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This paper reports on the synthesis of new hydroxymethylene-(phosphinyl)phosphonates (HMPPs). A methodology has been developed to propose an optimized one-pot procedure without any intermediate purifications. Various aliphatic and (hetero)aromatic HMPPs were synthesized in good to excellent yields (53–98%) and the influence of electron withdrawing/donating group substitution on aromatic substrates was studied. In addition, the one-pot synthesis of HMPP was monitored by 31P NMR spectroscopy, allowing effective control of the end of the reaction and identification of all phosphorylated intermediate species, which enabled us to propose a reaction mechanism. Optimized experimental conditions were applied to the preparation of biological relevant aminoalkyl-HMPPs. A preliminary study of the complexation to hydroxyapatite (bone matrix) was carried out in order to verify its lower affinity towards bone compared to bisphosphonate molecules. Moreover, in vitro anti-tumor activity study revealed encouraging antiproliferative activities on three human cancer cell lines (breast, pancreas and lung).

Among phosphorylated derivatives, phosphinates occupy a prominent place due to their ability to be bioisosteres of phosphates and carboxylates. These properties imply the necessity to develop efficient methodologies leading to phosphinate scaffolds. In recent years, our team has explored the nucleophilic potential of silylated phosphonite towards various electrophiles. In this paper, we propose to extend our study to other electrophiles. We describe here the implementation of a cascade reaction between (trimethylsilyl)imidates and hypophosphorous acid mediated by a Lewis acid allowing the synthesis of aminomethylenebisphosphinate derivatives. The present study focuses on methodological development including a careful NMR monitoring of the cascade reaction. The optimized conditions were successfully applied to various aliphatic and aromatic substituted (trimethylsilyl)imidates, leading to the corresponding AMBPi in moderate to good yields.

Single crystals of B-DNA and Z-DNA oligomers were analyzed under high hydrostatic pressure and their behavior was compared to the A-DNA crystals already known. The amplitude of the base compression, when compared to the A-form of DNA (0.13 Å/GPa), was higher for the Z-DNA (0.32 Å/GPa) and was the highest for the B-DNA (0.42 Å/GPa). The B-DNA crystal degraded rapidly around 400–500 MPa, while the Z-structure was more resistant, up to 1.2 GPa.

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.

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 ± 2.5 nm and 8 ± 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’ 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 ≤ νL ≤ 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. νL behavior that can be described by the Roch’s heuristic model. The fitting procedure provided the distance of the minimum approach and the value of the Néel reversal time (τ ≈ 3.5 ÷ 3.9·10−9 s) at room temperature, confirming the superparamagnetic nature of these compounds.

Lignocellulosic biomass is considered the feedstock of the future to produce bioactive oligosaccharides, due to its low cost and increased availability. In this study, the valorization of the hemicellulose from olive solid residue through structural characterization, oligosaccharide production, and antiproliferative activity was investigated. Three hemicellulose fractions (A, B1, and B2) were isolated by alkaline extraction (NaOH, 10–17.5%). It was observed that the extraction yield of hemicelluloses varied between 0.9 and 32.5% on the basis of the raw materials. The results of FT-IR, 1H and 13C NMR, and MALDI-TOF analyses on the hemicellulose HEM A 17.5 supported a structure based on a linear polymer of xylopyranose units linked β-(1 → 4) bonds substituted at C2 by glucuronic acid units. The hydrolysis conditions performed by an acid kaolin catalyst (0.05 N HCl) at 80 °C gave access to ketooligosaccharide (OS 1 ). OS 1 and HEM A 17.5 were more potent on human breast cancer cells MDA-MB 231 (IC50 ≈ 175 µg, IC50 = 125 µg) and MDA-MB435 (IC50 ≈ 375, IC50 = 500) than neridronate, which was more cytotoxic against epidermoid carcinoma cells A 431. Overall, the findings suggested that olive solid residue presents a promising natural source of bioactive polysaccharides and anticancer agents. Graphical Abstract

Although there was growing evidence in the potential use of Bisphosphonates (BPs) in cancer therapy, their strong osseous affinities that contrast their poor soft tissue uptake limited their use. Here, we developed a new strategy to overcome BPs hydrophilicity by masking the phosphonic acid through organic protecting groups and introducing hydrophobic functions in the side chain. We synthesized non-nitrogen BPs (non N-BPs) containing bromobenzyl group (BP7033Br) in their side chain that were symmetrically esterified with hydrophobic 4-methoxphenyl (BP7033BrALK) and assessed their effects on breast cancer estrogen-responsive cells (T47D, MCF-7) as well as on non responsive ones (SKBR3, MDA-MB-231 and its highly metastatic derived D3H2LN subclone). BP7033Br ALK was more efficient in inhibiting tumor cell proliferation, migration and survival when compared to BP7033Br. Although both compounds inhibited tumor growth without side effects, only BP7033Br ALK abrogated tumor angiogenesis and D3H2LN cells-induced metastases formation. Taken together these data suggest the potential therapeutic use of this new class of esterified Bisphosphonates (BPs) in the treatment of tumor progression and metastasis without toxic adverse effects.

