Search

The chloride-bridged dimer (I) (synthesized through classical palladation of the corresponding ligands using Pd acetate followed by anion metathesis with LiCl) is converted in situ into the cationic species (III).

The complexes (IV) are obtained from the reaction of (I) with PdCl2(SEt2)2 or PdCl2(PPh3)2.

N-Methyl-N-allyl-2-(1-acetoxyallyl)benzylamine reacts in the presence of tetrakis(triphenylphosphine)palladium to afford a mixture of an isoindole, a 2-benzazepine and allyl acetate; the likely reaction pathway involves a multistep procedure whereby each Pd atom is implicated at least four times, the formation of the isoindole occuring first, followed by an isomerisation to the benzazepine derivative.

8-Vinylquinoline and α-methyl-8-vinylquinoline have been prepared in 40–67% overall yield from 8-methyl- and 8-ethyl quinoline, respectively. These unsaturated compounds undergo nucleophilic addition with carbon and oxygen nucleophiles at the terminal vinyl carbon atom in the presence of Pd11 compounds affording, exclusively, five-membered metallacyclic rings.

The cationic cyclopalladated complexes derived from N,N-dimethylbenzylamine 4, N-benzylidene-(S)-(−)-α-methylbenzylamine 5 and 8-methyl quinoline 6 have been prepared and their properties as catalyst precursors for the telomerization of butadiene with methanol were investigated. The butadiene conversion was 60–70% for the three complexes and a mixture of butadiene dimers and telomers containing 2, 4 and 6 butadiene units were formed. The product selectivity is strongly influenced by the nature of the cyclopalladated complex. Thus, with complex 6 the C16 and C24 telomers were formed preferentially (more than 85%). On the other hand, with complex 4 the amount of butadiene dimers is greater than 40%. Complex 6 is also active for the telomerization of other aliphatic alcohols, but in these cases the 1- and 3-alkoxy octadiene telomers were produced preferentially.

o-N,N-Dimethylaminobenzyl-lithium reacted with NiCl2(PR3)2 to give cyclonickelated compounds; hexafluorobut-2-yne was inserted into their Ni–C bonds giving rise to a seven-membered organometallic ring when the phosphine was PMe3, whereas in the case of PEt3 a dimeric compound was obtained.

Reactions between iodide or cationic derivatives of cyclopalladated complexes and alkynes lead to the synthesis of heterocyclic compounds through insertion of one or two alkynes into the Pd–C bonds, the new N–C bonds being formed via reductive elimination of palladium(0).

Bis(1-methoxynaphthanene-8-C,O)palladium(II) reacts stoicheiometrically with both nucleophiles and electrophiles to afford organic compounds viaselective carbon–carbon bond formation.

Bis(cyclo-octa-1,5-diene)platinum reacts with methyl vinyl ketone at ca.–20 °C to give either [Pt{η2-CH2:CHC(Me):O}2(cod)](cod = cyclo-octa-1,5-diene) or [Pt{η2-CH2:CHC(Me):O}3]. The former complex readily isomerises to a platinacyclopentane [[graphic omitted]H[C(Me):O]}(cod)], from which the cod group may be replaced by CNBut or PPh3 to give [[graphic omitted]H[C(Me):O]}L2](L = CNBut or PPh3). In order to establish the molecular structure of this class of complex a single-crystal X-ray diffraction study was made on the PPh3 derivative crystals of which are triclinic, space group P, Z= 2, in a unit cell with lattice parameters a= 10.755(3), b= 18.172(3), c= 11.780(2)A, α= 110.26(1), β= 114.89(2), and γ= 95.77(2)°. The structure has been refined to R 0.044 (R′ 0.041) for 8 596 independent reflections to 2θ⩽ 60°(Mo-KαX-radiation) collected at room temperature. The platinacyclopentane ring has a head-to-tail arrangement for the CH2·CH[C(Me):O] groups, is non-planar, and is disordered about the β-carbon atom carrying a C(Me):O group, revealing for this derivative the presence of two isomers. Reaction of [Pt{η2-CH2:CHC(Me):O}2(cod)] with oxygen, hexafluoroacetone. or (CF3)2C:C(CN)2 affords five-membered platina-ring complexes [[graphic omitted]H2}(cod)][X·Y = O·O, O·C(CF3)2, or C(CN)2·C(CF3)2], while treatment with PPh3, CNBut, or C2F4 gives [Pt{η2-CH2:CHC(Me):O}L2](L = PPh3 or CNBut) and [[graphic omitted]F2)(cod)], respectively. The latter dimerises in solution to yield [Pt2(µ-CF2·CF2)2(cod)2].

