Total synthesis of aeruginazole A

The first total synthesis of Aeruginazole A, prepared via a convergent strategy that involved both solid-phase peptide synthesis and solution phase chemistry and that enabled conservation of the stereochemistry of the intermediates, is reported.

Synthesis and multi-target biological profiling of a novel family of rhein derivatives as disease-modifying anti-Alzheimer agents

We have synthesized a family of rheinhuprine hybrids to hit several key targets for Alzheimer"s disease. Biological screening performed in vitro and in Escherichia coli cells has shown that these hybrids exhibit potent inhibitory activities against human acetylcholinesterase butyrylcholinesterase, and BACE-1, dual Aβ42 and tau anti-aggregating activity, and brain permeability. Ex vivo studies with the leads (+)- and ()-7e in brain slices of C57bl6 mice have revealed that they efficiently protect against the Aβ-induced synaptic dysfunction , preventing the loss of synaptic proteins and/or have a positive effect on the induction of long term potentiation. In vivo studies in APP-PS1 transgenic mice treated i.p. for 4 weeks with (+)- and ()-7e have shown a central soluble Aβ lowering effect, accompanied by an increase in the levels of mature amyloid precursor protein (APP). Thus, (+)- and ()-7e emerge as very promising disease-modifying anti-Alzheimer drug candidates.

Synthesis and multi-target biological profiling of a novel family of rhein derivatives as disease-modifying anti-Alzheimer agents

We have synthesized a family of rheinhuprine hybrids to hit several key targets for Alzheimer"s disease. Biological screening performed in vitro and in Escherichia coli cells has shown that these hybrids exhibit potent inhibitory activities against human acetylcholinesterase butyrylcholinesterase, and BACE-1, dual Aβ42 and tau anti-aggregating activity, and brain permeability. Ex vivo studies with the leads (+)- and ()-7e in brain slices of C57bl6 mice have revealed that they efficiently protect against the Aβ-induced synaptic dysfunction , preventing the loss of synaptic proteins and/or have a positive effect on the induction of long term potentiation. In vivo studies in APP-PS1 transgenic mice treated i.p. for 4 weeks with (+)- and ()-7e have shown a central soluble Aβ lowering effect, accompanied by an increase in the levels of mature amyloid precursor protein (APP). Thus, (+)- and ()-7e emerge as very promising disease-modifying anti-Alzheimer drug candidates.

Convergent Approaches for the Synthesis of the Anti-tumoral Peptide, Kahalalide F. Study of Orthogonal Protecting Groups

Kahalalide compounds are peptides that are isolated from a Hawaiian herbivorous marine species of mollusc, Elysia rufescens, and its diet, the green alga Bryopsis sp. Kahalalide F and its synthetic analogues are the most promising compounds of the Kahalalide family because they show anti-tumoral activity. Linear solid-phase syntheses of Kahalalide F have been reported. Here we describe several new improved synthetic routes based on convergent approaches with distinct orthogonal protection schemes for the preparation of Kahaladide analogues. These strategies allow a better control and characterization of the intermediates because more reactions are performed in solution. Five derivatives of Kahalalide F were synthesized using several convergent approaches.

Isolation, structural assignment and total synthesis of Barmumycin

Barmumycin was isolated from an extract of the marine actinomycete Streptomyces sp. BOSC-022A and found to be cytotoxic against various human tumor cell lines. Based on preliminary one- and two-dimensional 1H- and 13C-NMR spectra, the natural compound was initially assigned the structure of macrolactone-type compound 1, which was later prepared by two different routes. However, major spectroscopic differences between isolated barmumycin and 1 led to revision of the proposed structure as E-16. Based on synthesis of this new compound, and subsequent spectroscopic comparison of it to an authentic sample of barmumycin, the structure of the natural compound was indeed confirmed as that of E-16.

