Pascal Janvier

Surface modification using phosphonic acids and esters.

Cleḿence Queffeĺec,† Marc Petit,†,‡ Pascal Janvier,† D. Andrew Knight, and Bruno Bujoli*,† †LUNAM Universite,́ CNRS, UMR 6230, Chimie Et Interdisciplinarite:́ Synthes̀e Analyse Modeĺisation (CEISAM), UFR Sciences et Techniques, 2, rue de la Houssinier̀e, BP 92208, 44322 NANTES Cedex 3, France ‡Universite ́ Pierre et Marie Curie (UPMC), CNRS, UMR7201, Institut Parisien De Chimie Molećulaire (IPCM), 4 place Jussieu, 75252 Paris Cedex 05, France Chemistry Department, Florida Institute of Technology, 150 West University Boulevard, Melbourne, Florida 32901, United States

Synthesis of Oligothiophene-Bridged Bisporphyrins and Study of the Linkage Dependence of the Electronic Coupling

A set of twelve porphyrin dimers has been prepared to give information on how the type of connectivity between a porphyrin core and a bridge can influence the interporphyrin electronic interaction. The new porphyrin systems are substituted directly at the meso position with an oligothiophene chain tethered either with a single C-C sigma bond, a trans ethylenyl group, or a acetylenyl group. The compounds are easily obtained by palladium-catalyzed cross-coupling reactions (Stille, Heck, and Sonogashira) between 5-iodo-10,15,20-(3,5-ditert-butylphenyl)porphyrin and the appropriate oligothiophene derivative. This synthetic approach is straightforward and very effective for preparing oligothiophene-based prophyrin systems. The absorption spectra and the fluorescence properties of the dimers demonstrated the crucial importance of the characteristics of the chemical bond used to connect the bridge to the porphyrin unit. The magnitude of the electronic communication can thus be significantly modulated by altering the type of bond connectivity used to link the chromophore to the bridge. The present work shows that an oligothiophene spacer is a viable class of linker for connecting porphyrins, and that a quaterthiophene appended with ethynyl linkages affords a high electronic interaction over a distance as large as 28 A. A detailed computational study of these dimers has clarified the conditions needed for a conjugated system to behave as a molecular wire. These conditions are full planarity of the molecule and proper energy matching between the frontier orbitals of the bridge and the porphyrin. Intermolecular energy transfer in asymmetrical dyads composed of a zinc porphyrin and a freebase porphyrin has been studied by fluorescence spectroscopy. In all systems, this process is more than 98% efficient, and its rate constant decreases steadily in the order 4ZH > 1ZH > 3ZH approximately 2ZH. Thus, the largest rate (kEnT = 1.2 x 10(11) s-1) was found in the dyad linked with bisethynyl quaterthiophene, which represents the longest bridge within the series. These results clearly demonstrate that strong communication and also efficient photoinduced processes can be promoted over a large distance if the electronic structure of the molecular connector is appropriately chosen.

In vivo bone augmentation in an osteoporotic environment using bisphosphonate-loaded calcium deficient apatite

Resorbable calcium phosphate (CaP) biomaterials have demonstrated considerable efficacy in bone reconstructive surgery. Furthermore, bisphosphonates (BPs) are well known anti-resorptive agents largely used in clinical treatments for osteoporosis. An injectable BP-combined CaP matrix has been developed in order to biologically reinforce osteoporotic bone by increasing the bone fraction and improving bone micro-architecture. Our previous in vitro studies have shown that CaP is effective for loading and releasing BPs at doses that can inhibit excessive bone resorption without affecting osteoblasts. In vivo studies in relevant animal models are necessary to explore the effect of our injectable BP-combined biomaterial on femur bone structure by performing three-dimensional microtomography analysis, histological studies and SEM observations. Firstly, in rat model, our BP-combined CaP matrix significantly improved the bone micro-architecture as compared to CaP alone. The implantation of the BP-loaded biomaterial within proximal femurs of osteoporotic ewes led to a significant increase in relative bone content and an improvement of its micro-architecture. These modifications were confirmed by histological and SEM observations, which revealed CaP granule resorption and new bone trabeculae formation. This approach could be considered in the future for preventing osteoporotic fractures that are preferentially localized in the proximal femur, vertebral bodies or wrist.

Controlled release of bisphosphonate from a calcium phosphate biomaterial inhibits osteoclastic resorption in vitro

Calcium phosphate biomaterials such as calcium deficient apatite (CDA) have been contemplated as carrier for delivery of bisphosphonate in bone tissues. In the present work, we have investigated the in vitro biological properties of Zoledronate-loaded CDA. CDA was loaded with zoledronate according to a previously described coating process. 31P MAS NMR spectra demonstrated the effective loading of zoledronate onto CDA. Using 14C labeled zoledronate, we then demonstrated the in vitro release of zoledronate from CDA. In a first set of experiments, we confirmed that Zoledronate reduced the number of TRAP-, vitronectin receptor-, and F-actin ring-positive cells as well as the resorption activity of osteoclasts obtained from a total rabbit bone cell culture. Interestingly, Zoledronate-loaded CDA and its extractive solutions decreased the osteoclastic resorption. Finally, zoledronate-loaded CDA did not affect the viability and alkaline phosphatase activity of primary osteoblastic cells. These data demonstrate that CDA is effective for loading and release of zoledronate. The released zoledronate inhibited osteoclastic resorption without affecting osteoblasts. Our findings therefore suggest that such a drug delivery system would allow an increase in the efficiency of bisphosphonates by being locally available. Further experiments are now required to evaluate the in vivo antiresorptive activity of this concept.

