Supramolekulare Chemie mit Cyclodextrinen

Zusammenfassung Die vorliegende Arbeit gliedert sich in zwei Teilgebiete, die beide unter dem Gesichtspunkt der Supramolekularen Chemie mit Cyclodextrinen bearbeitet wurden. Der erste Teil befasste sich mit der Synthese und Charakterisierung von chemisch modifizierten Cyclodextrinen, die fl��ssigkristalline Eigenschaften besitzen sollten. Die verwendeten Cyclodextrine wurden mit verschieden substituierten Benzoes��urederivaten umgesetzt und durch polarisationsmikroskopische Untersuchungen auf fl��ssigkristalline Phasen��berg��nge hin untersucht. Weitere Untersuchungen erfolgten mittels DSC und R��ntgendiffraktometrie.In wie weit die fl��ssigkristallinen Eigenschaften eine Selbstorganisation zu ��berstrukturen induzierten, sollten Untersuchungen als Monoschichten auf der Luft/Wasser-Grenzfl��che mittels einer Filmwaage zeigen. Daraus ergaben sich weitergehende Untersuchungen mit der AFM-Technik. Es zeigte sich, dass besonders die quasi symmetrischen, ��ber Esterverkn��pfungen modifizierten Cyclodextrine fl��ssigkristalline Eigenschaften zeigten. Es konnte auch gezeigt werden, dass sie sich in Mono- und Multischichten zu Lipid-Strukturen organisieren. Der zweite Teil dieser Arbeit befasste sich mit der Wechselwirkung von Cyclodextrinen mit LCST-Copolymeren, die supramolekulare Komplexe bilden. Als Schl��sselgruppe fungierte das polymergebundene Adamantanmolek��l. Mittels Tr��bungsphotometrie wurden verschiedene Additive auf ihren Einfluss auf den LCST-Phasen��bergang der synthetisierten Copolymer untersucht. Hier konnte gezeigt werden, dass die adamantanhaltigen LCST-Copolymere durch Cyclodextrinzus��tze in ihrem LCST-Verhalten drastisch zu beinflussen sind. Damit konnte ein System gefunden werden, das mit einfachen analytischen Mitteln eine supramolekulare Erkennung erm��glicht.

(S)-(-)-Curvularin als Leitstruktur f��r die Synthese neuartiger antiinflammatorischer Wirkstoffe

Ziel dieser Arbeit war die Darstellung antiinflammatorischer Wirkstoffe basierend auf (S)-(-)-Curvularin. Zur Ermittlung von Struktur-Aktivit��ts-Beziehungen sollte eine m��glichst gro��e Zahl an Derivaten dargestellt und in Zusammenarbeit mit pharmakologischen und mikrobiologischen Arbeitsgruppen. Es wurde ein neuer und effizienter totalsynthetischer Zugang zu Curvularin sowie analogen Ringsystemen erarbeitet mit einer Ringschluss-Metathese als Schl��sselschritt zur Bildung des Makrocyclus. Ausgehend von den Synthesebausteinen 3,5-Dihydroxyphenylessigs��ure und (S)-Propenoxid gelang die Darstellung des Naturstoffes (S) ( )-Curvularin mit einer Gesamtausbeute von 10 % ��ber sieben Stufen. Der Naturstoff Curvularin selbst wurde durch Modifikationen an den phenolischen Funktionen, durch elektrophile aromatische Substitution, Reduktion sowie konjugierte Addition an den Naturstoff 10,11-Dehydrocurvularin derivatisiert. Mit diesen synthetischen Ans��tzen konnten die Strukturelemente des Naturstoffes systematisch variiert werden und es konnten insgesamt 28 Makrolactone synthetisiert werden. Anhand der biologischen Evaluierung der Verbindungen lie��en sich R��ckschl��sse auf die pharmakophoren Gruppen des Naturstoffes ziehen, bei vier der synthetisierten Verbindungen konnten im Vergleich zu Curvularin eine h��here biologische Aktivit��t erzielt werden. Anhand der Erkenntnisse aus den biologischen Tests lie��en sich strukturell einfachere Verbindungen als potentielle Wirkstrukturen entwerfen. Es wurden verschiedene ortho-acylierte 3,5-Dihydroxyphenylessigs��urederivate sowie substituierte 6,8-Dihydoxytetralon- und 6,8-Dihydroxyisochinolon-Verbindungen synthetisiert. Diese vereinfachten Partialstrukturen zeigten eine geringere biologischen Aktivit��t als der Naturstoff.

