This thesis is concerned with attempts to establish solid-state NMR as a complementary technique to X-ray crystallography for providing information on crystal structure, i.e. information regarding conformation, packing and inter- or intra-molecular interactions. Methods of assigning the solid-state NMR spectrum have been used which rely upon (^1)H-(^13)C dipolar interactions and upon the shielding anisotropy experienced by the nuclei. Single pulse experiments have also been used to identify solvate molecules. Of particular importance, the anisotropy and asymmetry have been found for a number of steroids, and the values used to assign the high frequency region of the spectrum. This has enabled chemical shifts to be linked to the hydrogen bonds that are present. Thus, the mode of hydrogen bonding can be predicted in forms of cortisone acetate for which the crystal structure is not available. Chemical shifts have also been linked with the conformation of the D ring. In this way, important crystallographic information has been gleaned from the solid-state NMR spectrum. The effect of the formation of hydrogen bonds upon the shielding tensor components of carbonyl and ester carbons has been studied, and found to cause a high frequency shift in δ22, which is probably oriented along the C=0 bonds. This leads to a high frequency shift in the isotropic chemical shift. The effect of the spinning speed upon the centreband intensity of a peak as the anisotropy and asymmetry are varied has been investigated. It has been found that at low spiiming speeds, the centreband intensity does not vary in a simple fashion. Thus it is recommended that full shielding tensor analysis is performed. The effect of the spinning speed on the sample temperature has also been studied. Results show that at low spinning speeds (up to 2 kHz) there is sample cooling as the spinning speed increases (attributed to the Joule -Thompson effect). But at higher spinning speeds (above 2 kHz) then there is sample heating as the spinning speed increases. The importance of this result is discussed. The effect of quadrupolar nuclei (35C1 and (^14)N) upon the spectrum of a spin-(^1)(_2) nucleus ((^13)C) has been studied. In favourable cases, the anisotropy in the spin-spin coupling constant has been found, whilst in other cases, the sign and magnitude of the quadrupolar coupling constant have been obtained. The broadening of resonances of carbon atoms adjacent to quadrupolar nuclei has been valuable in assigning the solid-state NMR spectra. The broadening effect has also been observed at more distant sites. It has not been possible to distinguish the effects of (^37)C1 and (^35)C1 on the carbon spectra of chlorine containing steroids.

Hokkaido University (北海道大学) / 博士 / 医学

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18647号 / 医博第3946号 / 新制||医||1006(附属図書館) / 31561 / 京都大学大学院医学研究科医学専攻 / (主査)教授 福山 秀直, 教授 平岡 眞寛, 教授 宮本 享 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DGAM

Nanoparticles have become increasingly useful in the fields of drug delivery and biosensing. In these applications, nanoparticles are frequently exposed to biological fluids, where proteins will spontaneously adsorb to the nanoparticle surface when exposed to a mixture of proteins. This project aims to present a predictive host-guest system for quantifying each residue’s contribution to nanoparticle binding. Initial studies revealed that lysine at position 13 plays a crucial role in the adsorption of GB3 to 15 nm citrate-coated spherical gold nanoparticles (AuNPs). Therefore, we have constructed a library of K13X GB3 variants, and our initial findings confirm that basic residues (Arg) interact more favorably with AuNPs than other polar (Asn) and acidic side (Glu) chains, and a rank-ordering of side-chain affinity for AuNP surfaces could be inferred in further studies. A simple mechanism can be used to interpret these rankings with respect to thermodynamic vs. kinetic control in future studies.