Conflict-based Method for Conceptual Process Synthesis

The changing business environment demands that chemical industrial processes be designed such that they enable the attainment of multi-objective requirements and the enhancement of innovativedesign activities. The requirements and key issues for conceptual process synthesis have changed and are no longer those of conventional process design; there is an increased emphasis on innovative research to develop new concepts, novel techniques and processes. A central issue, how to enhance the creativity of the design process, requires further research into methodologies. The thesis presentsa conflict-based methodology for conceptual process synthesis. The motivation of the work is to support decision-making in design and synthesis and to enhance the creativity of design activities. It deals with the multi-objective requirements and combinatorially complex nature of process synthesis. The work is carriedout based on a new concept and design paradigm adapted from Theory of InventiveProblem Solving methodology (TRIZ). TRIZ is claimed to be a `systematic creativity' framework thanks to its knowledge based and evolutionary-directed nature. The conflict concept, when applied to process synthesis, throws new lights on design problems and activities. The conflict model is proposed as a way of describing design problems and handling design information. The design tasks are represented as groups of conflicts and conflict table is built as the design tool. The general design paradigm is formulated to handle conflicts in both the early and detailed design stages. The methodology developed reflects the conflict nature of process design and synthesis. The method is implemented and verified through case studies of distillation system design, reactor/separator network design and waste minimization. Handling the various levels of conflicts evolve possible design alternatives in a systematic procedure which consists of establishing an efficient and compact solution space for the detailed design stage. The approach also provides the information to bridge the gap between the application of qualitative knowledge in the early stage and quantitative techniques in the detailed design stage. Enhancement of creativity is realized through the better understanding of the design problems gained from the conflict concept and in the improvement in engineering design practice via the systematic nature of the approach.

Wet Oxidation of Concentrated Wastewaters: Process Combination and Reaction Kinetic Modeling

The accumulation of aqueous pollutants is becoming a global problem. The search for suitable methods and/or combinations of water treatment processes is a task that can slow down and stop the process of water pollution. In this work, the method of wet oxidation was considered as an appropriate technique for the elimination of the impurities present in paper mill process waters. It has been shown that, when combined with traditional wastewater treatment processes, wet oxidation offers many advantages. The combination of coagulation and wet oxidation offers a new opportunity for the improvement of the quality of wastewater designated for discharge or recycling. First of all, the utilization of coagulated sludge via wet oxidation provides a conditioning process for the sludge, i.e. dewatering, which is rather difficult to carry out with untreated waste. Secondly, Fe2(SO4)3, which is employed earlier as a coagulant, transforms the conventional wet oxidation process into a catalytic one. The use of coagulation as the post-treatment for wet oxidation can offer the possibility of the brown hue that usually accompanies the partial oxidation to be reduced. As a result, the supernatant is less colored and also contains a rather low amount of Fe ions to beconsidered for recycling inside mills. The thickened part that consists of metal ions is then recycled back to the wet oxidation system. It was also observed that wet oxidation is favorable for the degradation of pitch substances (LWEs) and lignin that are present in the process waters of paper mills. Rather low operating temperatures are needed for wet oxidation in order to destruct LWEs. The oxidation in the alkaline media provides not only the faster elimination of pitch and lignin but also significantly improves the biodegradable characteristics of wastewater that contains lignin and pitch substances. During the course of the kinetic studies, a model, which can predict the enhancements of the biodegradability of wastewater, was elaborated. The model includes lumped concentrations suchas the chemical oxygen demand and biochemical oxygen demand and reflects a generalized reaction network of oxidative transformations. Later developments incorporated a new lump, the immediately available biochemical oxygen demand, which increased the fidelity of the predictions made by the model. Since changes in biodegradability occur simultaneously with the destruction of LWEs, an attempt was made to combine these two facts for modeling purposes.

Synthesis of the two isomers of the potential sex pheromone of Thaumetopoea pityocampa (Lepidoptera, Notodontidae) and related model compounds

The synthesis of the major component of the sex pheromone secretion of the processionary moth, Tkawnztopoeja pltyocampa (Denis and Schiff.) (Lepidoptera, Notodontidae), (Z)-13-hexadecen-ll-ynyl acetate (1), the corresponding (E)-isomer (2) and the four structurally related model compounds (Z⁄E,Z,Z)-5,9,13-hexadecatrienyl acetate (3), (Z⁄E,Z,Z)-3,7,ll-hexadecatrienyl acetate (4), (Z⁄E,E,Z)-7,9,13-hexadecatrienyl acetate (5) and (Z)-7-hexadecen-5-ynyl acetate (6) is described.

