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D11, a novel glycosylated diphyllin derivative, exhibits potent anticancer activity by targeting topoisomerase IIα
- Source :
- Investigational New Drugs. 29:800-810
- Publication Year :
- 2010
- Publisher :
- Springer Science and Business Media LLC, 2010.
-
Abstract
- Glycosylated natural products are reliable platforms for the development of anticancer drugs, simply due to the important features added by sugar appendages to the shape and the stereoelectronic properties of natural scaffolds. Herein, we indentified D11, a novel diphyllin glycoside with acetylated D-quinovose sugar moiety, as a potent topoisomerase IIα (Topo IIα) inhibitior. This peculiar sugar moiety endows D11 an optimal conformation with a high binding affinity for Topo IIα via hydrogen bonding to the entrance of ATPase pocket, thereby helping achieve more potent Topo II inhibition activity compared to the aglycon diphyllin. Further biochemical insights manifested that D11 significantly inhibited Topo IIα ATPase-catalyzed ATP hydrolysis in an ATP-dependent, but a DNA-independent manner. All these underlie the consequent superiority of D11 in the in vitro proliferation inhibition, apoptosis induction and the in vivo remarkable antitumor potency in xenograft mouse model. Moreover, D11 treatment also displayed no obvious body weight loss and other apparent toxicities, indicative of the restricted side effects by the virtue of sugar attachment. Taken together, a defined glycosylated manipulation of diphyllin may be a promising alternative approach in the development of novel Topo II inhibitors.
- Subjects :
- Topoisomerase iiα
Glycosylation
ATPase
Antineoplastic Agents
Apoptosis
Lignans
Mice
chemistry.chemical_compound
Adenosine Triphosphate
Glucosides
Antigens, Neoplasm
ATP hydrolysis
In vivo
Cell Line, Tumor
Animals
Humans
Topoisomerase II Inhibitors
Pharmacology (medical)
Benzodioxoles
Adenosine Triphosphatases
Pharmacology
chemistry.chemical_classification
Mice, Inbred BALB C
biology
Hydrolysis
Glycoside
Dioxolanes
DNA
Xenograft Model Antitumor Assays
DNA-Binding Proteins
DNA Topoisomerases, Type II
DNA Topoisomerases, Type I
Oncology
Biochemistry
chemistry
Acetylation
Biocatalysis
biology.protein
Female
Topoisomerase-II Inhibitor
Derivative (chemistry)
Subjects
Details
- ISSN :
- 15730646 and 01676997
- Volume :
- 29
- Database :
- OpenAIRE
- Journal :
- Investigational New Drugs
- Accession number :
- edsair.doi.dedup.....941341ef5d9ad8054c443a1f5ede9c03