Nott Katherine (2007). Synthèse de dérivés tensioactifs de virginiamycine et étude de leurs propriétés (Thèse de doctorat). Gembloux, Académie universitaire Wallonie-Europe, Faculté Universitaire des Sciences Agronomiques, 317 p., 66 tabl., 79 fig. Résumé : Suite à la purification du facteur M1 de la virginiamycine, des dérivés ont été synthétisés et purifiés. Deux types de mono-dérivés ont été obtenus : des esters avec des acides gras (modification de M1 au niveau de lhydroxyle en C-14) et des oximes (liaison chimiosélective) dérivées dacides aminés (réaction avec le carbonyle cétonique en C-16). Des di-dérivés ont également été produits en modifiant simultanément ces deux sites réactionnels avec un acide gras dune part et un aminooxy acétyle acide aminé dautre part. Lidentité des dérivés a été confirmée par un ensemble de techniques spectrales (infrarouge, masse et résonance magnétique nucléaire). Leurs propriétés tensioactives fondamentales ont été étudiées et un criblage de leurs activités antimicrobiennes a été réalisé. Laugmentation simultanée des caractères hydrophobe et hydrophile de M1 (cas des di-dérivés) est nécessaire pour lui conférer un caractère tensioactif marqué. Les di-dérivés présentent des caractéristiques tensioactives (cinétique dadsorption et formation de micelles) similaires voire supérieures à celles dautres tensioactifs classiques de la littérature et de certains biosurfactants tels que les lipopeptides de Bacillus subtilis. La synthèse de di-dérivés a augmenté la capacité de M1 à pénétrer dans un modèle membranaire. Le rôle favorable de M1 sur certaines propriétés de surface a été mis en évidence par comparaison des propriétés des di-dérivés avec celles de molécules témoins de type amide formées entre un acide gras et un acide aminé. La gamme de di-dérivés synthétisés a permis de contribuer aux études des relations structure fonction dans le domaine des tensioactifs. Le criblage des activités antibactériennes des dérivés a montré limportance des fonctions hydroxyle et cétone pour lactivité antibiotique initiale de M1. Les di-dérivés ainsi que les molécules témoins synthétisées présentent une activité vis-à-vis de certaines bactéries et moisissures. Cela pourrait être attribué à la capacité de ces molécules à déstabiliser les membranes de ces microorganismes. Nott Katherine (2007). Synthesis of surface active derivatives of virginiamycin and study of their properties (PhD thesis in french). Gembloux, Belgium, University Academy Walloon Region-Europe, Gembloux Agricultural University, 317 p., 66 tabl., 79 fig. Summary : Following the purification of the M1 factor of virginiamycin, derivatives have been synthesised and purified. Two types of mono-derivatives have been obtained : esters with fatty acids (modification of M1 at its C-14 hydroxyl) and oximes (chemoselective ligation) with aminooxylated amino acids (reaction with the ketone carbonyl at C-16). Bis-derivatives have also been produced by simultaneously modifying the two reactive sites with a fatty acid on one side and an aminooxylated amino acid on the other. The identity of each derivative has been confirmed by a combination of spectral techniques (infrared, mass and nuclear magnetic resonance). Their fundamental tensioactive properties have been studied and screening of their activity against microorganisms has been undertaken. The simultaneous increase of M1s hydrophobic and hydrophilic character (the case of the bis-derivatives) was necessary to render M1 surface active. The bis-derivatives have surface active characteristics (adsorption kinetics and micelle formation) similar or even superior to those of classical surfactants of the literature and of some biosurfactants such as Bacillus subtiliss lipopeptides. The synthesis of the bis-derivatives has enhanced M1s capacity to penetrate a biological membrane model. M1s positive impact on some surface properties has been shown by comparison with amide type molecules obtained by reacting a fatty acid with an amino acid. The range of the synthesised bis-derivatives has allowed this work to contribute to the studies of the relationships between surfactants structures and their properties. The screening of the derivatives antibacterial activities has shown the importance of the hydroxyl and ketone groups for M1s initial antibiotic activity. The bis-derivatives and the reference molecules show an activity against some bacteria and fungi. This may be due to their capacity to destabilise the microorganisms membranes.

