used in the assignment to investigate the complementarity of the three techniques.

Degradation of bare and silanized silicon wafer surfaces by constituents of biological fluids.

The 24 h stability of bare silicon wafers as such or silanized with CH(3)O-(CH(2)-CH(2)-O)(n)-C(3)H(6)-trichlorosilane (n=6-9) was investigated in water, NaCl, phosphate and carbonate solutions, and in phosphate buffered saline (PBS) at 37 °C (close to biological conditions regarding temperature, high ionic strength, and pH). The resulting surfaces were analyzed using ellipsometry, X-ray Reflectometry (XRR), X-ray Photoelectron Spectroscopy (XPS), and Atomic Force Microscopy (AFM). Incubation of the silanized wafers in phosphate solution and PBS provokes a detachment of the silane layer.

Characterization of an endophytic whorl-forming Streptomyces from Catharanthus roseus stems producing polyene macrolide antibiotic.

An endophytic whorl-forming Streptomyces sp. designated as TS3RO having antifungal activity against a large number of fungal pathogens, including Sclerotinia sclerotiorum, Rhizoctonia solani, Colletotrichum gloeosporioides, Cryphonectria parasitica, Fusarium oxysporum, Pyrenophora tritici-repentis, Epidermophyton floccosum, and Trichophyton rubrum, was isolated from surface-sterilized Catharanthus roseus stems. Preliminary identification showed that Streptomyces cinnamoneus subsp.

Targeting of tumor endothelium by RGD-grafted PLGA-nanoparticles.

The destruction of the neovessels in solid tumors can cause the death of tumor cells resulting from the lack of oxygen and nutrients. Peculiarities of the tumor vasculature, however, also position angiogenic endothelial cells as obvious targets to address cytotoxic drugs into the tumor. In particular, the identification of a three-amino acids sequence, arginine-glycine-aspartate (RGD), as a fundamental recognition site for proliferating endothelial attachment to the extracellular matrix leads to the development of tumor-targeting ligands for nanoparticles.

Synthesis of poly(lactide-co-glycolide-co-ε-caprolactone)-graft-mannosylated poly(ethylene oxide) copolymers by combination of "clip" and "click" chemistries.

Poly(lactide-co-glycolide) (PLGA) is extensively used in pharmaceutical applications, for example, in targeted drug delivery, because of biocompatibility and degradation rate, which is easily tuned by the copolymer composition. Nevertheless, synthesis of sugar-labeled amphiphilic copolymers with a PLGA backbone is quite a challenge because of high sensitivity to hydrolytic degradation. This Article reports on the synthesis of a new amphiphilic copolymer of PLGA grafted by mannosylated poly(ethylene oxide) (PEO).

A phosphonated triarylmethyl radical as a probe for measurement of pH by EPR.

A new water soluble phosphonated tetrathiatriarylmethyl radical has been synthesized and its application for pH measurement in a physiological range by EPR is reported.

Inhibitors of the endocannabinoid-degrading enzymes, or how to increase endocannabinoid's activity by preventing their hydrolysis.

Endocannabinoids are lipid transmitters binding and activating the cannabinoid receptors. Both cannabinoid receptors and endocannabinoids, such as 2-arachidonoylglycerol and anandamide, have been shown to control numerous physiological and pathological processes, including in the central nervous system. Thus regulating endocannabinoid levels in-vivo represents an interesting therapeutic perspective in several CNS-related diseases.

Non-symmetrically substituted phenoxazinones from laccase-mediated oxidative cross-coupling of aminophenols: an experimental and theoretical insight.

Oxidative cross-coupling reactions of substituted o-aminophenols were catalyzed by a commercial laccase to produce non-symmetrically substituted phenoxazinones for the first time. Identification by (1)H-, (13)C- and (31)P-NMR, and by HPLC-PDA and HPLC-MS/MS of exclusively two kinds of substituted phenoxazinones out of four potential heterocyclic frameworks was confirmed by a DFT study. The redox-properties of the substrates, their relative rates of conversion and the rigid docking of selected substrates led to a revisited mechanistic pathway for phenoxazinones biosynthesis.

12- to 22-membered bridged β-lactams as potential penicillin-binding protein inhibitors.

As potential inhibitors of penicillin-binding proteins (PBPs), we focused our research on the synthesis of non-traditional 1,3-bridged β-lactams embedded into macrocycles. We synthesized 12- to 22-membered bicyclic β-lactams by the ring-closing metathesis (RCM) of bis-ω-alkenyl-3(S)-aminoazetidinone precursors. The reactivity of 1,3-bridged β-lactams was estimated by the determination of the energy barrier of a concerted nucleophilic attack and lactam ring-opening process by using ab initio calculations.

LDV peptidomimetics equipped with biotinylated spacer-arms: synthesis and biological evaluation on CCRF-CEM cell line.

The tripeptide Leu-Asp-Val (LDV) is known to bind α(4)β(1) integrin in leukemia cells. Here we have synthesized a LDV peptidomimetic equipped with a biotin-conjugated spacer-arm. Compound 9 acts as an inhibitor of the α(4)β(1) integrin in an adhesion assay using fluorescently labeled, α(4)β(1) integrin-expressing leukemia CCRF-CEM cells.

DOSY-NMR analysis of ring-closing metathesis (RCM) products from β-lactam precursors.

The discrimination between cyclomonomers and various oligomers formed during a ring-closing metathesis (RCM) process is not an easy task. Their (1)H NMR patterns are often very similar, and the use of mass spectrometry techniques is usually recommended. Here, we show that the DOSY-NMR method is a reliable tool to help in the identification of cyclomonomers versus cyclodimers by comparing the translational diffusion coefficient of the compounds issued from RCM reactions with the diffusion coefficient of their respective precursors.

Benzisothiazolinone as a useful template for the design of new monoacylglycerol lipase inhibitors: investigation of the target residues and comparison with octhilinone.

The regulation of 2-arachidonoylglycerol (2-AG) levels is a major issue as 2-AG has been proven to participate in numerous physiopathological phenomena such as neuroprotection or analgesia. Octhilinone, a cysteine-reagent compound, has recently been shown to inhibit in the nanomolar range monoacylglycerol lipase (MAGL), the major enzyme responsible for the degradation of 2-AG. Here, we further investigate the mechanism by which octhilinone and its benzisothiazolinone analog inhibit human MAGL.

Spin transition sensors based on β-amino-acid 1,2,4-triazole derivative.

A β-aminoacid ester was successfully derivatized to yield to 4H-1,2-4-triazol-4-yl-propionate (βAlatrz) which served as a neutral bidentate ligand in the 1D coordination polymer [Fe(βAlatrz)(3)](CF(3)SO(3))(2)·0.5H(2)O (1·0.5H(2)O).