Functionalization of hyperbranched polycarbosilanes - block copolymers and electrochemistry

Polycarbosilanes are a class of polymers at the interface between organic and inorganic chemistry. They are characterized by a high thermal and chemical inertness and high flexibility, especially pronounced for branched structures. Linear polycarbosilanes are well known as precursors for the preparation of SiCx ceramics. Additionally, more sophisticated architectures like dendrimers, hyperbranched polymers or block copolymers have been the subject of research for more than a decade. The scope of this work was to expand the properties and fields of application for polycarbosilane-containing structures. Thus, the work is divided in two major parts. The first part covers the synthesis and characterization of hyperbranched polycarbosilanes containing organometallic moieties. Hyperbranched poly-carbosilanes were synthesized using hydrosilylation of diallylmethylsilane and methyldiundecenylsilane. The degree of branching for polydiallymethylsilane was determined using standard 1H-NMR spectroscopy. The functional building blocks ferrocenyldimethylsilane and diferrocenylmethylsilane were synthesized which contain an isolated ferrocene unit or two ferrocenes bridged by silicon, respectively. Hyperbranched polycarbosilanes functionalized with ferrocenyl moieties were synthesized by modification of preformed polymers or by copolymerization of AB2 carbosilane monomers with AX-type ferrocenylsilanes. Polymers with Mn = 2500-9000g/mol and ferrocene contents of up to 67wt% were obtained. Electrochemical characterization by cyclic voltammetry revealed that polymers functionalized with isolated ferrocene units showed a single reversible oxidation wave, while voltammograms for polymers functionalized with diferrocenyl silane exhibited two well-separated reversible oxidation-reduction waves. This shows that the polymer bound ferrocenes bridged by silicon are electronically communicating and thus oxidation of the first ferrocene shifts the oxidation potential for the adjacent one. The polymers were utilized successfully for the preparation of modified electrodes with persistent and reproducible electrochemical response in organic solvents as well as in aqueous solution. The presented work has proven that ferrocenyl-functionalized hyperbranched polymers exhibit similar electrochemical properties as the analogous dendrimers. In a further approach it was shown that hyperbranched polymers containing organometallic moieties can be synthesized by polymerization of a new ferrocene-containing AB2 monomer - diallylferrocenylsilane. The second part of this work is dedicated to the preparation of core-functional hyperbranched polycarbosilanes. Low molecular weight ambifunctional molecules were synthesized that contain double bonds for the attachment of a polycarbosilane polymer as well as a second functionality available for further reaction and modification. Reactive vinyl groups in the core molecule allow an efficient attachment of hyperbranched polycarbosilane which was proven by MALDI-ToF and GPC. In combination with slow monomer addition techniques molecular weight and polydispersity of the polymers were controlled successfully. Core-functional polymers were characterized by NMR-spectroscopy, MALDI-ToF and GPC. Polymers with polydispersities <2 and molecular weights up to 5300g/mol were obtained. Transformation of the double bonds of the carbosilane was demonstrated with various silanes using hydrosilylation reaction or hydrogenation. Additionally, the core-functionality was varied resulting in polymers with bromo-, phthalimide-, amine- or azide moieties. Thus, a versatile synthetic strategy was developed that allows the synthesis of tailor-made polymers.A promising approach is the application of the polymer building blocks in copolymer synthesis. Bisglycidolization of amine-functional polycarbosilanes produces macro-initiators that are suitable for the multibranching-ring opening polymerization of glycidol. This experiments lead to the first example of hyperbranched-hyperbranched amphiphilic block copolymers, hb-PG-b-hb-PCS. Furthermore, the implementation of copper-catalyzed cycloaddition between azide-functional polycarbosilane and alkyne-functional poly(ethoxyethyl glycidylether) resulted in linear-hyperbranched block copolymers. The facile removal of acetal protecting groups provided convenient access to lin-PG-b-hb-PCS.

