- A new series of N5 derivatives of the 1,1,5-trimethyl furo[3,4-c]pyridine-3,4-dione (cerpegin) selectively inhibits the post-acid activity of mammalian 20S proteasomes
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A large set of N5-derivatives of cerpegin (1,1,5-trimethyl furo[3,4-c]pyridine-3,4-dione) was designed and synthesized in high yields by a simple and handy method using various primary amines for a pyridine cycle synthesis. The effects of 29 derivatives on the three types of catalytic sites of purified mammalian 20S proteasomes (CT-L, T-L and PA) were measured. Most of the new compounds specifically inhibited the PA activity, in the micromolar range. Docking experiments support these results. Moreover, neither calpain I nor cathepsin B were inhibited.
- Pham, The Hien,Hovhannisyan, Anna,Bouvier, Dominique,Tian, Lei,Reboud-Ravaux, Michèle,Melikyan, Gagik,Bouvier-Durand, Michelle
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- Cerpegin-derived furo[3,4-c]pyridine-3,4(1H,5H)-diones enhance cellular response to interferons by de novo pyrimidine biosynthesis inhibition
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There is an increasing interest in the field of cancer therapy for small compounds targeting pyrimidine biosynthesis, and in particular dihydroorotate dehydrogenase (DHODH), the fourth enzyme of this metabolic pathway. Three available DHODH structures, fe
- Alves de Sousa, Rodolphe,Arnould, Stéphanie,Bekaddour, Nassima,Dairou, Julien,Diaz, Olivier,Ermellino, Laura,Hayek, Simon,Herbeuval, Jean-Philippe,Hovhannisyan, Anna A.,Lotteau, Vincent,Melikyan, Gagik,Nisole, Sébastien,Pietrancosta, Nicolas,Sardet, Claude,Tramontano, Enzo,Vidalain, Pierre-Olivier
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- 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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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 (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 C4 and dimethylated at C1 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 (IC50cT-L of 9.9 μM and IC50iT-L of 6.7 μM). 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.
- Hovhannisyan, Anna,Pham, The Hien,Bouvier, Dominique,Piroyan, Alexander,Dufau, Laure,Qin, Lixian,Cheng, Yan,Melikyan, Gagik,Reboud-Ravaux, Michèle,Bouvier-Durand, Michelle
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supporting information
p. 1571 - 1580
(2014/03/21)
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- Two versatile routes towards Cerpegin and analogues: Applications of a one pot reaction to new analogues of Cerpegin
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Simple and efficient routes to the natural alkaloid Cerpegin and new analogues are described herein. In a first approach, we extend the scope of a one pot three steps reaction, which permits the synthesis of new analogues of Cerpegin, substituted in different ways. In a second line of approach, we present an unprecedented synthesis of Cerpegin and analogues where methylfuranones are condensed with dimethylformamide diethylacetal (DMFDEA) to yield enaminolactone esters, which react easily with various primary amines affording Cerpegin and new analogues. We applied this second approach to the synthesis of new bis-Cerpegins and N-amino-Cerpegins. Most of the syntheses are performed under environmental friendly conditions.
- Villemin, Didier,Cheikh, Nawel,Liao, Liang,Bar, Nathalie,Lohier, Jean-Fran?ois,Sopkova, Jana,Choukchou-Braham, Noureddine,Mostefa-Kara, Bachir
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experimental part
p. 4906 - 4918
(2012/07/28)
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- 'One-pot' four-step synthesis of cerpegin
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Cerpegin (1) was synthesized through a 'one-pot' reaction in 71% overall yield. Lithiation of commercially available 2-methoxynicotinic acid (2) as its lithium salt using LTMP, followed by addition of acetone at low temperature and a specific acidic treatment of the intermediate 3 thus obtained, gave the 1,1-dimethyl-3,4-dioxo-1,3,4,5-tetrahydrofuro[3,4-c]pyridine (4). The latter was finally selectively alkylated using methyl iodide and caesium carbonate to afford cerpegin (1).
- Lazaar, Jalal,Hoarau, Christophe,Mongin, Florence,Trécourt, Francois,Godard, Alain,Quéguiner, Guy,Marsais, Francis
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p. 3811 - 3813
(2007/10/03)
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- One-pot three steps synthesis of cerpegin
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Cerpegin 1 was synthesized in a one-pot reaction at room temperature catalysed by cesium carbonate with an overall of 75% yield. 3-Hydroxy-3-methyl-2-butanone 2 reacted with diethyl malonate 3 to give 2-ethoxycarbonyl-3,4,4-trimethyl-2-buten-4-olide 4. Then 4 with s-triazine gave to 1,1-dimethylfuro[3,4-c]pyridine-3,4(1H, 5H)-dione 5 and which was alkylated with methyliodide to cerpegin.
- Villemin, Didier,Liao, Liang
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p. 8733 - 8734
(2007/10/03)
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- Metalation of pi-deficient heterocycles a facile synthesis of cerpegin
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The first total synthesis of the naturally occuring cerpegin is described. Metalation of a pyridine derivative has been used in the key step.
- Guillier, Fabricee,Nivoliers, Francois,Bourguignon, Jean,Dupas, Georges,Marsais, Francis,Godard, Alain,Queguiner, Guy
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p. 7355 - 7356
(2007/10/02)
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