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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.

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.

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.

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.

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 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)...

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.

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 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.

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.

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

International audience; Anovel bifunctional organocatalyst library combiningboth aminocatalysis and phosphonic acid activation was used for the first time as an efficient tool for the stereoselective Michael addition of aldehydes with several aromaticnitroalkenes with good selectivities up to 95:5 dr and 93:7 er. Due to their high water solubility,the catalysts were easily recyclable andcould be reused over several cycles without anysignificant lo ss of selectivity.

A novel bifunctional organocatalysts library was developed as efficient tool for the stereoselective Michael addition of aldehydes with several aromatic nitroalkenes. Therefore, a phosphonic acid w...

Bisphosphonates (BPs) have interesting antitumor effects as well in vitro as in vivo, despite their poor bioavailability in the organism after oral ingestion. To overcome this problem and reduce drug doses and secondary effects, we report the chemical synthesis of new bioconjugates. They were built with a nitrogen-containing BP as the drug covalently coupled to the carboxymethyldextran. This polysaccharide was used as a carrier, in order to increase BP lifetime in bloodstream and to target tumor cells which have a strong affinity with dextran. The efficiency of our vectorization system was biologically proved in vitro and in vivo on mammalian carcinoma models in mice.

1 - Article; Aim of the study: Renal protection and antiurolithiasic effects of two extracts of Paronychia argentea (PA), a traditional Algerian plant commonly known as Algerian tea, were evaluated. This study was carried out to determine whether the aqueous extract (APA) or the butanolic extract (BPA) of aerial parts could prevent or reduce calculi aggregation in experimental calcium oxalate (Ox) nephrolithiasis in Wistar rats. Materials and methods: The two extracts (APA and BPA) were administrated orally and daily, during 28 days to nephrolithiasic treated rats at the dose of 250, 500 mg/kg b.w. and 10, 20 mg/kg b.w. respectively. Body weight, renal index, liver index, serum level of creatinine, uric acid, urea, K(+), Ca(2+), Mg(2+), Na(+) and transaminase (alanine aminotransferase, ALT; aspartate aminotransferase, AST), phosphatase alkaline activity (PAL) were evaluated following the 28 days treatment in rats. In addition histopathological changes in kidney and liver were stained in hematoxylin eosin (HE). Results: The effect of the extracts could be advantageous in preventing urinary stone retention by reducing renal necrosis and thus inhibit crystal retention. In contradiction with APA, the two doses of BPA attenuated elevation in the serum creatinine (p

1 - Article; Bisphosphonates, and more specially nitrogen-containing bisphosphonates, which are in current use for the treatment of bone diseases, demonstrate proapoptotic, antiproliferative, antiangiogenic and anti-invasive properties on tumor cells. The amino-bisphosphonate alendronate is considered as a potential anticancer drug. In the case of A431 cells, which express high levels of VEGF, it had a two-step effect. At 24 h, the antitumor properties of alendronate were counterbalanced by a survival process, which consisted of an enhancement of VEGF expression (mRNA and protein secretion) and TGF[alpha] secretion. It was only at 48 h that alendronate displayed the expected antiproliferative and antiangiogenic properties. The first step, in which the PI3K pathway was engaged, could be prevented by the use of a VEGF-antisense oligonucleotide. The combination of such an antisense with small concentrations of alendronate (~2 [mu]M), which is of the order of clinically used concentrations, was shown to have an antiangiogenic effect as soon as 12 h.

1 - Article; New upper-rim polyphosphorylated calix[4]arenes were designed for decorporation of uranium in case of nuclear contamination. A ligand system containing four preorganized 1-hydroxymethylene-1,1-bisphosphonic acid moieties anchored onto a calix[4]arene platform has been developed. Three calix[4]arene-bisphosphonates were efficiently prepared in multi-step syntheses with a variable carbon chain length between the bisphosphonate and the calix[4]arene. Affinity constants towards uranyl ion were determined and compared with those of bis(HEDP) and tris(HEDP) phosphonates, known as efficient ligands for uranyl.

1 - Article; The title compound, C8H12O7P2 center dot CH4O, is a monoesterified bisphosphonate (or 1-hydroxymethylene-1,1-bisphosphonic acid). These synthetic compounds are widely used in medicine to inhibit bone resorption in diseases like osteoporosis, and are characterized by a stable P-C-P group and are thus analogs of inorganic pyrophosphate. By masking one or several ionizable groups, introduced as phosphonoester, it was anticipated the formation of prodrugs with higher lipophilicity that could facilitate the drug delivery and metabolization. Molecules are paired by intermolecular hydrogen bonds involving the phosphonic groups. In addition, dimers are connected side-by-side, building infinite ribbons along the a-axis direction; these ribbons are cross-linked perpendicularly along the b-axis direction via a methanol solvent molecule (disordered over two sites with occupancy factors ca 0.6 and 0.4), forming an extended intermolecular hydrogen-bonded network. The H atoms of the methyl group in the main molecule are disordered equally over two positions.

The behaviour of the d(GGTATACC) oligonucleotide has been investigated by X-ray crystallography at 295 K in the range from ambient pressure to 2 GPa (approximately 20,000 atm). Four 3D-structures of the A-DNA form (at ambient pressure, 0.55, 1.09 and 1.39 GPa) were refined at 1.60 or 1.65 A resolution. In addition to the diffraction pattern of the A-form, the broad meridional streaks previously explained by occluded B-DNA octamers within the channels of the crystalline A-form matrix were observed up to at least 2 GPa. This work highlights an important property of nucleic acids, their capability to withstand very high pressures, while keeping in such conditions a nearly invariant geometry of base pairs that store and carry genetic information. The double-helix base-paired architecture behaves as a molecular spring, which makes it especially adapted to very harsh conditions. These features may have contributed to the emergence of a RNA World at prebiotic stage.

Enamine catalysis is a widespread activation mode in the field of organocatalysis and is often encountered in bifunctional organocatalysts. We previously described H-Pro-Pro-pAla-OMe as a bifunctional catalyst for Michael addition between aldehydes and aromatic nitroalkenes. Considering that opposite selectivities were observed when compared to H-Pro-Pro-Glu-NH2 , an analogue described by Wennemers, the activation mode of H-Pro-Pro-pAla-OMe was investigated through kinetic, linear effect studies, NMR analyses, and structural modifications. It appeared that only one bifunctional catalyst was involved in the catalytic cycle, by activating aldehyde through an (E)-enamine and nitroalkene through an acidic interaction. A restrained tripeptide structure was optimal in terms of distance and rigidity for better selectivities and fast reaction rates. Transition-state modeling unveiled the particular selectivity of this phosphonopeptide.