Synthesis And Activity Determination Of 2-(1H)-quinolinonecarboxylic Acid Derivatives

Malignant tumors are the uncontrollable growth of cancer cells,which also migrate to different parts of the body.Molecular targeted therapy has many advantages,such as strong specificity,obvious therapeutic effect and less normal tissue damage,therefore,it is a new means to achieve precise treatment of tumors.Starting from targeted therapy,the classification of anti-tumor targeted drugs was briefly reviewed.The existing drugs with imidazo[1,2-a]pyridine or 2-?1H?-quinolone as mother nuclei were listed,and their research progress in anti-tumor target inhibitors were summarized.Based on the principle of splicing in computer aided drug design?CADD?,a series of potential antineoplastic compounds with 2-?1H?-quinolone and imidazo[1,2-a]pyridine as mother nuclei were designed.In this paper,three kinds of intermediates and target compounds were synthesized,the cytotoxicity of target compounds was determined,and the targets of target compounds were predicted by virtual screening.?1?Synthesis of 2-?1H?-quinolinone-4-carboxylic acid derivatives:2-?1H?-quinolinone-4-formic acid derivatives were synthesized from indigo,malonic acid and anhydrous sodium acetate by three steps of ring opening,carbonization and cyclization.The reaction ratio of each reactant and the influence of reaction time on the yield were optimized,and the optimal reaction conditions were determined.?2?Synthesis of 2-substituted imidazo[1,2-a]pyridine-8-methanol compounds:firstly,starting from the starting material 2-aminonicotinic acid,it was converted into methyl 2-aminonicotinate,which was then reduced to 2-amino-3-pyridinemethanol under the catalysis of LiAlH₄.And it was combined with the?-bromoacetophenone derivative,six imidazo[1,2-a]pyridine-8-methanol intermediates were synthesized.We optimized for the reaction to achieve optimum reaction conditions.?3?Synthesisof2-phenylimidazo[1,2-a]pyridin-3-aminederivatives:3-Amino-2-phenylimidazo[1,2-a]pyridine derivatives were synthesized by one-pot method using 2-aminopyridine,benzaldehyde and nitromethane as raw materials and cuprous bromide as catalyst.The synthesized 2-phenylimidazo[1,2-a]pyridine-3-aminoderivativeswerereducedwithhydrazinehydratetogive3-amino-2-phenylimidazo[1,2-a]pyridine derivative.?4?Synthesis of target compounds:Esterification reaction between2-?1H?-quinolinone-4-carboxylic acid and imidazo[1,2-a]pyridine-8-methanol in DMF using DCC and DMAP as dehydrating agent and catalyst,finally obtained four target compounds not reported.?5?Activity assay and research on virtual screening:Inhibitory activities of four target compounds on human hepatocellular carcinoma cell line Hep G2 were determined,and their targets were predicted by virtual screening study.