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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

By Anna Hovhannisyan, The Hien Pham, Dominique Bouvier, Alexander Piroyan, Laure Dufau, Lixian Qin, Yan Cheng, Gagik Melikyan, Michele Reboud-Ravaux and Michelle Bouvier-Durand

Abstract

International audienceA 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 (gamma- and delta-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 (IC50cPA of 600 nM) 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 (IC50T-L of 9.9 lM and IC50T-L of 6.7 mu M). 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

Topics: Furo[3, 4-c] pyridine-3-ones, Furo-and thieno[2, 3-d] pyrimidine-4-ones, CT-L, T-L and PA proteolytic activities, Constitutive c20S proteasome, Immunoproteasome i20S, In silico docking, [SDV.BC]Life Sciences [q-bio]/Cellular Biology
Publisher: 'Elsevier BV'
Year: 2014
DOI identifier: 10.1016/j.bmcl.2014.01.072
OAI identifier: oai:HAL:hal-01544059v1
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