This thesis describes the synthesis of a host of polynuclear iron complexes synthesised with phenolic oxime ligands, fundamentally developing the coordination chemistry of iron with these ligands. The metallic cores that occur within iron phenolic oxime clusters were found to contain almost exclusively oxo-centred triangles and oxo-centred tetrahedra. We found that we could alter the reaction conditions or derivatise the ligands and develop these basic building blocks into more elaborate arrays, exerting a degree of control over creating larger or smaller clusters. Chapter one describes the syntheses, structures and magnetic properties of new iron complexes alongside previously synthesised related complexes (4, 5, 8, 9 and 15) containing salicylaldoxime (saoH2) or derivatised salicylaldoximes (RsaoH2). These are [Fe3O(OMe)(Ph-sao)2Cl2(py)3]·2MeOH (1·2MeOH), [Fe3O(OMe)(Ph-sao)2Br2(py)3]·Et2O (2·Et2O), [Fe4(Ph-sao)4F4(py)4]·1.5MeOH (3·1.5MeOH), [Fe6O2(OH)2(Et-sao)2(Et-saoH)2(O2CPh)6] (4), [HNEt3]2[Fe6O2(OH)2(Et-sao)4(O2CPh(Me)2)6]·2MeCN (5·2MeCN), [Fe6O2(O2CPh)10(3-tBut-5-NO2-sao)2(H2O)2]·2MeCN (6·2MeCN), [Fe6O2(O2CCH2Ph)10(3-tBut-sao)2(H2O)2]·5MeCN (7·5MeCN), {[Fe6Na3O(OH)4(Me-sao)6(OMe)3(H2O)3(MeOH)6]·MeOH}n (8·MeOH) and [HNEt3]2[Fe12Na4O2(OH)8(sao)12(OMe)6(MeOH)10] (9). The predominant building block appears to be the triangular [Fe3O(R-sao)3]+ species which can self-assemble into more elaborate arrays depending on reaction conditions. The four hexanuclear and two octanuclear complexes of formulae [Fe8O2(OMe)4(Mesao) 6Br4(py)4]·2Et2O·MeOH (10·2Et2O·MeOH), [Fe8O2(OMe)3.85(N3)4.15(Mesao) 6(py)2] (11), [Fe6O2(O2CPh-4-NO2)4(Me-sao)2(OMe)4Cl2(py)2] (12), [Fe6O2(O2CPh-4-NO2)4(Et-sao)2(OMe)4Cl2(py)2]·2Et2O·MeOH (13·2Et2O·MeOH), [HNEt3]2[Fe6O2(Me-sao)4(SO4)2(OMe)4(MeOH)2] (14) and [HNEt3]2[Fe6O2(Etsao) 4(SO4)2(OMe)4(MeOH)2] (15) all are built from series of edge-sharing [Fe4( μ4- O)]10+ tetrahedra. Complexes 10 and 11 display a new μ4-coordination mode of the oxime ligand and join a small group of Fe-phenolic oxime complexes with nuclearity greater than six. Chapter three then introduces co-ligands to the reaction scheme to compete with the salicylaldoxime ligands for metal coordination sites. Five tetranuclear and two nononuclear complexes are stabilised with salicylaldoxime (saoH2) or derivatised salicylaldoximes (R-saoH2) in conjunction with either 1,4,7- triazocyclononane (tacn), 2-hydroxymethyl pyridine (hmpH) or 2,6-pyridine dimethanol (pdmH2), [Fe4O2(sao)4(tacn)2]·2MeOH (16·MeOH), [Fe4O2(Mesao) 4(tacn)2]·2MeCN (17·2MeCN), [Fe4O2(Et-sao)4(tacn)2]·MeOH (18·MeOH), [Fe9NaO4(Et-sao)6(hmp)8]·3MeCN·Et2O (19·3MeCN·Et2O), [Fe4 (Etsao) 4(hmp)4]·Et-saoH2 (20·Et-saoH2), [Fe4(Ph-sao)4(hmp)4]·2MeCN (21·2MeCN) [Fe9O3(sao)(pdm)6(N3)7(H2O)] (22). Chapter four straps two salicylaldoxime units together in the 3-position, using ligands with aliphatic a,W-aminomethyl links, allowing the assembly of the polynuclear complexes [Fe7O2(OH)6(H2L1)3(py)6](BF4)5·6H2O·14MeOH (23·6H2O·14MeOH), [Fe6O(OH)7(H2L2)3][(BF4)3]·4H2O·9MeOH (24·4H2O·9MeOH) and [Mn6O2(OH)2(H2L1)3(py)4(MeCN)2](BF4)5(NO3)·3MeCN·H2O·5py (25·3MeCN·H2O·5py). In each case the metallic skeleton of the cluster is based on a trigonal prism in which two [MIII 3O] triangles are tethered together via three helically twisted double-headed oximes. The latter are present as H2L2- in which the oximic and phenolic O-atoms are deprotonated and the amino N-atoms protonated, with the oxime moieties bridging across the edges of the metal triangles. Both the identity of the metal ion and the length of the straps connecting the salicylaldoxime units have a major impact on the nuclearity and topology of the resultant cage, with, perhaps counter-intuitively, the longer straps producing the “smallest” clusters.