Mit der palliativen transarteriellen Chemoembolisation (TACE) läßt sich eine Verkleinerung von malignen Lebertumoren und eine Verlängerung des Überlebens erreichen. Im Verlauf des Therapiezyklus diente die Phosphor-Magnetresonanzspektroskopie mittels Chemical-Shift-Imaging einem nichtinvasiven Einblick in den zellulären Energie- und Membranstoffwechsel. Eine Differenzierung zwischen primären und sekundären Lebertumoren war anhand der 31P-Spektren nicht möglich. Posttherapeutisch zeigten die Patienten einen Anstieg des anorganischen Phosphats bei Abfall des ß-NTP-Signals, die sich während des sechswöchigen Intervalls vor der nächsten Intervention wieder normalisierten. Therapieansprechen und -versagen zeigten während des Therapiezyklus unterschiedliche spektroskopische Quotientenverläufe. Eine deutliche Volumenreduktion als auch eine homogene und dauerhafte Lipiodoleinlagerung im Tumor gehen zuverlässig mit einem spektroskopischen Therapieansprechen einher. Dies zeigte sich bei der ersten Patientengruppe während der Untersuchung direkt nach der Embolisation und bei der zweiten Gruppe erst vor der nächsten Intervention. Therapieversagen, Tumorprogression und geringe Lipiodoleinlagerung bzw. rasche Entspeicherung im Verlauf ließen sich spektroskopisch nach-weisen. Schwierig bleibt die Zuordnung der Patienten mit uneinheitlichen Quotienten-verläufen. Die MRS kann früher als die klinische Routinediagnostik eine Aussage über das Therapieansprechen treffen. Für den Patienten ergibt sich die Vermeidung einer ineffektiven Therapie. Bei nachgewiesenem Ansprechen hingegen profitiert der Patient durch die wiederholte Anwendung der TACE. Der hohe personelle, technische und zeitliche Aufwand für die Phosphorspektroskopie verhindert bisher den klinischen Routineeinsatz dieses Verfahrens. Im Rahmen der klinischen Forschung, insbe-sondere in der onkologischen Therapiekontrolle, hat die MRS als nichtinvasive Methode heute einen großen Stellenwert. / Using palliative transarterial chemoembolization (TACE) a reduction of malignant liver neoplasms and a prolongation of survival time can be achieved. During the course of therapy phosphorous magnetic resonance spectroscopy by means of chemical-shift-imaging was used for noninvasive examination of the cellular metabolism of energy and membranes. Differentiation between primary and secondary liver tumors was not feasible using 31P-spectra. After therapy patients had shown increased inorganic phosphate signal and reduction of the ß-NTP-signals, which normalized during six week intervall before next intervention. Response and non-response to therapy showed different courses of spectroscopic quotients during therapy cycle. Prominent reduction of volume as well as homogeneous and continous retention of lipiodol within the tumor are reliable combined with spectroscopic response to therapy. The first group of patients showed these signs at the examination immediately after embolization whereas patients of the second group showed these signs not before next intervention. Failure of therapy, progression of tumor and slight retention of lipiodol or rapid elemination during course of therapy were detectable by spectroscopy. Categorization of patients with non-uniform courses of quotients remains difficult. Magnetic resonance spectroscopy is able to determine response to therapy earlier than standard diagnostic methods. As a result ineffective therapy is avoided for the patient. On the other hand the patient profits from repeated administration of TACE. Great expense of personnel, equipment and time so far prevents clinical use of phosphorous spectroscopy as a matter of routine. In conjunction with clinical research MRS is an important non-invasive method especially for oncological therapy monitoring.

No description available.

