| Cancer is the leading cause of human death.At present,the main methods for treating cancer include surgical resection,cytotoxic chemotherapy,targeted therapy,radiotherapy,endocrine therapy and immunotherapy.Many classic chemotherapeutic drugs have high toxicity to human normal cells,and there is an urgent need to develop new antitumor drugs with better activity and selectivity.Compounds containing quinazolinone structure have a wide range of pharmacological activities in anti-tumor,anti-bacterial,anti-malarial,anti-inflammatory,anticonvulsant and other aspects.Many studies have found that there are many targets of quinazolinone compounds in vivo.It has good anti-tumor activity and human tolerance,and has broad medicinal development prospects.In recent years,cancer treatment strategies targeting mitochondria have received extensive attention.The most effective way to specifically deliver drugs to mitochondria is to covalently connect lipophilic cations with target pharmacophores.Due to the negative membrane potential of the mitochondrial inner membrane,positively charged compounds can accumulate in the mitochondrial matrix in a reverse concentration gradient.Triphenylphosphine cations have strong mitochondrial targeting ability,which can cross the cell membrane and drive the pharmacophore to accumulate in the mitochondria of the cells.Therefore,quinazolinone was selected as the parent compound in this paper,and its structure was modified by introducing triphenylphosphine in order to obtain compounds with better antitumor activity.The research work of this paper mainly includes the following parts:The first part introduces the background,basis and design ideas of the topic,including the antitumor activity of quinazolinone derivatives as tyrosine kinase inhibitors,cancer treatment strategies targeting mitochondrial membrane potential,and methods of compounds targeting mitochondria.In the second part,the structural modification of quinazolinone was introduced.A series of triphenylphosphine-quinazolinone derivatives were designed and synthesized.By changing the connection site of triphenylphosphine and the length of the connection chain,a total of 30 target compounds were synthesized.In the third part,the inhibitory effects of the target compounds on the growth of tumor cells were studied.The inhibitory effects of the compounds on the growth of human breast cancer cells MCF-7,human hepatoma cells HepG2,human non-small cell lung cancer cells A549 and normal liver cells QSG-7701 were tested by MTT method,and the structure-activity relationship of the target compounds was discussed.In the fourth part,the compounds with the best antitumor activity were selected for molecular docking,and their binding modes with EGFR and VEGFR-2 receptor tyrosine kinases were predicted.The fifth part summarizes the full text,clarifies the innovation of this paper and prospects. |