C-terminal binding proteins (CtBPs) are transcriptional co-repressors involved in developmental processes, and also implicated in a number of breast, ovarian, colon cancers, and resistance against cancer chemotherapy. CtBP is a validated novel potential anti-cancer target. In this project we sought to develop potent and selective small-molecule inhibitors of CtBP. Using a combination of classical medicinal chemistry and modern computational approaches, we designed a potent inhibitor HIPP (hydroxyimino-3-phenylpropanoic acid) that showed an IC50 of 0.24 μM against recombinant CtBP. Further elucidation of the structure-activity relationship (SAR) of HIPP led to the design of more potent inhibitors 3-Cl HIPP (CtBP IC50 = 0.17 μM) and 4-Cl HIPP (CtBP IC50 = 0.18 μM). These compounds also showed inhibition in HCT-116 colon cancer cells with GI50 values ~ 1-4 mM. The compounds showed no off-target toxicity against a closely related protein. This is a starting point for the development of CtBP inhibitors as anti-cancer therapeutics. The second part of this dissertation focuses on C–H activation chemistry. C–H activation is the most atom-economical method of introducing complexity into a molecule, even at late stages of drug/product development. We have used solid-supported palladium nanoparticle catalyst (Pd-MWCNT) to investigate the scope of C–H activation reactions it can catalyse. Pd-MWCNT was found to efficiently catalyse N-chelation directed C-H activation reactions – halogenations, oxygenations and arylations. The turn-over numbers for these reactions were significantly higher than that of the reported homogenous catalyst. The added advantages of reuse/recyclability of catalyst, low contamination of metal in the final product make this catalyst very attractive on an industrial scale. This work serves as a foundation for the further development of Pd-MWCNT catalyst in late-stage synthesis of drugs and/or diversification of products.

Le travail effectué au cours de cette thèse se situe dans le cadre d'une approche anti-tumorale par immunothérapie. Le cœur de ce projet a consisté à développer une méthodologie permettant de synthétiser des mimes de la forme tumorale de la glycoprotéine MUC1 par multiligation chimique sur support solide. La stratégie de synthèse repose sur une approche convergente basée sur la condensation par liaison oxime entre un peptide aminooxy (Aoa) et un peptide aldéhyde. Le développement d'une approche utilisant la déprotection sélective du groupe Aoa sur le fragment médian a permis de coupler plusieurs motifs MUC1 par ligation chimique sur support solide et d'obtenir deux longs peptides comportant deux unités et demi de répétition de la protéine MUC1 pour l'un et un épitope T-auxiliaire supplémentaire pour l'autre composé.<br /> Ce travail ouvre la voie à la synthèse de chimères de MUC1 qui seront glycosylées par voie chimioenzymatique. Ces petites glycoprotéines synthétiques, bien que calquées sur des glycoprotéines naturelles, seront élaborées dans le but d'étudier différentes présentations des antigènes pour optimiser leur immunogénicité.

