Author(s):
Lucas, Susana Dias, 1980- 
Date: 2009
Persistent ID: http://hdl.handle.net/10451/1586
Origin: Repositório da Universidade de Lisboa
Subject(s): Aminoácidos; Química orgânica; Teses de doutoramento
Document details
Oxetane &-amido acids : synthesis and derivatisation
Description
Tese de doutoramento em Química (Química Orgânica), apresentada à Universidade de Lisboa através da Faculdade de Ciências, 2009 In the present work the potential of oxetane δ-amino acids as scaffolds was evaluated. While there is an ample precedence for the use of 6- and 5-membered carbohydrate-derived amino acids as scaffolds, there are no reports on oxetanebased libraries. The oxetane ring is an interesting source of rigidity and well-defined exit vectors, and this unit is present in some important naturally occurring bioactive molecules, such as taxol, oxetanocin or oxetin. Nevertheless, the intrinsic chemical and pharmacological properties or inherent advantages of the oxetanes are far from clear. Oxetane δ-amino acids with the general structure i were synthesised using carbohydrates as starting materials in order to obtain different and well-defined stereochemistry. On a scaffold synthesis level, the oxetane moiety was decorated with different R groups such as hydroxyl, methoxyl or fluorine, and the resulting final scaffolds i exhibited D-lyxo, D-ribo, D-arabino and D-xylo configurations. Scaffold derivatisation was performed introducing valuable pharmacophores such as 1,2,4-oxadiazoles or 1,2,3-triazoles to generate small libraries of compounds with general structures ii and iii, respectively. 1,2,4-Oxadiazoles were obtained by reaction of oxetane δ-amino acids i, with different hydroxyamidines via a basic activation followed by cyclodehydration. The scaffold was further derivatised so that the resulting compounds ii exhibited tert-butoxycarboxyl, hydrogen, acetyl or mesyl as group R1. 1,2,3-Triazoles were obtained by the so called click reaction of an oxetane δ-azido ester with different acetylenes catalysed by Cu(I). Oxetanes proved to be stable under the chosen derivatisation conditions with exception of the 3- hydroxy derivatives which decomposed under basic conditions. Moreover, corresponding 1,2,4-oxadiazole libraries were synthesised on two diastreomeric bicyclic δ-amino acids leading to a new family of compounds with general structure iv. The synthesised compounds were characterised by techniques such as NMR, MS, HRMS, optical rotation, elemental analysis and, for crystalline compounds, by X-Ray crystallography. Physicochemical and metabolic properties of the synthesised molecules were evaluated. Prediction of properties such as octanol/water partition coefficient, polar surface area, effective intestinal permeability, pKa, blood-brain barrier penetration and Andrew binding score was possible by the use of in silico tools. Moreover, some of the compounds experimental data on octanol/water partition coefficients, thermodynamic solubility, permeability and susceptibility towards metabolic degradation in human and mouse microsomes were obtained. All target compounds exhibited the physicochemical and metabolic properties desired in medicinal chemistry.
Tese de doutoramento em Química (Química Orgânica), apresentada à Universidade de Lisboa através da Faculdade de Ciências, 2009 In the present work the potential of oxetane δ-amino acids as scaffolds was evaluated. While there is an ample precedence for the use of 6- and 5-membered carbohydrate-derived amino acids as scaffolds, there are no reports on oxetanebased libraries. The oxetane ring is an interesting source of rigidity and well-defined exit vectors, and this unit is present in some important naturally occurring bioactive molecules, such as taxol, oxetanocin or oxetin. Nevertheless, the intrinsic chemical and pharmacological properties or inherent advantages of the oxetanes are far from clear. Oxetane δ-amino acids with the general structure i were synthesised using carbohydrates as starting materials in order to obtain different and well-defined stereochemistry. On a scaffold synthesis level, the oxetane moiety was decorated with different R groups such as hydroxyl, methoxyl or fluorine, and the resulting final scaffolds i exhibited D-lyxo, D-ribo, D-arabino and D-xylo configurations. Scaffold derivatisation was performed introducing valuable pharmacophores such as 1,2,4-oxadiazoles or 1,2,3-triazoles to generate small libraries of compounds with general structures ii and iii, respectively. 1,2,4-Oxadiazoles were obtained by reaction of oxetane δ-amino acids i, with different hydroxyamidines via a basic activation followed by cyclodehydration. The scaffold was further derivatised so that the resulting compounds ii exhibited tert-butoxycarboxyl, hydrogen, acetyl or mesyl as group R1. 1,2,3-Triazoles were obtained by the so called click reaction of an oxetane δ-azido ester with different acetylenes catalysed by Cu(I). Oxetanes proved to be stable under the chosen derivatisation conditions with exception of the 3- hydroxy derivatives which decomposed under basic conditions. Moreover, corresponding 1,2,4-oxadiazole libraries were synthesised on two diastreomeric bicyclic δ-amino acids leading to a new family of compounds with general structure iv. The synthesised compounds were characterised by techniques such as NMR, MS, HRMS, optical rotation, elemental analysis and, for crystalline compounds, by X-Ray crystallography. Physicochemical and metabolic properties of the synthesised molecules were evaluated. Prediction of properties such as octanol/water partition coefficient, polar surface area, effective intestinal permeability, pKa, blood-brain barrier penetration and Andrew binding score was possible by the use of in silico tools. Moreover, some of the compounds experimental data on octanol/water partition coefficients, thermodynamic solubility, permeability and susceptibility towards metabolic degradation in human and mouse microsomes were obtained. All target compounds exhibited the physicochemical and metabolic properties desired in medicinal chemistry.
Document Type
Doctoral Thesis
Advisor(s) Rauter, Amélia Pilar, 1950-; Wessel, Hans Peter
Advisor(s) Rauter, Amélia Pilar, 1950-; Wessel, Hans Peter
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