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Aims: This study aims, on the one hand, to establish the chemical composition and to evaluate the antioxidant potential of essential oils (EO) of Guarea cedrata leaves and root bark, and on the other hand, to determine the antimicrobial activity of the leaf EO. Methodology: The EOs were analyzed by a combination of GC (Ir), GC-MS and 13C NMR. The antibacterial and antifungal activity of the essential oils was determined and then the antioxidant activity was also evaluated. Results: 40 hydrocarbon (19.8%) and oxygenated (73.3%) sesquiterpenes were identified from root bark EO, representing 93.1% of the total composition, and 55 compounds were identified from leaf EO, representing 91.5% of the total composition, with 58.1% sesquiterpene hydrocarbons, 32.4% oxygenated sesquiterpenes and 1.0% hydrocarbon monoterpenes. An evaluation of the antioxidant potential of these EOs revealed moderate free radical scavenging activity of G. cedrata leaf EO compared to quercetin. Leaf EO tested on bacteria and yeast showed bacteriostatic activity against bacterial strains of Escherichia coli, Salmonella typhimurium, Bacillus subtilis and Candida albicans at a concentration of 6.3 mg/ml and bactericidal activity at a concentration of 50 mg/ml. Conclusion: This study highlighted the chemical composition, the antiradical and biological activity of the essential oils of two organs (leaf and trunk bark) organs of G. cedrata.

Time lapse showing cell aggregation during neurosphere formation in control condition.

Supplementary figures providing additionnal information concerning: - The cells glycome before and after PST3.1a treatment as measured by mass spectrometry (Supp. Figure 1) or Glycoprofile (Supp. Figure 2) - The absence of effect of PST3.1a on O-Glycosylation (Supp. Figure 3) - Western blot quantifications (Supp. Figure 4) - The inhibition of cell invasion in matrigel by PST3.1a (Supp. Figure 5) - The absence of cytotoxicity on non-proliferating PBMC cells (Supp. Figure 6).

Time lapse showing cell aggregation during neurosphere formation in PST3.1a-treated condition. In this condition, less cell aggregation is visible as compared to the control condition.

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor and accounts for a significant proportion of all primary brain tumors. Median survival after treatment is around 15 months. Remodeling of N-glycans by the N-acetylglucosamine glycosyltransferase (MGAT5) regulates tumoral development. Here, perturbation of MGAT5 enzymatic activity by the small-molecule inhibitor 3-hydroxy-4,5-bis-benzyloxy-6-benzyloxymethyl-2-phenyl2-oxo-2λ5-[1,2]oxaphosphinane (PST3.1a) restrains GBM growth. In cell-based assays, it is demonstrated that PST3.1a alters the β1,6-GlcNAc N-glycans of GBM-initiating cells (GIC) by inhibiting MGAT5 enzymatic activity, resulting in the inhibition of TGFβR and FAK signaling associated with doublecortin (DCX) upregulation and increase oligodendrocyte lineage transcription factor 2 (OLIG2) expression. PST3.1a thus affects microtubule and microfilament integrity of GBM stem cells, leading to the inhibition of GIC proliferation, migration, invasiveness, and clonogenic capacities. Orthotopic graft models of GIC revealed that PST3.1a treatment leads to a drastic reduction of invasive and proliferative capacity and to an increase in overall survival relative to standard temozolomide therapy. Finally, bioinformatics analyses exposed that PST3.1a cytotoxic activity is positively correlated with the expression of genes of the epithelial–mesenchymal transition (EMT), while the expression of mitochondrial genes correlated negatively with cell sensitivity to the compound. These data demonstrate the relevance of targeting MGAT5, with a novel anti-invasive chemotherapy, to limit glioblastoma stem cell invasion. Mol Cancer Res; 15(10); 1376–87. ©2017 AACR.

