新型鬼臼毒素拼接抗肿瘤活性分子衍生物的合成及抗肺癌活性研究

Synthesis and Antiproliferation Activities of New Podophyllotoxin Spliced Antitumor Active Molecule Derivatives on Lung Cancer

研究新型鬼臼毒素拼接抗肿瘤活性分子衍生物的抗肺癌活性及其机制。以鬼臼毒素为原料,丁二酰基为linker,分别与奎宁、喜树碱、1-Boc-3-羟甲基-2-甲基吲哚反应得到3个目标化合物,采用MTT法评价其对人肺腺癌耐顺铂细胞株(A549/DDP)、人非小细胞肺癌细胞株(A549)的抗增殖活性;不同浓度的新型鬼臼毒素拼接抗肿瘤活性分子衍生物2a作用于A549/DDP细胞后,PI染色法检测细胞周期,DAPI染色法检测细胞核状态,Annexin V-FITC/PI双染法检测细胞凋亡,细胞划痕实验检测细胞的迁移能力。对A549细胞、A549/DDP细胞具有非常好的细胞毒性,均明显优于阳性对照药(依托泊苷、顺铂),其中化合物2a对A549/DDP细胞的细胞毒性是依托泊苷的80多倍,具有很好的抗耐药作用,显著的阻滞A549/DDP细胞周期的G_(0)/G_(1)期,诱导其发生凋亡,抑制迁移能力,且与剂量呈正相关。

This study was performed to investigate the inhibitory effects of new podophyllotoxin spliced antitumor active molecule derivatives on lung cancer cells and its mechanism.Using podophyllotoxin as raw material and succinic acyl group as linker,three target compounds were obtained by reacting with quinine,camptothecin,and 1-Boc-3-hydroxymethyl-2-methylindole,respectively.Its antiproliferative activity in vitro against cisplatin-resistant human lung adenocarcinoma cells(A549/DDP)and human non-small cell lung cancer cells(A549)was evaluated using the MTT method.After A549/DDP cells were treated with new podophyllotoxin spliced antitumor active molecule derivative 2a at different concentrations,the cell cycle,nuclear state,apoptosis,and migration ability of cells were individually detected by PI staining,DAPI staining,Annexin V-FITC/PI double staining,and cell scratch assays.Three target compounds showed very high cytotoxicity against A549 cells and A549/DDP cells,which were significantly better than the positive control drugs(etoposide and cisplatin).Among them,the cytotoxicity of compound 2a against A549/DDP cells was more than 80 times that of etoposide,with superior anti-drug resistance.Compound 2a significantly blocked the G_(0)/G_(1)phase of A549/DDP cells,induced their apoptosis,and inhibited their migration abilities.These influences were positively correlated with the doses of compound 2a.