3-芳基-5-吡唑基-1,2,4-噁二唑类HIF-1抑制剂的结构优化与构效关系研究

Structural Modification and SAR Study of 3-Aryl-5-pyrazol-1,2,4-oxadiazole Derivatives as HIF-1 Inhibitor

关键词:  HIF-1抑制剂  3-芳基-5-吡唑基-1,2,4-噁二唑  构效关系研究  肿瘤转移

Key words:  HIF-1 inhibitor  3-aryl-5-pyrazol-1,2,4-oxadiazole  SAR study  tumor metastasis

摘要:

目的 对3-芳基-5-吡唑基-1，2，4-噁二唑类HIF-1抑制剂进行结构优化。方法 以3-芳基-5-对氯苄基吡唑基-1，2，4-噁二唑化合物8 为先导，对连接链和苯环取代基进行系统改造，获得全新结构的目标分子，并测定HIF-1抑制活性。结果 所设计的18个新化合物均显示出中等到强的HIF-1抑制活性，其中化合物11m 活性最强，IC₅₀达到0.35 μmol·L^–1，其作用机制为抑制HIF-1α蛋白表达，划痕试验显示其能够显著抑制SKOV3细胞的侵袭和迁移。结论 3-芳基-5-吡唑基-1，2，4-噁二唑类的构效关系研究为后续HIF-1抑制剂研发提供了较为扎实的基础。

Abstract:

OBJECTIVE To design, synthesis and biological evaluation of a series of 3-aryl-5-pyrazol-1,2,4-oxadiazole compounds as HIF-1 inhibitor.METHODS Through systematic modification on the linker and the substituents of phenyl ring, a series of novel target compounds were designed and evaluated HIF-1 inhibitory activity based on 3-aryl-5-para-Cl-benzyl- pyrazole-1,2,4-oxadiazole derivative 8.RESULTS Eighteen compounds exhibited moderate to good HIF-1 inhibitory activity and compound 11m was the most potent HIF-1 inhibitor with IC₅₀ value of 0.35 μmol·L^–1.Further biological evaluation of 11m revealed that it could inhibit HIF-1α protein expression and significantly prevented SKOV3 cells hypoxia-driven migration.CONCLUSION The SAR study of 3-aryl-5-pyrazol-1,2,4-oxadiazole derivatives as HIF-1 inhibitor pave the way for the further development of HIF-1 inhibitor.