Τα λιποσώματα αποτελούν ένα από τα πιο διαδεδομένα συστήματα μεταφοράς φαρμάκων. Ένα από τα κυριότερα προβλήματά τους αποτελεί η γρήγορη απομάκρυνσή τους από τον οργανισμό που αντιμετωπίστηκε με την επικάλυψη της επιφάνειάς τους με πολυμερή και κυρίως πολυαιθυλενογλυκόλες (PEG). Η ύπαρξη του PEG στην επιφάνεια αύξησε κατά πολύ τον χρόνο παραμονής των λιποσωμάτων στον οργανισμό αλλά λόγω μειονεκτημάτων, όπως το φαινόμενο αυξημένης εκκαθάρισης απ’τον οργανισμό μετά την δεύτερη δόση όπως και η ύπαρξη πολλών πατεντών, δημιουργούν την ανάγκη για την διερεύνηση νέων μορφών επικάλυψης των λιποσωμάτων. Σκοπός αυτής της εργασίας ήταν η σύνθεση νέων λιπιδικών παραγώγων από κυκλοδεξτρίνες και αιθέρες στέμματος και ο σχηματισμός λιποσωμάτων από αυτά τα παράγωγα. Έναυσμα για την χρήση αυτών των χημικών ουσιών αποτέλεσε η ήδη χρησιμοποίηση τους στην μεταφορά βιοδραστικών ενώσεων καθώς και οι χημικές ιδιότητές τους. Θεωρητικά η ύπαρξη ογκωδών υποκαταστατών στην επιφάνεια των λιποσωμάτων προκαλεί στερεοχημική παρεμπόδιση στις αλληλεπιδράσεις με ουσίες στον οργανισμό, που θα μπορούσαν να προκαλούν την γρήγορη εκκαθάριση από τον οργανισμό, αυξάνοντας έτσι τον χρόνο παραμονής τους. Αρχικά συντέθηκαν τα λιπιδικά παράγωγα από DSPE (δι-στεάρυλοφωσφατιδυλοαιθανολαμίνη) και 18-crown-6-ether καθώς και β-κυκλοδεξτρίνη όμως ο καθαρισμός του παραγώγου με την κυκλοδεξτρίνη δεν κατέστει δυνατός και έτσι σχηματίστηκαν λιποσώματα μόνο από το λιπιδικό παράγωγο του αιθέρα στέμματος. Ως υλικά για την παρασκευή των λιποσωμάτων χρησιμοποιήθηκαν φωσφατιδυλοχολίνη αυγού (egg-PC), το λιπιδικό παράγωγο του αιθέρα, δι-στεάρυλοφωσφατιδυλοαιθανολαμινη-πολυαιθυλενογλυκόλη(DSPE-PEG) και χοληστερόλη (CHOL) Παρασκευάστηκαν με την μέθοδο του λεπτού υμενίου πολυστοιβαδιακά λιποσώματα (MLVs) και με την χρήση υπέρηχων (probe sonicator) μικρά μονοστοιβαδιακά λιποσώματα (SUVs) και στη συνέχεια μελετήθηκε η σταθερότητα αυτών σε ορό αίματος χοίρου (FCS) Επίσης, προκειμένου να αποκτηθούν περισσότερες πληροφορίες για τα λιποσώματα που μελετήθηκαν, πραγματοποιήθηκε προσδιορισμός του μεγέθους καθώς και του ζ-δυναμικού. Η μελέτη σταθερότητας των λιποσωμάτων που περιείχαν το λιπιδικό παράγωγο με τον αιθέρα στέμματος έδειξε ότι σε ποσοστά αντίστοιχα με αυτά του PEG ο αιθέρας στέμματος δεν προσδίδει μεγαλύτερη σταθερότητα. Θα μπορούσε να μελετηθεί μια σειρά λιποσωμάτων με μεγαλύτερο ποσοστό του λιπιδικού παραγώγου ούτως ώστε να αυξηθεί ο όγκος των υποκαταστατών στην επιφάνεια των λιποσωμάτων και συνεπώς η παρεμπόδιση των αλληλεπιδράσεων. / Liposomes are one of the most common drug delivery systems. One of their main problems is their rapid clearance from the blood stream which was encountered by coating the surface with polymers and especially poly-ethylenoglyglycols (PEG). The coating of the surface with PEG increased the time of stay of liposomes in the blood stream but due to disadvantages, such as the phenomenon of increased clearance after the second dose as well as the existence of many patents, created the need for new forms of coating of the liposomes. The main purpose of this thesis was the synthesis of new lipidic derivatives from cyclodextrins and crown ethers as well as the formation of liposomes from these novel derivatives. The reason behind the choice of these chemical substances was that they are already being used in drug delivery as well as their chemical properties. In theory the existence of bulk substituents on the surface of liposomes causes stereochemical hindrance in interactions with substances in the body, which could cause the rapid clearance from the body, thereby increasing the time of stay in the blood stream. Initially lipid derivatives from DSPE (di-stearylophosphatidylethanolamine) and 18-crown-6-ether-and β-cyclodextrin were synthesized but the purification of the cyclodextrin derivative was not made possible and thus liposomes were formed only from the crown ether lipid-derivative. As starting material for the formation of liposomes was used egg phosphatidylcholine (egg-PC), the crown ether lipid-derivative, di-stearylophosphatidylethanolamine- polyethyleneglycol (DSPE-PEG) and cholesterol (CHOL). Multilamellar vesicles (MLVs) were prepared by the thin film method and with the use of ultrasounds (probe sonicator) small unilamellar vesicles (SUVs) were formed, and then their stability in fetal calf serum (FCS) was studied. In addition, in order to obtain more information about the liposomes that were formed, measurements were carried to determine their size as well as magnitude of the z-potential. The study on the stability of liposomes containing the lipid derivative with the crown ether showed that coating of the surface with the crown ether derivative in percentages equivalent to those of PEG does not confer greater stability on the contrary their stability is the same with conventional liposomes. Α study of liposomes with a higher proportion of the lipid derivative in order to increase the bulkiness of the substituents on the surface of the liposomes and thus preventing interactions resulting in the increase of the stability should be considered.

