Synthesis, Stability and Relaxivity of TEEPO-Met : An Organic Radical as a Potential Tumour Targeting Contrast Agent for Magnetic Resonance Imaging

Cancer is a widespread and life-threatening disease and its early-stage diagnosis is vital. One of the most effective, non-invasive tools in medical diagnostics is magnetic resonance imaging (MRI) with the aid of contrast agents. Contrast agents that are currently in clinical use contain metals, causing some restrictions in their use. Also, these contrast agents are mainly non-specific without any tissue targeting capabilities. Subsequently, the interest has notably increased in the research of organic, metal-free contrast agents. This study presents a new, stable organic radical, TEEPO-Met, where a radical moiety 2,2,6,6-tetraethylpiperidinoxide (TEEPO) is attached to an amino acid, methionine (Met), as a potentially tumour-targeting moiety. We describe the synthesis, stability assessment with electron paramagnetic resonance (EPR) spectroscopy and relaxation enhancement abilities by an in vitro nuclear magnetic resonance (NMR) and phantom MRI studies of TEEPO-Met. The new compound proved to be stable notably longer than the average imaging time in conditions mimicking a biological matrix. Also, it significantly reduced the relaxation times of water, making it a promising candidate as a novel tumour targeting contrast agent for MRI.Peer reviewe

Biomimetic zinc chlorin-poly(4-vinylpyridine) assemblies : doping level dependent emission-absorption regimes

Peer reviewe

Chlorophyll tailored 20-trifluoroacetamide and its azacrown derivative as pH sensitive colorimetric sensor probe with response to AcO-, F- and CN- ions

Peer reviewe

Assessment of the Relaxation-Enhancing Properties of a Nitroxide-Based Contrast Agent TEEPO-Glc with In Vivo Magnetic Resonance Imaging

Magnetic resonance imaging examinations are frequently carried out using contrast agents to improve the image quality. Practically all clinically used contrast agents are based on paramagnetic metals and lack in selectivity and specificity. A group of stable organic radicals, nitroxides, has raised interest as new metal-free contrast agents for MRI. Their structures can easily be modified to incorporate different functionalities. In the present study, a stable nitroxide TEEPO (2,2,6,6-tetraethylpiperidin-1-oxyl) was linked to a glucose moiety (Glc) to construct a water-soluble, potentially tumor-targeting compound with contrast-enhancing ability. The ability was assessed with in vivo MRI experiments. The constructed TEEPO-Glc agent proved to shorten the T-1 relaxation time in tumor, while the T-1 time in healthy brain tissue remained the same. The results indicate the potential of TEEPO-Glc as a valuable addition to the growing field of metal-free contrast enhancement in MRI-based diagnostics.Peer reviewe