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Reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) and the hydroxyl radical (•OH) have specific functions in biological processes, while their uncontrolled production and reactivity are known to be determining factors in pathophysiology. Methionine (Met) residues act as endogenous antioxidants, when they are oxidized into methionine sulfoxide (MetSO), thus depleting ROS and protecting the protein. We employed tandem mass spectrometry combined with IR multiple photon dissociation spectroscopy to study the oxidation induced by OH radicals produced by γradiolysis on model cyclic dipeptides c(LMetLMet), c(LMetDMet), and c(GlyMet). Our aim was to characterize the geometries of the oxidized peptides in the gas phase and to understand the relationship between the structure of the 2-center 3-electron (2c-3e) free radical formed in the first step of the oxidation process and the final compound. Density functional theory calculations were performed to characterize the lowest energy structures of the final product of oxidation and to interpret the IR spectra. Collision-induced dissociation tandem mass spectrometry (CID-MS2) experiments of oxidized c(LMetLMet)H+ and c(LMetDMet)H+ led to the loss of one or two oxidized sulfenic acid molecules, indicating that the addition of one or two oxygen atoms occurs on the sulfur atom of both methionine side chains and no sulfone formation was observed. The CID-MS2 fragmentation mass spectrum of oxidized c(GlyMet)H+ showed only the loss of one oxidized sulfenic acid molecule. Thus, the final products of oxidation are the same regardless of the structure of the precursor sulfur-centered free radical.

International audience; Phosphoramidates obtained according to the ProTide strategy are known for their ability to increase the biological activity of various nucleosides. A series of such prodrugs of SRO-91, a non-natural ribofuranosyl-1,2,3-triazole C-nucleoside obtained by a synthetic sequence involving an indium mediated alkynylation and a Huisgen cycloaddition, was prepared and the antitumor activity on 3 strains of tumor cells was investigated. Two compounds 9a and 9c exhibited interesting cell proliferative inhibitions (IC50 = 2.5–12.1 µM) on two cell lines (pancreas and lung). Moreover, concerning the antiviral activity, another phosphoramidate 14 bearing a different aryl masking group exhibited an IC50 of 5 µM on Crimean-Congo Hemorrhagic Fever orthonairovirus. In both cases, free SRO-91 presented no activity on these cell lines.

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Phosphonates and its derivatives widely represent important pharmacophores in various classes of therapeutic agents from antivirals to antibiotics. Among these phosphonylated compounds, 1-hydroxymethylene-1,1-bisphosphonates (HMBPs) have occupied a very important place for thirty years now and are currently used in medicine for their inhibitory properties of bone resorption. HMBPs also exhibit direct and indirect antitumor effects in vitro against a broad variety of tumor cell lines, including melanoma, mesothelioma, prostate and breast, lung and myeloma cancer cells. This review will discuss the various syntheses of bisphosphonates with the goal of illustrating their potential interest for the development of therapeutic agents. We will also disclose our latest achievements in phosphinate chemistry.

International audience; The design of high-performance energy-converting materials is an essential step for the development of sensors, but the production of the bulk materials currently used remains costly and difficult. Therefore, a different approach based on the self-assembly of nanoparticles has been explored. We report on the preparation by solvothermal synthesis of highly crystalline CeF 3 nanodiscs. Their surface modification by bisphosphonate ligands led to stable, highly concentrated, colloidal suspensions in water. Despite the low aspect ratio of the nanodiscs (∼6), a liquidcrystalline nematic phase spontaneously appeared in these colloidal suspensions. Thanks to the paramagnetic character of the nanodiscs, the nematic phase was easily aligned by a weak (0.5 T) magnetic field, which provides a simple and convenient way of orienting all of the nanodiscs in suspension in the same direction. Moreover, the more dilute, isotropic, suspensions displayed strong (electric and magnetic) fieldinduced orientation of the nanodiscs (Kerr and Cotton−Mouton effects), with fast enough response times to make them suitable for use in electro-optic devices. Furthermore, an emission study showed a direct relation between the luminescence intensity and magnetic-field-induced orientation of the colloids. Finally, with their fast radiative recombination decay rates, the nanodiscs show luminescence properties that compare quite favorably with those of bulk CeF 3. Therefore, these CeF 3 nanodiscs are very promising building blocks for the development and processing of photosensitive materials for sensor applications.