Magnetic properties of a new 3D-cobalt phosphonate: Co3(O3PC2H4CO2)2

The magnetic properties of a new cobalt(II) phosphonate have been investigated. The compound is isostructural with the pillared layered metal phosphonates M 3 (O 3 PC 2 H 4 CO 2 ) 2 , M=Zn, Mn. In this structure, the magnetic transition metal ions are arranged within layers formed by the interconnection of CoO 4 tetrahedra and CoO 6 octahedra. The ac and dc magnetic susceptibilities and magnetization measurements show that Co 3 (O 3 PC 2 H 4 CO 2 ) 2 is a canted antiferromagnet at T N =15.5 K. Below T N , the hysteresis cycles exhibit an S shape related to a spin flop effect. The specific heat measurements indicate that large short-range correlations are present above T N in relation with the layered character of the structure.

Investigation of alendronate-doped Apatitic Cements as a Potential Technology for the Prevention of Osteoporotic Hip Fractures: Critical Influence of the Drug Introduction Mode on the In Vitro Cement Properties.

Combination of a bisphosphonate (BP) anti-osteoporotic drug, alendronate, with an apatitic calcium phosphate cement does not significantly affect the main properties of the biomaterial, in terms of injectability and setting time, provided that the BP is introduced chemisorbed onto calcium-deficient apatite, one of the components of the cement. In contrast to other modes of introducing the BP into the cement formulation, this mode allows to minimize alendronate release in the cement paste, thus limiting the setting retardant effect of the BP. An original approach based on high frequency impedance measurements is found to be a convenient method for in situ monitoring of the cement setting reaction. The release profile of the drug from a cement block under continuous flow conditions can be well described using a coupled chemistry/transport model, under simulated in vivo conditions. The results show that the released alendronate concentration is expected to be much lower than the cytotoxic concentration.

Gallium modulates osteoclastic bone resorption in vitro without affecting osteoblasts

Background and purpose:  Gallium (Ga) has been shown to be effective in the treatment of disorders associated with accelerated bone loss, including cancer‐related hypercalcemia and Pagets disease. These clinical applications suggest that Ga could reduce bone resorption. However, few studies have studied the effects of Ga on osteoclastic resorption. Here, we have explored the effects of Ga on bone cells in vitro.

Characterization and properties of novel gallium-doped calcium phosphate ceramics.

Addition of a gallium (Ga) precursor in the typical reaction protocols used for the preparation of β-tricalcium phosphate (β-TCP) led to novel Ga-doped β-TCP ceramics with rhombohedral structures (R3c space group). From the refinement of their X-ray diffraction patterns, it was found that the incorporation of Ga in the β-TCP network occurs by substitution of one of the five calcium (Ca) sites, while occupation of another Ca site decreases in inverse proportion to the Ga content in the structure. The Ga local environment and the modification of the phosphorus environments due to the Ga/Ca substitution in Ga-doped β-TCP compounds are probed using (31)P and (71)Ga magic-angle spinning NMR. A decrease of the unit cell volume is observed with increasing Ga content, together with improved mechanical properties. Indeed, the compressive strength of these new bioceramics is enhanced in direct proportion of the Ga content, up to a 2.6-fold increase as compared to pure β-TCP.

The in vivo degradation of a ruthenium labelled polysaccharide-based hydrogel for bone tissue engineering.

In this paper we report a new method that permitted for the first time to selectively track a polysaccharide-based hydrogel on bone tissue explants, several weeks after its implantation. The hydrogel, which was developed for bone healing and tissue engineering, was labelled with a ruthenium complex and implanted into rabbit bone defects in order to investigate its in vivo degradation. 1, 2, 3 and 8 weeks after surgery, the bone explants were analyzed by synchrotron X-ray microfluorescence, infrared mapping spectroscopy, scanning electron microscopy, and optical microscopy after histological coloration. The results showed that the labelled polysaccharide-based hydrogel was likely to undergo phagocytosis that seemed to occur from the edge to the center of the implantation site up to at least the 8th week.

Copper(I) mediated highly diastereoselective conjugate addition of Grignard reagents to functionalised cycloalkenols: a general and efficient route for the stereoselective synthesis of 5- and 6-membered ring trisubstituted cycloalkanols

Abstract The conjugate addition of magnesium cuprates to various 2-silyloxycyclopentene and 2-silyloxycyclohexene carboxylates leads diastereoselectively to related syn–anti cyclopentanols and cyclohexanols in fair overall yields. The β-elimination occurring with free hydroxylic derivatives is also partially or totally avoided by concomitant in situ trapping of the generated enolates. Attempts to rationalise our results are discussed.