伊马替尼类似物的合成及抑制K562细胞生长活性  

Synthesis of imatinib analogues and evaluation of their antiproliferative abilities in K562 cells

作　　者：昌盛[1,2] 殷世亮[3] 徐莉英[1] 景永奎 董金华[1] 

机构地区：[1]沈阳药科大学基于靶点的药物设计与研究教育部重点实验室,辽宁沈阳110016 [2]吉林医药学院药学院,吉林吉林132013 [3]沈阳医学院基础医学院,辽宁沈阳110034 [4]Department of Medicine, Mount Sinai School of Medicine, New York, NY10029, USA

出　　处：《中国药物化学杂志》2013年第2期92-98,共7页Chinese Journal of Medicinal Chemistry

摘　　要：目的设计、合成含2-苯胺基嘧啶结构的2-苯氧乙酰胺衍生物和芳酰基硫脲类衍生物,并对其体外抑制慢性粒细胞白血病生长活性进行初步的评价。方法以3-乙酰基吡啶、N,N-二甲基甲酰胺二甲基缩醛、邻甲基苯胺为起始原料,经硝化、加成、环合、还原反应得中间体6-甲基-N1-(4-(吡啶-3-基)嘧啶-2-基)-1,3-苯二胺,经与不同的酰化试剂酰化得到目标产物。采用台盼蓝排染法,以伊马替尼为阳性对照药、以K562细胞为测试细胞株对目标化合物进行体外抗慢性粒细胞白血病活性评价。结果与结论所合成的16个新化合物经1H-NMR和HR-MS确证结构。初步药理实验结果表明,目标化合物抑制慢性粒细胞白血病生长活性低于阳性对照药。Imatinib with a 2-phenylaminopyrimidine （PAP） structure is the first Bcr-Abl targeted anticancer drug for the treatment of chronic myeloid leukemia （ CML）, and has been successfully applied in CML therapy. However, patients treated with imatinib can develop resistance to this drug, leading to leukemia progression. The mutations of the kinase-binding region were considered to be the main cause. In order to investigate the structure-activity relationships of PAP derivatives, two novel series of imatinib analogues with modified 2-phenyloxyacetamide or with an aroylthiourea bearing PAP moiety were designed. Sixteen novel compounds were synthesized via alkylation of 2-chloro-N- （ 4-methyl-3 - （ 4- （ pyridin-3 -yl ） pyrimidin-2-yl ） aminophenyl ） acetamide with substituted phenols or via acylation of 6-methyl-N1 -（4-（pyridine-3-yl） pyramidin-2-yl）benzene-1,3-diamine with substituted benzoyl isothiocyanates. The structures of the target compounds were characterized by 1H-NMR and MS spectra. The antiproliferative effects of these target compounds against CML K562 cells were tested using trypan blue exclusion staining with imatinib as a positive control. Preliminary pharmacological results showed that these analogues had decreased abilities of inhibiting K562 cell growth compared to imatinib.

关 键 词：伊马替尼 2-苯胺基嘧啶衍生物 芳酰基硫脲 抗白血病活性 

分 类 号：R914[医药卫生—药物化学]