The Synthesis Of Novel Based Piperazine Benzamide Derivatives And Study On Cycle Proliferation Inhibition In Glioma

Purpose:Glioma is one of the most common primary brain tumors,accounting for approximately 30%of primary CNS tumors and 80%of primary malignant tumors of the CNS.Glioma is also one of the most deadly cancers in human beings,with poor patient prognosis and difficult treatment.Glioblastoma（GBM）,the most malignant,has a median survival of 12 to 15 months at best,despite current aggressive surgery,radiation,and chemotherapy,so in most cases,patients with this malignancy do not benefit from this treatment that includes symptom control and cytoreduction.Chemotherapy is recognized as one of the important postoperative adjuvant therapy strategies,but the presence of high drug resistance and the blood-brain barrier greatly reduces drug efficacy.Recently,the deep insights of the pathogenesis of cancer have led to the rapid development of drug therapies,compared to the limited improvements and advances in surgery and radiotherapy.therefore,our efforts were focused on looking for new and effective drugs,especially from the perspective of improving blood-brain barrier permeability,increasing drug availability and reducing concomitant toxicity.Methods:Twenty-six novel piperazine based benzamide derivatives were designed and synthesized,and the anti-proliferative and migratory effects of target compound 22on malignant glioma cells and cell cycle arrest were determined.Then in vivo toxicity,blood-brain barrier permeability and anti-GBM activity of compound 22 were evaluated in animal experiments and in vivo tumor models.Results:The target compound 22 exhibited good anti-glioma activity in vitro,with IC₅₀ values of 0.15μM,0.29μM and 1.28μM for GBM C6,U87 MG and U251 cells,respectively,In specific in vitro activity assay experiments,it well inhibited the proliferation,migration and invasion of GBM cell lines,induced apoptosis and cell cycle G0/G1 phase arrest,and showed good ability to fight against glioma by down-regulating the protein expression of pRB,cyclin D1,and CDK4/6.In addition,animal experiments showed lower toxicity to temozolomide at the same dose and a cerebral plasma ratio of 1.07,suggesting that compound 22 is a promising candidate for glioma treatment.