C-1 and N-5 derivatives of cerpegin: Synthesis of a new series based on structure-activity relationships to optimize their inhibitory effect on 20S proteasome - Biological Adaptation and Ageing Accéder directement au contenu
Article Dans Une Revue Bioorganic and Medicinal Chemistry Letters Année : 2013

C-1 and N-5 derivatives of cerpegin: Synthesis of a new series based on structure-activity relationships to optimize their inhibitory effect on 20S proteasome

Résumé

Thirty-two new derivatives of cerpegin (1,1,5-trimethylfuro[3,4-c]pyridine-3,4-dione) were designed and synthesized in high yield by a new method, combining several C-1 and N-5 substituents. All compounds were tested for their inhibitory effect on the CT-L, T-L and PA proteolytic activities of a purified mammalian 20S proteasome. Only one molecule inhibited both CT-L and PA activities. Sixteen molecules specifically inhibited PA at the micromolar range, out of which fourteen had IC50 values around 5 mu M and two had IC50 values closer to 2 mu M. Except in one case, neither calpain I nor cathepsin B was inhibited. In silico docking suggests a unique mode of binding of the most efficient compounds to the beta 1 catalytic site (PA activity) in relation to the chemical nature of C-1 substituents.

Dates et versions

hal-01544066 , version 1 (21-06-2017)

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Anna Hovhannisyan, The Hien Pham, Dominique Bouvier, Lixian Qin, Gagik Melikyan, et al.. C-1 and N-5 derivatives of cerpegin: Synthesis of a new series based on structure-activity relationships to optimize their inhibitory effect on 20S proteasome. Bioorganic and Medicinal Chemistry Letters, 2013, 23 (9), pp.2696-2703. ⟨10.1016/j.bmcl.2013.02.079⟩. ⟨hal-01544066⟩
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