新型含缩氨基硫脲结构的喹唑啉衍生物的合成及体外抗癌活性

Synthesis and In vitro Anticancer Activity of Novel Quinazoline Derivatives Containing Thiosemicarbazone Structure

以4,5-二甲氧基-2-氨基苯甲酸和醋酸甲脒为原料,经环化、氯化、胺化和缩合反应,合成了15个新的喹唑啉哌嗪缩氨基硫脲衍生物,其结构经1H NMR,13C NMR,HRMS及元素分析确认.采用MTT法测试了化合物6a^6o对表皮生长因子受体(EGFR)过度表达的人乳腺癌MCF-7、人肺癌A549和人前列腺癌PC3的体外抗癌活性.结果表明,部分化合物表现出较强的抗癌活性,其中,化合物6a和6o对3种癌细胞的抗癌活性优于对照药拉帕替尼(Lapatinib),略低于对照药阿霉素(ADM).化合物6a和6o对MCF-7的IC50值分别为6.97和6.99μmol/L,对A549的IC50值分别为5.15和3.11μmol/L,而对PC3的IC50值分别为2.30和1.42μmol/L.本文还初步探讨了化合物结构与抗癌活性之间的关系.

To find new EGFR inhibitors, 15 novel quinazoline derivatives containing thiosemicarbazone struc-ture were designed and synthesized from 2-amino-4 ,5-dimethoxybenzoic acid and formamidine acetate by the cyclization, chlorination, amination and condensation reactions. All structures of target compounds were con-firmed by 1 H NMR,13 C NMR, HRMS and elemental analysis. The in vitro anticancer activities of compounds 6a—6o against EGFR over-expressing of MCF-7（Human breast cancer）, A549（Human pulmonary adenocar-cinoma） and PC3（Human prostate cancer） cell lines were tested using colorimetric MTT assay. The results indicated that several compounds showed potent activity. Compounds 6a and 6o were more potent than Lapa-tinib, but slightly weaker than ADM against the three cell lines. The IC50 values of compounds 6a and 6o against MCF-7 cell line were 6. 97 and 6. 99 μmol/L, against A549 were 5. 15 and 3. 11 μmol/L and against PC3 were 2. 30 and 1. 42μmol/L, respectively. Preliminary structure-activity relationship was also discussed.