Identification de nouvelles structures inhibitrices de kinases : conception synthèse et évaluation biologique

Abstract : In the introduction, the main functions of cyclin dependent kinases are detailed. Whenever it was possible the link with pathologies where these kinases are overexpressed is presented. This is followed by the description of the inhibitors which are actually undergoing clinical testing. Most of these clinical studies are targeting cancer and leukemia. Impressive clinical results have been disclosed for Dinaciclib, Palbociclib and Roscovitine. The synthesis of two series of compounds is then envisioned. The first series of products are purine derivatives bearing a hydroxybiarylmethyl group on the 6 position of the purine scaffold.  Two approaches were compared in the synthesis of the hydroxylbiarylmethylamino group. In both approaches the key step was the orthoformylation of phenols using magnesium chloride as catalyst. The prepared compounds were evaluated against kinases and a tumor cell line. They were found more potent than homologous products without hydroxyls. The second families of products are thieno[3,2-d]pyrimidines. A new general route to these products based on the preparation of 7-bromo-2,4-dichloro-thieno[3,2-d]pyrimidine which can allow the synthesis of a large diversity of trisubstituted derivatives.
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Olfa Gloulou. Identification de nouvelles structures inhibitrices de kinases : conception synthèse et évaluation biologique. Chimie thérapeutique. Université René Descartes - Paris V, 2013. Français. ⟨NNT : 2013PA05P637⟩. ⟨tel-01132397⟩

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