La recherche sur le cancer s'oriente vers le développement de « stratégies ciblées » comme la vectorisation de composés actifs permettant d'augmenter l'efficacité thérapeutique et de réduire la toxicité du traitement. Dans ce contexte, ces travaux ont été consacrés à la conception de vecteurs peptidiques pour des applications anticancéreuses. Ces systèmes ont été élaborés à partir d'un châssis moléculaire cyclodécapeptidique présentant des propriétés conformationnelles particulières. Deux approches différentes ont été envisagées. La première a consisté à rechercher de nouveaux ligands de récepteurs tumoraux en s'inspirant du domaine de reconnaissance d'un anticorps monoclonal thérapeutique. Dans ce contexte, nous proposons la conception de mime du Rituximab ciblant l'antigène CD20 utilisé dans le traitement des lymphomes Non-Hodkinien. Dans la seconde approche, nous avons développé des vecteurs destinés à des applications d'imagerie tumorale. Pour cela, des châssis multivalents présentant des ligands peptidiques RGD ciblant l'intégrine alpha-v-beta-3 ont été conjugués avec différents agents de détection puis évalués par techniques d'imagerie TEP, IRM et imagerie optique. Dans ces deux stratégies, les systèmes de vecteurs sont constitués d'un domaine de reconnaissance présentant un ou plusieurs ligands, et d'un module effecteur composé d'un élément de détection, le tout assemblé sur le châssis moléculaire. Nous nous sommes donc intéressés à développer des procédures d'assemblages biomoléculaires permettant de moduler les sites d'accrochages du châssis. Pour cela, nous avons mis au point des méthodologies de synthèse originales combinant plusieurs ligations chimiosélectives orthogonales. On démontrera que cette stratégie offre de multiples avantages et permet un assemblage macromoléculaire en une seule étape sans déprotection ni purification intermédiaire.

The thesis entitled “Synthetic and Mechanistic Studies in Oxime and Amide Chemistry” consists of two chapters. Chapter 1 contains 3 parts, dealing with the Beckmann rearrangement under solvent free conditions, Mitsunobu conditions, and with catalytic succinic anhydride-ZnCl2. Chapter 2 deals with bond length and reactivity studies with several oxime esters. CHAPTER 1 Part 1: This describes studies aimed at the development of the Beckmann rearrangement in the solid state using phenylboronic acid. The adsorption of ketoximes on a mixture of phenylboronic acid and neutral alumina followed by heating >120 °C, afforded the expected amides, although with competing hydrolysis to corresponding ketones. It appeared that phenylboronic acid was being converted under the reaction conditions to triphenyl boroxine, which was presumably the active species effecting the Beckmann rearrangement. This was experimentally confirmed when the amide products were obtained in good yields when the reaction was performed with triphenyl boroxine. Part 2: This describes the Beckmann rearrangement under Mitsunobu conditions. Triphenyl phosphine and diethyl azodicarboxylate can react with various oximes to produce corresponding amides. Part 3: This describes the Beckmann rearrangement of oximes to amides by a combination of succinic anhydride and zinc chloride as catalyst. Zinc chloride can activate succinic anhydride, the activated succinic anhydride then reacting with the oximes. This forms the oxime ester of succinic acid, which undergoes the Beckmann rearrangement as shown. CHAPTER 2: This describes bond length and reactivity studies with several oxime esters. It was of interest to obtain a correlation between bond length and reactivity in ketoxime derivatives which are known to undergo the Beckmann rearrangement. Towards this end the crystal structures of a variety of oxime esters have been determined. The results indicate that the alkyl group anti to the oxime hydroxyl group is pre-disposed towards migration onto the nitrogen center. (pl refer the thesis for structural formula)

京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第21120号 / 工博第4484号 / 新制||工||1697(附属図書館) / 京都大学大学院工学研究科物質エネルギー化学専攻 / (主査)教授 大江 浩一, 教授 辻 康之, 教授 中尾 佳亮 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DGAM

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Organophosphates are neurotoxic compounds that inhibit acetylcholinesterase producing excess cholinergic stimulation. This produces various toxic signs including excitotoxic neuronal damage. Oximes can be used as a treatment for organophosphate poisoning by reactivating inhibited acetylcholinesterase. Traditional oximes do not penetrate the blood-brain barrier, limiting protection of the central nervous system. Novel, brain-penetrating oximes have the potential to protect the brain from organophosphate induced damage. Adult male rats were used to examine the ability of model organophosphates to produce neuropathology and the ability of novel oximes to prevent this damage. Additionally, adult male rats were used to examine changes in gene expression of the MAP kinase system resultant of treatment with model organophosphates and novel oximes. Results of these experiments support that the model organophosphates can be used to study neurodegeneration, the novel oximes may prevent neurodegeneration, and both organophosphates and novel oximes affect expression of MAP kinase genes.

The purpose of this investigation is to examine reactions of anions of oximes, oxime ethers and imines with acylating agents and other electrophiles. It is also an attempt to utilize the phenomenon of geometrical enantiomeric isomerism, in which absolute configuration is determined by double bond geometry, and the concept of regiospecific anion formation, also determined by double bond geometry, for stereospecific synthesis of tropinone derivatives.