Neste trabalho foi realizada a síntese, purificação e caracterização de uma tetra crowned porfirina, a 5,10,15,20-tetraquis[2-(hexaoxacicloexadecano-3-amidafenil)]-porfirina, H2TCP, bem como a correspondente ferroporfirina, (FeTCP)Cl. Foi investigado a atividade catalítica desta ferroporfirina e da ferroporfirina mono-crowned substituída, (FeMCP)Cl, sintetizada anteriormente, na oxidação dos substratos (z)-ciclooocteno, estireno, cicloexano e do fármaco carbamazepina, por vários oxidantes: iodosilbenzeno, ácido meta-cloroperbenzóico e hipoclorito de sódio, em meio homogêneo (MeOH ou ACN) e bifásico (C2H4Cl2/H2O). Os resultados revelaram que estes sistemas metaloporfirinicos podem ser considerados bons modelos biomiméticos das enzimas citocromo P450, para oxidação dos substrados estudados, levando ao mesmo produto obtido in vivo na oxidação do fármaco carbamazepina, o cabamazepina-epóxido. Os rendimentos dos produtos de oxidação catalisada pelas ferro crowned porfirinas são, na maioria dos casos, mais expressivos do que aqueles observados com as metaloporfirinas amino-substituídas precursoras. Estes resultados indicam que o substituinte éter coroa confere maior estabilidade e reatividade ao catalisador, e leva à maior seletividade, resultado da interação do éter corôa com o substrato, direcionando-o para o sítio catalítico. Uma outra propriedade importante das crowned porfirinas estudadas é sua capacidade de atuar como agente transferidor de fases nas reações em meio bifásico, utilizando hipoclorito de sódio como oxidante. Os resultados catalíticos nestes sistemas mostraram que as unidades éter corôa foram capazes de carregar o oxidante do meio aquoso para o meio orgânico, onde se encontra o substrato. Foram avaliadas também as propriedades destas novas porfirinas e metaloporfirinas em extrair íons metálicos sódio e potássio do meio aquoso para o meio orgânico. As crowned porfirinas foram bastante eficientes na extração destes metais, principalmente utilizando a técnica de extração por fase única, levando a extrações superiores a 90 % do cátion potássio, e mostrando maior seletividade para este cátion, devido ao tamanho adequado da cavidade do éter corôa para ligar este íon. Foi realizada também a caracterização das porfirinas e ferroporfirinas crowned substituídas por voltametria cíclica, visando sua aplicação futura na análise eletroanalítica de íons potássio e/ou sódio. Observou-se que as porfirinas crowned substituídas sofrem reduções mais fáceis e oxidações mais difíceis quando comparadas com as porfirinas precursoras, mostrando o efeito sacador de elétrons dos substituintes éter corôa. Estes resultados ajudam a explicar os melhores resultados catalíticos obtidos com as ferro porfirinas crowned substituídas, mostrando o efeito do éter coroa em formar a metaloporfirina mais eletrofílica e aumentando a reatividade da espécie catalítica. / In this work we carried out the synthesis, purification and characterization of a tetra crowned porphyrin, 5,10,15,20-tetrakis[2- (hexaoxacyclohexanedecane-3-amidephenyl)]porphyrin, H2TCP, and its corresponding ironporphyrin, (FeTCP)Cl. We investigated the catalytic activity of both this ironporphyrin and the previously synthesized mono-crowned substituted (FeMCP)Cl in the oxidation of the substrates Z-cyclooctene, styrene, cyclohexane and the drug carbamazepine by oxidants like iodosylbenzene, metachloroperbenzoic acid and sodium hypochlorite, in homogeneous (methanol or acetonitrile) and biphasic (C2H2Cl2/H2O) media. Our results demonstrated that these metalloporphyrin systems can be considered good biomimetic models of the cytochrome P450 enzymes in the case of the substrates studied herein, since they led to the same product obtained in the in vivo oxidation of carbamazepine, the carbamazepine-epoxide. The product yields obtained in the oxidation reactions catalyzed by the crowned ironporphyrins were, in the majority of the cases, higher than those achieved with the precursor aminosubstituted metalloporphyrins. This indicates that the crown-ether substituent renders the catalyst more stable and reactive, thus leading to higher selectivity. This selectivity results from the interaction between the crown-ether and the substrate, which directs the latter toward the catalytic site. Another important feature of the studied crowned ironporphyrins is their ability to act as phase-transfer agent in the reactions carried out in biphasic medium, using sodium hypochlorite as oxidant. The catalytic results using such a system gave evidence that the crown ether entities were capable of carrying the oxidant from the aqueous to the organic medium, where the substrate was located. We also evaluated the ability of these novel porphyrins and ironporphyrins to extract sodium and potassium ions from aqueous solution to organic medium. The crowned porphyrins were efficient at extracting these metals, especially when the one-phase extraction technique was employed, leading to potassium ion extraction as high as 90 %. The complexes were more selective toward this latter ion due to the fact that the size of the crown ether cavity was more suitable for binding the larger K+. The crowned porphyrins and ironporphyrins were also characterized by cyclic voltammetry, aiming at their future application in the electroanalytical determination of sodium and potassium ions. When compared with the precursor aminosubstituted porphyrins, we observed that the crowned porphyrins undergo reduction more easily, but their oxidation is harder to achieve. This gives evidence of the electronwithdrawing effect of the crownether substituent. These results help explain the better catalytic results obtained with the crowned ironporphyrins, showing that the crown-ether entity must render the metalloporphyrin more electrophilic, thus increasing the reactivity of the active species.

