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International audience; A simple and effective biocompatible domino reaction triggered by a model protease and leading to formation of strongly fluorescent quinoxalin-2(1H)-one N-heterocycles is described. Some positive attributes including versatility and ability to provide outstanding fluorescence "OFF-ON" responses were revealed by this work. They open the way for practical applications of this novel type of "covalent-assembly" based fluorescent probes in the fields of sensing and bioimaging. Among the myriad of synthetic transformations and catalysts currently available for concise and efficient synthesis of organic molecules, bioinspired approaches based on the use of enzymes often intertwined with cascade/domino processes, occupy a special place and are receiving greater attention of late. 1 They have also contributed to the emergence of in vivo chemistry (often named as intracellular chemistry) 2 that can be defined as the use of living cells as reaction vessels and their constituents (e.g., enzymes) possibly together with abiotic metal catalysts, 3 to achieve one or several reactions for internal construction of sophisticated nano-objects from exogenous synthetic precursors. In addition to possible applications devoted to the production of high-value chemicals, one of the most striking achievements in this emerging area is undoubtedly the biocompatible "click" reaction between an aromatic nitrile (e.g., 6-amino-2-cyanoben-zothiazole (CBT)) and D-cysteine leading to D-luciferin scaffold , 4 discovered by the Rao group in 2010 (Figure 1, top). 5 Its ability to be effective for the controlled assembly of nanoparti-cles in living cells together with its possible triggering by a bio-stimulus (pH, redox status and/or hydrolytic enzymes) has fostered the emergence of cutting-edge reactivity-based sensing approaches for in vivo molecular imaging, especially through the bioluminescence modality, for addressing challenges associated to light-based diagnosis. 6 These remarkable achievements perfectly illustrate both utility and benefits of biocompatible/bioorthogonal transformations that are capable of generating a bright luminescence output signal upon the action of a biological trigger. In the field of activity-based fluorescent sensing, a new probe design principle namely the "covalent-assembly" approach, pioneered by the Swager group with the design of a "smart" semiconduc-tive polymer for fluorogenic detection of fluoride ions, 7 and next rationalized by Anslyn and Yang to address relevant biological questions, 8,9 has emerged in the mid-2000s. This cutting edge strategy is based on in situ formation of a fluorophore from a caged compound (not belonging to major classes of fluorescent dyes and, in theory at least, devoid of light emission ability) through a domino reaction triggered by the species to be detected and ideally designed to work properly in aqueous media (Figure 1, middle and bottom). Since this novel class of ac-tivatable fluorescent probes are supposed to dramatically improve signal-to-noise ratio (S/N) responses, thus providing optimal detection sensitivity, it is not really surprising that they have rapidly become popular tools for specific detection and imaging of enzyme activities (mainly, hydrolases and reduc-tases). The vast majority of "covalent-assembly" based fluorescent probes devoted to enzyme biosensing involve in situ formation of blue-green emitting (2-imino)coumarins or related fluorophores through analyte-triggered lactonization or Pinner cyclization reactions 10,11,12 even if some of these published examples are also regarded as fluorogenic probes undergoing ri-gidification of their floppy pre-existing push-pull system upon the action of the bioanalyte. 8b Our group, inspired by work of Yang et al., 13 have recently contributed to this research field by expanding the scope to longer-wavelength fluorophores belonging to the popular class of xanthene dyes (i.e., unsymmetrical pyronins with fluorescence features within the yellow-orange spectral region). 14 Some notable results were obtained with

A simple and effective biocompatible domino reaction triggered by a model protease and leading to the formation of strongly fluorescent quinoxalin-2(1

