Synthesis and biological evaluation of NQO1-activated prodrugs of podophyllotoxin as antitumor agents.
Animals
Antineoplastic Agents
/ chemical synthesis
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
Neoplasms
/ drug therapy
Podophyllotoxin
/ chemistry
Prodrugs
/ chemistry
Rats
Transplantation, Heterologous
Antitumor
NQO1
NQO1-activatable prodrug
Podophyllotoxin
Journal
Bioorganic & medicinal chemistry
ISSN: 1464-3391
Titre abrégé: Bioorg Med Chem
Pays: England
ID NLM: 9413298
Informations de publication
Date de publication:
15 12 2020
15 12 2020
Historique:
received:
02
09
2020
accepted:
05
10
2020
pubmed:
23
10
2020
medline:
3
7
2021
entrez:
22
10
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33091789
pii: S0968-0896(20)30651-9
doi: 10.1016/j.bmc.2020.115821
pii:
doi:
Substances chimiques
Antineoplastic Agents
0
Drug Carriers
0
Prodrugs
0
NAD(P)H Dehydrogenase (Quinone)
EC 1.6.5.2
NQO1 protein, human
EC 1.6.5.2
Podophyllotoxin
L36H50F353
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
115821Informations de copyright
Copyright © 2020 Elsevier Ltd. All rights reserved.