title: New C(4)- and C(1)-derivatives of furo[3,4-c]pyridine-3-ones and related compounds: evidence for site-specific inhibition of the constitutive proteasome and its immunoisoform.
abstract: A set of 18 new C(4) and C(1) derivatives of nor-cerpegin (1,1-dimethyl furo[3,4-c]pyridine-3-one), 6 model compounds (γ- and δ-lactones) and 20 furo- or thieno[2,3-d]-pyrimidine-4-one related compounds were designed and synthesized. Each compound was assayed for inhibition of CT-L, T-L and PA proteolytic activities of 20S constitutive proteasome (c20S). Most performant compounds were also assayed on 20S immunoproteasome (i20S). Compound 10 with a benzylamino group at C(4) and dimethylated at C(1) of the furopyridine ring was the most efficient PA site-specific inhibitor of the c20S (IC50(cPA) of 600nM) without noticeable inhibition of the i20S PA site (iPA). In silico docking assays for 10 at the iPA catalytic site revealed the absence of poses normally observed for this compound and related ones at the constitutive PA site (cPA). The thieno[2,3-d]pyrimidine-4-one 40 was T-L site-specific with a mild inhibition of both c20S and i20S in vitro (IC50(cT-L) of 9.9μM and IC50(iT-L) of 6.7μM). In silico docking assays of 40 at T-L sites of c20S and i20S revealed almost identical first rank poses in the two types of sites with no possibility left for nucleophilic attack by Thr1 as observed for the fused furopyridine-3-one 10.
authors.affiliation: Department of Organic Chemistry, Yerevan State University, A. Manoogian Str. 1, 0025 Yerevan, Armenia. Electronic address: annahovh@gmail.com.
authors.forename: Anna
authors.initials: A
authors.lastname: Hovhannisyan
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR 8256, ERL U1164, B2A, Biological Adaptation and Ageing, Integrated Cellular Ageing and Inflammation, Molecular & Functional Enzymology, Case 256, 7 Quai St Bernard, F-75005 Paris, France; CNRS, UMR 8256, B2A, Biological Adaptation and Ageing, F-75005 Paris, France. Electronic address: bsthehien@yahoo.com.
authors.forename: The Hien
authors.initials: TH
authors.lastname: Pham
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, Atelier de Bioinformatique, Case courrier 1202, 4 Place Jussieu, F 75252 Paris Cedex 05, France. Electronic address: dbouvier@snv.jussieu.fr.
authors.forename: Dominique
authors.initials: D
authors.lastname: Bouvier
authors.affiliation: Department of Organic Chemistry, Yerevan State University, A. Manoogian Str. 1, 0025 Yerevan, Armenia. Electronic address: aleksandr.piroyan@gmail.com.
authors.forename: Alexander
authors.initials: A
authors.lastname: Piroyan
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR 8256, ERL U1164, B2A, Biological Adaptation and Ageing, Integrated Cellular Ageing and Inflammation, Molecular & Functional Enzymology, Case 256, 7 Quai St Bernard, F-75005 Paris, France; CNRS, UMR 8256, B2A, Biological Adaptation and Ageing, F-75005 Paris, France. Electronic address: dufaulaure@yahoo.fr.
authors.forename: Laure
authors.initials: L
authors.lastname: Dufau
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR 8256, ERL U1164, B2A, Biological Adaptation and Ageing, Integrated Cellular Ageing and Inflammation, Molecular & Functional Enzymology, Case 256, 7 Quai St Bernard, F-75005 Paris, France; CNRS, UMR 8256, B2A, Biological Adaptation and Ageing, F-75005 Paris, France. Electronic address: lixian.qin@free.fr.
authors.forename: Lixian
authors.initials: L
authors.lastname: Qin
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR 8256, ERL U1164, B2A, Biological Adaptation and Ageing, Integrated Cellular Ageing and Inflammation, Molecular & Functional Enzymology, Case 256, 7 Quai St Bernard, F-75005 Paris, France; CNRS, UMR 8256, B2A, Biological Adaptation and Ageing, F-75005 Paris, France. Electronic address: cyan86520@hotmail.com.
authors.forename: Yan
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of Organic Chemistry, Yerevan State University, A. Manoogian Str. 1, 0025 Yerevan, Armenia. Electronic address: acect@yahoo.com.
authors.forename: Gagik
authors.initials: G
authors.lastname: Melikyan
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR 8256, ERL U1164, B2A, Biological Adaptation and Ageing, Integrated Cellular Ageing and Inflammation, Molecular & Functional Enzymology, Case 256, 7 Quai St Bernard, F-75005 Paris, France; CNRS, UMR 8256, B2A, Biological Adaptation and Ageing, F-75005 Paris, France. Electronic address: Michele.Reboud@upmc.fr.
authors.forename: Michèle
authors.initials: M
authors.lastname: Reboud-Ravaux
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR 8256, ERL U1164, B2A, Biological Adaptation and Ageing, Integrated Cellular Ageing and Inflammation, Molecular & Functional Enzymology, Case 256, 7 Quai St Bernard, F-75005 Paris, France; CNRS, UMR 8256, B2A, Biological Adaptation and Ageing, F-75005 Paris, France. Electronic address: mbouvier@snv.jussieu.fr.
authors.forename: Michelle
authors.initials: M
authors.lastname: Bouvier-Durand
mesh_terms: D000818:Animals; D001665:Binding Sites; D002244:Carbon / Q000737:chemistry; D020134:Catalytic Domain; D051379:Mice; 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; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism
chemical_list: D061988:Proteasome Inhibitors; D020033:Protein Isoforms; D011728:Pyridones; D002244:Carbon; D046988:Proteasome Endopeptidase Complex
keywords: CT-L; Constitutive c20S proteasome; Furo- and thieno[2,3-d]pyrimidine-4-ones; Furo[3,4-c]pyridine-3-ones; Immunoproteasome i20S; In silico docking; T-L and PA proteolytic activities