A simple and effective biocompatible domino reaction triggered by a model protease and leading to formation of strongly fluorescent quinoxalin-2(1H)-one N-heterocycles is described. Some positive attributes including versatility and ability to provide outstanding fluorescence "OFF-ON" responses were revealed by this work. They open the way for practical applications of this novel type of "covalent-assembly" based fluorescent probes in the fields of sensing and bioimaging.; A simple and effective biocompatible domino reaction triggered by a model protease and leading to formation of strongly fluorescent quinoxalin-2(1H)-one N-heterocycles is described. Some positive attributes including versatility and ability to provide outstanding fluorescence "OFF-ON" responses were revealed by this work. They open the way for practical applications of this novel type of "covalent-assembly" based fluorescent probes in the fields of sensing and bioimaging. Among the myriad of synthetic transformations and catalysts currently available for concise and efficient synthesis of organic molecules, bioinspired approaches based on the use of enzymes often intertwined with cascade/domino processes, occupy a special place and are receiving greater attention of late. 1 They have also contributed to the emergence of in vivo chemistry (often named as intracellular chemistry) 2 that can be defined as the use of living cells as reaction vessels and their constituents (e.g., enzymes) possibly together with abiotic metal catalysts, 3 to achieve one or several reactions for internal construction of sophisticated nano-objects from exogenous synthetic precursors. In addition to possible applications devoted to the production of high-value chemicals, one of the most striking achievements in this emerging area is undoubtedly the biocompatible "click" reaction between an aromatic nitrile (e.g., 6-amino-2-cyanoben-zothiazole (CBT)) and D-cysteine leading to D-luciferin scaffold , 4 discovered by the Rao group in 2010 (Figure 1, top). 5 Its ability to be effective for the controlled assembly of nanoparti-cles in living cells together with its possible triggering by a bio-stimulus (pH, redox status and/or hydrolytic enzymes) has fostered the emergence of cutting-edge reactivity-based sensing approaches for in vivo molecular imaging, especially through the bioluminescence modality, for addressing challenges associated to light-based diagnosis. 6 These remarkable achievements perfectly illustrate both utility and benefits of biocompatible/bioorthogonal transformations that are capable of generating a bright luminescence output signal upon the action of a biological trigger. In the field of activity-based fluorescent sensing, a new probe design principle namely the "covalent-assembly" approach, pioneered by the Swager group with the design of a "smart" semiconduc-tive polymer for fluorogenic detection of fluoride ions, 7 and next rationalized by Anslyn and Yang to address relevant biological questions, 8,9 has emerged in the mid-2000s. This cutting edge strategy is based on in situ formation of a fluorophore from a caged compound (not belonging to major classes of fluorescent dyes and, in theory at least, devoid of light emission ability) through a domino reaction triggered by the species to be detected and ideally designed to work properly in aqueous media (Figure 1, middle and bottom). Since this novel class of ac-tivatable fluorescent probes are supposed to dramatically improve signal-to-noise ratio (S/N) responses, thus providing optimal detection sensitivity, it is not really surprising that they have rapidly become popular tools for specific detection and imaging of enzyme activities (mainly, hydrolases and reduc-tases). The vast majority of "covalent-assembly" based fluorescent probes devoted to enzyme biosensing involve in situ formation of blue-green emitting (2-imino)coumarins or related fluorophores through analyte-triggered lactonization or Pinner cyclization reactions 10,11,12 even if some of these published examples are also regarded as fluorogenic probes undergoing ri-gidification of their floppy pre-existing push-pull system upon the action of the bioanalyte. 8b Our group, inspired by work of Yang et al., 13 have recently contributed to this research field by expanding the scope to longer-wavelength fluorophores belonging to the popular class of xanthene dyes (i.e., unsymmetrical pyronins with fluorescence features within the yellow-orange spectral region). 14 Some notable results were obtained with

Dialkoxide diorganotin(IV) complexes are known to readily react with carbon dioxide under pressure and they are considered as suitable catalyst precursor models for the direct synthesis of organic carbonates. To gain a better understanding of CO2 insertion processes with Sn-OR bonds, the reactivity of n-Bu2Sn(OCH(CH3)(2))(2) (2) was investigated using high-pressure NMR (HP-NMR) spectroscopy. In deuterated solvents (isopropanol-d(8) and toluene-d(8)) under 50 bar of CO2 pressure at 80 degrees C, Sn-119{H-1} NMR experiments revealed the exclusive formation of an unprecedented tetraorganodistannoxane species, characterized as the bis[diisopropycarbonatotetrabutyldistannoxane] complex, {[n-Bu2Sn(OC(O)OCH(CH3)(2))(2)](2)O}(2) {7}(2). The formation of hemicarbonato ligands resulting from CO2 insertion was also confirmed by FT-IR and C-13 NMR spectroscopies. To the best of our knowledge, spectroscopic detection of the distannoxane species 7 is unprecedented. (C) 2015 Elsevier B.V. All rights reserved.

While N-heterocyclic carbenes (NHC) are ubiquitous ligands in catalysis for organic or industrial syntheses, their potential to form transition metal complexes for medicinal applications has still to be exploited. Within this frame, we synthesized new homo- and heterobimetallic complexes based on the Au(I)-NHC scaffold. The compounds were synthesized via a microwave-assisted method developed in our laboratories using Au(I)-NHC complexes carrying a pentafluorophenol ester moiety and another Au(I) phosphane complex or a bipyridine ligand bearing a pendant amine function. Thus, we developed two different methods to prepare homo- and heterobimetallic complexes (Au(I)/Au(I) or Au(I)/Cu(II), Au(I)/Ru(II), respectively). All the compounds were fully characterized by several spectroscopic techniques including far infrared, and were tested for their antiproliferative effects in a series of human cancer cells. They showed moderate anticancer properties. Their toxic effects were also studied ex vivo using the precision-cut tissue slices (PCTS) technique and initial results concerning their reactivity with the seleno-enzyme thioredoxin reductase were obtained.

Two p-cymene-ruthenium complexes 1 and 2 were isolated in high yields by treating the [RuCl2(p-cymene)]2 dimer with new hybrid phosphane- or NHC-linked diene ligands. Both complexes were fully characterized by NMR spectroscopy, and the molecular structure of the ruthenium–p-cymene complex 1, containing the phosphane–diene ligand system, was determined by X-ray diffraction analysis. The catalytic activities of both compounds were probed in atom-transfer radical addition (ATRA) and polymerization (ATRP), in the cyclopropanation of olefins, in the ring-opening metathesis polymerization (ROMP) of norbornene, and in the synthesis of enol esters from hex-1-yne and 4-acetoxybenzoic acid.