The transmetallation reaction of bis(8-dimethylaminonaphthyl)mercury, [Hg(dman)2], with [PdCl2(SEt2)2] or [{PdCl2(PPh3)}2] and palladium acetate afforded, by transfer of the substituted naphthyl group from mercury, a high yield of monoarylated palladium compounds, [Pd(dman)-Cl(L)]. Although no reaction occurred between [Hg(dman)2] and [PtCl2(SEt2)2] or [{PtCl2(PEt3)}2] the reaction between [Pt(dman)2] and Hg(O2CMe)2 resulted in [Pt(dman)2Hg(O2CMe)2] which contains an unsupported Pt–Hg bond. Transmetallation from bis(8-methoxynaphthyl)palladium to [PdL2Cl2][L2= cyclo-octa-1,5-diene (cod); L = SEt2 or PhCN], Li2[PdCl4], and HgX2(X = O2CMe or Cl) provided several new arylpalladium complexes originating from exchange of ligands between the metal centres. For one of these products, [{Pd(mxn)(O2CMe)}2](mxn = 8-methoxynaphthyl), the structure in the solid state was determined by X-ray crystallography [monoclinic, space group P21/n, a= 19.539(2), b= 9.396(2), c= 13.893(3)A, β= 110.75(1)°]. It shows a dimeric molecule in which the square-planar co-ordinated palladium atoms are bridged by the acetato groups [Pd–O 2.11(1)A(average)] and each mxn group is C,O-chelate bonded to one palladium centre [Pd–C 1.97(2)A(average), Pd–O 2.10(2)A(average)]. The molecule is folded such that the Pd ⋯ Pd distance is 2.842(4)A with the two naphthyl rings facing each other.

The cyclopalladation reactions of several sulphur-containing ligands have been investigated. The thioethers benzyl methyl sulphide, methyl naphthyl sulphide, 2,6-dimethylphenyl methyl sulphide, and neopentyl phenyl sulphide have been metallated by palladium acetate in acetic acid at either aryl or alkyl carbon atoms to afford, after reaction with lithium chloride in acetone, dimeric chloride bridged cyclopalladated complexes in moderate (22%) to good (81%)yields. In these products each metal is part of a five-membered ring. The same reaction with 2-biphenyl methyl sulphide afforded a dimeric complex containing a six-membered cyclopalladated ring through palladation of the ortho position of the biphenyl group. 4,4′- Dimethoxythiobenzophenone and N,N,N′,N′-tetramethyl-thiourea have been palladated by using a ligand-exchange reaction with [{[graphic omitted]Me2-2)Cl}2] in the presence of stoicheiometric amounts of trifluoroacetic acid. This afforded good yields of dimeric palladocyclic complexes through the metallation of a carbon ortho to the thioketone, or of a methyl group of the thiourea respectively. With 1,3-bis(methylthiomethyl)benzene this latter reaction, by metallation of the 2 position of the aryl ring, afforded excellent yields of a monomeric compound in which both sulphur atoms are co-ordinated to the palladium centre.

