Macromoléculas y ligandospéptido-nucleótidos y b-aminoácidos morfánicos. Síntesis, modelización molecular y evaluación biológica

Abstract

The thesis presents a combined theoretical and experimental research in organic chemistry and biochemistry. Six different chapters, covering macromolecules and ligands preparation and simulation, are described: - [1] New Mechanistical Insights in the Asymmetric Michael Addition of Chiral Lithium Amides. It has been lapsed 20 years without any revising ot the mechanis originally proposed by Davies in 1994 about the conjugate addition of chiral liyhium amides to unsaturated esters. New ideas based in QM/DFT state-of-the-art theories are proposed. - [2] Asymmetric Synthesis of Morphan Type b-Amino Acids. The synthesis of several morphan structures, 2-azabiciclo[3.3.1]nonane scaffold, are discussed, several of them being b-Amino acids. - [3] Structure-based Design and Synthesis of Novel mu Opioid Receptor Ligands. The morphan core is used in a structure-based design using Docking approaches and MD simulations to discover new potential opioid ligands. The leads are synthesized in few steps taking the initial morphan b-amino acid obtained in chapter 2. - [4] Biological Evaluation of Novel mu Opioid Receptor Ligands. The synthesized compounds in chapter 3 are submiitted to biological trials, which describes the acitivity of these series of candidates. - [5] Asymmetric Synthesis of Flexible Peptide-Nucleotides (PNA). Several peptide-nucleotides were prepared following asymmetric Michael additions together with several nucleobase insertion protocols to synthesize PNA-monomers. - [6] Molecular Dynamics Simulations of Flexible Peptide-Nucleotides. The Leumman¿s PNA-monomer are theoretically studied through MD simulations to gain insigth in the hybridization properties with natural nucleic acid systems.