含3-羟基-4-吡啶酮片段的EGFR酪氨酸激酶抑制剂的合成及抗肿瘤活性研究

刘燊1 邵加安2 俞永平1

(1.浙江大学药学院浙江省抗肿瘤重点实验室, 浙江杭州 310058)
(2.浙江理工大学理学院化学系, 浙江杭州 310018)

【摘要】目的设计合成含具备铁离子螯合功能的3-羟基-4-吡啶酮片段的4-芳胺基喹唑啉类衍生物,并评价其体外抑制肿瘤增殖活性。方法4-芳胺基-6-硝基-7-氟喹唑啉与3-苄氧基吡啶-4-酮脂肪醇发生取代反应,再经过硝基还原得到4-芳胺基-6-氨基-7-(3-苄氧基-4-吡啶酮)烷氧基喹唑啉中间体,该中间体与各种酰氯或者酸缩合后再脱去苄基得到目标化合物1~6;4-芳胺基-6-氨基-7-烷氧基喹唑啉与3-苄氧基吡啶-4-酮-1-乙酸经缩合后脱苄基得到目标化合物7~12。采用MTT法,以吉非替尼(gefitinib)为阳性对照药,测定目标化合物对人表皮癌细胞系A431、人肺腺癌细胞系H1975和人宫颈癌细胞系He La的增殖抑制活性。结果与结论合成了12个未见文献报道的新化合物,其结构经1H-NM R、M S谱确证;初步体外生物活性筛选结果显示,该类化合物具有较好的抗肿瘤细胞增殖活性,其中化合物1~4、7~10在人表皮癌A431细胞株上的抗增殖活性与阳性对照吉非替尼相当。

【关键词】 EGFR酪氨酸激酶抑制剂; 4-芳胺基喹唑啉; 3-羟基-4-吡啶酮; 多靶标; 抗肿瘤活性;

【DOI】

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This Article

ISSN:1005-0108

CN:21-1313/R

Vol 27, No. 01, Pages 1-7

February 2017

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摘要

  • 1 化合物的设计及合成路线
  • 2 合成实验
  • 3 体外抗肿瘤细胞增殖活性试验
  • 参考文献