Novel cage-functionalized azacrown ethers, i.e. 51, 52, 53, 55, 57, 61 and 62, which have various crown cavity and different number of nitrogen atoms incorporated, have been prepared. X-ray structures of 53, 55 and 57 have been obtained for the study of the crown topological structure. The complexation properties of crown 51, 52, 57, 61 and 62 have been evaluated via alkali metal picrate extraction, silver picrate extraction and ESI-MS study. The novel cage-fuctionalized azacrown ethers generally exhibit high avidity and selectivity towards Ag+ versus alkali metal ions and some transition metals i.e. Cu2+, Mn2+, Zn2+, Ni2+ and Pb2+. Crown 61 displays significant avidity and selectivity toward K+ in alkali metal picrate extraction experiments vis-à-vis the remaining alkali metal picrates. Three types of ditopic ion-exchange receptors for sodium hydroxide extraction study have been designed. All of the crown ether molecules have proper cavity for selective sodium complexation and have weakly acidic ionizable alcohols for sodium-proton exchange under strongly basic conditions. Crown 80 and 81 were synthesized; key intermediates for the synthesis of crown 82, 83 and 84 have been prepared. The preparation of 99 afforded an unexpected crown 103. The preparation of 109 had been attempted, but could not be successfully isolated. Four novel cage-functionalized calix[4]arene crown-5, i.e. 113-116, have been synthesized. The structures of 113 and 116 have been established by X-ray crystal structural analysis and NMR spectral analysis. The complexation properties of the four ionic receptors have been studied via alkali metal picrate extraction experiments. Crown 115 and 116 display more than modest avidity toward alkali metal ions and are most selective toward K+ vis-à-vis 113 and 114.

