Synthesis Of Acetylenic Phenol Analogs And Inhibitory Study Of HIF-1 Activity

Selaginellins,a class of compounds containing unique structures of ethynyl phenol and methylene quinone,are isolated from Selaginella sinensis or Selaginella pulvinata.The research on such compounds has also developed from extraction and separation to total synthesis and the discovery of its potential biological activity.It has been reported that such compounds have multiple activities including antioxidant,neuroprotective,antibacterial and antiviral,PTP1B inhibitory activities and anti-tumor effects.Its wide range of pharmacological activities aroused our interest.During the total synthesis of Selaginellin A,we found that compound 1a with a biphenyl diaryl acetylene structure showed strong hypoxia-inducible factor-1 inhibitory activity and lower cytotoxicity..On this basis,this topic took 1a as the lead compound,used Suzuki coupling and Sonogashira coupling to construct the main skeleton,designed and synthesized 33 analogues and discussed the structure-activity relationship.All the obtained analogues have no obvious cytotoxicity.The HIF-1 inhibitory activity was detected by the dual luciferase reporter gene detection system,and the results showed that compound 9i has the strongest HIF-1 inhibitory activity(IC₅₀=1.5±0.03μM).After verification in vitro by Wound-Healing assay,invasion assay,tubule formation assay,clone formation assay,etc.,the results show that compound 9i can inhibit the migration,invasion and proliferation of Hela cells induced by hypoxia.Western blot experiments and q PT-PCR experiments show that 9i has no effect on HIF-1?protein expression in Hela cells under hypoxic conditions,but it can significantly reduce HIF-1 downstream related target genes—VEGF m RNA expression.In the mouse orthotopic breast cancer model,9i（15 mg/kg）shows a certain ability to inhibit tumor growth,and has no effect on the body weight of mice,and has no acute toxicity to multiple organs,indicating that 9i is almost non-toxic in mice and is expected to be developed into a new type of HIF-1 inhibitor.