International audience; The synthesis and characterization of a series of arene ruthenium complexes bearing either (3,5-cycloheptadienyl)diphenylphosphine or (cycloheptyl)-diphenylphosphine are reported. Upon irradiation or heating, all these complexes lose their arene ligand but then exhibit a different behavior depending on the nature of the phosphine ligand. (Cycloheptadienyl)phosphine complexes 1 and 3 give a cationic dinuclear Ru complex 5 for which the two Ru atoms are bridged by three chlorido ligands and flanked by two tridendate (cycloheptadienyl)phosphines. (Cycloheptyl)-diphenylphosphine complexes 2 and 4 undergo arene exchange when toluene is used as solvent or degrade in dithloromethane. ATRA catalytic trials conducted in parallel with these complexes using CCl4 and styrene as standard substrates, highlighted the deep impact of the dienyl moiety on the results. Under smooth conditions (UV irradiation or moderate heating), only (cycloheptyl)phosphine derivatives give Karasch adduct in satisfactory yields. Their performance was considerably improved by combining irradiation and heating. At higher temperature, cationic dinuclear complex 5 was revealed as active and robust, giving turnover numbers as high as 9700 when tetradecene and CCl4 were used as substrates.

While N-heterocyclic carbenes (NHC) are ubiquitous ligands in catalysts for organic or industrial synthesis, their potential to form transition metal complexes for medicinal applications has still to be exploited. Within this frame, new Au(I)-NHC compounds have been synthesized and structurally characterized via different methods. The solid state structure of one of these compounds was also established by X-ray crystallography. Of note, three of them bear a pentafluorophenolic ester group as a possible "activable" moiety for further functionalization, which allowed tethering an alkyl amine ligand or another Au(I)-phosphine complex featuring a pendant amine function via microwave activation. The obtained compounds have been tested for their antiproliferative effects in human ovarian cancer A2780 cells, and in non-tumorigenic human embryonic kidney HEK-293T cells, showing promising anticancer properties and a certain selectivity towards cancerous cells. (C) 2014 Elsevier B.V. All rights reserved.

A series of novel (C^N) cyclometallated Au(III) complexes of general formula [Au(py(b)-H)L(1)L(2)](n+) (py(b)-H = C^N cyclometallated 2-benzylpyridine, L(1) and L(2) being chlorido, phosphane or glucosethiolato ligands, n = 0 or 1) have been synthesized and fully characterized using different techniques, including NMR, IR and far-IR, mass spectrometry, as well as elemental analysis. The crystal structure of one compound has been solved using X-ray diffraction methods. All compounds were tested in vitro in five human cancer cell lines including the lung, breast, colon and ovarian cancer cells. For comparison purposes, all compounds were also tested in a model of healthy human cells from the embryonic kidney. Notably, all new compounds were more toxic than their cyclometallated precursor bearing two chlorido ligands, and the derivative bearing one phosphane ligand presented the most promising toxicity profile in our in vitro screening, displaying a p53 dependent activity in colorectal cancer HCT116 cells. Finally, for the first time C^N cyclometallated gold(III) complexes were shown to be potent inhibitors of the zinc finger protein PARP-1, involved in the mechanism of cisplatin resistance.

International audience; Two new gold(I)–BODIPY–imidazole based trackable therapeutic bimetallic complexes have been synthesized and fully characterized. They display strong antiproliferative properties on several types of cancers including colon, breast, and prostate and one of them presents a significant anti-inflammatory effect. Additionally, the two compounds could be visualised in vitro by confocal microscopy in the submicromolar range.

A new series of gold(I) N-heterocyclic carbene (NHC) complexes based on xanthine ligands have been synthesized and characterized by mass spectrometry, NMR, and X-ray diffraction. The compounds have been tested for their antiproliferative properties in human cancer cells and nontumorigenic cells in vitro, as well as for their toxicity in healthy tissues ex vivo. The bis-carbene complex [Au(caffein-2-ylidene)(2)] [BF4] (complex 4) appeared to be selective for human ovarian cancer cell lines and poorly toxic in healthy organs. To gain preliminary insights into their actual mechanism of action, two biologically relevant in cellulo targets were studied, namely, DNA (more precisely a higher-order DNA structure termed G-quadruplex DNA that plays key roles in oncogenetic regulation) and a pivotal enzyme of the DNA damage response (DDR) machinery (poly-(adenosine diphosphate (ADP)-ribose) polymerase 1 (PARP-1), strongly involved in the cancer resistance mechanism). Our results indicate that complex 4 acts as an efficient and selective G-quadruplex ligand while being a modest PARP-1 inhibitor (i.e., poor DDR impairing agent) and thus provide preliminary insights into the molecular mechanism that underlies its antiproliferative behavior.

Conjugated alkynes are recurring building blocks in natural products and in a wide range of important compounds, such as pharmaceuticals, agrochemicals, or molecular materials. The palladium-catalysed cross-coupling reaction between the sp 2 -hybridized carbon atoms of aryl, heteroaryl, and vinyl halides with the sp -hybridized carbon atoms of terminal alkynes is one of the most important developments in the field of alkyne chemistry over the past 50 years. Room for improvement still exists in these important reactions of direct arylation of terminal alkynes. In this prospect, the present authors have developed several strategies aiming at improving the reactivity, the selectivity, and several aspects of processes involving the palladium-catalysed alkyne arylation and heteroarylation reactions, in relation with sustainable chemistry. Various original approaches have thus been adopted: (i) the development of catalytic systems efficient at low metal loading below 1 mol% of palladium and copper (to reduce metal contamination) from polydentate ligands chemistry, (ii) the limitation of diyne formation by undesired side-reaction, this from a better mechanistic understanding and the innovating use of copper adducts, (iii) and the development of cost-efficient catalytic reactions in ionic liquid solvents. These topics have been developed with the general outlook of a large scope in organic synthesis. In addition, the investigation of recycling opportunities and the unprecedented production of extendedly conjugated bis(aryl)diynes has been also achieved. The present account reviews all this work, as it has been presented by the corresponding author at GECOM–CONCOORD 2012 as recipient of the 2012 European journal of Inorganic Chemistry Young Investigator Award.