Among phosphorylated derivatives, phosphinates occupy a prominent place due to their ability to be bioisosteres of phosphates and carboxylates. These properties imply the necessity to develop efficient methodologies leading to phosphinate scaffolds. In recent years, our team has explored the nucleophilic potential of silylated phosphonite towards various electrophiles. In this paper, we propose to extend our study to other electrophiles. We describe here the implementation of a cascade reaction between (trimethylsilyl)imidates and hypophosphorous acid mediated by a Lewis acid allowing the synthesis of aminomethylenebisphosphinate derivatives. The present study focuses on methodological development including a careful NMR monitoring of the cascade reaction. The optimized conditions were successfully applied to various aliphatic and aromatic substituted (trimethylsilyl)imidates, leading to the corresponding AMBPi in moderate to good yields.

Objectives Inflammation and angiogenesis are two tightly linked processes in arthritis, and therapeutic targeting of pro-angiogenic factors may contribute to control joint inflammation and synovitis progression. In this work, we explored whether vaccination against vascular endothelial growth factor (VEGF) ameliorates collagen-induced arthritis (CIA). Methods Anti-VEGF vaccines were heterocomplexes consisting of the entire VEGF cytokine (or a VEGF-derived peptide) linked to the carrier protein keyhole limpet hemocyanin (KLH). Two kinds of vaccines were separately tested in two independent experiments of CIA. In the first, we tested a kinoid of the murine cytokine VEGF (VEGF-K), obtained by conjugating VEGF-A to KLH. For the second, we selected two VEGF-A-derived peptide sequences to produce heterocomplexes (Vpep1-K and Vpep2-K). DBA/1 mice were immunized with either VEGF-K, Vpep1-K, or Vpep2-K, before CIA induction. Clinical and histological scores of arthritis, anti-VEGF, anti-Vpep Ab titers, and anti-VEGF Abs neutralizing capacity were determined. Results Both VEGF-K and Vpep1-K significantly ameliorated clinical arthritis scores and reduced synovial inflammation and joint destruction at histology. VEGF-K significantly reduced synovial vascularization. None of the vaccines reduced anti-collagen Ab response in mice. Both VEGF-K and Vpep1-K induced persistently high titers of anti-VEGF Abs capable of inhibiting VEGF-A bioactivity. Conclusion Vaccination against the pro-angiogenic factor VEGF-A leads to the production of anti-VEGF polyclonal Abs and has a significant anti-inflammatory effect in CIA. Restraining Ab response to a single peptide sequence (Vpep1) with a peptide vaccine effectively protects immunized mice from joint inflammation and destruction.

Background Angiogenesis is a key pathophysiological process in rheumatoid arthritis (RA). VEGF-A is considered the major player in both physiological and pathological angiogenesis. VEGF–VEGFR system blockade delays synovitis onset and ameliorates collagen-induced arthritis (CIA). We previously demonstrated the effectiveness of active anti-cytokine immunisation in RA models, with a class of therapeutics called kinoids. The kinoids (heterocomplexes consisting of a cytokine conjugated to a carrier protein, the keyhole limpet hemocyanin, KLH) induce the endogenous production of polyclonal anti-cytokine Abs. Here we tested the effectiveness in CIA of two distinct peptidic vaccines obtained by conjugation of one of two different VEGF-derived peptides to KLH. Objectives To demonstrate the inhibitory effect on CIA of sustained VEGF blockade by vaccines based on VEGF-derived peptides linked to KLH (Vpep-K). Materials and Methods Two peptides were chosen in the sequence of the VEGF murine isoformVEGF-A164 (90% identity and 93% homology with the human VEGF-A165): Vpep1 (16 aminoacids (aa), position 98-113) localised in the region cleaved by the plasmin between the exons 4 and 5, and Vpep2 (77 carboxy-terminal aa) which comprises the Arginine 164, essential for binding of VEGF to Neuropilin-1 (NRP1). Each peptide was linked to keyhole limpet hemocyanin (KLH) to form Vpep1-kinoid (Vpep1-K) and Vpep2-kinoid (Vpep2-K), respectively. CIA was induced in 48 DBA/1 male mice with two injections of 100µg of bovine collagen type II (day 0 and 21). Mice were divided in 4 groups to receive one of the following: Vpep1-K, Vpep2-K, KLH or PBS emulsified in Incomplete Freund Adjuvant (IFA, 5 intra muscular injections at days -36, -22, -8, 7 and 37). Sera were sampled from each mouse three times during the experiment (days -44, -2, 48). Results Vpep1-K group showed lower arthritic scores compared to KLH and PBS groups (p<0.05). At histological analysis, inflammation and destruction scores of the paws were lower in Vpep1-K group versus KLH and PBS group (p<0.005). Vpep1-K and Vpep2-K groups showed anti-VEGF Ab production as assessed by ELISA at day -2 and sacrifice. Conclusions Active immunotherapy with the kinoid of a single VEGF-derived peptide (Vpep1-K) induces anti-VEGF antibodies and ameliorates collagen-induced arthritis. Active anti-angiogenic immunotherapy based on peptidic vaccines might be a potential strategy to control chronic inflammation.