The theoretical model of Beratan and Onuchic predicts a large attenuation of ET rates through hydrogen bonds; however, the effect of individual hydrogen bond on electron transfer reaction has not been systematically studied. The organic complexes in this study are a series of crown ether/ammonium salt, which incorporate a redox partner on each component of the complex. The dimethoxynaphthalene redox donor was attached to the crown ether and a series of ammonium salts was synthesized which bear substituted quinone and naphthoquinone acceptor. The complexes characterization and preliminary electron transfer rate measurement were completed with UV/Vis and steady-state emission spectroscopy.

A novel cryptand was synthesized which contained a 3,5-disubstituted-4- oxahexacyclo[5.4.1.02,6.03,10.05,9.08,11] dodecane "cage" moiety. In alkali metal picrate extraction experiments the cryptand exhibited high avidity towards Rb+ and Cs+, when compared with the corresponding model compound. A computational study of a series of cage-functionalized cryptands and their alkali metal-complexes was performed. The X-ray crystal structure of a K+-complexed bis-cage-annulated 20-crown-6 was obtained. The associated picrate anion was found to be intimately involved in stabilization of the host-guest complex. The interaction energy between the host-guest complex and picrate anion has been calculated, and the energy thereby obtained has been corrected for basis set superposition error.

Symmetrical cage-annulated podands were synthesized via highly efficient synthetic strategies. Mechanisms to account for the key reaction steps in the syntheses are proposed; the proposed mechanisms receive support from the intermediates that have been isolated and characterized. An unusual complexation-promoted elimination reaction was studied, and a mechanism is proposed to account for the course of this reaction. This unusual elimination may generalized to other rigid systems and thus may extend our understanding of the role played by the host molecules in "cation-capture, anion-activation" via complexation with guest molecules. Thus, host-guest interaction serves not only to activate the anion but also may activate the leaving groups that participate in the complexation. Complexation-promoted elimination provides a convenient method to desymmetrize the cage while avoiding protection/deprotection steps. In addition, it offers a convenient method to prepare a chiral cage spacer by introducing 10 chiral centers into the host system in a single synthetic step. Cage-annulated monocyclic hosts that contain a cage-butylenoxy spacer were synthesized. Comparison of their metal ion complexation behavior as revealed by the results of electrospray ionization mass spectrometry (ESI-MS), alkali metal picrate extraction, and pseudohydroxide extraction with those displayed by the corresponding hosts that contain cage-ethylenoxy or cage-propylenoxy spacers reveals the effect of the length of the cage spacer upon the host-guest behavior. A series of cage-annulated cryptands, cavitands and the corresponding non-cage-annulated model compounds have been synthesized. These host molecules display unusual behavior when examined by using ESI-MS techniques, i.e., they bind selectively to smaller alkali metal ions (i.e., Li+ and Na+), a result that deviates significantly from expectations based solely upon consideration of the size-fit principle. It seems likely that this behavior results from the effect of the host topology on host-guest behavior. A series of non-cage-annulated cryptands also have been synthesized. These compounds can serve as starting materials for cavitand construction.

Afin d'obtenir une meilleure compréhension de l'étape clé du système photosynthétique (la formation d’un état à charges séparées), une nouvelle famille de systèmes donneur-accepteur supramoléculaires a été préparée.Nous avons notamment acquis une meilleure compréhension de la nature des interactions π-π entre le C60 et les porphyrines (résultant d'un processus régi principalement par des forces de van der Waals) et de l'affinité des éthers couronnes vis-à-vis des fullerènes (résultant d'une combinaison entre interactions π-π, n-π et CH-π). Les propriétés supramoléculaires des dimères de porphyrines ont été aussi explorées, prouvant leur communication électronique à travers leurs sous-unités. Finalement, la coopérativité chélate d'un de nos systèmes a été évaluée par la molarité efficace. / In order to gain a better understanding of the key step of the photosynthetic system (formation of a charged separated stated), a series of new supramolecular crown ether containing donnor-aceptor ensembles have been obtained.Notably we have gained further insight in the nature of π-π stacking between C60 and porphyrins (arising from a process mainly governed by van der Waals forces) and the affinity of crown ethers towards fullerenes(arising from an interplay of π-π, n-π and CH-π interactions). The properties of porphyrin arrays have been explored, evidencing the electronic communication through subunits. Finally, the chelate cooperativity of one our systems has also been assessed through the effective molarity.

