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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。
OBJECTIVE To design and synthesize 4-arylaminoquinazoline derivatives containing 3-hydroxy-4-pyridone fragments with iron chelation function and evaluate their in vitro inhibition of tumor proliferation. Method 4-arylamino-6-nitro-7-fluoroquinazoline is substituted with 3-benzyloxypyridin-4-one fatty alcohol, followed by nitro reduction to give 4-arylamino-6-amino -7- (3-benzyloxy-4-pyridone) alkoxyquinazoline intermediates, this intermediate is condensed with various acid chlorides or acids and then benzyl is removed to obtain target compounds 1-6; 4-aryl Amino-7-alkoxyquinazoline and 3-benzyloxypyridin-4-one-1-acetic acid are debenzylated to give the target compounds 7-12. MTT assay was used to determine the inhibitory activity of the target compound on human epidermal carcinoma cell line A431, human lung adenocarcinoma cell line H1975 and human cervical cancer cell line HeLa, using gefitinib as positive control. RESULTS AND CONCLUSION Twelve new compounds were synthesized and their structures were confirmed by ~ 1H-NMR and MS spectra. The results of preliminary in vitro bioassay showed that these compounds have good anti-tumor cell proliferation activity The antiproliferative activity of compounds 1 ~ 4 and 7 ~ 10 on human epidermal carcinoma A431 cell line was comparable to the positive control gefitinib.