Loidreau Yvonnick, Deau Emmanuel, Marchand Pascal, Nourrisson Marie-Renée, Logé Cédric, Coadou Gaël, Loaëc Nadège, Meijer Laurent, Besson Thierry
Normandie Univ, COBRA, UMR 6014 & FR 3038; Univ Rouen; INSA Rouen; CNRS, Bâtiment IRCOF, 1 rue Tesnière, 76821 Mont St Aignan Cedex, France.
Université de Nantes, Nantes Atlantique Universités, Laboratoire de Chimie Thérapeutique, Cibles et Médicaments des Infections et du Cancer, IICiMed UPRES EA 1155, UFR des Sciences Pharmaceutiques et Biologiques, 1 rue Gaston Veil, 44035 Nantes, France.
Eur J Med Chem. 2015 Mar 6;92:124-34. doi: 10.1016/j.ejmech.2014.12.038. Epub 2014 Dec 23.
This paper reports the design and synthesis of a novel series of 8-arylpyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-amines via microwave-assisted multi-step synthesis. A common precursor of the whole series, 3-amino-5-bromothieno[2,3-b]pyridine-2-carbonitrile, was rapidly synthesized in one step from commercially-available 5-bromo-2-chloronicotinonitrile. Formylation with DMF-DMA led to (E)-N'-(5-bromo-2-cyanothieno[2,3-b]pyridin-3-yl)-N,N-dimethylformimidamide (4) which was conveniently functionalized at position 8 by palladium-catalyzed Suzuki-Miyaura cross-coupling to introduce a heteroaromatic ring. High-temperature formamide-mediated cyclization of the cyanoamidine intermediate gave seventeen 8-arylpyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-amines. The inhibitory potency of the final products was evaluated against five protein kinases (CDK5/p25, CK1δ/ε, GSK3α/β, DYRK1A and CLK1) and revealed that 8-(2,4-dichlorophenyl)pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-amine 1g specifically inhibits CK1δ/ε and CLK1 (220 and 88 nM, respectively) while its 7-(2,4-dichlorophenyl)pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-amine isomer 10 showed no activity on the panel of tested kinases. Molecular modelling of 10 and 1g in the ATP binding sites of CK1δ/ε and CLK1 showed that functionalization at position 7 of pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4-amines is likely to induce a steric clash on the CK1δ/ε P-loop and thus a complete loss of inhibitory activity.
本文报道了通过微波辅助多步合成法设计并合成的一系列新型8-芳基吡啶并[3',2':4,5]噻吩并[3,2-d]嘧啶-4-胺。该系列的一个常见前体，3-氨基-5-溴噻吩并[2,3-b]吡啶-2-甲腈，由市售的5-溴-2-氯烟腈一步快速合成。用DMF-DMA进行甲酰化反应得到（E）-N'-（5-溴-2-氰基噻吩并[2,3-b]吡啶-3-基）-N，N-二甲基甲脒（4），其通过钯催化的铃木-宫浦交叉偶联在8位方便地官能化，以引入一个杂芳环。高温甲酰胺介导的氰基脒中间体环化反应得到了十七种8-芳基吡啶并[3',2':4,5]噻吩并[3,2-d]嘧啶-4-胺。对最终产物针对五种蛋白激酶（CDK5/p25、CK1δ/ε、GSK3α/β、DYRK1A和CLK1）的抑制活性进行了评估，结果表明8-（2,4-二氯苯基）吡啶并[3',2':4,5]噻吩并[3,2-d]嘧啶-4-胺1g特异性抑制CK1δ/ε和CLK1（分别为220和88 nM），而其7-（2,4-二氯苯基）吡啶并[3',2':4,5]噻吩并[3,2-d]嘧啶-4-胺异构体10在测试的激酶组中没有活性。对10和1g在CK1δ/ε和CLK1的ATP结合位点进行分子模拟表明，吡啶并[3',2':4,5]噻吩并[3,2-d]嘧啶-4-胺7位的官能化可能会在CK1δ/ε的P环上引起空间冲突，从而导致抑制活性完全丧失。
