Vers la synthèse totale du FR225654 inhibiteur de la gluconéogenèse

Abstract : Type 2 diabetes mellitus (T2DM) is a growing worldwide health concern that is expected to afflict over 366 million people by 2030. FR225654 is a novel gluconeogenesis (GNG) inhibitor recently isolated from the culture broth of Phoma sp.. This compound selectively inhibits GNG of primary rat hepatocytes and shows highly hypoglycemic effects in several in vivo mouse models (80% decrease of glycemia). However, to date, the mechanism of action and molecular target remain unknown. From a structural point of view, FR225654 exhibits a highly oxygenated trans-decalin ring substituted by a β-keto-enol moiety and a side-chain bearing a conjugated carboxylic acid and a trisubstituted olefin. Project specific objectives were to design an efficient total synthesis which could also permit a straightforward access to diverse analogues. This feature would constitute a crucial step for the further understanding of Structure Activity Relationship of FR225654. The work consists in synthesizing separately a side chain and a trans-decalin core by means of an intramolecular Diels-Alder reaction from a precursor. To date, synthesis of the precursor has been achieved in 13 steps as well as the side chain. The Intramolecular Diels-Alder reaction has also been validated in order to accomplish the first total synthesis of FR225654.
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Shabbair Mohammad. Vers la synthèse totale du FR225654 inhibiteur de la gluconéogenèse. Autre. Université René Descartes - Paris V, 2013. Français. ⟨NNT : 2013PA05P615⟩. ⟨tel-00932775⟩

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