The purpose of this thesis was to investigate how crown ethers behave and interact with different cations and to optimise the setup of the electrophoretic NMR. To get a good electrophoretic NMR measurement the electrophoretic phase shift needs to be big. To increase the phase shift some parameters needed to be adjusted, parameters such as the concentration of crown ether and cation, the duration of magnetic field gradient pulse δ, the magnetic field gradient strength g, the diffusion time Δ and the applied voltage V. The main focus then put on crown ethers 15-crown-5 and 18-crown-6. The cations used were lithium (Li), sodium (Na), potassium (K), caesium (Cs), calcium (Ca) and barium (Ba). The effective charge was obtained by using pulsed gradient NMR to derive the diffusion coefficient and electrophoretic NMR to get the electrophoretic mobility. These data were used to calculate the equilibrium constant of the formed complex. The outcome of the investigation: the affinity for 18-crown-6 was in the following order barium > potassium > caesium > sodium > calcium > lithium and for 15-crown-5 barium > sodium > calcium >  caesium >  potassium > lithium.

京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第19744号 / 工博第4199号 / 新制||工||1648(附属図書館) / 32780 / 京都大学大学院工学研究科高分子化学専攻 / (主査)教授 中條 善樹, 教授 赤木 和夫, 教授 松原 誠二郎 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DGAM

Production of efficiently synthesizable, strongly associating crown ether-based cryptands is desired for pseudorotaxane complexation of bipyridinium guests to produce suprapolymers and supramolecularly-linked block copolymers. Cryptands based on bis(meta-phenylene)-32-crown-10 (BMP32C10) were synthesized. The functionality of phenylenemethanol-BMP32C10 cryptand III-3 (Ka = 2.0 x 104 M-1) did not negatively affect binding strength, although the strength of complexation is marginal to achieve the desired suprapolymers. The cryptand dimethylpyridyl-BMP32C10 IV-2 was synthesized in an attempt to improve over the binding ability of the pyridyl-BMP32C10 cryptand IV-1; instead, interesting host design insights were discovered as binding strengths were reduced over 1000-fold. The crystal structure of IV-2 shows acyl-aryl conjugation which limits the host's ability to accept guests. Synthesis of larger cis-di(carbomethoxybenzo)-3n-crown-n crown ethers was explored using the high concentration, template technique previously reported for cDB24C8 diester. cDB30C10 diester (V-1c) was produced in 93% yield; the desired pyridyl-cDB30C10 cryptand V-12 binds paraquat strongly (Ka = 1-2x105 M-1) and diquat stronger than any other host (Ka = 1.9x106 M-1), both in 1:1 fashions; association constants were measured by ITC. X-ray crystallography of the complexes shows the cryptand's para arm is too far away to interact with paraquat and the host has numerous bifurcated interactions with diquat, explaining the difference in binding strengths. Syntheses of the regioisomers of cDB27C9 diester was also explored; the cyclization yields (cDB27C9S, VI-2: 59% and cDB27C9L, VI-3: 44%) are lower, likely due to poor attack angles due to mismatched arm length in cyclization, than the equivalent length ethyleneoxy-armed cDB24C8 and cDB30C10. Modeling of the cryptand isomers, pyridyl-cDB27C9S and pyridyl-cDB27C9L, showed that the former should improve para arm interaction with paraquat, but should be sterically hindered for diquat and the latter should have a highly flexible, poorly preorganized interaction with either type of guest. ITC, MS, and crystallography data supported the predictions. Derivatization of the pyridyl-cDB30C10 cryptand V-12 was explored using chelidamic acid (VII-1). Schemes yielding alcohol, alkyl halide, alkyne, and TEMPO functionality were followed, but failed. Currently, functionalized cryptand derivatives have not been achieved, future directions are proposed. / Ph. D.