Rupture forces of split aptamers

Rupture forces of ligand-receptor interactions, such as proteins-proteins, proteins-cells, and cells-tissues, have been successfully measured by atomic force spectroscopy (AFS). For these measurements, the ligands and receptors were chemically modified so that they can be immobilized on the tip and on a substrate, respectively. The ligand interact the receptor when the tip approaches the substrate. This interaction can be studied by measuring rupture force upon retraction. However, this technique is not feasible for measurements involving small molecules, since they form only few H-bonds with their corresponding receptors. Modifying small molecules for immobilization on surfaces may block or change binding sites. Thus, recorded rupture forces might not reflect the full scope of the involved small ligand-receptor interactions.rnIn my thesis, a novel concept that allows measuring the rupture force of small involved ligand-receptor interactions and does not require molecular modification for immobilization was introduced. The rupture force of small ligand-receptor interaction is not directly measured but it can be determined from measurements in the presence and in the absence of the ligand. As a model system, the adenosine mono phosphate (AMP) and the aptamer that binds AMP were selected. The aptamer (receptor) is a single stranded DNA that can partially self-hybridize and form binding pockets for AMP molecules (ligands). The bonds between AMP and aptamer are provided by several H-bonds and pair stacking.rnIn the novel concept, the aptamer was split into two parts (oligo a and oligo b). One part was immobilized on the tip and the other one on the substrate. Approaching the tip to the substrate, oligo a and oligo b partially hybridized and the binding pockets were formed. After adding AMP into the buffer solution, the AMP bound in the pockets and additional H-bonds were formed. Upon retraction of the tip, the rupture force of the AMP-split aptamer complex was measured. In the presence of excess AMP, the rupture force increased by about 10 pN. rnThe dissociation constant of the AMP-split aptamer complex was measured on a single molecular level (~ 4 ��M) by varying the AMP concentrations and measuring the rupture force at each concentration. Furthermore, the rupture force was amplified when more pockets were added to the split aptamer. rnIn the absence of AMP, the thermal off-rate was slightly reduced compared to that in the presence of AMP, indicating that the AMP stabilized the aptamer. The rupture forces at different loading rates did not follow the logarithmic fit which was usually used to describe the dependence of rupture forces at different loading rates of oligonucleotides. Two distinguished regimes at low and high loading rates were obtained. The two regimes were explained by a model in which the oligos located at the pockets were stretched at high loading rates. rnThe contribution of a single H-bond formed between the AMP molecule and the split aptamer was measured by reducing the binding groups of the AMP. The rupture forces reduce corresponding to the reduction of the binding groups. The phosphate group played the most important role in the formation of H-bond network between the AMP molecule and the split aptamer. rn

Investigations into the effect of nucleoside modifications on the physicochemical properties and biological function of DNA and RNA

This thesis explores the effect of chemical nucleoside modification on the physicochemical and biological properties of nucleic acids. Positional alteration on the Watson-Crick edge of purines and pyrimidines, the ���C-H��� edge of pyrimidines, as well as both the Hoogsteen and sugar edges of purines were attempted by means of copper catalyzed azide-alkyne cycloaddition. For this purpose, nucleic acid building blocks carrying terminal alkynes were synthesized and introduced into oligonucleotides by solid-phase oligonucleotide chemistry. rnOf particular interest was the effect of nucleoside modification on hydrogen bond formation with complementary nucleosides. The attachment of propargyl functionalities onto the N2 of guanosine and the N4 of 5-methylcytosine, respectively, followed by incorporation of the modified analogs into oligonucleotides, was successfully achieved. Temperature dependent UV-absorption melting measurements with duplexes formed between modified oligonucleotides and a variety of complementary strands resulted in melting temperatures for the respective duplexes. As a result, the effect that both the nature and the site of nucleoside modification have on base pairing properties could thus be assisted. rnTo further explore the enzymatic recognition of chemically modified nucleosides, the oligonucleotide containing the N2-modified guanosine derivative on the 5���-end, which was clicked to a fluorescent dye, was subjected to knockdown analyses of the eGFP reporter gene in the presence of increasing concentrations of siRNA duplexes. From these dose-dependent experiments, a clear effect of 5���-labeling on the knockdown efficiency could be seen. In contrast, 3���-labeling was found to be relatively insignificant.rn

