Camptothecin derivatives induce apoptosis and inhibit proliferation of prostate cancer PC-3M cells through downregulation of PI3K/Akt signaling pathway

Abstract

• Synthesis of novel camptothecin derivatives. • All compounds showed good in vitro cytotoxicity against five tumour cell lines. • 3D-QSAR, molecular docking to explore conformational relationships. Malignant tumors are increasing the human mortality rate year by year, so there is an urgent need to develop novel and highly effective drugs. Camptothecin (CPT) is a natural medicinal product with broad-spectrum antitumor activity. In this study, 11 CPT derivatives were synthesized. Their antitumor activities were evaluated by CCK-8, morphological observation, plate cloning, scratching, DAPI staining, cell cycle, and apoptosis. The conformational relationships were also analyzed by molecular docking and 3D-QSAR. The results showed that the CPT derivatives showed significant inhibitory effects on all five tumor cell lines, A549, HepG2, MCF-7, HemECs, and PC-3M, with the best inhibitory ability against PC-3M in prostate cancer. Among all derivatives, compound 5 had the lowest IC50 value of 0.0881 μM. In addition, compound 5 regulated the downstream cascade response by inhibiting the PI3K-Akt signaling pathway, causing cycle arrest and apoptosis. The predicted results of molecular docking and 3D-QSAR were consistent with those of the experimental group. This demonstrates the anti-tumor potential of compound 5.