2. Academic Validation
  3. 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

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

  • Bioorg Med Chem Lett. 2014 Mar 15;24(6):1571-80. doi: 10.1016/j.bmcl.2014.01.072.
Anna Hovhannisyan 1,  The Hien Pham 2,  Dominique Bouvier 3,  Alexander Piroyan 4,  Laure Dufau 5,  Lixian Qin 6,  Yan Cheng 7,  Gagik Melikyan 8,  Michèle Reboud-Ravaux 9,  Michelle Bouvier-Durand 10
Affiliations

Affiliations

  • 1 Department of Organic Chemistry, Yerevan State University, A. Manoogian Str. 1, 0025 Yerevan, Armenia. Electronic address: annahovh@gmail.com.
  • 2 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.
  • 3 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.
  • 4 Department of Organic Chemistry, Yerevan State University, A. Manoogian Str. 1, 0025 Yerevan, Armenia. Electronic address: aleksandr.piroyan@gmail.com.
  • 5 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.
  • 6 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.
  • 7 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.
  • 8 Department of Organic Chemistry, Yerevan State University, A. Manoogian Str. 1, 0025 Yerevan, Armenia. Electronic address: acect@yahoo.com.
  • 9 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.
  • 10 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.
PMID: 24534487 DOI: 10.1016/j.bmcl.2014.01.072
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.

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.

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