Betuliinijohdannaiset

Opinnäytetyön aiheena oli betuliinijohdannaiset. Tavoitteena oli tehdä synteesisarja, jossa betuliiniin ja betulonihappoon liitettiin esteröintireaktiolla erilaisia happoja, terpeenialkoholeja ja fenoleja. Lisäksi tavoitteena oli saada selvyys bioaktiivisista ominaisuuksista ja mahdollisista muista soveltuvuuksista. Työ tehtiin osana VTT:n Kuori- tutkimusprojektia, jossa betuliinille ja muille puiden kuori- ja uuteaineille pyritään löytämään kaupallisia käyttökohteita esimerkiksi lääkeaineina, pestisideinä ja kosmetiikka-alan raaka-aineina. Betuliini on pentasyklinen triterpeenialkoholi, jota saadaan eristettyä varsin tehokkaasti koivun kuoresta ja tuohesta uuttamalla. Betuliinilla ja sen johdannaisilla on todistettu olevan useita lääkinnällisiä vaikutuksia kuten esimerkiksi tulehduksia estäviä, antiviraalisia, antimalaarisia, antitumoraalisia sekä anti-HIV-aktiivisuutta. Betuliinissa, lup-20(29)-ene-3β,28-diolissa, on käytännössä kolme reaktiivista ryhmää, primäärinen hydroksyyliryhmä hiilessä 28, sekundäärinen hydroksyyliryhmä hiilessä 3 sekä alkeenirakenne hiilessä 20, joista jokaisen ryhmän reaktioilla voidaan helposti saada aikaan betuliinijohdannaisia. Betuliinin ja betulonihapon reaktioihin valittiin erilaisia esteröintimenetelmiä, joissa katalyytteinä käytettiin mm. p-tolueenisulfonihappoa, titaani(IV)isopropylaattia, N,N-dimetyyli-4-aminopyridiini ja N-(3-dimetyyliaminopropyyli)-N-etyylikarbodiimidihydroklori-dia. Synteesituotteiden puhdistusmenetelminä käytettiin uudelleen kiteyttämistä ja pylväskromatografiaa. Synteesituotteet analysoitiin NMR:llä, GC-MS:llä, IR-spektrometrillä ja alkuaineanalyysillä. Lisäksi reaktiotuotteista mitattiin sulamispisteet ja Rf-arvot. Synteesisarjaan suunnitelluista betuliini- ja betulonihappojohdannaisista onnistuivat betuliini-28-ferulihappoesteri, betulonihappo-28-vaniliiniesteri ja betulonihappo-28-karva-kroliesteri. Tuotteille on tehty ja tullaan tekemään erilaisia bioaktiivisuustestejä ja näin ollen kaikkia tuloksia ei ole vielä saatu. Osassa testeistä kyseiset tuotteet ovat osoittautuneet jo lievästi aktiivisiksi, joten kyseisten tuotteiden testaamista sekä betuliiniin ja sen johdannaisiin liittyvää syntetiikkaa ja tutkimustyötä kannattaa ehdottomasti jatkaa, koska betuliinijohdannaisilla voi olla ratkaiseva merkitys esimerkiksi sairauksien hoidossa.

Role of ErbB2 and ErbB4 in Cancer Growth, Prognosis and as Targets for Immunotherapy

ErbB receptors (EGFR, ErbB2, ErbB3 and ErbB4) are growth factor receptors that regulate signals of cell differentiation, proliferation, migration and survival. Inappropriate activation of these receptors is associated with the development and severity of many cancers and has prognostic and predictive value in cancer therapy. Drugs, such as therapeutic antibodies, targeted against EGFR and ErbB2, are currently used in therapy of breast, colorectal and head and neck cancers. The role of ErbB4 in tumorigenesis has remained relatively poorly understood. Alternative splicing produces four different isoforms of one ErbB4 gene. These isoforms (JM-a, JM-b, CYT-1 and CYT-2) are functionally dissimilar and proposed to have different roles in carcinogenesis. The juxtamembrane form JM-a undergoes regulated intramembrane proteolysis producing a soluble receptor ectodomain and an intracellular domain that translocates into the nucleus and regulates transcription. Nuclear signaling via JM-a isoform stimulates cancer cell proliferation. This study aimed to develop antibodies targeting the proposed oncogenic ErbB4 JM-a isoform that show potential in inhibiting ErbB4 dependent tumorigenesis. Also, the clinical relevance of ErbB4 shedding in cancer was studied. The currently used monoclonal antibody trastuzumab, targeting ErbB2, has shown efficacy in breast cancer therapy. In this study novel tissues with ErbB2 amplification and trastuzumab sensitivity were analyzed. The results of this study indicated that a subpopulation of breast cancer patients demonstrate increased shedding and cleavage of ErbB4. A JM-a isoform-specific antibody that inhibited ErbB4 shedding and consequent activation of ErbB4 had anti-tumor activity both in vitro and in vivo. Thus, ErbB4 shedding associates with tumor growth and specific targeting of the cleavable JM-a isoform could be considered as a strategy for developing novel ErbB-based cancer drugs. In addition, it was demonstrated that ErbB2 amplification is common in intestinal type gastric cancers with poor clinical outcome. Trastuzumab inhibited growth of gastric and breast cancer cells with equal efficacy. Thus, ErbB2 may be a useful target in gastric cancer.

