Synthesis and evaluation of novel podophyllotoxin derivatives as potential antitumor agents.

Abstract

Cancer multidrug resistance (MDR) is a common cause of treatment failure in cancer patients. Increased expression of permeability glycoprotein (P-gp), which is also known as MDR-1, is the main cause of multidrug resistance. Podophyllotoxin derivatives hold great promise in the battle to overcome multidrug resistance, as they can induce cytotoxicity through multiple mechanisms. Here, we synthesized sixteen novel podophyllotoxin derivatives and evaluated their cytotoxicities in human cancer cell lines, HeLa, K562 and K562/A02. Some of these compounds were more potent than etoposide, a clinically relevant inhibitor of DNA repair enzymes. In particular, compound 5p exhibited the most potent activity toward drug-resistant K562/A02 cells, as it robustly inhibited tumor cell proliferation and induced apoptosis. Furthermore, preliminary investigation suggested that 5p inhibited the expression of MDR-1 in K562/A02 cells more effectively than etoposide.

• Authors: Wei-Hua Cheng, Bo Cao, Hai Shang, Cong Niu, Li-Ming Zhang, Zhong-Heng Zhang, Dan-Li Tian, Shi Zhang, Hong Chen, Zhong-Mei Zou
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 85 Pg. 498-507 (Oct 06 2014) ISSN: 1768-3254 [Electronic] France
• PMID: 25113878 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antineoplastic Agents
• RNA, Messenger
• Podophyllotoxin

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (genetics)
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Apoptosis (drug effects)
• Cell Proliferation (drug effects)
• Chemistry Techniques, Synthetic
• Drug Resistance, Multiple (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• HeLa Cells
• Humans
• K562 Cells
• Podophyllotoxin (analogs & derivatives, chemical synthesis, pharmacology)
• RNA, Messenger (genetics, metabolism)