Wet Oxidation of Paper Mill Evaporation Concentrates

Tämän työn tarkoituksena oli tutkia lämpötilan pH:n ja vetyperoksidin vaikutusta kuorimoveden haihdutuskonsentraatin märkähapetuksessa. Kirjallisuusosassa esitellään massan ja paperin valmistusta sekä kuorintaprosessi. Lisäksi tarkastellaan kuoren kemiallista koostumusta, jäteveden ja prosessiveden käsittelymenetelmiä sekä märkähapetuksen periaatteita. Kokeellinen osa käsittää erään suomalaisen paperitehtaan kuorimoveden haihdutuskonsentraatin märkähapetuskokeet. Hapetuskokeet tehtiin useammassa eri lämpötilassa, pH:ssa ja vetyperoksidikonsentraatiossa. Em. muuttujien vaikutusta tutkittiin kemialliseen hapenkulutukseen (COD), biologiseen hapenkulutukseen (BOD), välittömästi saatavana olevan biologiseen hapenkulutukseen (IABOD), orgaaniseen kokonaishiileen (TOC) ja tanniini/ligniini pitoisuuteen. Koetulokset osoittivat, että korkeimmat COD- ja TOC-reduktiot saavutettiin H2O2-katalysoidulla märkähapetuksella jäteveden alkuperäisessä pH:ssa (60 % reduktio COD:lla ja 45 % reduktio TOC:lla lämpötilassa 170 °C ja 0.2 g H2O2/g COD). Toisaalta, parhaat tulokset biohajoavuuden paranemisen suhteen saavutettiin emäksisissä olosuhteissa, jossa 170 °C:ssa saavutettiin BOD/COD-arvo 76 %. Emäksisissä olosuhteissa saavutettiin lähes täydellinen tanniinin reduktio lämpötila-alueella 130-170 °C, mutta näissä lämpötiloissa orgaanisen kuorman alenemista ei havaittu.

Removal of Lipophilic Wood Extractives from TMP Process Waters by Wet Oxidation

Työssä tutkittiin kokeellisesti rasvaliukoisten uuteaineiden poistamista TMP -prosessin vesikierroista märkähapetuksen avulla. Työn tavoitteena oli tutkia mahdollisuudet hyödyntää TMP -prosessissa vallitsevaa korkeaa lämpötilaa rasvaliukoisten uuteaineiden poistamiseen hapettamalla niitä puhtaalla hapella. Kirjallisuusosassa tarkasteltiin märkähapetuksen teknologiaa, reaktiomekanismia, käytettyjä katalyyttejä, käyttökohteita sekä kustannuksia. Kokeita suoritettiin autoklaavireaktorissa lämpötiloissa 140 °C, 160 °C ja 180 °C. Vetyperoksidia käytettiin katalyyttinä lisätyn vetyperoksidin määrän ollessa 100 - 1800 mg/l ja hapen osapaineen ollessa 0 ( typpiatmosfääri) - 15 baria. Kokeissa tarkasteltiin kemiallisen hapenkulutuksen (COD), rasvaliukoisten uuteaineiden konsentraation, orgaanisen kokonaishiilen (TOC) ja värin muutoksia kokeiden aikana eri lämpötiloilla, hapen osapaineilla ja lisätyn vetyperoksidin määrillä. Kokeissa saavutettiin 30 %:n COD:n vähenemä sekä 90 %:n vähenemä rasvaliukoisissa uuteaineissa lämpötiloissa 160 °C ja 180 °C. Lisäämällä vetyperoksidia katalyyttinä saavutettiin lähes sama tulos lämpötilassa 140 °C. Suurin tässä työssä havaittu ongelma oli lisääntynyt värinmuodostus vedessä olevassa hienojakoisessa kiintoaineessa hapetuksen aikana. Tämän vuoksi lisätutkimukset ovat tarpeellisia sen seikan selvittämiseksi, voidaanko muodostunut väri mahdollisesti poistaa massan valkaisussa.