A molecularly defined new phosphine–diolefin cubane copper pre-catalyst used at 1.25 mol % under mild conditions promotes the coupling of pyrazoles to functionalised aryl and heteroaryl bromides, which hold a variety of functional groups. This versatile phosphorus-based system was thus successfully used, under identical conditions, for the coupling of a large scope of heteroaromatics to selectively produce pyridinyl- and pyrimidinyl-pyrazoles, as well as several novel furyl-, thienyl- and thiazolyl-substituted pyrazoles. The careful investigation of coupling with the analogous aryl and heteroaryl chlorides clearly indicated that for specifically activated chloroarenes a direct nucleophilic aromatic substitution (SNAr) is easily achieved in the absence of any copper and ligand. These results are pertinent with regards to the reported protocols in which copper–ligand systems have been claimed as useful for coupling activated chloroarenes.

The targeting of higher-order DNA structures has been thoroughly developed with G-quadruplex DNA but not with other structures like branched DNA (also known as DNA junctions). Because these alternative higher-order DNA architectures might be of high biological relevance, we implemented a high-throughput version of the FRET melting assay that enabled us to map the interactions of a candidate with four different DNA structures (duplex- and quadruplex DNA, three- and four-way junctions) in a rapid and reliable manner. We also introduce a novel index, the BONDS (branched and other noncanonical DNA selectivity) index, to conveniently quantify this differential affinity.

(3,5-Cycloheptadienyl)diphenylphosphine is easily synthesized from the reaction of diphenylphosphine with 1,3,5-cycloheptatriene. This new phosphine-diene has been coordinated as a monodentate P ligand with Pt, Pd, Au, Ni, and Ru; as a bidentate (P, olefin) ligand with Pt and Pd; and as a tridentate (P, diene) ligand with Rh. Fluxional properties of several complexes have been studied via NMR experiments and theoretical consideration.

Several novel palladium triphosphine complexes have been synthesized and tested as recyclable catalysts for the methoxylation of alkynes into acetals in ionic liquids. A complete conversion of phenylacetylene was achieved with only 0.2% of (Pd(Triphos)NCMe)((PF6)2) in a methanol/(BMIM)(BF4) mixture. We discovered that the addition of an ionic liquid to methanol allowed not only to increase the activity of the palladium catalyst but also to provide a recyclable catalyst which can be reused several times with a weaker drop of activity. To complete these catalytic studies, we describe the synthesis of the first poor -electron-donating/strong -electron-acceptor linear Triphosphine which, after palladium coordination, led to a better selectivity compared to its Triphos analogue. The performances of recovered ionic liquid re- action mixtures show for the first time that P-tridentate ligands efficiently immobilize palladium catalysts and lead to se- lective catalytic systems benign for environment.

The reactivity of five di-n-butyltin(IV) complexes, n-Bu2Sn(OR)(2) (1), n-Bu2SnO (3), [n-Bu2Sn(OR)](2)O (4), (n-Bu2SnO)(2)(CO2) (6) and (n-Bu2SnO)(6)[(n-Bu2SnOR)(2)(CO3)](2) (7) (R = CH3), with CO2, suggested as possible catalyst precursors and key-intermediates for the direct synthesis of dimethyl carbonate from carbon dioxide and methanol, has been investigated using high-pressure Sn-119{H-1} NMR (HP-NMR) spectroscopy. Four of the five precursors studied, i.e. 3, 4, 6 and 7 give rise to an identical Sn-119{H-1} NMR pattern which can be explicitly attributed to the fingerprint of the dimeric form of the 1-methoxy-3-methylcarbonatotetrabutyldistannoxane {5}(2). However, with 1, a new pair of signals is observed in addition to the characteristic Sn-119{H-1} NMR resonances of the dimeric hemicarbonato species {2}(2) and {5}(2), which can be attributed to the in situ formation of an unprecedented species suggested to be the trinuclear carbonato di-n-butyltin(IV) complex, 8. (C) 2011 Elsevier B. V. All rights reserved.

A series of bimetallic titanium-ruthenium complexes of general formula [(η(5)-C(5)H(5))(μ-η(5):κ(1)-C(5)H(4)(CR(2))(n)PR'R'')TiCl(2)](η(6)-p-cymene)RuCl(2) (n = 0, 1, 2 or 4; R = H or Me; R' = H, Ph, or Cy; R'' = Ph or Cy) have been synthesized, including two novel compounds as well as two cationic derivatives of formula [(η(5)-C(5)H(5))(μ-η(5):κ(1)-C(5)H(4)(CH(2))(n)PPh(2))TiCl(2)] [(η(6)-p-cymene)RuCl](BF(4)) (n = 0 or 2). The solid state structure of two of these compounds was also established by X-ray crystallography. The complexes showed a cytotoxic effect on human ovarian cancer cells and were markedly more active than their Ti or Ru monometallic analogues titanocene dichloride and RAPTA-C, respectively. Studies of cathepsin B inhibition, an enzyme involved in cancer progression, showed that enzyme inhibition by the bimetallic complexes is influenced by the length of the alkyl chain in between the metal centers. Complementary ESI-MS studies provided evidence for binding of a Ru(II) fragment to proteins.

