Abstract: Aiming to search for novel anti-lung cancer active compounds, 1,3 dipoles were obtained by decarboxylation of isatin with sarcosine, proline and thioproline respectively for the first time, and then 1,3 dipole cycloaddition reactions were carried out with 3-(1H-indol-4-yl)-1-(2-pyrimidinyl)-2-propen-1-one as the dipole philophore to obtain a total of 33 target compounds. Their structures were characterized by 1H NMR, 13C NMR and HRMS, and the relative configurations was determined by X-ray single crystal diffraction. The in vitro inhibitory activities of the target compound on cisplatin-resistant human lung adenocarcinoma cell line (A549/DDP) and human non-small cell lung cancer cell line (A549) were determined by the CCK-8. This type of compound had good inhibitory activity against both A549 and A549/DDP cells, and had high selectivity against the drug-resistant strain A549/DDP. Compound 4cj showed excellent inhibitory activity (IC50 = 0.037 ± 0.002 μmol?L-1) and selectivity against A549/DDP, which was more than 60 times that of the positive control drug cisplatin (IC50 = 2.496 ± 0.117 μmol?L-1), and could significantly block the G0/G1 phase of A549/DDP cells, induce cell apoptosis and inhibit cell migration ability, its mechanism of action may be associated with the JAK and P-gp targets. The above results indicated that compound 4cj can be used as a lead compound for further research and development into a highly efficient and selective anti-lung cancer drug.

Key words: 3-Spirooxindole; Pyrimidine, Derivatives, Antitumor activity