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

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

doi:10.3389/fchem.2019.00253

Abstract

A series of novel podophyllotoxin derivatives obtained by 4β-N-acetylamino substitution at C-4 position was designed, synthesized, and evaluated for in vitro 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 12h showed high activity with IC50 values ranging from 1.2 to 22.8 μM, with much better cytotoxic activity than the control drug etoposide (IC50: 8.4 to 78.2 μM). Compound 12j exhibited a promising cytotoxicity and selectivity profile against T24 and HaCaT cell lines with IC50 values of 2.7 and 49.1 μM, respectively. Compound 12g 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, 12g 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 12g merits further optimization and development as a new podophyllotoxin-derived lead compound.

Highlights

Cancer has become one of the most serious threats to public health across the globe, and it is considered the leading cause of death in developed countries and the second leading cause of death in developing countries (Jemal, 2011)
Aiming to find novel PPT derivatives with high efficiency and low toxicity, researchers carried out a series of structural modifications with podophyllin ingredients and obtained three potent semisynthetic glucoconjugates based on 4′-demethylpodophyllotoxin (DPPT, 2), including etoposide (3), teniposide (4), and a water-soluble prodrug of etoposide, named etopophos (Figure 1) (Keller-Juslen et al, 1971; Greco and Hainsworth, 1996; Damayanthi and Lown, 1998; Hande, 1998)
This paper reported the design and synthesis of a series of PPT/DPPT-derived derivatives with the C-4 position of PPT/DPPT coupling 4β-N-acetylamino side chains which contained different types of substituted aliphatic hydrocarbons or aromatic hydrocarbons

Summary

Introduction

Cancer has become one of the most serious threats to public health across the globe, and it is considered the leading cause of death in developed countries and the second leading cause of death in developing countries (Jemal, 2011).

Results

Conclusion