Synthesis and biological evaluation of NQO1-activated prodrugs of podophyllotoxin as antitumor agents.

Abstract

Podophyllotoxin (PPT), a toxic polyphenol derived from the roots of genus Podophyllum, had been reported with strong inhibition on both normal human cells and tumor cells, which hindered the development of PPT as the candidate antitumor agent. In the present work, multiple NQO1-activatable PPT prodrugs were synthesized for reducing normal cell toxicity and keeping tumor cell toxicity. The antiproliferative activities in vitro showed prodrug 3 was greatly selectively toxic to tumor cells over-expressing NQO1, taxol-resistant A549, hypoxia A549 and HepG2, and lower damage to normal cells in comparison with podophyllotoxin, prodrug 1 and 2. As elucidated by further mechanistic research, prodrug 3 was activated via NQO1 to efficiently while gently produce cytotoxic PPT units and kill tumor cells. In additions, in vivo study revealed that 3 significantly suppressed cancer growth in HepG2 xenograft models without obvious toxicity. Therefore, this NQO1-activatable prodrug delivery system exhibits good biosafety and provides a novel strategy for the development of drug delivery systems.

• Authors: Yan Qu, Chong Zhang, Xin Ma, Yunhui Gao, Jing Liu, Liqiang Wu
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 28 Issue 24 Pg. 115821 (12 15 2020) ISSN: 1464-3391 [Electronic] England
• PMID: 33091789 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Drug Carriers
• Prodrugs
• NAD(P)H Dehydrogenase (Quinone)
• NQO1 protein, human
• Podophyllotoxin

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, metabolism, pharmacology, therapeutic use)
• Binding Sites
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Carriers (chemistry)
• Humans
• Mice
• Mice, Nude
• Molecular Docking Simulation
• NAD(P)H Dehydrogenase (Quinone) (chemistry, metabolism)
• Neoplasms (drug therapy, pathology)
• Podophyllotoxin (chemistry, pharmacology)
• Prodrugs (chemistry, metabolism, pharmacology, therapeutic use)
• Rats
• Transplantation, Heterologous