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

Design,synthesis and antiproliferative activity evaluation of EGFR inhibitors containing 3-hydroxy-4-pyridinone fragment

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HeLa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、MS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。

The development of multi-targeted tyrosine kinase inhibitors is of great significance for anti-cancer therapy. EGFR signaling pathway plays a crucial role in the apoptosis, proliferation, differentiation, migration and cell cycle of cancer ceils. Meanwhile, Fe chelators are effective antitumor agents. By incorporating 3-hy- droxy-4-pyridinone fragment（ a Fe chelator motif） into the conventional quinazoline scaffold of the epider- mal growth factor receptor （EGFR） inhibitors, 12 compounds which may target multiple drug targets were synthesized. The general procedure for the synthesis of target compounds was described and all of them were characterized by 1H-NMR, MS and melting point. In the tumor cell lines tested, most of the compounds exhibit efficient antiproliferative activity on the human epidermal carcinoma cell A431 （ with EGFR overex- pression） and HeLa, albeit a moderate inhibition in gefitinib-resistant NSCLC cell H1975 （bearing EGFR[L858R/T790M]）.