The complexation of UO(2)(2+) with NO(3)(-) has been investigated in the ionic liquid 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide by UV-vis spectroscopy at T = 18.5 degrees C. The complexation is evidenced through the appearance of four peaks at 425, 438, 453, and 467 nm. EXAFS data indicate that the trinitrato complex, UO(2)(NO(3))(3)(-), is dominating the speciation for a reagent ratio of [NO(3)(-)]/[UO(2)(2+)]3. Assuming three successive complexation steps, the conditional stability constants are calculated, the individual absorption spectra are derived, and a speciation plot is presented.

International audience; The preparation of first lysidinyl-triphosphine ligand (named Triphosline) is described in three steps which are first a Michael type addition of imidazolidine (or lysidine) to diethylvinylphosphonate, second a phosphonate reduction with LiAlH4 and third an anti-Markovnikov radical addition of the primary phosphine to diphenylvinylphosphine. The Triphosline behaves as a tridentate P-coordinating ligand in palladium(II) complexes. The dangling lysidine function is then cleanly and totally alkylated by methyl iodide to lead to a new kind of lysidinium-triphosphine complexes. Subsequent anion exchange with TlPF6 affords the first example of a chloride free lysidinium-triphosphine palladium complex which has been fully characterized by spectroscopic and analytical methods.

The straightforward synthesis of a new donor-stabilized phosphenium ligand 3d by addition of bromodifurylphosphine to 1,3-dimethylimidazolium-2-carboxylate 1 is described. The obtained ligand exhibits a very strong π-acceptor character, comparable to that of triphenyl phosphite [P(OPh) 3 ] or of tris-halogenophosphines, with a v CO (A 1 ) at 2087 cm ―1 for its nickel tricarbonyl complex. This ligand, as well as the related 3a which was obtained from chlorodiphenylphosphine, were tested in palladium-catalyzed aryl alkynylation and in the platinum-catalyzed selective hydrogenation of chloronitrobenzenes, both in an ionic liquid phase. In C―C bond cross-coupling we observed that the increase of the π-acceptor character in ligand 3d, due to the introduction of an additional electron-withdrawing group, provides a very efficient catalyst in the alkynylation reaction of aryl bromides with phenylacetylene, including the deactivated 4-bromoanisole or the sterically hindered 2-bromonaphthalene. The catalytic activity decreases with recycling due to the sensitiveness of ligands to protonation in the ionic phase. Conversely, a multiple recycling of the metal/ligand system in non-acidic media was achieved from platinum-catalyzed hydrogenation of m-chloronitrobenzene. The catalytic results obtained by employing the complex of platinum(II) chloride with 3a [trans-PtCl 2 (3a) 2 ] in comparison with the non-ionic related trans-tris(triphenylphosphine)platinum dichloride [trans-PtCl 2 (PPh 3 ) 2 ] complex clearly indicate that the simultaneous existence of a strong π-acceptor character and a positive charge within the ligand 3a significantly increases the life-time of the platinum catalyst. The selectivity of the reaction is also improved by decreasing the undesirable formation of dehalogenation products. This cationic platinum complex trans-PtCl 2 (3a) 2 is the first example of a highly selective catalyst for hydrogenation of chloronitroarenes immobilized in an ionic liquid phase. The system was recycled six times without noticeable metal leaching in the organic phase, and no loss of activity.

International audience; A series of new heterodinuclear luminescent complexes with two different organic ligands have been synthesized and characterized. A luminescent Ru-II(polypyridine) moiety and a metal-based anticancer fragment (AuCl, (p-cymene)RuCl2, (p-cymene)OsCl2, (Cp*)RhCl2, or Au-thioglucose) are the two general features of these complexes. All of the bimetallic compounds have been evaluated for their antiproliferative properties in vitro in human cancer cell lines. Only the complexes containing an Au(I) fragment exhibit antiproliferative activity in the range of cisplatin or higher. The photophysical and electrochemical properties of the bimetallic species have been investigated, and fluorescence microscopy experiments have been performed successfully. The most promising bimetallic cytotoxic complexes (i.e., with the Au-thioglucose scaffold) have shown to be easily taken up by cancer cells at 37 degrees C in the cytoplasm or in specific organelles. Interestingly, experiments repeated at 4 degrees C showed no uptake of the bimetallic species inside cells, which confirms involvement of active transport processes. To evaluate the role of glucose transporters in the cell uptake of the gold complexes, inhibition of the GluT-1 (glucose transporter isoform with high level of expression in cancer cells) was achieved, showing only scarce influence on the compounds' uptake. Finally, the observed absence of interactions with nucleic acid model structures suggests that the gold compounds may have different intracellular targets with respect to cisplatin.

Ionic liquids (ILs) are more and more suggested as substitutes for traditional solvents in organic synthesis and catalysis. They are suitable candidates for the dissolution of ionic complexes. They can activate and retain them in a polar state: in fact, they act as sequestrands, opening the route to two-phase processes and easier catalyst recovery. This paper reviews authors' results with the development of new syntheses of ILs and applications in carbon–carbon bond formation (dimerisation of methyl acrylate) and redistribution (ring closing metathesis) reactions using ionic precatalysts.

Protonation of 1-alkylimidazoles provides halogen-free salts which act as ionic liquids and proton reservoir in proton- and metal-assisted catalytic processes like dimerisation of methyl acrylate and ring closing metathesis, and lead to significant improvements both in activity and selectivity.

