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

Abstract

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 µM 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 G₂/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 Å) and HIS-406 (d = 2.5 Å) at the colchicine site of tubulin. Compound 3l could provide lead compound for the development of new multi-drug resistant anti-tumor drugs.

GRAPHICAL ABSTRACT

Keywords:

• Podophyllotoxin
• derivatives
• antitumor activity

Additional information

Funding

This work was supported by the [Guizhou Provincial Natural Science Foundation of China #1] under Grant [number [2020]1Y397]； [Science and Technology Project of Zunyi City #2] under Grant [number Zun Shi Ke He She Zi[2019] 210].