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Synthesis of novel fluorinated building blocks and α-helix peptidomimetics

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Synthesis of novel fluorinated building blocks and α-helix peptidomimetics

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dc.contributor.advisor	Fustero Lardiés, Santos
dc.contributor.advisor	Barrio Fernández, Pablo
dc.contributor.author	Sedgwick, Daniel Mark
dc.contributor.other	Departament de Quimica Orgànica	es_ES
dc.date.accessioned	2018-11-08T11:09:10Z
dc.date.available	2018-11-09T05:45:05Z
dc.date.issued	2018	es_ES
dc.date.submitted	13-11-2018	es_ES
dc.identifier.uri	http://hdl.handle.net/10550/67913
dc.description.abstract	At its heart, the present PhD thesis is based on the premise of two important areas in modern organic chemistry: firstly, the development of new methodologies to incorporate fluorine into organic molecules; and secondly, the design and synthesis of small molecules with high therapeutic potential. The work presented in the first three chapters will therefore focus on the incorporation of fluorine into organic molecules and the synthesis of fluorinated building blocks. In each chapter, we aim to obtain biologically relevant small molecules containing fluorine atoms or fluorinated groupings. The introduction of fluorine is a commonly used method in drug discovery to fine-tune the properties of drug candidates and therefore, given the scarcity of fluorine-containing molecules in natural sources, new synthetic methods towards new fluorinated scaffolds represent an important goal for organic chemists. On the other hand, the fourth and final chapter will explore the possibilities of novel p-terphenyl structures as peptidomimetics to exploit important biological targets. In this context, the present PhD thesis will have the following structure: Chapter 1. Synthesis of enantioenriched 1-amino-1,2-dihydronaphthalenes. This work builds upon past efforts in our research group in the area of diversity oriented synthesis, utilising ortho-bromobenzaldehyde as a common precursor. In this study, we will synthesise an unprecedented fluorinated scaffold containing a trifluoromethyl group, during which we will explore the effect of fluorinated groups during the ring-closing metathesis reaction (RCM). Chapter 2. Synthesis of 1,2-fluorohydrins via 1,2-difunctionalisation of olefins. This chapter focuses on simplicity and practicality. Fluorohydrins are an important class of fluorinated organic molecules; fludrocortisone was the first fluorinated drug to obtain FDA approval. Their synthesis has traditionally relied on the opening of epoxides, but in this chapter we will bypass this intermediate to form fluorohydrins directly from olefins, one of the most widely available and inexpensive classes of chemical. Chapter 3. Synthesis and reactivity of β-fluorovinyl sulfones. In this chapter we will develop methodologies for the stereodivergent synthesis of both (E)- and (Z)-β-fluorovinyl sulfones, a scarcely studied structure with potential as a fluorinated building block. We will also explore the reactivity of these structures. Finally, the hydrogenation reaction of fluorovinyl sulfones will be explored more in depth, as well as preliminary studies into the asymmetric hydrogenation of other vinyl fluorides. Chapter 4. Synthesis and biological evaluation of novel p-terphenyls as α-helix mimetics. The work described in this chapter is part of a long-term project within our research group, in collaboration with J. Gallego (UCV) and J. Alcamí (ISCIII). We found that p-terphenyls can be used to mimic the α-helix in the Rev protein of HIV-1. In this way, these small molecules are able to inhibit the replication of the virus. This chapter will build upon this work, exploring different structures and substitution patterns in order to learn more about the structure-activity relationship of these compounds, as well as designing a new derivative to tackle a protein-protein interaction that is key in the parasitic cycle of malaria. In conclusion to this chapter, 18+ new terphenyl structures will be synthesised and biologically tested against these important interactions present in HIV and malaria, all bearing structural modifications to the lead compound. It's worth noting that this represents the first development of a terphenyl scaffold active against the MyoA-MTIP protein-protein interaction in the malaria infection.	es_ES
dc.format.extent	410 p.	es_ES
dc.language.iso	en	es_ES
dc.subject	fluorine	es_ES
dc.subject	organic synthesis	es_ES
dc.subject	peptidomimetics	es_ES
dc.subject	terphenyl	es_ES
dc.title	Synthesis of novel fluorinated building blocks and α-helix peptidomimetics	es_ES
dc.type	doctoral thesis	es_ES
dc.subject.unesco	UNESCO::QUÍMICA::Química orgánica	es_ES
dc.embargo.terms	0 days	es_ES