Design, Synthesis And Antitumor Activity Of 4, 5-disubstituted Pyrido[4,3-d]pyrimidine Compound

Tumours pose a serious threat to human health,with rates of morbidity and mortality continuing to rise.Abnormalities in kinase signaling pathways are often thought to be closely related to some of the characteristic features of malignancies,and kinases have become one of the hottest targets in anti-tumour drug research in recent years.Researchers have identified a large number of small molecule kinase inhibitors with different backbone structures and pharmacodynamic activities,and dozens of small molecule kinase inhibitors have been used for tumour treatment,but there is a general problem of drug resistance and toxic side effects,so there is an urgent need to develop new anti-tumour drugs.Pharmacological studies have shown that pyridoxymidine thickening heterocycles have a wide range of pharmacological activities and have great potential in the field of anti-tumour research.Combined with the results of present-day studies on the activity of pyrido[4,3-d]pyrimidines,a series of pyrido[4,3-d]pyrimidine derivatives were designed and synthesized using pyrido[4,3-d]pyrimidines as the parent nucleus,which were tested for in vitro anti-tumour activity in the hope of obtaining target compounds with good anti-tumour activity.The target compounds were analyzed by inverse synthesis and 31structurally novel pyrido[4,3-d]pyrimidine analogues were obtained by designing synthetic routes using malononitrile as the starting material for three synthetic routes and undergoing addition,cyclization,substitution,addition and Suzuki coupling reactions.The structures of the target compounds were confirmed by ¹H NMR,¹³C NMR,and HRMS.The anti-tumour activity of the 31 synthesized compounds was determined by MTT using human lung cancer cells A549,human colon cancer cells HCT-116 and human breast cancer cells MCF-7 as test cell lines and the broad-spectrum anti-cancer drugs paclitaxel and 5-fluorouracil as positive controls.The results showed that most of the compounds had some inhibitory effect on all three types of cancer cells,with the IC₅₀ values of 25.56μM and 23.52μM for compound C1 against HCT-116 and MCF-7 respectively.Preliminary conformational relations indicate that the long chains of the4-position aliphatic amines favor activity enhancement.When the substituents are electron-absorbing groups,the substituents in the 4-site substituted aromatic amines are more active than the donor group.The substitution in the 6-position aliphatic long chain is more favorable to enhance the suppression rate of the target compound.This study laid a foundation for the development of pyridine[4,3-d]pyrimidine compounds.