Fluoride-containing podophyllum derivatives exhibit antitumor activities through enhancing mitochondrial apoptosis pathway by increasing the expression of caspase-9 in HeLa cells.

Wei Zhao,Tao Chen,Xin-Hua Liang,Hong-Mei Li,Ya-Ling Tang,Chen Zhou,Ya-Jie Tang,Ya-Xuan Zhang,Yong Yang

doi:10.1038/srep17175

Wei Zhao, Tao Chen + Show 7 more

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https://doi.org/10.1038/srep17175

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Abstract

This work aims to provide sampling of halogen-containing aniline podophyllum derivatives and their mode of action with an in-depth comparison among fluorine, chloride and bromide for clarifying the important role and impact of fluorine substitution on enhancing antitumor activity, with an emphasis on the development of drug rational design for antitumor drug. The tumor cytotoxicity of fluoride-containing aniline podophyllum derivatives were in general improved by 10–100 times than those of the chloride and bromide-containing aniline podophyllum derivatives since fluoride could not only strongly solvated in protic solvents but also forms tight ion pairs in most aprotic solvents. When compared with chloride and bromide, the higher electronegativity fluoride substituted derivatives significantly enhanced mitochondrial apoptosis pathway by remarkably increasing the expression of caspase-9 in HeLa cells. The current findings would stimulate an enormous amount of research directed toward exploiting novel leading compounds based on podophyllum derivatives, especially for the fluoride-substituted structures with promising antitumor activity.

Highlights

Its derivative 4′ -demethylepipodophyllotoxin (DMEP, 1′) are lignans of aryltetralin family found in the plants of podophyllum genus, exhibiting anti-tumor activity[1]
For systematically comparing the effect of halogen (i.e., F, Cl, Br) on the antitumor activity of podophyllum derivatives and determining their precise apoptosis mechanism, a series of halogen-containing aniline podophyllum derivatives based on the structure of the target protein tubulin and topoisomerase II (Topo II) were designed
The results show that the Topo II inhibition activity of compounds 17′, 18′, and 19′ has regularity: as in the case of 17′, such higher electronegativity of haloid could further enhance Topo II inhibition activities of aniline-substituted 4′ -demethylepipodophyllotoxin derivatives

Summary

Introduction

Its derivative 4′ -demethylepipodophyllotoxin (DMEP, 1′) are lignans of aryltetralin family found in the plants of podophyllum genus, exhibiting anti-tumor activity[1]. By taking podophyllum compounds (1 and 1′) as model structures, the research is aiming to systematically investigate the effect of halogen atoms (i.e., F, Cl, Br) on the antitumor activity of podophyllum derivatives and identify their preliminary mechanism of apoptosis induction. These results would provide the determinants of tubulin and Topo II binding affinity for this important class of anti-tumor agents and pave the way for further rational structural modification

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