« Etude du comportement paramagnétique des actinides en solution avec des ligands polyaminocarboxylates cycliques »Le comportement paramagnétique des cations actinide (éléments 5f) peut être étudié via la spectroscopie RMN liquide en suivant deux axes de recherche complémentaires : les susceptibilités magnétiques et les déplacements chimiques.Dans un premier temps, lorsque les interactions entre le cation actinide et le ligand sont négligeables, la susceptibilité magnétique molaire est accessible par la méthode d’Evans. Cette méthode est applicable pour des échantillons en solution autour de la température ambiante. Elle a été confrontée à la mesure SQUID sur échantillon solide à très basses températures pour le complexe [NpO2(DPC)2Li2]. Les deux méthodes ont donné des susceptibilités magnétiques molaires du même ordre de grandeur même si ce composé n’est pas optimal pour la comparaison.La méthode d’Evans a été utilisée pour compléter les données expérimentales de la littérature. La mesure de la susceptibilité magnétique du cation PuVO2+ (5f3) en milieu non complexant a été mesurée au laboratoire. Les calculs de susceptibilités magnétiques molaires réalisés par la méthode SO-CASPT2 pour les cations actinide aux degrés d’oxydation (+IV), (+V) et (+VI) (AnIV = UIV, NpIV, PuIV et AnV/VI = NpV/VI, PuV/VI) en milieux non complexant puis complexants chlorure et nitrate ont été comparés avec les valeurs expérimentales. Les cations actinide ont montré une sensibilité à la nature et géométrie de leur première sphère de coordination. Il a été mis en évidence que le cation NpVI (5f1) possède un état fondamental sensiblement affecté par la modification de la symétrie du complexe. A partir des niveaux électroniques calculés, des premiers calculs de spectres d’absorption de ces mêmes complexes ont pu être réalisés. L’absorbance principale calculée est en bon accord avec les spectres d’absorption expérimentaux malgré un décalage systématique des spectres calculés vers le rouge, assimilable à un effet néphélauxétique.Dans un deuxième temps, l’utilisation de la Théorie de Bleaney a permis l’étude des déplacements chimiques et plus précisément, du terme de contact des complexes de symétrie C4 d’actinide au degré d’oxydation (+IV) avec le ligand DOTA (AnIV = ThIV, UIV, NpIV, PuIV). Cette contribution de contact a été accessible par la RMN de l’oxygène 17 (17O), atome directement lié au centre paramagnétique. Le DOTA a été enrichi en 17O avant la synthèse du complexe en phase organique DMSO/CHCl3. Ces complexes ont été caractérisés par spectrophotométrie UV-Visible-NIR et spectroscopie RMN 1H et 13C. Une difficulté de synthèse a été rencontrée pour le complexe de ThIV-D17OTA, composante diamagnétique nécessaire à l’extraction des termes de contact purement paramagnétiques. D’autres voies de synthèses ont été explorées.Mots Clés : Actinides, RMN, Paramagnétisme, Susceptibilité magnétique, Déplacement chimique, DOTA.2018 – Commissariat à l’Energie Atomique et aux Energies Alternatives – Laboratoire d’interactions Ligand-Actinide – France / “Study of actinide’s paramagnetic behavior in solution with cyclic polyaminocarboxylate ligands”The actinide cation’s (5f elements) paramagnetic behavior may be studied by liquid NMR spectroscopy. Two complementary lines of research have been pursued: molar magnetic susceptibility and chemical shift.Firstly, magnetic susceptibility is easy to determine by the Evans’ method when there is no interaction between actinide cations and ligands. This method, with samples in solution at room temperature, has been compared to SQUID measurements using solid samples at very low temperatures for the [NpO2(DPC)2Li2] complex. Both methods produce molar magnetic susceptibilities with the same order of magnitude even if this compound is not the best one to the comparison.The Evans’ method has been used to complete experimental data from literature. The molar magnetic susceptibility measurement in a non-complexing medium for the PuVO2+ (5f3) cation has been measured in the laboratory. Molar magnetic susceptibility calculations were carried out using the SO-CASPT2 method for (+IV), (+V) and (+VI) actinide cations (AnIV= UIV, NpIV, PuIV and AnV/VI: NpV/VI, PuV/VI) in a non-complexing medium, then in chloride and nitrate complexing media. They have been compared with experimental values. The molar magnetic susceptibilities of actinide cations have been shown to be sensitive to the nature and geometry of their first coordination sphere. It has been revealed that the fundamental state of NpVI (5f1) cation is affected by changing the symmetry of the complex. From calculated electronic states, first absorption spectra calculations of these complexes have been carried out. A good matching between major calculated and experimental absorbances has been obtained. A red-shift was applied to the calculated absorption spectra to fit better with the experimental ones. This shift may be related to a nephelauxetic effect.Secondly, the use of Bleaney’s Theory has allowed the study of chemical shifts. And precisely, this work has been focused on the contact contribution for C4 symmetry AnIV complexed with DOTA ligand (AnIV= ThIV, UIV, NpIV, PuIV). This contact contribution is observable via NMR of oxygen-17 (17O) because oxygen atoms are directly linked to the paramagnetic cation. Therefore, the DOTA ligand was enriched in 17O before the actinide complex synthesis in a DMSO/CHCl3 organic phase. These complexes have been characterized by UV-Visible-NIR spectrophotometry and 1H, 13C NMR spectroscopy. But, some synthesis difficulties have been encountered to the diamagnetic ThIV-D17OTA (5f0) complex. This diamagnetic component is required to extract pure paramagnetic contact contribution. In that case, other ways of synthesis have been investigated.Keywords: Actinides, NMR, Paramagnetism, Magnetic susceptibility, Chemical shift, DOTA ligand.2018 – Commissariat à l’Energie Atomique et aux Energies Alternatives – Laboratoire d’interactions Ligand-Actinide – France