Neuroinflammation is a process common to several brain pathologies. Despites its medical relevance, it still remains poorly understood; there is therefore a need to develop new in vivo preclinical imaging strategies to monitor inflammatory processes longitudinally. We here present the development of a hybrid imaging nanoprobe named NP3, that was specifically designed to get internalized by phagocytic cells and imaged in vivo with MRI and bi-photon microscopy. NP3 is composed of a 16 nm core of gadolinium fluoride (GdF3), coated with bisphosphonate polyethylene glycol (PEG) and functionalized with a Lemke-type fluorophore. It has a hydrodynamic diameter of 28 ± 8 nm and a zeta potential of -42 ± 6 mV. The MR relaxivity ratio at 7 T is r1/r2 = 20; therefore, NP3 is well suited as a T2/T2* contrast agent. In vitro cytotoxicity assessments performed on four human cell lines revealed no toxic effects of NP3. In addition, NP3 is internalized by macrophages in vitro without inducing inflammation or cytotoxicity. In vivo, uptake of NP3 has been observed in the spleen and the liver. NP3 has a prolonged vascular remanence, which is an advantage for macrophage uptake in vivo. The proof-of-concept that NP3 may be used as a contrast agent targeting phagocytic cells is provided in an animal model of ischemic stroke in transgenic CX3CR1-GFP/+ mice using three complementary imaging modalities: MRI, intravital two-photon microscopy and phase contrast imaging with synchrotron X-rays. In summary, NP3 is a promising preclinical tool for the multiscale and multimodal investigation of neuroinflammation.

International audience; Neuroinflammation is a process common to several brain pathologies. Despites its medical relevance, it still remains poorly understood; there is therefore a need to develop new in vivo imaging strategies to monitor inflammatory processes longitudinally. We here present the development of a hybrid imaging nanoprobe named NP3, that was specifically designed to get internalized by phagocytic cells and imaged in vivo with MRI and bi-photon microscopy. NP3 is composed of a 16 nm core of gadolinium fluoride (GdF3), coated with bisphosphonate polyethylene glycol (PEG) and functionalized with a Lemke-type fluorophore (LEM-A). It has a hydrodynamic diameter of 28±8 nm and a zeta potential of-42±6 mV. The MR relaxivity ratio at 7T is r1/r2 = 20; therefore, NP3 is well suited as a T2/T2* contrast agent. In vitro cytotoxicity assessments performed on four human cell lines revealed no toxic effects of NP3. In addition, NP3 is internalized by macrophages in vitro without inducing inflammation or cytotoxicity. In vivo, uptake of NP3 has been observed in the spleen and the liver. NP3 has a prolonged vascular remanence, which is an advantage for macrophage uptake in vivo. The proof-of-concept that NP3 may be used as a contrast agent targeting phagocytic cells is provided in an animal model of ischemic stroke in transgenic CX3CR1-GFP/+ mice using three complementary imaging modalities: MRI, intravital two-photon microscopy and phase contrast imaging with synchrotron X-rays. In summary, 2 NP3 is a promising preclinical tool for the multiscale and multimodal investigation of neuroinflammation.

The synthesis of a new set of triazole bisphosphonates 8a-d and 9a-d presenting an alkyl or phenyl substituent at the C-4 or C-5 position of the triazole ring is described. These compounds have been evaluated for their antiproliferative activity against MIA PaCa-2 (pancreas), MDA-MB-231 (breast) and A549 (lung) human tumor cell lines. 4-hexyl- and 4-octyltriazole bisphosphonates 8b-c both displayed remarkable antiproliferative activities with IC50 values in the micromolar range (0.75–2.4 μM) and were approximately 4 to 12-fold more potent than zoledronate. Moreover, compound 8b inhibits geranylgeranyl pyrophosphate biosynthesis in MIA PaCa-2 cells which ultimately led to tumor cells death.

We present a 1H Nuclear Magnetic Resonance (NMR) relaxometry experimental investigation of two series of magnetic nanoparticles, constituted of a maghemite core with a mean diameter dTEM = 17 &plusmn, 2.5 nm and 8 &plusmn, 0.4 nm, respectively, and coated with four different negative polyelectrolytes. A full structural, morpho-dimensional and magnetic characterization was performed by means of Transmission Electron Microscopy, Atomic Force Microscopy and DC magnetometry. The magnetization curves showed that the investigated nanoparticles displayed a different approach to the saturation depending on the coatings, the less steep ones being those of the two samples coated with P(MAA-stat-MAPEG), suggesting the possibility of slightly different local magnetic disorders induced by the presence of the various polyelectrolytes on the particles&rsquo, surface. For each series, 1H NMR relaxivities were found to depend very slightly on the surface coating. We observed a higher transverse nuclear relaxivity, r2, at all investigated frequencies (10 kHz &le, &nu, L &le, 60 MHz) for the larger diameter series, and a very different frequency behavior for the longitudinal nuclear relaxivity, r1, between the two series. In particular, the first one (dTEM = 17 nm) displayed an anomalous increase of r1 toward the lowest frequencies, possibly due to high magnetic anisotropy together with spin disorder effects. The other series (dTEM = 8 nm) displayed a r1 vs. &nu, L behavior that can be described by the Roch&rsquo, s heuristic model. The fitting procedure provided the distance of the minimum approach and the value of the N&eacute, el reversal time (&tau, &asymp, 3.5 &divide, 3.9&middot, 10&minus, 9 s) at room temperature, confirming the superparamagnetic nature of these compounds.

