Browsing by Subject "orgaaninen kemia"

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  • Lilienkampf, Annamaria (Helsingin yliopisto, 2007)
    Breast cancer is the most common cancer in women in Western countries. In the early stages of development most breast cancers are hormone-dependent, and estrogens, especially estradiol, have a pivotal role in their development and progression. One approach to the treatment of hormone-dependent breast cancers is to block the formation of the active estrogens by inhibiting the action of the steroid metabolising enzymes. 17beta-Hydroxysteroid dehydrogenase type 1 (17beta-HSD1) is a key enzyme in the biosynthesis of estradiol, the most potent female sex hormone. The 17beta-HSD1 enzyme catalyses the final step and converts estrone into the biologically active estradiol. Blocking 17beta-HSD1 activity with a specific enzyme inhibitor could provide a means to reduce circulating and tumour estradiol levels and thus promote tumour regression. In recent years 17beta-HSD1 has been recognised as an important drug target. Some inhibitors of 17beta-HSD1 have been reported, however, there are no inhibitors on the market nor have clinical trials been announced. The majority of known 17beta-HSD1 inhibitors are based on steroidal structures, while relatively little has been reported on non-steroidal inhibitors. As compared with 17beta-HSD1 inhibitors based on steroidal structures, non-steroidal compounds could have advantages of synthetic accessibility, drug-likeness, selectivity and non-estrogenicity. This study describes the synthesis of large group of novel 17beta-HSD1 inhibitors based on a non-steroidal thieno[2,3-d]pyrimidin-4(3H)-one core. An efficient synthesis route was developed for the lead compound and subsequently employed in the synthesis of thieno[2,3-d]pyrimidin-4(3H)-one based molecule library. The biological activities and binding of these inhibitors to 17beta-HSD1 and, finally, the quantitative structure activity relationship (QSAR) model are also reported. In this study, several potent and selective 17beta-HSD1 inhibitors without estrogenic activity were identified. This establishment of a novel class of inhibitors is a progressive achievement in 17beta-HSD1 inhibitor development. Furthermore, the 3D-QSAR model, constructed on the basis of this study, offers a powerful tool for future 17beta-HSD1 inhibitor development. As part of the fundamental science underpinning this research, the chemical reactivity of fused (di)cycloalkeno thieno[2,3-d]pyrimidin-4(3H)-ones with electrophilic reagents, i.e. Vilsmeier reagent and dimethylformamide dimethylacetal, was investigated. These findings resulted in a revision of the reaction mechanism of Vilsmeier haloformylation and further contributed to understanding the chemical reactivity of this compound class. This study revealed that the reactivity is dependent upon a stereoelectronic effect arising from different ring conformations.
  • Deb, Somdatta (Helsingin yliopisto, 2011)
    Estrogens the female sex hormones have numerous biological actions. Estradiol is the most abundant estrogen in women before menopause. It influences the development, maturation and function of the female reproductive tract. It also plays a role in mammary cancer. Accordingly determinations of estradiol level in body fluids assist in the evaluation of ovarian function and diagnosis for malignancies. Estriol is the primary estrogen in pregnant women and secreted from the fetoplacental unit. Measurement of estriol in maternal body fluids is the basis of fetoplacental monitoring test. Concentration of estrogens in body fluids is determined by immunoassay. Accuracy of this measurement depends on the availability of a specific antibody. As estrogens are not antigenic, their derivatives (haptens) are coupled with a carrier and this hapten-protein conjugate is used to generate antibodies. Specificity of the generated antibody largely depends on the structure of hapten. Therefore the synthesis of a hapten with a right structure is crucial for the accurate measurement of a steroid. We have synthesised new haptens for estradiol and estriol by adding an alkyl or alkoxy side chain at the C-7 of estrane skeleton. The side chains carry a terminal amino group, which can be used for conjugation with a carrier molecule. Estrogens and their biosynthetic precursor androgens both exist as fatty acid esters. They are known to act as hormone storage but their physiological role is not completely known yet. Our collaborator is studying their effect in cardiovascular diseases. We synthesised fatty acid ester derivatives of several steroids in high yield by a very rapid procedure (in 1 min) under microwave irradiation in an ionic liquid (IL). An expedient regioselective hydrolysis at C-3 of estradiol diesters is also reported. 8-Isoestrogens are compounds of pharmaceutical interests, their synthesis, structure, conformation and biological activity studies are ongoing. 7-Hydroxy-8-isoestradiol and 7-alkyl ether of it were synthesised as well. During this study we have developed a selective O-debenzylation method. A mild route for selective removal of benzylic protection on phenol in presence of benzyl protected alcohol was explored.
  • Nousiainen, Paula (Helsingin yliopisto, 2017)
    Eco-efficient biotechnological applications are important innovations for modern industrial developments, such as production of chemicals and fuels from renewable biomass. Lignocellulosic biomass is the only sustainable organic resource that can be converted to both energy and various value-added products. The effective use of wood and plants for feedstock in biorefineries is in most cases dependent on the plant cell wall recalcitrance and especially the extent of lignification of the cell wall. Oxidative enzymes such as laccases and manganese peroxidases (MnPs), provide interesting possibilities for plant biomass modification as they are the key catalysts in modification and degradation of the most recalcitrant component of the lignocellulose biopolymers, lignin, in nature. Both peroxidases and laccases exhibit low substrate specificity and produce organic radicals through one-electron abstraction reactions. In many cases these enzymes require low molecular weight co-substrates to mediate oxidation to the more recalcitrant parts of lignin polymer. In the first study of this thesis, various types of lignin model compounds were investigated both as mediators and as final targets to screen their effect and potential in laccase-catalyzed oxidation reactions. Especially acetosyringone and methyl syringate were found to mediate the laccase-catalyzed oxidation even with low-redox potential laccase that generally shows only fair oxidation activity on lignocellulosic oxidation. Secondly, in two of the articles, the mediating rate and effectivity were enhanced by using high redox potential laccases and suitable reaction conditions to retain the stability of the mediator. Oxidation potentials, pH and chemical stability of the mediator were found to affect the oxidation efficiency. These simple phenolics were, for the first time, also proved to mediate the MnP-catalyzed reactions of non-phenolic compounds. The problematic stability of peroxidases was circumvented by utilizing reaction system with no external addition of hydrogen peroxide. Finally, to prove the effect on polymer material a new reaction set-up was developed for oxidation of synthetic lignin (DHP, dehydrogenation polymer) and the structural analysis of the oxidized polymers showed clear modifications in the polymer outcome. In all cases, mediated reactions gave selective alpha-oxidation products of benzylic alcohol moieties, the prevailing structural moiety in lignin. These oxidations provide valuable intermediates for further treatments in various lignin valorization processes. In the near future, this oxidative laccase-mediator oxidative system will be explored in an EU Horizon 2020 project for valorization of biorefinery lignin by combination of biotechnical and chemical means to added-value products such as marine biofuel, engine octane boosters and valuable low-molecular weight chemicals.