From defined polymer architectures to structure-property relationships in vivo

Makromolekulare Wirkstofftr��gersysteme sind von starkem Interesse bez��glich der klinischen Anwendung chemotherapeutischer Agenzien. Um ihr klinisches Potential zu untersuchen ist es von besonderer Bedeutung das pharmakokinetische Profil in vivo zu bestimmen. Jede Ver��nderung der Polymerstruktur beeinflusst die K��rperverteilung des entsprechenden Makromolek��ls. Aufgrund dessen ben��tigt man detailliertes Wissen ��ber Struktur-Eigenschaftsbeziehungen im lebenden Organismus, um das Nanocarrier System f��r zuk��nftige Anwendungen einzustellen. In dieser Beziehung stellt das pr��klinische Screening mittels radioaktiver Markierung und Positronen-Emissions-Tomographie eine n��tzliche Methode f��r schnelle sowie quantitative Beobachtung von Wirkstofftr��gerkandidaten dar. Insbesondere poly(HPMA) und PEG sind im Arbeitsgebiet Polymer-basierter Therapeutika stark verbreitet und von ihnen abgeleitete Strukturen k��nnten neue Generationen in diesem Forschungsbereich bieten.rnDie vorliegende Arbeit beschreibt die erfolgreiche Synthese verschiedener HPMA und PEG basierter Polymer-Architekturen ��� Homopolymere, Statistische und Block copolymere ��� die mittels RAFT und Reaktivesterchemie durchgef��hrt wurde. Des Weiteren wurden die genannten Polymere mit Fluor-18 und Iod-131 radioaktiv markiert und mit Hilfe von microPET und ex vivo Biodistributionsstudien in tumortragenden Ratten biologisch evaluiert. Die Variation in Polymer-Architektur und darauffolgende Analyse in vivo resultierte in wichtige Schlussfolgerungen. Das hydrophile / lipophile Gleichgewicht hatte einen bedeutenden Einfluss auf das pharmakokinetische Profil, mit besten in vivo Eigenschaften (geringe Aufnahme in Leber und Milz sowie verl��ngerte Blutzirkulationszeit) f��r statistische HPMA-LMA copolymere mit steigendem hydrophoben Anteil. Au��erdem zeigten Langzeitstudien mit Iod-131 eine verst��rkte Retention von hochmolekularen, HPMA basierten statistischen Copolymeren im Tumorgewebe. Diese Beobachtung best��tigte den bekannten EPR-Effekt. Hinzukommend stellen ��berstrukturbildung und damit Polymergr����e Schl��sselfaktoren f��r effizientes Tumor-Targeting dar, da Polymerstrukturen ��ber 200 nm in Durchmesser schnell vom MPS erkannt und vom Blutkreislauf eliminiert werden. Aufgrund dessen wurden die hier synthetisierten HPMA Block copolymere mit PEG Seitengruppen chemisch modifiziert, um eine Verminderung in Gr����e sowie eine Reduktion in Blutausscheidung zu induzieren. Dieser Ansatz f��hrte zu einer erh��hten Tumoranreicherung im Walker 256 Karzinom Modell. Generell wird die K��rperverteilung von HPMA und PEG basierten Polymeren stark durch die Polymer-Architektur sowie das Molekulargewicht beeinflusst. Au��erdem h��ngt ihre Effizienz hinsichtlich Tumorbehandlung deutlich von den individuellen Charakteristika des einzelnen Tumors ab. Aufgrund dieser Beobachtungen betont die hier vorgestellte Dissertation die Notwendigkeit einer detaillierten Polymer-Charakterisierung, kombiniert mit pr��klinischem Screening, um polymere Wirkstofftr��gersysteme f��r individualisierte Patienten-Therapie in der Zukunft ma��zuschneidern.rn

Designed functional defects in colloidal photonic crystals: switching, biomonitoring and modified photoluminescence