Fraud detection in the banking sector : a multi-agent approach

Fraud is an increasing phenomenon as shown in many surveys carried out by leading international consulting companies in the last years. Despite the evolution of electronic payments and hacking techniques there is still a strong human component in fraud schemes. Conflict of interest in particular is the main contributing factor to the success of internal fraud. In such cases anomaly detection tools are not always the best instruments, since the fraud schemes are based on faking documents in a context dominated by lack of controls, and the perpetrators are those ones who should control possible irregularities. In the banking sector audit team experts can count only on their experience, whistle blowing and the reports sent by their inspectors. The Fraud Interactive Decision Expert System (FIDES), which is the core of this research, is a multi-agent system built to support auditors in evaluating suspicious behaviours and to speed up the evaluation process in order to detect or prevent fraud schemes. The system combines Think-map, Delphi method and Attack trees and it has been built around audit team experts and their needs. The output of FIDES is an attack tree, a tree-based diagram to ”systematically categorize the different ways in which a system can be attacked”. Once the attack tree is built, auditors can choose the path they perceive as more suitable and decide whether or not to start the investigation. The system is meant for use in the future to retrieve old cases in order to match them with new ones and find similarities. The retrieving features of the system will be useful to simplify the risk management phase, since similar countermeasures adopted for past cases might be useful for present ones. Even though FIDES has been built with the banking sector in mind, it can be applied in all those organisations, like insurance companies or public organizations, where anti-fraud activity is based on a central anti-fraud unit and a reporting system.

α-Pinene oxide and verbenol oxide isomerizations over heterogeneous catalysts

Terpenes are a valuable natural resource for the production of fine chemicals. Turpentine, obtained from biomass and also as a side product of softwood industry, is rich in monoterpenes such as α-pinene and β-pinene, which are widely used as raw materials in the synthesis of flavors, fragrances and pharmaceutical compounds. The rearrangement of their epoxides has been thoroughly studied in recent years, as a method to obtain compounds which are further used in the fine chemical industry. The industrially most desired products of α-pinene oxide isomerization are campholenic aldehyde and trans-carveol. Campholenic aldehyde is an intermediate for the manufacture of sandalwood-like fragrances such as santalol. Trans-carveol is an expensive constituent of the Valencia orange essence oil used in perfume bases and food flavor composition. Furthermore it has been found to exhibit chemoprevention of mammary carcinogenesis. A wide range of iron and ceria supported catalysts were prepared, characterized and tested for α-pinene oxide isomerization in order to selective synthesis of above mentioned products. The highest catalytic activity in the preparation of campholenic aldehyde over iron modified catalysts using toluene as a solvent at 70 °C (total conversion of α-pinene oxide with a selectivity of 66 % to the desired aldehyde) was achieved in the presence of Fe-MCM-41. Furthermore, Fe-MCM-41 catalyst was successfully regenerated without deterioration of catalytic activity and selectivity. The most active catalysts in the synthesis of trans-carveol from α-pinene oxide over iron and ceria modified catalysts in N,N-dimethylacetamide as a solvent at 140 °C (total conversion of α-pinene oxide with selectivity 43 % to trans-carveol) were Fe-Beta-300 and Ce-Si-MCM-41. These catalysts were further tested for an analogous reaction, namely verbenol oxide isomerization. Verbenone is another natural organic compound which can be found in a variety of plants or synthesized by allylic oxidation of α-pinene. An interesting product which is synthesized from verbenone is (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol. It has been discovered that this diol possesses potent anti-Parkinson activity. The most effective way leading to desired diol starts from verbenone and includes three stages: epoxidation of verbenone to verbenone oxide, reduction of verbenone oxide and subsequent isomerization of obtained verbenol oxide, which is analogous to isomerization of α-pinene oxide. In the research focused on the last step of these synthesis, high selectivity (82 %) to desired diol was achieved in the isomerization of verbenol oxide at a conversion level of 96 % in N,N-dimethylacetamide at 140 °C using iron modified zeolite, Fe-Beta-300. This reaction displayed surprisingly high selectivity, which has not been achieved yet. The possibility of the reuse of heterogeneous catalysts without activity loss was demonstrated.