This PhD thesis presents structural investigations of amorphous inorganic materials: oxide and oxynitride glasses and mesoporous bioactive glasses (MBGs), by solid-state Nuclear Magnetic Resonance (NMR). Lanthanum oxide and oxynitride [La-Si-(Al)-O-(N)] glasses have a large number of potential applications due to their physical properties. In our work we have studied, compared to previous investigations, significantly expanded ranges of glass compositions (for oxynitride glasses, including samples of very high nitrogen content, up to 53 % out of the anions). We have estimated local environments of 29Si and 27Al structural units (their coordination, polymerization degree and number of N incorporated into tetrahedral units) in the materials. We have suggested a random Al/Si distribution along with almost uniform non-bridging oxygen atoms distribution in aluminosilicate glasses. Silicon nitride was used as precursor in the oxynitride glass synthesis. We studied both α- and β-modifications of silicon nitride, 15N-enriched, as well as fully (29Si, 15N)-enriched samples. We have shown that the linewidths of 15N NMR spectra are dominated by J(29Si-15N) coupling in 29Si315N4 sample. Mesoporous bioactive glasses in the CaO-SiO2-P2O5 system show superior bioactivity (the ability to form a hydroxycarbonate apatite layer on the glass surface when exposed to body fluids) compared to conventional bioactive glasses due to their large surface area and uniform pore-size distribution. Previous studies suggested a homogeneous cation distribution over the MBG samples on a 10−20 nm length-scale. From our results, on the other hand, we may conclude that Si and P is not intimately mixed. We propose a structural model, in which the pore walls of MBGs are composed of a silica network, and a phosphate phase is present as nanometer-sized clusters that are dispersed on the pore wall.

The results of a solid-state 11B NMR study of a series of boronic acids, boronic esters, and boronic acid catechol cyclic esters with aromatic substituents are reported in this thesis. Boron-11 electric field gradient (EFG) and chemical shift (CS) tensors obtained from analyses of spectra acquired in magnetic fields of 9.4 T and 21.1 T are demonstrated to be useful for gaining insight into the molecular and electronic structure about the boron nucleus. It can be concluded that when adequate electronic variation is present in the compounds being studied, Ω is generally the most characteristic boron NMR parameter of the molecular and electronic environment for boronic acids and esters. Importantly, these data are only reliably accessible in ultrahigh magnetic fields. The experimental span values result from a delicate interplay of several competing factors, including hydrogen bonding, the value of the dihedral angle, and the type of aromatic ring system present.

The results of a solid-state 11B NMR study of a series of boronic acids, boronic esters, and boronic acid catechol cyclic esters with aromatic substituents are reported in this thesis. Boron-11 electric field gradient (EFG) and chemical shift (CS) tensors obtained from analyses of spectra acquired in magnetic fields of 9.4 T and 21.1 T are demonstrated to be useful for gaining insight into the molecular and electronic structure about the boron nucleus. It can be concluded that when adequate electronic variation is present in the compounds being studied, Ω is generally the most characteristic boron NMR parameter of the molecular and electronic environment for boronic acids and esters. Importantly, these data are only reliably accessible in ultrahigh magnetic fields. The experimental span values result from a delicate interplay of several competing factors, including hydrogen bonding, the value of the dihedral angle, and the type of aromatic ring system present.