The activity and stability of cationic palladium complexes [Pd(PBu3)2S2]2+ used for the selective tail-to-tail dimerisation of methyl acrylate are significantly improved with the utilisation of ionic liquids like [BMIM][BF4] or the protonated N-butyl-imidazole, [HBIM][BF4]. Problems related to product inhibition and catalyst recycling are overcome by running the reaction in a two-phase mode, toluene being used as extractant. Catalyst stabilisation is further improved by trapping the ancillary ligand into the ionic liquid with an ionic tail: with the use of 1-dibutylphosphino-2-dimethylaminoethane, the catalyst is stable for more than 100 h, therefore demonstrating the feasibility of a continuous process for methyl acrylate dimerisation.

Ionic liquid 1-n-butyl-3-methylimidazolium tetrafluoroborate and supercritical CO2 have been used for the biphasic palladium-catalysed dimerisation of methyl acrylate. Substrate and product distribution between the two phases and extraction capability of scCO2 are evaluated. The effect of the biphasic medium on the catalyst performance is also addressed. The selectivity for the tail-to-tail dimers is >98%, as high as under monophasic conditions. The same trend stands for turnover number and frequency although there is a lower substrate to palladium ratio in the IL phase. The CO2-rich phase acts as a substrate and product reservoir, a suitable case for studying the reaction under continuous feed and extraction regime.

By combining an ever-increasing number of catalysts or catalytic functions, cooperative catalysis is a research area that grows fast. In the field, “early–late” heterobimetallic complexes are rather old objects but they still continue to fascinate chemists because of their latent reactivity. After a brief and concise overview of cooperative catalysis, this review focuses on “early–late” heterobimetallic complexes that were used in catalysis over the last decades. Examples of dual catalysis using early and late metal partners are also described. This chapter ends with an opening towards therapeutic applications of “early–late” heterobimetallic complexes.

The reaction of the titanocene monophosphanes ( 1 – 4 ) with the dimer [( p -cymene)RuCl 2 ] 2 gives the heterobimetallic compounds ( p -cymene)[(η 5 -C 5 H 5 )(μ-η 5 :η 1 -C 5 H 4 (CR 2 ) n PR′ 2 )TiCl 2 ]RuCl 2 ( 5 – 8 ). The structure of 8 , determined by X-ray diffraction, is reported here. A preliminary assessment of the performance of these complexes in ring-closing metathesis (RCM) revealed an excellent Ti–Ru–allenylidene pre-catalyst 12 .

Terminal titanium imido complexes of the general formula [Ti(N(t)Bu)Cl{CH(Ph2PNR)2}] 4 (R = Ph, (i)Pr, (t)Bu) are reported. These compounds were synthesized from the corresponding Li adducts 3 of BIPMH (bis(iminophosphoranyl)methanide) and Mountford's complex [Ti(N(t)Bu)Cl2(Py)3]. The crystal structures of two of the Ti complexes (R = Ph, (t)Bu) and two of the Li compounds (R = (i)Pr, (t)Bu) are reported. Dynamic solution NMR spectroscopy reveals a dynamic isomerisation process in the case of the Ti complex 4c (R = (t)Bu). DFT studies showed that this dynamic process comes from steric repulsion between the imido ligand and the (t)Bu N-substituents on the BIPMH ligand. Complexes 4 were tested in alkyne hydroamination; 4a (R = Ph) displayed modest catalytic activity in the reaction of aniline with phenylacetylene.

A series of mono- and heterodinuclear gold(I) and platinum(II) complexes with a new bipyridylamine-phosphine ligand have been synthesized and characterized. The X-ray structures of the ligand precursor 4-iodo-N,N-di(pyridin-2-yl)benzamide, and of one gold derivative are reported. All the complexes display antiproliferative properties in vitro in human cancer cells in the range of cisplatin or higher, which appear to correlate with compounds' uptake. Interestingly, studies of the interactions of the compounds with models of DNA indicate different mechanisms of actions with respect to cisplatin. The biological activity study of these complexes provides useful information about the interest of designing multimetallic complexes for enhanced cytotoxic properties.

The electrophilic imino esters XF2CC(=NPG)CO2Me and imino phosphonates CF3CC(=NPG)P(O)(OR)2 (PG = SO2Ph, Cbz, Boc) were transformed by nucleophilic and then electrophilic additions into fluorine-containing amino esters and amino phosphonates with two pendent alkene chains (XF2C)(CH2=CH(CH2)nC(NPG)(Z)(CH2)mCH=CH2 [Z = CO2Me, P(O)(OR)2]. The ring-closing metathesis was performed on the α-amino ester dienes with Ru=CHPh(Cl)2(PCy3)2 catalyst and afforded five-, six-, and seven-membered cyclic amino esters, whereas the α-aminophosphonate dienes were transformed with RCM catalyst [Ru=C=C=CPh2(Cl)(PCy3)(p-cymene)]OTf to give six- and seven-membered cyclic α-amino-α-(trifluoromethyl)phosphonates.

A two-step ruthenium(II) and acid-catalysed one-pot selective transformation of 2-propyn-1-ols into α,β-unsaturated aldehydes has been developed. The complex [(dppe)Ru(η3-CH2C(Me)CH2)2] (dppe = Ph2PCH2CH2PPh2) is an efficient precatalyst for the anti-Markovnikov addition of benzoic acid to 2-propyn-1-ols with the formation of 3-hydroxy-1-propen-1-yl benzoates in good yields. The latter readily undergo rapid transformation into α,β-unsaturated aldehydes on treatment with a catalytic amount of an acid such as PTSA or HBF4 at room temperature.