Related to antimicrobial research, we synthesized tin compounds derived from undecylenic, ricinoleic and caprylic acids and we found that they show very high activity against some strains of bacteria and yeast, even in nM range, being up to four thousand times more potent against Staphylococcus aureus than against mammalian cells. For ruthenium compounds, in turn, we have confirmed that the mode of action of some compounds that were synthesized recently is undoubtedly different from Cisplatin or other ruthenium compounds, because of their high stability toward substitution reactions. Finally, during the vectorization of compounds derived from Ru with Affitin we have gained important knowledge about a possible mechanism of action of this type of molecule: it could indeed be possible that these compounds which have a very reduced redox potential compared to corresponding compounds can cause polymerization of proteins by electron transfer., Nous avons synthétisé des composés d'étain avec des acides undécylénique, ricinoléique et caprylique. Ils ont une activité importante contre certaines souches de microrganismes, puisque ils agissent pour certains d’entre eux à des concentrations nanomolaires. Staphylococcus aureus semble être 4000 fois plus sensible à leur toxicité que les cellules de mammifères. Nous avons obtenu des composés du ruthénium qui présentent cytotoxicité contre des cellules cancéreuses suivant un mécanisme d'action différent de ceux observés pour le Cisplatine ou d'autres composés de Ru, grâce à leur grande stabilité dans les réactions de substitution. Enfin, pendant la vectorisation des composés dérivés du Ru avec une Affitine nous avons pu acquérir des connaissances importantes sur un éventuel mécanisme d'action de ce type de molécules dont le potentiel redox très abaissé par rapport aux composés correspondants pourrait être responsable de la polymérisation de protéines cibles par transfert d’électron.

The general area of this thesis is the study of physico-chemical processes involved in can- cer development and / or their therapies. The first part is devoted to the characterization of the interactions involved in the association of ruthenium complexes with the DNA macromolecule. Experimental characterization of this equilibrium is made by UV-visible absorption and circular dichroism experiments. An original method of analysis is used to highlight the simultaneous presence of two association modes. A two equilibria model fits correctly the experimental data and permits the identification of these two association modes. The second part is a preliminar work about cell movements on a soft substrate. Characterizations of cell behavior depending on the substrate rigidity has been highlighted and give similar results in the literature.; Le domaine général de cette thèse est l’étude des procédés physico-chimiques impliqués dans le développement du cancer et/ou leurs thérapies. La première partie est consacrée à la caractérisation des interactions mises en jeu lors de l’association de complexes du ruthénium avec la macromolécule d’ADN. La caractérisation expérimentale de cet équilibre est faite par des manipulations d’absorption UV-visible et de dichroïsme circulaire. Une méthode d’analyse originale est utilisée pour arriver à mettre en évidence la présence simultanée de deux modes d’associations. Un modèle à deux équilibres traduisant convenablement ces observations et permettant d’identifier les deux modes d’association est alors proposé. La deuxième partie constitue un travail préliminaire à l’étude des mouvements cellulaires sur un substrat mou. Des caractérisations du comportement des cellules en fonction de la rigidité de leur substrat a pu être mis en évidence et donnent des résultats similaires à la littérature.

