新型酪氨酸激酶抑制剂的合成及其活性评价

Synthesis and activity evaluation of novel tyrosine kinase inhibitors

目的以L029为先导化合物,设计合成具有蛋白酪氨酸激酶(PTK)抑制活性的化合物。方法以L029为原料,通过还原和(或)在其活泼H等位点接入侧链3-二甲基氨基-1-丙烷、乙酸甲酯、丙酸甲酯等基团,设计合成了一系列L029衍生物,并用酶联免疫吸附法(ELISA)测定其PTK活性,计算抑制率。结果成功合成5个目标化合物,结构经1H NMR和MS确证。其中3个化合物T2、T3、T5具有较强的PTK抑制活性。结论本文研究的目标化合物合成路线方法简单,反应条件温和,3个目标化合物具有较强PTK抑制活性,为进一步开展此类分子的设计合成提供了参考。

Objective To design and synthesize compounds with protein tyrosine kinase（PTK）inhibitory activity with L029 as the lead compound. Methods L029 derivatives were designed and synthesized from L029 by reduction and/or substitution with the3-dimethylamino-1-propyl,methyl acetate,methyl propionate in its active H and other sites. PTK activity was measured by enzymelinked immunosorbent assay（ELISA）. The inhibitory rate was calculated to screen out the compounds with PTK inhibitory activity. Results Five target compounds were synthesized and their structures were confirmed by1 H NMR and MS. Three compounds T2,T3 and T5 were screened out with strong PTK inhibitory activity. Conclusion The synthetic routes of the target compounds are simple with mild reaction condition,and 3 compounds show strong inhibitory activity by ELISA. These results can provide reference for the further design and synthesis of this kind of molecules.