After the Rift valley fever (RVF) epidemic of 1987 in the Senegal River Basin, RVF surveillance based on serosurveys has been conducted for 10 years. Serum samples were obtained from 1336 persons and from sheep and goats in selected areas, and these were tested for IgG/IgM RVF antibodies by ELISA. After a period of regular decrease in RVF prevalence in domestic animals until 1993, an epizootic was observed in all herds in 1994-95 with increases in IgM levels and abortions. During the same period, no human cases or RVF IgM were detected. The RVF IgG prevalence significantly correlated with date of birth: children born after 1987 have a low prevalence (5%) in clear contrast to the older population (25.3%) in Podor district. A retrospective analysis of rainfall and RVF prevalence in small domestic animals over the last 10 years showed that the re-emergence correlated with heavy rainfall. A general analysis of the risk of re-emergence and the efficiency of this RVF surveillance system are presented.

This paper describes the present epidemiological situation of Schistosoma haematobium in 4 villages in the middle valley of the Senegal River Basin, in terms of level and intensity of infection, seasonality of transmission, and intermediate hosts, and the effect of different treatment schedules with praziquantel on the overall infection levels and re-infection rates. The longitudinal study involving 7 surveys was carried out between June 1995 and March 1997 in Diatar, Guia, Donaye and Niandane. The prevalence and intensity of infection remained low throughout the survey (55% and12 eggs/10 mL urine), and there were no systematic differences in the prevalence or intensity of infection between men and women. Before treatment, infections were highly aggregated in individuals and were concentrated in children (aged15 years) with 85% of the potential contamination; no individual aged24 years produced50 eggs/10 mL urine. Using WHO guidelines mass treatment was given to all Diatar and Guia villagers in December 1995, whereas in Donaye and Niandane only individuals positive for eggs were treated. Six weeks post-treatment cure rates in all villages were80%, with marked declines in levels of infection (20% and4.5 eggs/10 mL). By March 1997 infection levels in Donaye and Niandane had returned to pre-treatment levels, whereas in the 2 mass-treated villages (Diatar and Guia) infection levels were still markedly reduced compared to pre-treatment levels. Rates of conversion were very low between all surveys; however, there was an apparent high level of reversion (20%), due to the alternation of individuals apparently positive and negative between surveys. Water and infected snails were present from June to March. Therefore, owing to the high aggregation of infections in children, the low overall infection levels and the transmission period, it is suggested that in this area the best treatment schedule would be selective treatment of school-aged children in March/April, probably on an annual basis.

Seven years after the completion of two dams in the Senegal River basin, 203 individuals from four villages around Podor in the middle valley, where Schistosoma haematobium infections were present, were examined in June 1995. In December 1995 a single dose of praziquantel (40 mg/kg) was given to each of these subjects, who were re-examined in April 1996. Clinical and parasitological signs of infection were investigated at both examinations, and ultrasonography was performed to check for lesions of the urinary tract induced by S. haematobium. As uninfected controls, 200 people from four villages where S. haematobium was absent were similarly examined, in November 1995. Prior to treatment, bladder irregularities were observed in 43% of the subjects from Podor but only 6% of the uninfected controls. The severity of the bladder lesions visible by ultrasonography was significantly associated with intensity of infection, despite the generally low levels of infection in the subjects mean = 13.1 eggs/10 ml urine). Four months after treatment, however, the frequency of bladder irregularities among the subjects (11%) was similar to that in the uninfected controls and intensities of infection and other clinical signs of disease had also significantly declined. The prevalence of haematuria, for example, fell from 35% pre-treatment to 10% post-treatment. The results indicate that the onset of S. haematobium morbidity can be relatively rapid even in areas with seasonal and low levels of transmission, and demonstrate that treatment to reduce morbidity in such areas is important and could be relatively simple and very effective.

Two treatments with praziquantel (PZQ) 40 mg/kg, 40 d apart, were given to individuals in a recently established (6 years) Schistosoma mansoni focus in the Senegal River Basin (SRB). Efficacy of treatment was evaluated 4 weeks after each treatment. Among 130 individuals who provided stool samples on days 0, 118 and 153 and were treated on days 85 and 125, 113 (87%) were infected with S. mansoni before treatment. The overall geometric mean faecal egg count of the infected individuals was 478 eggs/g. Four weeks after the first treatment (day 118), the overall cure rate was only 42.5% and the overall reduction in intensity of infection was 70.7%. However, 4 weeks after the second treatment (day 153), the overall cure rate rose to 76.1% and the overall reduction in intensity was 88.1%. The greatest increase in cure rate between the 2 treatments was in those individuals who were initially the most heavily infected (1000 eggs/g). There was no apparent difference in cure rate between younger (20 years) and older individuals (20 years). No evidence for the existence of a PZQ tolerant strain of S. mansoni was found. Two treatments of PZQ 40 mg/kg, 40 d apart, were sufficient to give an adequate cure rate and high reductions in the intensity of infection. As there was insufficient time for reinfection between treatment and follow-up to result in egg production, the low cure rate observed after one treatment was probably the result of a combination of high infection intensity and the maturation of pre-existing prepatents S. mansoni infections.