One of the main research domain in the laboratory of «Synthèse Metallo-Induites» consists in the development of new planar chiral metallacycles complexes. The challenge of this thesis was the development of new selective approaches for the synthesis of new cationic and neutral planar chiral metallacycles complexes in which the chelated metal is a pseudotetrahedral stereogenic center.The thesis project was initiated by the study of the unusual cycloruthenation of a 2-phenylpyridine ligand which was able to produce a tris-cationic homobimetallic planar chiral ruthenacycle as secondary product in a one step reaction starting from simple substrates. This type of homobimetallic product is only formed when a strong electrodonationg group as NMe2 is present on the starting ligand. In view of this result, we engaged a systematic study by synthesizing new planar chiral iridacycles compounds. The positively charged metal fragments (Cp*Ir2+, Cp*Ru+) and neutral (Cr(CO)3) may p-coordinate the electronic rich aryl fragment of the iridacyclic compound by virtue of the coulombic imbalance in the coordination sphere of the chelated metal center. One of the unexpected consequence of this research is the emergence of the concept ″deported constitutional chirality″, which appeared during the study of the conformational behaviour of an endodicationiciridacyclic complex where the methyl groups carried by the N,N-dimethylamino substituent diastereotopicity.To this fundamental quest for selectivity an explanation of the catalytic proprieties of our complexes was added. They were found to be good precatalysts for the promotion of the water oxidation catalysis and to be promising catalysts for tandem hydroamination/hydrosilation of terminal alkynes.; L’un des axes de recherche du laboratoire Synthèse Métallo-Induites consiste en le développement de nouveaux complexes métallacycliques à chiralité planaire. Le défi majeur de cette thèse, a été l’élaboration de nouvelles approches sélectives de synthèse de complexes cationiques et neutres métallacyliques à chiralité planaire dont le métal chélaté est un centrestéréogène pseudo-tétraédrique.Le projet de thèse fut initié lors de l’étude d’une réaction inhabituelle de cycloruthénation d’un ligand dérivé de la 2-phénylpyridine qui était capable de produire un complexe ruthénacyclique OC-6 triscationique, homobinucléaire et à chiralité planaire comme produit secondaire en une seule étape à partir de substrats simples. Ce type de produit homobinucléaire ne peut se former uniquement que lorsqu’un groupement fortement donneur comme le N,N-diméthylamino (-NMe2) est présent sur le ligand départ. C’est donc à la lumière de ce résultat que nous avons engagé une étude systématique de la synthèse de nouveaux composés iridacycliques à chiralité planaire. Les fragments métalliques positivement chargés (Cp*Ir2+, Cp*Ru+) et neutre (Cr(CO)3) pourraient p-coordiner un fragment aryle riche en électrons d’un composé cyclométallé suivant un cours stéréochimiqueconditionné par la nature des entités ainsi introduites. Une des conséquences inattendues de ces recherches est l’émergence du concept de chiralité constitutionnelle déportée qui a surgi lors de l’étude du comportement conformationnel du complexe endo dicationique IrIr(NMe2) dont les groupes méthyles portés par le substituant N,N-diméthylamino dénotent une diastéréotopicité remarquable en spectroscopie de RMN 1H.A cette quête fondamentale de sélectivité s’est aussi greffée une exploration des propriétés catalytiques de nos complexes qui se sont révélés comme d’excellents précatalyseurs pour la promotion de réactions comme l’oxydation de l’eau et l’hydroamination/hydrosilylation d’alcynes vrais.

