Comparison of carbon-sulfur and carbon-amine bond in therapeutic drug: 4β-S-aromatic heterocyclic podophyllum derivatives display antitumor activity

Jian-Long Li; Wei Zhao; Chen Zhou; Ya-Xuan Zhang; Hong-Mei Li; Ya-Ling Tang; Xin-Hua Liang; Tao Chen; Ya-Jie Tang

doi:10.1038/srep14814

Comparison of carbon-sulfur and carbon-amine bond in therapeutic drug: 4β-S-aromatic heterocyclic podophyllum derivatives display antitumor activity

Sci Rep. 2015 Oct 7:5:14814. doi: 10.1038/srep14814.

Authors

Jian-Long Li¹, Wei Zhao¹, Chen Zhou¹, Ya-Xuan Zhang¹, Hong-Mei Li¹, Ya-Ling Tang², Xin-Hua Liang², Tao Chen³, Ya-Jie Tang¹

Affiliations

¹ Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei Provincial Cooperative Innovation Center of Industrial Fermentation, Hubei University of Technology, Wuhan 430068, China.
² State Key Laboratory of Oral Diseases West China Hospital of Stomatology (Sichuan University), Chengdu Sichuan 610041,People's Republic of China.
³ Key Laboratory of Systems Bioengineering (Ministry of Education), School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China.

Abstract

Herein is a first effort to systematically study the significance of carbon-sulfur (C-S) and carbon-amine (C-NH) bonds on the antitumor proliferation activity of podophyllum derivatives and their precise mechanism of apoptosis. Compared with the derivative modified by a C-NH bond, the derivative modified by a C-S bond exhibited superior antitumor activity, the inhibition activity of target proteins tubulin or Topo II, cell cycle arrest, and apoptosis induction. Antitumor mechanistic studies showed that the death receptor and the mitochondrial apoptotic pathways were simultaneously activated by the C-S bond modified aromatic heterocyclic podophyllum derivatives with a higher cellular uptake percentage of 60-90% and induction of a higher level of reactive oxygen species (ROS). Only the mitochondrial apoptotic pathway was activated by the C-NH bond modified aromatic heterocyclic podophyllum derivatives, with a lower cellular uptake percentage of 40-50%. This study provided insight into effects of the C-S and C-NH bond modification on the improvement of the antitumor activity of Podophyllum derivatives.

Publication types

Comparative Study
Research Support, Non-U.S. Gov't

MeSH terms

Amines / chemistry
Antineoplastic Agents, Phytogenic / chemistry*
Antineoplastic Agents, Phytogenic / pharmacology
Apoptosis / drug effects
Biological Transport
Carbon / chemistry
Cell Cycle / drug effects
Cell Line
Cell Line, Tumor
DNA Topoisomerases, Type II / metabolism
Dose-Response Relationship, Drug
HeLa Cells
Hepatocytes / cytology
Hepatocytes / drug effects*
Hepatocytes / metabolism
Humans
Microtubules / drug effects
Microtubules / ultrastructure
Mitochondria / drug effects
Mitochondria / metabolism
Plant Extracts / chemistry
Podophyllotoxin / analogs & derivatives*
Podophyllotoxin / chemical synthesis
Podophyllotoxin / chemistry
Podophyllotoxin / pharmacology
Podophyllum / chemistry*
Quantitative Structure-Activity Relationship
Reactive Oxygen Species / agonists
Reactive Oxygen Species / metabolism
Sulfur / chemistry
Tubulin / metabolism

Substances

Amines
Antineoplastic Agents, Phytogenic
Plant Extracts
Reactive Oxygen Species
Tubulin
Sulfur
Carbon
DNA Topoisomerases, Type II
Podophyllotoxin
4'-demethylepipodophyllotoxin