Tesis doctorales: TESEO

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Ministerio de Universidades - Gobierno de España

Título: RATIONAL DESIGN AND SYNTHESIS OF NEW NUCLEOSIDE ANALOGUES BEARING A CYCLOHEXANE CORE
Autor: Domínguez Pérez, Beatriz
Universidad: Universidad Autónoma de Barcelona
Departamento: Quimica
Fecha de Lectura: 06/07/2015
Programa de doctorado: Quimica
Dirección:
- Busqué Sánchez, Félix (DIRECTOR)
- ALIBES ARQUES, RAMÓN (DIRECTOR)
Tribunal:
- PARDO CARRASCO, LEONARDO (PRESIDENTE)
- Díaz Giménez, María Yolanda (SECRETARIO)
- AGUILAR HUERGO, ENRIQUE (VOCAL)
Descriptores:
- DISEÑO SINTESIS Y ESTUDIO DE NUEVOS FARMACOS
- SINTESIS QUIMICA
- QUIMICA ORGANICA
- QUIMICA FISICA
Localización: BIBLIOTECA DE COMUNICACIÓN Y HEMEROTECA GENERAL UAB

2015dominratio.pdf

Marcador: https://www.educacion.gob.es/teseo/mostrarRef.do?ref=1162815Añadir a favoritos.
Resumen:
The application of nucleoside analogues in antiviral therapy has evolved into an important option over the last three decades. In recent years, attention has been focused on carbanucleosides, which are more resistant to hydrolytic processes and have better absorption and penetration through the cell membrane as a result of their higher lipophilicity. Cyclohexenyl nucleosides are a promising class of antiviral compounds, wherein replacement of the oxygen atom of the furanose ring by a double bond induces annular flexibility, similar to that of regular nucleosides. Recently, it has been described that both enantiomers of cyclohexenyl G (DCG and LCG) display potent and selective anti-herpes virus activity. On the other hand, molecular modelling techniques have been one of the cornerstones in the design and optimization of novel therapeutic agents. Specifically, molecular docking techniques, which are used to predict the binding affinity of an organic molecule to a macromolecule, have become a useful tool. In the field of nucleoside analogues, docking techniques may be applied to simulate both their activation process as well as their interaction with their target, the corresponding viral polymerase. The present thesis is focused on the rational design and synthesis of a series of six-membered carbocyclic nucleosides based on the skeleton of D- and L-Cyclohexenyl G as anti-herpes virus agents. In particular, a molecular modelling study on the whole activation process of a set of cyclohexene and bicyclo[4.1.0]heptane nucleosides has been carried out by means of protein-ligand docking calculations. As a result of the computational study, we decided to develop a new synthetic strategy towards the stereoselective synthesis of nucleoside analogues with a bicyclo[4.1.0]heptane structure. Specifically, it has been synthesised four novel bicyclo[4.1.0]heptane nucleosides bearing different purine and pyrimidine bases, starting from 1,4-cyclohexanedione in 14-16 steps and overall yields between 2% and 10%. In addition, it has been described a new procedure to synthesise (2R,3R,8R)-2,3-diphenyl-1,4-dioxaspiro[4.5]decan-6-ene-8-ol, which is an intermediate for the synthesis of these nucleoside analogues, along with the enantioselective synthesis of both enantiomers of (4R)-hydroxy-2-cyclohexenone and their O-silyl derivatives. These procedures compete positively with the published methodologies. The biological activity of the synthesised analogues against several viruses has been evaluated, although none of them displayed significant activity. In order to rationalise this lack of activity, the interaction of the drug candidates with their target has been evaluated. As there is no crystallographic structure of the replication process, a 3D model has been generated by means of a homology modelling like approach. This methodology allows the prediction of 3D structures of macromolecules based on known structures of homologous proteins (templates). The theoretical calculations have revealed that the antiviral activity of these candidates is restricted by their incorporation into the viral DNA.

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