AUTHOR=Wei Jinbao , Chen Jinghong , Ju Peijun , Ma Le , Chen Li , Ma Weidong , Zheng Tao , Yang Guangyi , Wang Yong-Xiang 

TITLE=Synthesis and Biological Evaluation of 4β-N-Acetylamino Substituted Podophyllotoxin Derivatives as Novel Anticancer Agents

JOURNAL=Frontiers in Chemistry

VOLUME=7

YEAR=2019

URL=https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2019.00253

DOI=10.3389/fchem.2019.00253

ISSN=2296-2646

ABSTRACT=<p>A series of novel podophyllotoxin derivatives obtained by 4β-N-acetylamino substitution at C-4 position was designed, synthesized, and evaluated for <italic>in vitro</italic> cytotoxicity against four human cancer cell lines (EC-9706, HeLA, T-24 and H460) and a normal human epidermal cell line (HaCaT). The cytotoxicity test indicated that most of the derivatives displayed potent anticancer activities. In particular, compound <bold>12h</bold> showed high activity with IC<sub>50</sub> values ranging from 1.2 to 22.8 μM, with much better cytotoxic activity than the control drug etoposide (IC<sub>50</sub>: 8.4 to 78.2 μM). Compound <bold>12j</bold> exhibited a promising cytotoxicity and selectivity profile against T24 and HaCaT cell lines with IC<sub>50</sub> values of 2.7 and 49.1 μM, respectively. Compound <bold>12g</bold> displayed potent cytotoxicity against HeLA and T24 cells with low activity against HaCaT cells. According to the results of fluorescence-activated cell sorting (FACS) analysis, <bold>12g</bold> induced cell cycle arrest in the G2/M phase accompanied by apoptosis in T24 and HeLA cells. Furthermore, the docking studies showed possible interactions between human DNA topoisomerase IIα and 12g. These results suggest that <bold>12g</bold> merits further optimization and development as a new podophyllotoxin-derived lead compound.</p>