title: C1 and N5 derivatives of cerpegin: synthesis of a new series based on structure-activity relationships to optimize their inhibitory effect on 20S proteasome.
abstract: 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 μM and two had IC50 values closer to 2 μM. 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 β1 catalytic site (PA activity) in relation to the chemical nature of C(1) substituents.
authors.affiliation: Department of Organic Chemistry, Yerevan State University, A. Manoogian Str. 1, 0025 Yerevan, Armenia. annahovh@gmail.com
authors.forename: Anna
authors.initials: A
authors.lastname: Hovhannisyan
authors.forename: The Hien
authors.initials: TH
authors.lastname: Pham
authors.forename: Dominique
authors.initials: D
authors.lastname: Bouvier
authors.forename: Lixian
authors.initials: L
authors.lastname: Qin
authors.forename: Gagik
authors.initials: G
authors.lastname: Melikyan
authors.forename: Michèle
authors.initials: M
authors.lastname: Reboud-Ravaux
authors.forename: Michelle
authors.initials: M
authors.lastname: Bouvier-Durand
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D015195:Drug Design; D062105:Molecular Docking Simulation; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry* / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D061988:Proteasome Inhibitors; D011728:Pyridones; C503349:cerpegin; D046988:Proteasome Endopeptidase Complex