DEVELOPMENT OF AN ENANTIOSELECTIVE ORGANOCATALYZED IODOLACTONIZATION REACTION

Omega-3 polyunsaturated fatty acids (PUFAs), or omega-3 for short, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), give several positive health effects. It is very often communicated in the media that these PUFAs are wonderful remedies against several human diseases. But how do these omega-3 acids exhibit such positive health effects? It is known that the two omega-3 fatty acid eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are connected with the health effects of the omega-3 fatty acids. The LIPCHEM-group has contributed significantly to new and groundbreaking knowledge on how omega-3 fatty acids possess their positive health effects. Recent research reported by Professor Charles N. Serhan, Harvard Medical School, Boston, USA, have shown that EPA and DHA are both transformed in the human body to oxygenated derivatives of EPA and DHA named lipid mediators. The body uses lipoxygenases and cyclooxygenases to form lipid mediators or the super family of fatty acids. Lipid mediators dampen the inflammatory processes resulting in the return to physiology hindering diseases to be developed. The lipid mediators are only able to do so when they have an exact three dimensional structural orientation in space, making it necessary to prepare mediators with such three dimensional structures. The LIPCHEM-group at the School of Pharmacy, University of Oslo, has over the last six years collaborated with the Serhan group resulting in several joint papers. This FRIPRO-project have two main aims: i) to develope novel methodology in order to prepare several lipid mediators with correct three-dimensional structural orientations. ii) To test these mediators in mice. The LIPCHEM-group has in this project contributed to the development of new and innovative synthetic methods that have enable the preparation of several super family of fatty acids with defined three dimensional structure. This part of the project has resulted in several scientific articles, such as Journal of Organic Chemistry (2016, 81, 8287), Chemistry - A European Journal (2019, 25, 1476 and 2014, 20, 14575), Journal of Natural Products (2018, 81, 1007) and Biomolecular and Organic Chemistry (2018, 16, 6818). The second part consists of biological testing using mice experiments. The super family of fatty acids prepared display interesting biological effects. Results published in the very well recognized journal Brain (2018, 141, 3130) shows that the super fatty acid PD1n-3DPA arrests epileptogenesis. Results presented in the journal Proceedings of the National Academy of Sciences of the United States of America (2017, 114, 3963) show that this super fatty acid protects very effective against inflammation in mice. Another article in the same journal (2016, 113, 13905) explains on a molecular level how to inhibit the development of inflammation in the brain of mice. Such knowledge and information may form the basis for future studies in drug development. Moreover, the project has proved, based on methodology developed in this project, how PD1n-3DPA is biosynthesized in mice with inflammation induced (Cell Chemical Biology, 2018, 25, 749 and Organic and Biomolecular Chemistry 2017, 15, 8606). These results will contribute to explain the exact cellular, chemical and biochemical reasons for why omega-3 fatty acids provides positive health effects. The LIPCHEM-group at the School of Pharmacy, University of Oslo, has over the last six years collaborated closely with the Serhan-group at Harvard Medical School. These collaborative efforts have resulted in eight joint articles and two review articles. The results from this FRIPRO-project are very interesting and have contributed to new fundamental knowledge that can be utilized as basis for innovation projects for the development of new drugs. In total 24 scientific articles and three review articles in the period 2014-2019 reporting results at the scientific frontier. Chemical and biomedical research as well as drug development using omega-3 fatty acids have a long and strong tradition in Norway. One example is the drug Omacor (Lovaza) from the Norwegian company Pronova Biopharma AS, now part of BASF. Our long-term aim is that the groundbreaking and fundamental research results from this FRIPRO-project should form the basis of new life science industry. Toward this long term aim it is a pleasure to report that scientist working in the big pharma company Astra Zeneca, Mølndal, Sweden, has identified the LIPCHEM-group at the School of Pharmacy as an interesting and attractive collaborator within drug development project using the new and groundbreaking knowledge on omega-3 fatty acids generated from this project.

Oppnådde virkninger og effekter: - økning i antall forskningsartikler publisert i meget anerkjente internasjonale tidsskrifter - en unik tverrfaglig kompetanse siden vi behersker både organisk kjemi og oppløsningsbiologi på et høyt internasjonalt nivå - en mer attraktiv samarbeidspartner innen livsvitenskap nasjonalt og internasjonalt. LIPCHEM-gruppen har blitt invitert som deltager på to EU-søknader (ERA-NET; Innovative Training Network) - prosjektet har gitt grunnlag for legemiddelutvikling av betennelsesdempende legemidler uten immunsuppressive effekter. Deler av prosjektet griper inn det biomedisinske paradigmeskiftet som beskriver det molekylære grunnlaget for at betennelser kan løses opp ved hjelp av små molekyler. Alle biomedisinske paradigmeskifter gir grunnlag for innovasjon - firmaet OXYPUFA AS hvor salg og fremstilling av betennelsesoppløsende molekyler var forretningsmodellen ble startet med midler fra den første STUD-ENT utlysningen til Norges Forskningsråd

Organic synthesis is the science that enables us to produce useful matter such as medicines, agrochemicals and polymers. Today the methods used for production of those materials should have a low negative impact on the environment, but at the same time, p roduce the desired molecules in a stereodefined way. Some molecules can exist with stereodefined three-dimensional geometry, similar to a pair of hands, and these molecules are called enantiomers. Enantiomers are mirror images and are non-superposable. Di fferent enantiomers often possess different biological activities. In drugs, for example, one enantiomer often is responsible for the desired physiological effects, while the other is less active or cause serious side effects. Therefore we are in need of methods that produce only one out of two possible enantiomers. Such methods are named enantioselective. Today, more and more methods should be both environmentally benign and enantioselective. However, for the useful synthetic method named iodolactonizat ion, we are still in need for a highly enantioselective process. This research proposal aims at developing a highly enantioselective and environmentally benign iodolactonization method using the environmental friendly method of organocatalysis. This will achieve the combined goals of this project. The newly developed protocol will be applied for the preparation of new anti-inflammatory agents that will be useful in the treatment of Parkinson´s disease. This part of the project will be conducted in colla boration with professor Charles N. Serhan, Harvard Medical School, Boston, USA.