Molecular Interactions : Chlorin Assemblies and NMR Separations

Photosynthesis is a chemical process in which the energy of the light quanta is transformed into chemical energy. Chlorophyll (Chl) molecules play a key role in photosynthesis; they function in the antennae systems and in the photosynthetic reaction center where the primary charge separation (CS) takes place. Bio-inspired mimicry of the CS is an essential unit in dye-sensitized solar cells. Aim of this study was to design and develop electron donor-acceptor (EDA) pairs from Chls and fullerenes (C60) or carbon nanotubes (CNT). The supramolecular approach was chosen, as long synthetic sequences required by the covalent approach lead to long reaction schemes and low yields. Here, a π-interaction between soluble CNTs and Chl was used in EDA construction. Also, a beta-face selective two-point bound Chl-C60 EDA was introduced. In addition, the photophysical properties of the supramolecular EDA dyads were analyzed. In organic chemistry, nuclear magnetic resonance (NMR) spectroscopy is the most vital analytical technique in use. Multi-dimensional NMR experiments have enabled a structural analysis of complex natural products and proteins. However, in mixture analysis NMR is still facing difficulties. In many cases overlapping signals can t be resolved even with the help of multi-dimensional experiments. In this work, an NMR tool based on simple host-guest chemistry between analytes and macromolecules was developed. Diffusion ordered NMR spectroscopy (DOSY) measures the mobilities of compounds in an NMR sample. In a liquid state NMR sample, each of the analytes has a characteristic diffusion coefficient, which is proportional to the size of the analyte. With normal DOSY experiment, provided that the diffusion coefficients of the analytes differ enough, individual spectra of analytes can be extracted. When similar sized analytes differ chemically, an additive can be introduced into the sample. Since macromolecules in a liquid state NMR sample can be considered practically stationary, even faint supramolecular interaction can change the diffusion coefficient of the analyte sufficiently for a successful resolution in DOSY. In this thesis, polyvinylpyrrolidone and polyethyleneglycol enhanced DOSY NMR techniques, which enable mixture analysis of similar in size but chemically differing natural products, are introduced.Auringon säteilyn energian kemialliseen muotoon muuttava prosessi, fotosynteesi, on aktiivisen tutkimuksen kohteena. Tämän monivaiheisen prosessin yksityiskohtainen tunteminen mahdollistaa bio-inspiroitujen orgaanisten valoenergiaa tuottavien/käyttävien nanokomponenttien valmistamisen. Klorofyllien rooli fotosynteesissä on keskeinen: ne toimivat sekä valoa keräävissä antennisysteemeissä että reaktiokeskuksissa, joissa primäärinen varauksen erottus tapahtuu. Juuri varauksen eroittuminen on välttämätön tavoiteltaessa esimerkiksi orgaanisia aurinkokennoja. Tämän väitöskirjan tavoitteena oli kehittää fotoindusoituvia elektroni luovuttaja vastaanottaja pareja, jotka koostuvat klorofylli-johdoksista ja joko fullereeneistä tai hiilinanoputkista. Lähestymistavaksi valittiin supramolekulaarinen kemia kovalenttisen kemian sijaan mm. pitkien synteesireittien ja huonojen kokonaissaantojen välttämiseksi. Ensimmäinen elektroni luovuttaja-vastaanottaja pari koostui pyreeni-muokatusta kloriinista ja liukoisista nanoputkista, jotka sitoutuivat toisiinsa pii-pii vuorovaikutuksen avulla. Toinen pari valmistettiin metalloidusta happokloriinista ja fulleronikotiinista. Niiden kompleksoituminen tapahtui ns. kaksi-piste-sitoutumisella metallikoordinaation ja happo-emäs kemian avulla. Valmistettujen supramolekulaaristen kompleksien fotofysikaaliset ominaisuudet tutkittiin varauksen erottumisen varmistamiseksi. Orgaanisessa kemiassa tärkein analyyttinen menetelmä on ydinmagneettinen resonanssispektroskopia eli NMR. Nykypäivänä kehittyneet spektrometrit ja moniulotteiset NMR kokeet ovat mahdollistaneet luonnonaineiden ja proteiinien rakenne-tutkimuksen. Seosten NMR analytiikka on kuitenkin edelleen hyvin haastavaa, sillä usein spektrien päällekkäisiä signaaleita ei saada eroamaan toisistaan edes kaikkein kehittyneimmillä moniulotteisilla NMR kokeilla. Tässä työssä esitellään uuden tyyppinen NMR-tekniikka, joka perustuu NMR-näytteeseen lisättävän polymeerin ja seoksen komponenttien välisiin vuorovaikutuksiin. Diffuusio-erotteinen NMR spektroskopia (DOSY) mittaa komponenttien liikenopeutta NMR-näytteessä. Nestemäisessä NMR näytteessä kullakin komponentilla on ominainen liikenopeus, eli diffuusiovakio, joka on suoraan verrannollinen molekyylin kokoon. Jos seoksen komponenttien diffuusiovakiot eroavat riittävästi, voidaan komponenttien spektrit erottaa toisistaan normaalilla DOSY:llä. Jos yhtä nopeasti liikkuvat molekyylit eroavat toisistaan kemiallisesti, on mahdollista, että niiden vuorovaikutus NMR-näytteeseen lisättävän polymeerin kanssa on erillainen. Koska makromolekyylien koko on suuri, ovat ne lähes stationäärisiä verrattuna seoksen komponentteihin. Heikkokin vuorovaikutus seoksen komponentin ja polymeerin välillä aiheuttaa muutoksen diffuusiovakioon ja mahdollistaa spektrien erottamisen toisistaan. Tässä väitöskirjatyössä esitellään polyvinyylipyrrolidoni ja polyetyleeniglykoli tehostettujen DOSY NMR kokeiden käyttö luonnonaineiden seosten analytiikassa

The Reactivity of Thymine and Thymidine 5,6-Epoxides with Organometallic Reagents – A Route to Thymidine (6-4) Photoproduct Analogues

This report describes an efficient procedure for the generation and isolation of various thymine and thymidine 5,6-epoxides from the corresponding <i>trans</i>-5,6-bromohydrins by reaction with triethylamine. The quantitative isolation of the epoxides, accomplished by solvent precipitation of triethylamine hydrobromide, enabled their regiospecific ring-opening at C6 position by organometallic nucleophiles. The reaction was amenable to a broad range of alkyl, aryl, alkenyl, and alkynyl organomagnesium, -zinc, -aluminum, or -boron reagents, although the reactivity was strongly affected by the electronic effects of N3 protecting group. Additionally, the reaction featured excellent <i>cis</i>-diastereoselectivity providing access to C6-carbon-functionalized dihydrothymidine <i>cis</i>-alcohols, which are synthetic derivatives of UV-induced DNA lesions, namely, thymidine (6-4) photoproducts