含芳氧吡啶酮结构片段的噻唑啉酮脲衍生物的设计、合成及抗肿瘤活性研究

Design, synthesis and study of anti-tumor activity of thiazolinone urea derivatives bearing aryloxypyridinone fragments

摘要: 本文以cabozantinib为先导物，基于已有的c-Met激酶抑制剂的构效关系，设计并合成了13个结构新颖的小分子抑制剂，其结构经¹H NMR、¹³C NMR和HR-MS确证。采用MTT法对所合成的化合物进行了体外抗肿瘤活性测试，采用实时动态活细胞成像法和流式细胞术对体外抗肿瘤作用机制进行了初步研究。结果表明，所设计的大多数化合物对人非小细胞肺癌细胞A549和人结直肠癌细胞HT-29有较好的抑制作用，活性优于cabozantinib；化合物对HT-29细胞除具有明显的杀伤作用外，还可抑制其增殖，促进细胞凋亡。

Abstract: Taking cabozantinib as leading compound, 13 novel small molecular c-Met inhibitors were designed and synthesized based on the obtained structure-activity relationships (SARs) of c-Met inhibitors. The structures of compounds were confirmed by ¹H NMR, ¹³C NMR and HR-MS. In vitro anti-tumor activity was evaluated by MTT method, and the mechanism was preliminarily disclosed by real-time dynamic living cell imaging and flow cytometry analysis. The results indicated that most of compounds showed good inhibition activity against human non-small-cell carcinoma cell A549 and human colorectal cancer cell HT-29 which was superior to cabozantinb. Compounds showed excellent cytotoxity and anti-proliferative activity against HT-29, and promoted cell apoptosis.