多靶标受体酪氨酸激酶抑制剂的合成与初步活性筛选

Synthesis and preliminary evaluation of multi-target RTK inhibitors

目的以查尔酮为先导化合物,设计并合成多靶标受体酪氨酸激酶(RTKs)抑制剂。方法查尔酮骨架上引入苯甲酰胺片段,设计、合成了35个不含共轭双键的查尔酮衍生物。采用ADP-Glo方法评价化合物对表皮生长因子受体(EGFR)、血管内皮细胞生长因子受体2(VEGFR-2)、成纤维细胞生长因子受体-1(FGFR1)3种肿瘤相关受体酪氨酸激酶的抑制活性;采用噻唑蓝(MTT)方法评价化合物对乳腺癌细胞(MCF-7)、非小细胞肺癌细胞(A549)、白血病细胞(K562)的细胞增殖抑制活性。结果大部分目标化合物具有较好的受体酪氨酸激酶抑制活性和抗肿瘤活性,部分化合物的活性接近阳性对照的水平。结论新型查尔酮衍生物具潜在抗肿瘤活性,为抗肿瘤药物的发现奠定了基础。

Objective To design and synthesize novel multi-target receptor tyrosine kinase(RTK)inhibitors with chalcone as lead compound.Methods 35 chalcone derivatives were synthesized and their structures were confirmed.All the title compounds were evaluated for their enzymatic inhibition against EGFR,KDR and FGFR1 using ADP-Glo assays.The anti-proliferative activity against MCF-7,A549,and K562 were identified by using MTT.Results Most of the title compounds exhibited potent multiple RTK inhibition and anti-proliferative activities,which was comparable to that of the positive control.Conclusion Initial studies provide a first generation of chalcone-based multi-target RTK inhibitors as anticancer agents,and are worth of further investigation.