An easily handled one-pot synthetic procedure was previously developed for the synthesis of bisphosphinates starting from acyl chlorides. Herein, other trivalent derivatives as acid anhydrides and activated esters were tested to form various bisphosphinates. This modulation of the reactivity can be controlled according to the nature of the acid derivative for the use of sensitive and functionalized substrates.

A general synthetic procedure was developed for H-α-hydroxyphosphinates via Abramov reaction. The present work is a complementary study to those reported till now. This methodology has the advantage that it can be applied to various aliphatic and (hetero)aromatic substrates. The H-α-hydroxyphosphinates were easily purified and obtained in good to excellent yields in shorter times. A 31P NMR spectroscopy study has shown that only 2 equivalents of a silylating agent were required.

The use of phosphonate ligands to modify the nanoparticle (NPs) surface has attracted a strong interest in the last years for the design of highly functional hybrid materials. Here, we applied a methodology to synthesize bisphosphonates having functionalized PEG side chains with a specific length in order to design a novel class of hybrid nanomaterials composed by tetraphosphonate-complex-gold COOH-terminated PEG-coated NPs (Bis-PO-PEG-AuNPs). The synthetic approach consist in three steps: (1) Complexation between new phosphonate ligands (Bis PO) and tetrachloroauric acid (HAuCl4) to form gold clusters; (2) adsorption of COOH-terminated PEG molecules (PEG) onto Bis PO-Au complex; (3) reduction of metal ions in that vicinity, growth of gold particles and colloidal stabilization. The obtained snow-shape-like hybrid nanoparticles, have been characterized by ultra-violet/visible, Raman spectroscopies, and electron microscopy imaging, involving their optical properties and photothermal activity in pancreatic adenocarcinoma cancer cells (PDAC).

A practical generalisable procedure to synthesize hydroxymethylene H-bisphosphinates has been optimised. Unlike previous reports, numerous alkyl (including an alendronate bisphosphinate analogue) or (hetero)aryl compounds were rapidly obtained in satisfactory to excellent yields. A side product could have been identified as a phosphino-phosphonate isomer and plausible mechanistic pathways are proposed here. Moreover to check the literature data, a pKa value study was also performed.

A fast and sensitive colorimetric assay for the determination of prostatic acid phosphatase (PAP) levels using biphosphonates-PEG-coated gold nanoparticles (BP-PEG-AuNPs) has been developed. Addition of different amounts of PAP to the AuNPs results in a significant change of color, from a red-wine color to purple, and finally to blue. The PAP should bind onto the AuNPs surface and crosslink the AuNPs inducing their aggregation and as a consequence a color change of the solution from wine red to purple/blue. The color change was monitored by UV–vis spectrophotometry or with the naked eye. The ensuing concentration-dependent red-shift of surface plasmon resonance absorption allows the determination concentration within the fg range in 10 min. Importantly, the visual detection limit (1 ng/mL) allows the rapid differential diagnosis with naked eye or image analyzer. This demonstrates that the color modification observed with BP-PEG-AuNP is effectively due to an interaction between PAP and BP. Keywords: Prostatic acid phosphatase, Gold nanoparticles, Bisphosphonates, Colorimetric detection, Localized surface plasmon resonance

A convenient and generalizable procedure has been optimized to access to 1-hydroxymethylene-1,1-bisphosphinate compounds. Several alkyl, including an alendronate bisphosphinate analog, and (hetero)...