Es werden zwei komplement��re "bottom-up" Methoden pr��sentiert, die den kontrollierten Einbau von "intelligenten" planaren Defekten in selbstorganisierte kolloidale photonische Kristalle (KPKs) erm��glichen. Die Defektschicht basiert auf einem funktionellen, nanometer-skalierten d��nnen Film, der entweder durch schichtweise ("layer-by-layer") Selbstorganisation und Mikrokontakttransfer��bertragung oder durch Aufschleudern und einer KPK-Opferf��llung hergestellt wird. Die entwickelten Techniken gestatten die Integration von ma��geschneiderten d��nnen Defektfilmen bestehend aus einer enorm gro��en Vielfalt an Materialien; sie sind kosteng��nstig und k��nnen im gr����eren Ma��stab angewendet werden. Optische Untersuchungen zeigen einen engen, durch den Defekt hervorgerufenen Transmissionszustand in der photonischen Bandl��cke. Die Defektwellenl��nge h��ngt von der optischen Dicke der Defektschicht ab. Aktives Schalten der Defektwellenl��nge wird erreicht, indem Defektschichten aus Makromolek��len hergestellt werden, die ��ber externe Erreger wie Licht, Temperatur, Redoxzyklen und mechanischen Druck adressiert werden k��nnen. Die Ergebnisse der Untersuchungen sind im Einklang mit separat durchgef��hrten Ellipsometrie-Messungen und theoretischen "scalar wave approximation"-Berechnungen. Dar��ber hinaus werden KPKs mit funktionellen biomolekularen Defekten vorgestellt. ��ber Verschiebungen der Defektmode k��nnen DNA-Konformations��nderungen, die enantioselektive Einlagerung eines chiralen Antitumormedikaments sowie Enzymaktivit��ten optisch beobachtet werden. Die Einlagerung von fluoreszierenden Farbstoffen und Quantenpunkten in Defekt-KPKs f��hrt zu einer eindeutigen, durch die photonische Bandl��cke und den Defektzustand hervorgerufenen Modifizierung der Photolumineszenz (PL)-Spektren. Schaltbare PL-Modifizierungen werden detektiert, wenn adressierbare Defekt-KPKs verwendet werden.

Developments for transactinide chemistry experiments behind the gas-filled separator TASCA

Topic of this thesis is the development of experiments behind the gas-filled separator TASCA(TransActinide Separator and Chemistry Apparatus) to study the chemical properties of the transactinide elements.rnIn the first part of the thesis, the electrodepositions of short-lived isotopes of ruthenium and osmium on gold electrodes were studied as model experiments for hassium. From literature it is known that the deposition potential of single atoms differs significantly from the potential predicted by the Nernst equation. This shift of the potential depends on the adsorption enthalpy of therndeposited element on the electrode material. If the adsorption on the electrode-material is favoured over the adsorption on a surface made of the same element as the deposited atom, the electrode potential is shifted to higher potentials. This phenomenon is called underpotential deposition.rnPossibilities to automatize an electro chemistry experiment behind the gas-filled separator were explored for later studies with transactinide elements.rnThe second part of this thesis is about the in-situ synthesis of transition-metal-carbonyl complexes with nuclear reaction products. Fission products of uranium-235 and californium-249 were produced at the TRIGA Mainz reactor and thermalized in a carbon-monoxide containing atmosphere. The formed volatile metal-carbonyl complexes could be transported in a gas-stream.rnFurthermore, short-lived isotopes of tungsten, rhenium, osmium, and iridium were synthesised at the linear accelerator UNILAC at GSI Helmholtzzentrum f��r Schwerionenforschung, Darmstadt. The recoiling fusion products were separated from the primary beam and the transfer products in the gas-filled separator TASCA. The fusion products were stopped in the focal plane of TASCA in a recoil transfer chamber. This chamber contained a carbon-monoxide ��� helium gas mixture. The formed metal-carbonyl complexes could be transported in a gas stream to various experimental setups. All synthesised carbonyl complexes were identified by nuclear decay spectroscopy. Some complexes were studied with isothermal chromatography or thermochromatography methods. The chromatograms were compared with Monte Carlo Simulations to determine the adsorption enthalpyrnon silicon dioxide and on gold. These simulations based on existing codes, that were modified for the different geometries of the chromatography channels. All observed adsorption enthalpies (on silcon oxide as well as on gold) are typical for physisorption. Additionally, the thermalstability of some of the carbonyl complexes was studied. This showed that at temperatures above 200 ��C therncomplexes start to decompose.rnIt was demonstrated that carbonyl-complex chemistry is a suitable method to study rutherfordium, dubnium, seaborgium, bohrium, hassium, and meitnerium. Until now, only very simple, thermally stable compounds have been synthesized in the gas-phase chemistry of the transactindes. With the synthesis of transactinide-carbonyl complexes a new compound class would be discovered. Transactinide chemistry would reach the border between inorganic and metallorganic chemistry.rnFurthermore, the in-situ synthesised carbonyl complexes would allow nuclear spectroscopy studies under low background conditions making use of chemically prepared samples.