N-苯基-4-三氟甲基-2-氨基喹唑啉衍生物的合成及抗肿瘤活性研究

Synthesis and Antitumor Activity of N-Phenyl-4-(Trifluoromethyl)-Quinazoline-2-Amine Derivatives

目的发现新型高效低毒的2-芳氨基喹唑啉类抗肿瘤目标化合物。方法以邻硝基苯甲醛和6-硝基藜芦醛为原料,通过亲核加成、氧化、还原、环合、氯代、偶联等反应,合成了16个N-苯基-4-三氟甲基-2-氨基喹唑啉衍生物,并通过核磁共振(NMR)和质谱(MS)对其进行结构表征;采用噻唑蓝(MTT)法评价了目标化合物对前列腺癌细胞(PC3、LNCaP)、人慢性髓系白血病细胞(K562)和宫颈癌细胞(HeLa)4种肿瘤细胞株的生长抑制活性,并对高活性化合物8b作了靶点预测。结果活性测试结果显示,化合物8b和8c都显示出良好的抗增殖活性,特别是化合物8b,对PC3、LNCaP和K562细胞的半数抑制浓度(IC_(50))分别为5.51、4.51和8.49μmol·L^(-1);分子对接结果显示,莫洛尼小鼠白血病病毒前病毒整合激酶1(provirus integration in maloney murine leukemia virus kinase-1,PIM-1)蛋白可能是8b的潜在作用靶点。结论含哌嗪结构的芳氨基喹唑啉化合物8b值得深入研究。

OBJECTIVE To find new arylaminoquinazoline-based antitumor target compounds with high efficacy and low toxicity.METHODS A series of N-phenyl-4-(trifluoromethyl)quinazoline-2-amine derivatives were synthesized starting from 2-nitrobenzaldehyde or 6-nitroveratraldehyde by a combination of nucleophilic addition,oxidation,reduction,cyclization,chlorination,and coupling reactions.The structures of the target compounds were characterized using NMR and MS.Their antitumor activities in vitro were then evaluated against four human cancer cell lines(PC3,LNCaP,K562,and HeLa)using MTT assay.The target prediction of active compound 8b was performed.RESULTS Compounds 8b and 8c exhibited promising anti-proliferative properties,particularly compound 8b,which exhibited excellent antitumor activity against PC3,LNCaP,and K562 with IC_(50)values of 5.51,4.51 and 8.49μmol·L~(-1),respectively.Molecular docking experiment demonstrated that PIM-1 is the potential target of 8b.CONCLUSION The piperazine ring containing compound 8b exhibits the strongest antitumor activity,which is worthy of further study.