Synthesis and biological evaluation of novel substituted pyrrolo[1,2-a]quinoxaline derivatives as inhibitors of the human protein kinase CK2

被引:100
作者
Guillon, Jean [1 ,2 ]
Le Borgne, Marc [3 ]
Rimbault, Charlotte [1 ,2 ]
Moreau, Stephane [1 ,2 ]
Savrimoutou, Solene [1 ,2 ]
Pinaud, Noel [4 ]
Baratin, Sophie [1 ,2 ]
Marchivie, Mathieu [1 ,2 ]
Roche, Severine [1 ,2 ]
Bollacke, Andre [5 ]
Pecci, Adali [6 ,7 ]
Alvarez, Lautaro [8 ,9 ]
Desplat, Vanessa [1 ,2 ]
Jose, Joachim [5 ]
机构
[1] Univ Bordeaux Segalen, FRE 3396, F-33000 Bordeaux, France
[2] CNRS, FRE 3396, F-33000 Bordeaux, France
[3] Univ Lyon 1, SFR Sante Lyon Est, EA Biomol Canc & Chimioresistances 4446, Fac Pharm,CNRS,ISPB,INSERM,UMR3453,US7, F-69373 Lyon 8, France
[4] Univ Bordeaux, CNRS, ISM, UMR 5255, F-33405 Talence, France
[5] Univ Munster, Inst Pharmazeut & Med Chem, D-48149 Munster, Germany
[6] Univ Buenos Aires, Fac Ciencias Exactas & Nat, Dept Quim Biol, Buenos Aires, DF, Argentina
[7] Univ Buenos Aires, Fac Ciencias Exactas & Nat, IFIBYNE, CONICET, Buenos Aires, DF, Argentina
[8] Univ Buenos Aires, Fac Ciencias Exactas & Nat, Dept Quim Organ, RA-1428 Buenos Aires, DF, Argentina
[9] Univ Buenos Aires, Fac Ciencias Exactas & Nat, UMYMFOR, CONICET, Buenos Aires, DF, Argentina
关键词
Pyrrolo[1,2-a]quinoxaline; Protein kinase CK2; Antiproliferative activity; Synthesis; STRUCTURAL DETERMINANTS; ANTIMALARIAL ACTIVITY; POTENTIAL INHIBITORS; MOLECULAR-DYNAMICS; SURFACE-AREA; PREDICTION; CX-4945; EGFR; SAR;
D O I
10.1016/j.ejmech.2013.04.051
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Herein we describe the synthesis and properties of substituted phenylaminopyrrolo[1,2-a]quinoxalinecarboxylic acid derivatives as a novel class of potent inhibitors of the human protein kinase CK2. A set of 15 compounds was designed and synthesized using convenient and straightforward synthesis protocols. The compounds were tested for inhibition of human protein kinase CK2, which is a potential drug target for many diseases including inflammatory disorders and cancer. New inhibitors with IC50 in the micro- and sub-micromolar range were identified. The most promising compound, the 4-[(3-chlorophenyl)amino]pyrrolo[1,2-a]quinoxaline-3-carboxylic acid 1c inhibited human CK2 with an IC50 of 49 nM. Our findings indicate that pyrrolo[1,2-a]quinoxalines are a promising starting scaffold for further development and optimization of human protein kinase CK2 inhibitors. (C) 2013 Elsevier Masson SAS. All rights reserved.
引用
收藏
页码:205 / 222
页数:18
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