摘要
以N′-(2-氰基-4-碘苯基)-N,N-二甲基甲脒和靛红为起始原料,N′-(2-氰基-4-碘苯基)-N,N-二甲基甲脒先与芳胺发生Dimroth重排,再进行Suzuki偶联生成化合物4a~4c;靛红经1-位取代、3-位成腙生成化合物7a~7c;最后经化合物4a~4c和7a~7c之间的亲核加成,合成了9个新型N-取代的靛红杂合喹唑啉类化合物8a~8i。利用核磁共振、红外光谱和高分辨质谱对目标化合物进行表征,并以SW480、A431、NCI-H1975和A549人肿瘤细胞为受试细胞,采用MTT法对9个目标化合物的抗肿瘤活性进行评价。结果表明:大部分化合物均具有较强的肿瘤细胞增殖抑制作用,其中化合物8a、8b、8e、8g对4种受试细胞均具有良好的生长抑制作用,优于阳性对照拉帕替尼和吉非替尼。可见,当在喹唑啉单元4-位引入3-乙炔基苯氨基时,对肿瘤细胞的增殖抑制活性较好;当引入3-氯-4-氟苯氨基和3-氯-4-(3-氟苄氧基)苯氨基时,对肿瘤细胞的增殖抑制活性次之。当靛红单元5-位无取代基或被F取代时,对肿瘤细胞的增殖抑制活性较好;当被Cl取代时,对肿瘤细胞的增殖抑制活性较差。
Nine novel heterozygous N-substituted isatin-quinazoline compounds(8a~8i)were synthesized using N′-(2-cyano-4-iodophenyl)-N,N-dimethylformamidine and isatin as the starting materials.Dimroth rearrangement of N′-(2-cyano-4-iodophenyl)-N,N-dimethylformamidine with arylamines,and subsequently Suzuki coupling with 2-formylfuran-5-boronic acid gave compounds 4a~4c.Meanwhile,compounds 7a~7c were synthesized by the substitution and hydrazone reactions of isatin at 1-position and 3-position,respectively.Finally,nine target compounds(8a~8i)were formed through nucleophilic addition reaction of 4a~4c and 7a~7c.The chemical structures of the synthesized compounds were characterized by NMR,IR and HRMS.The antitumor activities of these compounds on human colorectal carcinoma cells SW480,human epidermoid squamous carcinoma cells A431,human non-small cell lung cancer cells NCI-H1975 and A549 were tested through MTT method in vitro.The results indicated that most of the compounds had significant inhibition effect on the growth of tumor cells.Among which,compounds 8a,8b,8e,8g showed higher inhibitory activities on the proliferation of four cell lines than the positive controls of Lapatinib and Gefitinib.It can be seen that the activity of inhibiting tumor cell proliferation was good when the 4-position of quinazoline unit was 3-ethynylphenylamino,and compounds bearing 3-chloro-4-fluorophenylamino or 3-chloro-4-(3-fluorobenzyloxy)phenylamino at the 4-position of quinazoline unit also showed relatively good activity of inhibiting tumor cell proliferation.When the 5-position of isatin unit had no substituent or was substituted by F,the activity of inhibiting tumor cell proliferation was good,but the inhibiting activity was poor when the 5-position of isatin unit was substituted by Cl.
作者
王伟
冯志娟
吕梦娇
张娅玲
侯佳威
李宝林
WANG Wei;FENG Zhijuan;LYU Mengjiao;ZHANG Yaling;HOU Jiawei;LI Baolin(School of Chemistry&Chemical Engineering,Shaanxi Normal University,Xi'an 710119,Shaanxi,China)
出处
《陕西师范大学学报(自然科学版)》
CAS
CSCD
北大核心
2024年第1期29-38,共10页
Journal of Shaanxi Normal University:Natural Science Edition
基金
国家自然科学基金(82201493)。
关键词
N-取代靛红
喹唑啉
化合物合成
抗肿瘤活性
N-substituted isatin
quinazoline
compound synthesis
antitumor activity