Novel heparin mimics as inhibitors of HGF-induced activation of Met : design, synthesis and biological evaluation

Lagoutte, R 2010, Novel heparin mimics as inhibitors of HGF-induced activation of Met : design, synthesis and biological evaluation , PhD thesis, Salford : University of Salford.

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Abstract

In chapter one, hepatocyte growth factor HGF, its receptor, the tyrosine kinase Met and their biological implications are introduced, and the structure and role of the glycosaminoglycans (GAGs) heparan sulfate and heparin are described. An account of the previous work on the project is given, setting aims for this project. In chapter two, the syntheses of the two best compounds of the first generation of mimics is described, thereby resolving the structural ambiguities of those compounds. An efficient sulfation methodology is described. Docking results for the two mimics to NK1 using AutoDock Vina are reported. In chapter three, the design of a new generation of compounds is described, based on conformational restrictions: results of a virtual screen of 36 compounds are reported along with a newly written script for automated virtual screening. In chapter four, efforts towards the synthesis of 2-substituted chroman derivatives are described: an easy two-step methodology for the preparation of chroman-2-ones is described, from which a three-step sequence allows access to various 2-substituted chromans. In chapter five, efforts towards the synthesis of 3- and 4-substituted chroman derivatives are described. In chapter six, attempts to apply the 2-substituted chroman derivative prepared in chapter four to the total synthesis of erythrococcamide B are described. A new one-step methodology for the preparation of 2-allyl chroman derivatives from chroman-2-ones, via reductive allylation using EtsSiH-lnBrs-allylTMS, is reported with its application to the synthesis of Erythrococcamide B. In chapter seven, conclusions are drawn and directions for future work proposed. Roman LAGOUTTE - PhD Thesis - Salford 2010

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