Wet Oxidation of TMP Concentrated Paper Mill Process Water. Kinetics of the reaction

Työn tarkoituksena oli tutkia lämpötilan, paineen, pH:n ja katalyytin vaikutusta paperitehtaan TMP-konsentroidun prosessiveden märkähapetuksessa. Teoriaosio sisältää katsauksen sellu- ja paperiteollisuuteen, jätevesien käsittelyyn, nanosuodatuksen ja märkähapetusprosessin toimintaperiaatteet ja sovellukset hybriditeknologialle nanosuodatus-märkähapetuksessa. Empiirinen osa koostuu märkähapetuskokeista eri lämpötiloissa, paineissa, pH:ssa ja eri katalyyseillä. Työssä tutkittiin näiden vaikutusta kemialliseen hapenkulutukseen (COD), Biologiseen hapenkulutukseen (BOD), Välittömästi saatavana olevan biologisen hapenkulutukseen (IABOD), ligniiniin, täysin orgaanisen hiileen (TOC) ja rasvaliukoisten uuteaineiden (LWEs) pitoisuuteen. Tuloksina kokeellisesta työstä saatiin korkeimmat COD:n alenemat ja BOD/COD (biohajoavuus) suurimmilla lämpötilaolosuhteilla (COD:n alenema 70 % ja BOD/COD 97 % 200 °C:ssa ja hapen 10 bar osapaineella). Tutkimuksessa, jossa selvitettiin hapen osapaineen vaikutusta saatiin tuloksena, että hapen osapaineen kasvu parantaa orgaanisen kuormituksen poistoa: COD poisto oli olosuhteilla130°C, 5bar 5 %, olosuhteilla 130 °C, 15bar 15 %, olosuhteilla 170 °C, 5bar 20 % ja olosuhteilla 170 °C, 15bar 50 %. Lähes täydellinen LWEs –poisto saavutettiin 150 °C ja 10bar olosuhteilla, vaikka tässä lämpötilassa ei saavutettu korkeata orgaanisen kuormituksen poistoa. Emäksinen pH vaikutti suosivan hapettavia reaktioita, koska korkein COD:n poisto saavutettiin näissä olosuhteilla; kuitenkin alkalisen väliaineen tehokkuudelle löydettiin tärkeä lämpötilariippuvuus.

Stereoselective Synthesis of (-)-Spicigerolide

(-)-Spicigerolide was enantioselectively synthesized from a protected (S)-lactaldehyde. The synthesis of the polyacetylated framework relied on two Zn-mediated stereoselective additions of alkynes to aldehydes as well as a regiocontrolled [3,3]-sigmatropic rearrangement of an allylic acetate. The pyranone moiety was constructed via ring-closing metathesis.

Total synthesis of aeruginazole A

The first total synthesis of Aeruginazole A, prepared via a convergent strategy that involved both solid-phase peptide synthesis and solution phase chemistry and that enabled conservation of the stereochemistry of the intermediates, is reported.

Isolation, structural assignment and total synthesis of Barmumycin

Barmumycin was isolated from an extract of the marine actinomycete Streptomyces sp. BOSC-022A and found to be cytotoxic against various human tumor cell lines. Based on preliminary one- and two-dimensional 1H- and 13C-NMR spectra, the natural compound was initially assigned the structure of macrolactone-type compound 1, which was later prepared by two different routes. However, major spectroscopic differences between isolated barmumycin and 1 led to revision of the proposed structure as E-16. Based on synthesis of this new compound, and subsequent spectroscopic comparison of it to an authentic sample of barmumycin, the structure of the natural compound was indeed confirmed as that of E-16.

Synthesis of Janus compounds for the recognition of G-U mismatched nucleobase pairs

The design and synthesis of two Janus-type heterocycles with the capacity to simultaneously recognize guanine and uracyl in G-U mismatched pairs through complementary hydrogen bond pairing is described. Both compounds were conveniently functionalized with a carboxylic function and efficiently attached to a tripeptide sequence by using solid-phase methodologies. Ligands based on the derivatization of such Janus compounds with a small aminoglycoside, neamine, and its guanidinylated analogue have been synthesized, and their interaction with Tau RNA has been investigated by using several biophysical techniques, including UV-monitored melting curves, fluorescence titration experiments, and 1H NMR. The overall results indicated that Janus-neamine/guanidinoneamine showed some preference for the +3 mutated RNA sequence associated with the development of some tauopathies, although preliminary NMR studies have not confirmed binding to G-U pairs. Moreover, a good correlation has been found between the RNA binding affinity of such Janus-containing ligands and their ability to stabilize this secondary structure upon complexation.