The design of high-performance energy-converting materials is an essential step for the development of sensors, but the production of the bulk materials currently used remains costly and difficult. Therefore, a different approach based on the self-assembly of nanoparticles has been explored. We report on the preparation by solvothermal synthesis of highly crystalline CeF

Large series of novel N-bis-1,2,3-triazolo-linked-1,5-benzodiazepin-2-ones (BZD) have been synthesized under microwave irradiation through a Cu(I)-catalyzed double 1,3-dipolar alkyne-azide coupling reaction. This process is of considerable synthetic advantages in terms of time saving and remarkable yields. The chemical structures of the isolated compounds have been elucidated on the basis of extensive spectroscopic methods including 1D & 2D NMR, IR and HRMS. All the synthesized compounds have been evaluated for their antimicrobial and antioxidant activities. In vitro antimicrobial environment, almost all of compounds have shown an interesting activity. Among the dimers of 1,5-benzodiazepine-1,2,3-triazole compounds tested, the results revealed that the potent antibacterial was recorded to compounds 3g,l for Gram-positive (within MIC = 31.25 and 125 μg/mL), and 3h,k for Gram-negative (within MIC = 31.25 and 125 μg/mL). Besides, the results demonstrate that compounds 3h,k have demonstrated the strongest potential against all the tested fungus (within MIC = 62.5 and 125 μg/mL). The antioxidant evaluation indicated that most compounds exhibited a moderate to good biological activity.

Bisphosphonates are well established pharmaceutical drugs with wide applications in medicine. Nevertheless, the side chain and the nature of phosphorous groups could induce a poor aqueous solubility and act on their bioavailability. At the same time, cyclodextrins are cage molecules that facilitate transport of hydrophobic molecules to enhance the intestinal drug absorption of these molecules by forming inclusion complexes. Here we demonstrate that cyclodextrins could be used as a bisphosphonate carrier. The formation of cyclodextrins-bisphosphonate complexes was characterized by 1D and 2D NMR spectroscopy, Isothermal Titration Calorimetry and UV-vis spectroscopy. The results revealed that only the side chain of bisphosphonate was involved in the inclusion phenomenon and its length was a crucial parameter in the control of affinity. Findings from this study suggest that cyclodextrin will be a useful carrier for bisphosphonates.

International audience; Real time in vivo detection of Amyloid β (Aβ) deposits at an early stage may lead to faster and more conclusive diagnosis of Alzheimer’s disease (AD) and can facilitate the follow up of the effect of therapeutic interventions. In this work, the capability of new hybrid nanomaterials to target and detect Aβ aggregates using magnetic resonance (MRI) and fluorescence imaging is demonstrated. These smart contrast agents contain paramagnetic nanoparticles surrounded by luminescent conjugated oligothiophenes (LCOs) known to selectively bind to Aβ aggregates, with emission spectra strongly dependent on their conformations, opening the possibilities for several fluorescence imaging modes for AD diagnostics. Relaxivity is evaluated in vitro and ex vivo. The capability of these contrast media to link to Aβ fibrils in stained sections is revealed using transmission electron microscopy and fluorescence microscopy. Preliminary in vivo experiments show the ability of the contrast agent to diffuse through the blood–brain barrier of model animals and specifically stain amyloid deposits.

This paper describes the preparation and the biological evaluation of α-halogenated oxaphosphinanes. These halogen derivatives were synthetized from a short and stereoselective synthetic sequence starting by previously described hydroxy-precursors 1 and 2 with respectively a glucose and mannose-like configuration. The in vitro biological tests of these unnatural halogenated phosphinosugars, on several cell lines, highlighted, for some of them, their antiproliferative and anti migration and invasion properties at nanomolar concentration.

Eighteen different bisphosphonates, including four clinically used bisphosphonate acids and their phosphoesters, were studied to evaluate how the bisphosphonate structure affects binding to bone. Bisphosphonates with weak bone affinity, such as clodronate, could not bind to hydroxyapatite after the addition of one ester group. Medronate retained its ability to bind after the addition of one ester group, and hydroxy-bisphosphonates could bind even after the addition of two ester groups. Thus, several bisphosphonate esters are clearly bone binding compounds. The following conclusions about bisphosphonate binding emerge: (1) a hydroxyl group in the geminal carbon takes part in the binding process and increases the bisphosphonate's ability to bind to bone; (2) the bisphosphonate's ability to bind decreases when the amount of ester groups increases; and (3) the location of the ester groups affects the bisphosphonate's binding ability.

Three chiral phosphonoacetamides were prepared by an alternative method . For this purpose, 2-(diethoxyphosphoryl)acetic acid was prepared from ethyl 2-bromoacetate by treatment of P(OEt) 3 followed by saponification of the ester with K 2CO 3. BOP activated amidation of the 2-(diethoxyphosphoryl)acetic acid with (S)-amino acids gave the corresponding phosphonoaceteamides. Growth inhibition of two phosphonoacetamides on Paramecium sp. were studied.

