Résumé : A ce jour, lutilité des cyclodextrines comme adjuvant pharmaceutique nest plus à démontrer. En biologie cellulaire, la méthyl-b-cyclodextrine est un outil couramment utilisé par les expérimentateurs. La déstructuration quelle induit au niveau des microdomaines membranaires que sont les radeaux lipidiques ou les cavéoles est mise à profit pour létude des fonctions cellulaires qui y sont associées. Le but de notre recherche est détudier les interactions de différentes cyclodextrines couramment utilisées dans le domaine pharmaceutique avec les constituants des membranes liposomales ou biologiques afin de mieux comprendre les conséquences de ces interactions au niveau cellulaire. Lhypothèse dune interaction des cyclodextrines avec les constituants lipophiles des membranes cellulaires a souvent été énoncée pour expliquer la cytotoxicité de certains dérivés. Nous avons pu montrer à laide de liposomes unilamellaires utilisés comme modèles membranaires, que linteraction des cyclodextrines avec leurs constituants, en particulier le cholestérol, est en relation avec une perte de lintégrité de la membrane. Ces premières études nous ont permis de prédire quels seraient les dérivés qui induiraient la cytotoxicité la plus importante. La cytotoxicité importante de certains dérivés méthylés (D.S. proche de 2) a été corrélée avec une capacité dextraction du cholestérol cellulaire relativement élevée. A linverse, nous avons montré que les dérivés faiblement substitués extraient peu le cholestérol, ce qui permet dexpliquer la meilleure tolérance observée au niveau biologique avec la Crysmeb et lHP-b-CD. Nous nous sommes ensuite intéressés à leffet de la b-CD et de ses dérivés méthylés sur la déstructuration des microdomaines membranaires. Nous avons étudié la relation entre leur capacité de déstructuration des cavéoles et dextraction du cholestérol cellulaire. Une extraction relativement élevée du lipide induit un effet important au niveau des microdomaines voire très important dans le cas de la Dimeb, le dérivé ayant leffet le plus délétère sur lintégrité des membranes artificielles et biologiques. Un effet moins marqué a également pu être corrélé avec une extraction plus faible du cholestérol par certains dérivés (Crysmeb, Trimeb). Les taux dextraction du cholestérol cellulaire mesurés sont en bonne corrélation, mis à part pour la Trimeb et la b-CD, avec les résultats des diagrammes de solubilité. La capacité de solubilisation du cholestérol par les cyclodextrines est en accord avec les interactions plus ou moins importantes observées en RMN. Les résultats de mesure de lintégrité des membranes artificielles correspondent à ceux obtenus avec les membranes biologiques excepté pour la b-CD, cette dernière nayant pu être testée dans les mêmes conditions que les autres cyclodextrines sur les liposomes. Il est maintenant admis que les cyclodextrines pourraient avoir un intérêt thérapeutique potentiel. En effet, la modulation des taux de cholestérol par lutilisation de cyclodextrines pourrait être mise à profit pour traiter des maladies ou infections impliquant ces microdomaines membranaires. Summary : Nowadays, the usefulness of cyclodextrins as pharmaceutical adjuvants is obvious. In cell biology, methyl-b-CD is a tool commonly used by scientists. The disruption of membrane microdomains (such as lipid rafts and caveolae) caused by cyclodextrins is used to study cellular functions. The aim of this research is to study the interactions of various cyclodextrins currently used in pharmaceutical development with the components of liposomal and biological membranes for a better understanding of the consequences of these interactions at the cell level. The hypothesis of an interaction between cyclodextrins and lipophilic components of cell membranes has often been suggested to explain the cytotoxicity of some cyclodextrin derivatives. Using unilamellar liposomes as model membranes, this research has shown that the interaction between cyclodextrins and their components, especially cholesterol, is linked with a loss of membrane integrity. This preliminary study has allowed predicting which derivatives will be the most cytotoxic. The high cytotoxicity of some methylated derivatives (D.S. close to 2) has been correlated with a relatively strong extraction capacity of cell cholesterol. On the other hand, it has been shown that low substituted derivatives do not extract much cholesterol, which is in agreement with the better biological compatibility observed with Crysmeb and HP-b-CD. The research has then focused on the effect of b-CD and its methylated derivatives on membrane microdomains disruption. The relation between caveolae disruption and cell cholesterol extraction capacities has been studied. A relatively strong extraction of the lipid highly disturbs the microdomains and this effect is even more important for Dimeb, the derivative showing the highest loss of integrity of artificial and biological membranes. A less marked effect has also been correlated with the lowest cholesterol extraction capacities of some derivatives (Crysmeb, Trimeb). The measured cell cholesterol extraction rates are in good correlation, except for Trimeb and b-CD, with the results of the solubility diagrams. The cholesterol solubilisation capacity of cyclodextrins is in accordance with the intensity of the interactions observed by NMR. The effects on the integrity of artificial membranes correspond to those obtained with biological membranes except for b-CD, which was not tested on liposomes in the same conditions as those used for the other cyclodextrins. It is now agreed that cyclodextrins could have a therapeutical potential. Indeed, the modulation of cholesterol levels could be applied for treating raft-related infections and diseases.

