Synthesis And Antitumor Activity Of 4H-pyrido[1,2-a]pyrimidin-4-one Derivative

Objective:Our group found that quinazolinone 12d has good anti-proliferation activity.In order to clarify the effects of the properties of its key pharmacophores and substituents on the target inhibitory activity and anti-proliferation activity of compound 12d,this project intends to design and synthesize three types of4H-pyridino[1,2-a]pyrimidin-4-one compounds by conducting skeleton transitions and introducing different substituents to their quinazolinone and imidazopyridine fragments,and to preliminarily evaluate their anti-proliferation activity in vitro.The best active compound 10b was selected and target inhibition activity studies were carried out to investigate the effect of the above structural modifications on the anti-tumor activity of the lead compounds.Methods:1.Through inverse synthesis analysis of the target compound,a synthesis route was designed:the mother nucleus structure 4H-pyridino[1,2-a]pyrimidin-4-one was obtained through ring synthesis,and then coupled with related groups such as benzimidazole to obtain different series of intermediate products,which were structurally modified to obtain derivatives.2.The molecular structures of all compounds were characterized and confirmed with the help of HR-MS,¹H-NMR,¹³C-NMR and other spectral data.NMR and other spectral data were characterized and confirmed.3.The in vitro anti-proliferation activity of the compounds against different lung cancer cells was tested by MTT method,and the IC₅₀values were calculated.4.The effects of the target compounds on the cycle and apoptosis of tumor cells were verified by flow cytometry and immunoblotting.Results:Using 4H-pyridino[1,2-a]pyrimidin-4-one as the parent structure of the compound,a total of 20 derivatives were obtained and investigated for in vitro anti-tumor activity,and one active compound 10b was screened,which showed improved anti-tumor activity compared to 12d.Conclusions:The 4H-pyridino[1,2-a]pyrimidin-4-one derivatives obtained by synthesis were all new compounds.Among them,compound 10b showed the best tumor suppressive effect on human non-small cell lung adenocarcinoma cells（H1975）with an IC₅₀value of 0.572μM and induced apoptosis,and inhibited ROR1 and its downstream SRC,Akt and m TOR,suggesting that 10b could exert anti-tumor activity by inhibiting the ROR1/SRC/Akt signaling pathway.