Since the clinical success of platinum drugs (cisplatin and its derivatives) as anticancer agent, medicinal inorganic chemistry has become a field of growing interest because it offers an alternative for the design of therapeutic agents that are not readily available to organic compounds. Although cisplatin is one of the most widely used drugs in chemotherapy, it is not effective for all types of cancer. Moreover, platinum drugs are the cause of disabling side effects (neurotoxicity, nephrotoxicity, weight loss, nausea…) and their applicability is limited by innate or induced resistance to platinum in a narrow range of tumours. Therefore, this clinical success has promoted the search for cytotoxic compounds with enhanced activities and more acceptable toxicity profiles. This has stimulated interest in complexes containing other heavy metals of the platinum group such as ruthenium because these compounds show lower toxicity than drugs based on platinum. Some ruthenium compounds have already shown promising anticancer activity and two RuIII complexes trans-[RuCl4-(DMSO)(Im)]ImH (NAMI-A and trans-[RuCl4(Ind)2]IndH (KP1019) recently enter in clinical phase for their respectively antimetastatic and cytotoxic properties.In the essential aim of increasing activity and reducing side effects of anticancer agents, the Laboratoire de Synthèses Métallo-Induites has developed for several years organometallic ruthenium compounds RDC (Ruthenium Derivative Compound) in which one of the ligand is strongly bound to the metal via a strong σ C-Ru bond and stabilized by an intramolecular N-Ru bond. This thesis presents the recent advances of the laboratory in this field and the development of a second generation RDC in which the cylometallating ligand is stabilized by two N-Ru bonds. Thus, several complexes pass the symbolic barrier of the nanomolar range for their IC50 indicating a critical improvement. At the same time, we decided to focus our studies on osmium heavier congener, not only to complete the RDC chemical library, but also to verify the impact of exchanging the metal. An extensive chemical library ODC (Osmium Derivative Compound) of forty cyclometalated osmium complexes was synthesized and evaluated in vitro. Biological studies on these ODCs showed that osmium is another metal that deserves attention for the development of new effective antitumour drugs. The measurements of physicochemical properties such as red-ox potential and lipophylicity (log(Po/w)) allowed us to tentatively correlate these parameters to the level of activity, thus approaching a possible Property-Activity Relationship (P.A.R.). More insight into the role of the red-ox potential will probably become clearer as we progress into the mechanism of action of these species.; Suite au succès clinique des composés du platine (cisplatin et de ses dérivés) en tant qu’agent anticancéreux, la chimie inorganique médicinale a connu un essor considérable offrant ainsi une alternative à la conception d'agents thérapeutiques. Bien que le cisplatin et ses dérivés soient sans doute une des classes la plus réussie de médicaments anticancéreux, leur utilisation n’est pas efficace contre tous les types de cancer. De plus, ils sont à l’origine d’effets secondaires très invalidants (neurotoxicité, néphrotoxicité, perte de poids, nausées…) et sont également inactifs contre certains cancers présentant une résistance innée ou induite. Par conséquent, la recherche a développé des composés possédant des activités améliorées et des profils de toxicité plus acceptables. Ceci a ainsi stimulé l'intérêt pour les complexes contenant d'autres métaux de la mine du platine tels que le ruthénium, car ces composés présentent une plus faible toxicité que les complexes existants. Certains composés du ruthénium ont déjà montré une activité anticancéreuse prometteuse et deux complexes du RuIII le trans-[RuCl4-(DMSO)(Im)]ImH (NAMI-A) et le trans-[RuCl4(Ind)2]IndH (KP1019) sont entrés récemment en phase clinique.Dans le but d’améliorer l’activité et de réduire les effets secondaires des agents anticancéreux existants, le Laboratoire de Synthèses Métallo-Induites a développé depuis plusieurs années des complexes organométalliques du ruthénium RDC (Ruthenium Derivative Compound) dans lesquels un des ligands est fortement lié au métal par une liaison convalente σ C-Ru qui est elle-même stabilisée par une liaison intramoléculaire N-Ru. Cette thèse présente les avancées récentes du laboratoire dans ce domaine et plus particulièrement le développement d’une chimiothèque de RDC de seconde génération dans laquelle le ligand cyclométallé est stabilisé par deux liaisons N-Ru. Plusieurs complexes ont ainsi atteint des IC50 significativement inférieur à la micromole. En parallèle, le même type d’études a été réalisé sur des complexes de l’osmium aboutissant à une chimiothèque ODC (Osmium Derivative Compound) d’une quarantaine de composés. Cette étude est d’un intérêt particulier car non seulement elle complète la famille des RDC, mais elle permet également de vérifier l’impact du changement de métal. Les études biologiques ont ainsi montré que l'osmium présente un réel intérêt dans le développement de nouveaux médicaments antitumoraux particulièrement efficaces. Les mesures des propriétés physico-chimiques telles que le potentiel d’oxydo-réduction et la lipophilie (log(Po/w)) ont permis de corréler ces paramètres à leur activité in vitro, se rapprochant ainsi d’une éventuelle relation propriété-activité (P.A.R.). Le réel rôle du potentiel d’oxydo-réduction deviendra probablement plus clair au fur et à mesure de notre avancée dans la résolution du mécanisme d'action de ces espèces.