The work presented in this thesis has broadly established a few findings about the structure¬hyperpolarizability relation in molecular compounds: First, by measuring βHRS of an organic keto-enol tautomer, benzoylacetanilide in a binary solvent, I have shown that the first hyperpolarizability can be manipulated favourably by changing the composition of the solvent or by altering the pH of the solution. BA which exists in the pure keto form in water and as a keto-enol tautomer in ethanol, co-exists in equilibrium with the keto and enol forms at pH 11 in aqueous solution. The β value of the anion form is 709 x 10¬30 esu , whereas that of the enol is 232 x 10-30 esu and of the keto is 88 x 10-30 esu. There is an enhancement of β by ~ 8 times for the anion and ~3 times for the enol compared to the keto form. This opens up the possibility of finding large nonlinearities in organic molecules by simply ionizing it. Second, in organometallic complexes of divalent Ru, the first hyperpolarizability could be manipulated by altering the valence state of the metal center by oxidation or reduction or by introducing highly polarisable halogen atoms as substitutions in ligands attached to the metal center. The enhancement of first hyperpolarizability was observed in mononuclear [RuII(acac)2(CH3CN)2] complex by 1.7 times when the metal center was oxidized from RuII to RuIII. As it is already known that the complexes like [(acac)2Ru-bptz-Ru(acac)2] produce stable mixed valent compound, the enhancement of β by ~1.6 times is appearing because of that species only. Exploring Large Nonlinearity in Tautomers In this thesis I have taken a linear ketone for studying the effect of structure on β via the enol and anion formation mediated by solvent and pH of the medium. In the present study the proton transfer in BA took place in the ground state of the ketone and the enol or anion are produced in the ground states. The proton transfer reaction (tautomerism) can also happen in the excited state as well in some molecules where there is a substantial barrier to the proton transfer reaction in the ground state. In such systems, once the ketone is excited using ultraviolet light the barrier to proton transfer in the medium is overcome and a proton transfer in the excited state takes place and the enol is produced. Since such a system will be at higher energy, it will be interesting to do a two-laser experiment where the excited state hyperpolarizability is measured in a time resolved manner and the β value is determined in the excited state. Building Molecular Nonlinearity in Step-by-Step Electron Transfer In this thesis, I have dealt with a binuclear complex of Ru(II) which in one-step electrochemical oxidation produced a mixed valence compound which had substantially higher β value compared to the unoxidized complex. In this way it is possible to build a multicentered complex and see if sequential one-electron transfer and subsequent oxidation/reduction of the metal centers produce a mixed-valent metal compound with large molecular nonlinearity. The indication from the present study is that such a scheme should double the β value in each one-electron transfer step. Also the linker group/moiety between the successive metal centers will play an important role in dictating the efficiency of electron transfer. If the metal d-electrons in a multinuclear complex are linked through a π-conjugation, one would expect manifold enhancement of β. Such metal arrays can also be designed in 2 or 3 dimensions. The dimensionality of the multinuclear metal complexes can easily be changed by supramolecular design and synthesis strategy. Such metal networks may or may not generate large β molecules since electronic polarization in such systems may not be superimposable in a coherent fashion and may not add in a positive sense. All these remain to be tested and explored in the future.

Lanthanide elements display many remarkable and exciting properties which explain their widespread use in a number of very important biomedical tools like efficient MRI contrast agents or luminescent probes for highly sensitive assays of bioanalytes amongst other fields of application. In this context, the aim of the present work was to prepare and characterize lanthanide complexes of two ligands that feature a linear or a macrocyclic chelating unit compactly grafted onto a 1,10-phenanthroline derived moiety (phenDTPA and PhenHDO3A). The ditopic nature of the ligands allows the selective incorporation of a d6 metal ion and a lanthanide one in close proximity. The resulting rigid heterobimetallic supramolecular species show useful properties and constitute potential MRI contrast agents or new luminescent compounds depending on the type of the lanthanide and transition metal ions employed: for example, the selfassembly process of gadolinium(III) chelates around an iron(II) ion brings a remarkable increase of their relaxivity, a key parameter for use in MRI. On the other hand, association of a ruthenium and and a near infrared emitting 4f ion like ytterbium(III) gives mixed d-f structures able to harvest visible light and convert it into near infra-red signal. Visible light luminescent pH probes were also obtained with Eu3+ or Tb3+ phenHDO3A complexes.