Synthesis and antitumor activities of 4-(1H-indol-1-yl)-4-oxobutanoic acid spliced podophyllotoxin derivatives

To investigate the effects and mechanisms of 4-(1H-indol-1-yl)-4-oxobutanoic acid spliced podophyllotoxin derivatives (3a-3l) on tumor cells. The MTT method was adopted to evaluate (3a-3l) antitumor activity in vitro against A549 cells, A549/DDP cells, MCF-7 cells. The results showed that compound 3l had the most prominent inhibitory effect and high selectivity with IC50 18.53 +/- 1.51 mu M against A549/DDP cells. Meanwhile, the effects of compound 3l on the nuclear state, cell cycle and apoptosis of A549/DDP cells showed that compound 3l induced apoptosis by delaying the G(2)/M phase of A549/DDP cell cycle. In addition, molecular docking of compound 3l also showed that it could form a good hydrogen bond with ARG-158 (d = 2.6, 2.7 angstrom) and HIS-406 (d = 2.5 angstrom) at the colchicine site of tubulin. Compound 3l could provide lead compound for the development of new multi-drug resistant anti-tumor drugs.

Automated summary

This study investigated the effects and mechanisms of 4-(1H-indol-1-yl)-4-oxobutanoic acid spliced podophyllotoxin derivatives (3a-3l) on tumor cells. The antitumor activity of (3a-3l) against A549 cells, A549/DDP cells, and MCF-7 cells was evaluated using the MTT method. The results showed that compound 3l had the most inhibitory effect and selectivity against A549/DDP cells, suggesting it could be a lead compound for developing new multi-drug resistant anti-tumor drugs.