In recent years, bisphosphonate chemistry has undergone an exponential growth due to the potential applications of these compounds in medicine and nanobiomaterial research. In this paper we describe the synthesis methods of different families of methacrylic monomers bearing a bisphosphonate with varying lengths of the chain, PEG linkers and more or less hydrolysable functions such as ester, carbamate or amide.

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor and accounts for a significant proportion of all primary brain tumors. Median survival after treatment is around 15 months. Remodeling of N-glycans by the N-acetylglucosamine glycosyltransferase (MGAT5) regulates tumoral development. Here, perturbation of MGAT5 enzymatic activity by the small-molecule inhibitor 3-hydroxy-4,5-bis-benzyloxy-6-benzyloxymethyl-2-phenyl2-oxo-2λ5-[1,2]oxaphosphinane (PST3.1a) restrains GBM growth. In cell-based assays, it is demonstrated that PST3.1a alters the β1,6-GlcNAc N-glycans of GBM-initiating cells (GIC) by inhibiting MGAT5 enzymatic activity, resulting in the inhibition of TGFβR and FAK signaling associated with doublecortin (DCX) upregulation and increase oligodendrocyte lineage transcription factor 2 (OLIG2) expression. PST3.1a thus affects microtubule and microfilament integrity of GBM stem cells, leading to the inhibition of GIC proliferation, migration, invasiveness, and clonogenic capacities. Orthotopic graft models of GIC revealed that PST3.1a treatment leads to a drastic reduction of invasive and proliferative capacity and to an increase in overall survival relative to standard temozolomide therapy. Finally, bioinformatics analyses exposed that PST3.1a cytotoxic activity is positively correlated with the expression of genes of the epithelial–mesenchymal transition (EMT), while the expression of mitochondrial genes correlated negatively with cell sensitivity to the compound. These data demonstrate the relevance of targeting MGAT5, with a novel anti-invasive chemotherapy, to limit glioblastoma stem cell invasion. Mol Cancer Res; 15(10); 1376–87. ©2017 AACR.

Controlling the interactions of functional nanostructures with water and biological media represents high challenges in the field of bioimaging applicationS. Large contrast at low doses, high colloidal stability in physiological conditions, the absence of cell cytotoxicity, and efficient cell internalization represent strong additional needs. To achieve such requirements, we report on high-payload magnetofluorescent architectures made of a shell of superparamagnetic iron oxide nanoparticles tightly anchored around fluorescent organic nanoparticles. Their external coating is simply modulated using anionic polyelectrolytes in a final step to provide efficient magnetic resonance imaging (MRI) and fluorescence imaging of live cells. Various structures of PEGylated polyelectrolytes have been synthesized and investigated, differing from their iron oxide complexing units (carboxylic vs phosphonic acid), their structure (block-or tomblike), their hydrophobicity; and their fabrication process [conventional:or reversible addition fragmentation chain transfer (RAFT)-controlled radical polymerization] while keeping the central magnetofluorescent platforms the same. Combined photophysical, magnetic, NMRD, and structural investigations proved the superiority of RAFT polymer coatings containing carboxylate units and a hydrophobic tail to impart the magnetic nanoassemblies (NAs) with enhanced-MRI negative contrast, characterized by a high r(2)/r(1) ratio and a transverse relaxation r(2) equal to 21 and 125 s(-1) mmol(-1) L, respectively, at 60 MHz clinical frequency (similar to 1.5 T). Thanks to their dual Modality, cell internalization of the NAs in mesothelioma cancer cells could be evidenced by both confocal fluorescence microscopy and magnetophoresis. A 72 h follow-up showed efficient uptake after 24 h with no notable cell mortality. These studies again pointed out the distinct behavior of RAFT polyelectrolyte-coated bimodal NAs that internalize at a slower rate with no adverse cytotMdcity. Extension to multicellular tumor cell spheroids that mimic solid tumors revealed the successful internalization of the NAs in the periphery cells, which provides efficient deep-imaging labels thanks to their induced T-2* contrast, large emission Stokes shift, and bright dotlike signal, popping out of the strong spheroid autofluorescence.