The impact of malaria on low birthweight was investigated in Bougoula village (Sikasso region, Mali). In two successive years, pregnant women were followed until delivery. Phase I (1992) was observational, with 135 complete observations. Phase II (1993) included 126 participants, who were offered malaria prophylaxis with proguanil (200 mg/day) and chloroquine (300 mg/week). The results show that 1) infants of first and second pregnancies had lower birth weights (-382.7 +/- 62.6 g; P < 0.0001) compared with higher rank pregnancies; 2) strong seasonal variation in birthweight was observed in Phase I, with an annual cycle, a nadir in January, and an amplitude of 372.4 g (P = 0.0002); 3) parasitemia measured during pregnancy was associated with lower birthweight in infants from first and second pregnancies, but not from higher parity mothers; and 4) malaria prophylaxis taken for 20 weeks or more in Phase II suppressed the seasonal variation of birthweight and the effect of low parity (+423.4 +/- 118.8 g; P = 0.0004). We conclude that malaria in pregnancy has an important negative impact on birthweight in first and second pregnancies. Prophylaxis with proguanil and chloroquine is an effective prophylaxis when taken for 20 weeks or more.

A novel Ru(II) (arene) theranostic complex is presented. It is based on a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid macrocycle bearing a triarylphosphine and can be tracked in vivo by using the γ emission of (153) Sm atoms. Notably, the heteroditopic ligand can be selectively metalated with ruthenium at the phosphorus atom despite the presence of other functionalities that are prone to metal coordination. Subsequent labeling with radionuclides such as (153) Sm can then be performed easily. The resulting heterobimetallic complex exhibits favorable solubility and stability properties in biologically relevant media. It also shows in vitro cytotoxicity in line with that expected for this type of metallodrug, and is nontoxic to the organism as a whole. As a proof of concept, initial studies in healthy mice were performed to obtain information about the uptake, biodistribution, and excretion of the radiolabeled complex.

The combination of cubane (I)/PPH is found to catalyze the coupling of aryl and heteroaryl bromides with pyrazole (II) and its derivatives (V) under mild conditions.

Extensive water development has taken place in the north of Senegal over the last decade, resulting in a large increase in the amount of fresh water for irrigation. The objectives of the present study were to determine the prevalence and intensity of Schistosoma mansoni and S. haematobium in the Senegal river basin (SRB), and to ascertain the distribution of the snail species acting as intermediate hosts for both species of schistosomes. The schistosomiasis survey started in January 1994 and was completed in March 1995. Compared to studies before the construction of the Diama dam, there was a significant increase in both the prevalence and intensity of urinary and intestinal schistosomiasis in the human population in parts of the SRB. From the 9014 people who were registered from 180 villages and 4 towns (10 districts), 7750 were examined. S. mansoni was found in the lower valley (lower delta-Senegal river, lower delta-Lampsar river, upper delta, and diere ) but not in the middle valley. The mean prevalence ranged from 4.4% in the lower delta-Senegal River to 71.8% in the zone of Lac de Guiers, where prevalence and intensity of infection were higher on the eastern side of the lake (81.3% with a mean number of 2088 eggs/g of faeces) compared with the western side (50.3% with a mean 1111 eggs/g). S. haematobium was recorded throughout the area of study, ranging from a mean prevalence of 0.37% in diere (lower valley) to 41.5% in the lower valley (Lampsar river), where the mean egg count was 313/10 mL of urine. Physical and chemical changes to the environment have favoured the spread and increase in the populations of freshwater snails. The only snail involved in the transmission of S. mansoni was Biomphalaria pfeifferi . Five species of bulinid snails were present— Bulinus globosus, Bu. umbilicatus, Bu. senegalensis, Bu. forskalii and Bu. truncatus —but only the first 3 species were involved in the transmission of S. haematobium in the lower and middle valleys.

Malnutrition of children is a major public health problem in many African countries. Despite a relatively favourable geographical situation, the prevalence of malnutrition is high in the Sikasso region (Mali).Survey repeated annually during 5 years, to a sample of 491 families living in Sikasso. The determinants of wasting and stunting were analysed using logistic regression.The prevalence of stunting was about 25%. Prevalence of wasting was about 12%, which is very high, and had been increasing in the past years. No strong associations with socio-economic factors were observed for wasting. Stunting was strongly associated with the education level of both parents, and with the family assets.There is a high prevalence of malnutrition in the Sikasso region of Mali. The authors report their findings from a study of the determinants of wasting and stunting in the region using logistic regression. A survey was repeated annually over the course of five years in a sample of 491 families living in Sikasso. This group of families was randomly drawn from the administrative census of 1986 and represents 11% of the total number of families in the municipality. The overall prevalence of stunting was 27.2% at the first survey round and 23.2% at the fifth round, with no significant variations between the yearly rounds. The prevalence of wasting, however, was 6.5% on the first round and 12.5% on the fifth round, peaking at 17.9% on the fourth round. These differences were statistically significant. There were no statistically significant differences of malnutrition prevalence between the sexes. No strong association with socioeconomic factors was found for wasting, although stunting was strongly associated with the education level of both parents and with family assets.

[Ru(μ-O2CH)(CO)2(PPh3)]2 in acetonitrile is an efficient catalyst precursor for the Michael addition of soft carbonucleophiles to butenone. The utilization of terminal alkynes as donors makes possible the selective formation of γ,δ-ynones.