New C⁴- and C¹-derivatives of furo[3,4-c]pyridine-3-ones and related compounds: Evidence for site-specific inhibition of the constitutive proteasome and its immunoisoform

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• 作者：Anna Hovhannisyan^c ; ^&dagger ; ; ^{annahovh@gmail.com" class="auth_mail} ; The Hien Pham^a ; ^b ; ^&dagger ; ; ^{bsthehien@yahoo.com" class="auth_mail} ; Dominique Bouvier^d ; ^&dagger ; ; ^{dbouvier@snv.jussieu.fr" class="auth_mail} ; Alexander Piroyan^c ; ^{aleksandr.piroyan@gmail.com" class="auth_mail} ; Laure Dufau^a ; ^b ; ^{dufaulaure@yahoo.fr" class="auth_mail} ; Lixian Qin^a ; ^b ; ^{lixian.qin@free.fr" class="auth_mail} ; Yan Cheng^a ; ^b ; ^{cyan86520@hotmail.com" class="auth_mail} ; Gagik Melikyan^c ; ^{acect@yahoo.com" class="auth_mail} ; Michè ; le Reboud-Ravaux^a ; ^b ; ^{Michele.Reboud@upmc.fr" class="auth_mail} ; Michelle Bouvier-Durand^a ; ^b ; ^{mbouvier@snv.jussieu.fr" class="auth_mail}
• 关键词：DMF DMA ; dimethylformamide dimethylacetal ; DMSO ; dimethylsulfoxide ; c20S ; 20S constitutive proteasome catalytic core ; i20S ; immunoproteasome catalytic core ; CT-L ; chymotrypsin-like ; T-L ; trypsin-like ; PA ; post-acid or caspase-like ; AMC ; 7-amino-4-methyl-coumarin ; 尾-NA ; 尾-naphtylamide ; CPK ; Corey Pauling Koltun ; PDB ; protein data bank
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：15 March, 2014
• 年：2014
• 卷：24
• 期：6
• 页码：1571-1580
• 全文大小：6793 K

文摘

A set of 18 new C⁴ and C¹ derivatives of nor-cerpegin (1,1-dimethyl furo[3,4-c]pyridine-3-one), 6 model compounds (纬- and 未-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 C⁴ and dimethylated at C¹ of the furopyridine ring was the most efficient PA site-specific inhibitor of the c20S ( 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 ( of 9.9 渭M and of 6.7 渭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.