We investigated the biological effects of new synthesized bisphosphonates (BPs) on HuH7 hepatocarcinoma cells. BPs containing p-bromophenyl (R1 = p-Br, Ph, 2) in their side chain were the more potent to inhibit HuH7 cell viability. In addition, phenyl diesterified analogues (R2 = R3 = Ph, 2a) were more potent than methyl (R2 = R3 = Me, 2b) or non-esterified BPs (2) inducing more necrosis suggesting that they better entered into cells. Phosphodiesterase inhibitor (IBMX) reversed the effect of the esterified BPs and not that of non-esterified ones suggesting role of cell phosphodiesterases to release active BPs. BP analogues inhibited HuH7 cell migration but esterified ones had no effect on invasion due to the hiding of phosphonic groups. All together, these results indicated the therapeutic interest of these new BP prodrugs.

A new series of chiral 5-substituted bis-oxazolidinones containing an acylsulfonamide moiety has been synthesized starting from chlorosulfonyl isocyanate, (l)-ethyl lactate, and oxazolidin-2-ones. All the reactions were conducted at ambient temperature, and the N-acylsulfonamide bis-oxazolidin-2-ones were obtained with high yields within 2 h. Some of the newly synthesized compounds were evaluated in vitro against the virulent strain RH of Toxoplasma gondii and the human lymphocytes, and showed promising results.

A novel bifunctional organocatalyst library combining both aminocatalysis and phosphonic acid activation was used for the first time as an efficient tool for the stereoselective Michael addition of aldehydes with several aromatic nitroalkenes with good selectivities up to 95:5 dr and 93:7 er. Due to their high water solubility, the catalysts were easily recyclable and could be reused over several cycles without any significant loss of selectivity.

The synthesis of new series of oxazolidinones having sulfonamide moieties is described. These compounds are synthesized in good yield starting prochiral 1,3-dichloro-2-propanol and chlorosulfonyl isocyanate. This strategy involves the formation of carboxylsulfamide by carbamoylation–sulfamoylation reaction followed by intermolecular cyclization. In order to determine the enantioselectivity during the cyclization step, X-ray studies of products are performed.

1 - Article; Bisphosphonates have been used for decades in the standard therapy of bone-related diseases, including bone metastasis of various malignancies, and they might as well be toxic on early cancer cells themselves. In order to allow a better delivery of neridronate (a N-containing bisphosphonate with relatively poor activity), liposomes were evaluated in vitro on cancer cell lines (MDA-MB 231, U87-MG and Caco2). After chemical synthesis, this water-soluble molecule was encapsulated into liposomes containing DOPC:DOPG:Chol (72:27:1 molar ratio). The influence of neridronate (free or liposomal) on cell viability or proliferation after treatment was evaluated using the MTT method, as well as cell migration and invasion assays; these techniques showed a drastic improvement of the action of neridronate on MDA-MB-231 cells with an EC50 fifty times lower when neridronate was encapsulated. Internalization of liposomes was followed by flow cytometry and fluorescence microscopy, demonstrating internalization via the endocytic pathway. Furthermore, since over-expression of matrix metalloproteinases (particularly MMP-2 and MMP-9) has been correlated to poor prognosis in many cancer types, detection of MMP expression is a satisfactory indication of the therapy efficiency and was then performed on treated cells. On MDA-MB-231 cells, MPPs expression was also significantly reduced by neridronate while entrapped in liposomes.

A new synthesis of unsymmetrical phosphinic acids R′P(O)OHR″ has been evaluated. The first P–C bond was formed by base-promoted H-phosphinate alkylation of a protected H-phosphinate, which is easier and safer to handle. A one-pot methodology was developed for the second P–C bond formation reaction that involves the sila-Arbuzov reaction. This methodology was then extended to the synthesis of a dialkylphosphinic acid with an amino functionality. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

International audience; The use of nanotechnologies for biomedical applications took a real development during these last years. To allow an effective targeting for biomedical imaging applications, the adsorption of plasmatic proteins on the surface of nanoparticles must be prevented to reduce the hepatic capture and increase the plasmatic time life. In biologic media, metal oxide nanoparticles are not stable and must be coated by biocompatible organic ligands. The use of phosphonate ligands to modify the nanoparticle surface drew a lot of attention in the last years for the design of highly functional hybrid materials. Here, we report a methodology to synthesize bisphosphonates having functionalized PEG side chains with different lengths. The key step is a procedure developed in our laboratory to introduce the bisphosphonate from acyl chloride and tris(trimethylsilyl)phosphite in one step. 1366