新型TOPK抑制剂的设计、合成及抗肿瘤活性研究

Design,Synthesis and Antitumor Activity of a Novel TOPK Inhibitor

目的将TOPK抑制剂OTS514的母核噻吩并[2,3-c]喹啉酮环替换成喹唑啉,探究含有喹唑啉的新型TOPK抑制剂的抗肿瘤细胞增殖活性。方法以OTS514作为先导化合物设计并合成一系列4-氨基喹唑啉衍生物。采用MTT法测试目标化合物对肺癌细胞(A549)和乳腺癌细胞(MDA-MB-231)的抗增殖活性。结果合成了16个未见报道的新化合物,其结构经1H NMR和高分辨MS确证。手性因子对抗肿瘤活性影响不明显,暴露的氨基能增强化合物的抗肿瘤活性。体外抗肿瘤实验表明,化合物12a-12f的活性与OTS514相当。结论新骨架的TOPK抑制剂具有和OTS514相当的抗肿瘤活性,为进一步探索含有喹唑啉药效团的TOPK抑制剂研究打下了基础。

Objective To investigate the anti-tumor cell proliferation activity of a novel TOPK inhibitor containing quinazoline,the parental thiophene[2,3-c]quinolinone ring of TOPK inhibitor OTS514 was replaced by quinazoline.Methods A series of 4-aminoquinazoline derivatives were designed and synthesized with OTS514 as the lead compound.MTT method was used to test the antiproliferative activity of the target compound on lung cancer cells(A549)and breast cancer cells(MDA-MB-231).Results Sixteen new compounds were synthesized and their structures were confirmed by 1H NMR and high-resolution MS.The effect of chiral factors on antitumor activity was not obvious,and the exposed amino group can enhance the antitumor activity of the compounds.The antitumor activity of compound 12a-12f in vitro was similar to that of OTS514.Conclusion The new skeleton TOPK inhibitor has the same antitumor activity as OTS 514,which lays a foundation for further study of TOPK inhibitors containing quinazoline pharmacophore.