Design,Synthesis And Anti-tumor Activity Of Small Molecular Compounds Based On Targets

Excessive ROS can causes apoptosis of cancer cells.Piperlongumine have been demonstrate that it selectively increases ROS in tumor cells,inhibits proliferation,invasion and migration.High levels of nitric oxide?NO?can induce apoptosis and inhibit angiogenesis and metastasis of tumor cells.Furoxan,as a nitric oxide donor,has been widely used in the design and synthesis of anticancer drugs.Furoxan and Piperlongumine show a synergistic inhibitory effect on tumor cells.We take the advantages of hybridization strategy in drug design,hybrids Piperlongumine with furoxan and conducting structure-activity relationship?SAR?studies.Finally,24compoundswere designed,synthesized and evaluated against the HCT-116 cell lines.Most derivatives displayed potent antiproliferation activities.Among them,21d exhibited the strongest antiproliferation activity on the HCT-116 cell lines with IC₅₀values to 89 n M.These results also provide a new direction for the further study of Piperlongumine and furoxan compounds.The extracellular signal-regulated kinase?ERK?/ mitogenactivated protein kinase?MAPK?pathway plays a central role in the regulation of critical cellular processes.Activation of RAS leads to the recruitment and activation of RAF,a serine-threonine kinase.Activated RAF phosphorylates and activates MEK1/2,which then phosphorylates and activates ERK1/2.When activated,ERK1/2 phosphorylates several downstream targets involved in a multitude of cellular events including cytoskeletal changes and transcriptional activation.The ERK/MAPK pathway is activated in more than 30% of human cancers,most frequently via RAS and BRAF mutations,and thus has attracted significant interest as a therapeutic target for cancer.12 urea compounds17a–f and 18a–f contains morpholin rings were designed and synthesized in search of novel ERK inhibitors by using merging strategy.The structures of all compounds were confirmed by 1H NMR,13 C NMR and HRMS,meanwhile,the antitumor activities were evaluated at the cell level as well as kinase level.The results demonstrated that most compounds have moderate proliferation inhibition efficacy against human colorectal cancer cells SW480 and HCT-116,especially the IC50 of compound 18 f reaches 0.55?M and 0.36 ?M,respectively,and has low toxicity to normal cells L02?> 10?M?.At the kinase level,the IC50 of 18 f reached 51 n M.These research provides important reference for the further study of novel benzylpyridylurea ERK inhibitors.