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Identification of key structural characteristics of Schisandra chinensis lignans involved in P-glycoprotein inhibition
J. Slanina, G. Páchniková, M. Carnecká, L. Porubová Koubíková, L. Adámková, O. Humpa, K. Smejkal, I. Slaninová,
Language English Country United States
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
25302569
DOI
10.1021/np500521v
Knihovny.cz E-resources
- MeSH
- Cyclooctanes * chemistry isolation & purification pharmacology MeSH
- Doxorubicin pharmacology MeSH
- G2 Phase Cell Cycle Checkpoints drug effects MeSH
- Quantitative Structure-Activity Relationship MeSH
- Humans MeSH
- Lignans * chemistry isolation & purification pharmacology MeSH
- Molecular Structure MeSH
- ATP Binding Cassette Transporter, Subfamily B antagonists & inhibitors MeSH
- Polycyclic Compounds * chemistry isolation & purification pharmacology MeSH
- Schisandra chemistry MeSH
- Seeds chemistry MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Geographicals
- Russia MeSH
The aim of the present study was to determine the structural requirements for dibenzocyclooctadiene lignans essential for P-glycoprotein inhibition. Altogether 15 structurally related lignans isolated from Schisandra chinensis or prepared by modification of their backbone were investigated, including three pairs of enantiomers. P-Glycoprotein inhibition was quantified using a doxorubicin accumulation assay in human promyelotic leukemia HL60/MDR cells overexpressing P-glycoprotein. A preliminary quantitative structure-activity relationship analysis revealed three main structural features involved in P-glycoprotein inhibition: a 1,2,3-trimethoxy moiety, a 6-acyloxy group, and the absence of a 7-hydroxy group. The most effective inhibitors, (-)-gomisin N (1) and (+)-deoxyschizandrin [(+)-2], were selected for further evaluation of their effects. Both these lignans restored the cytotoxic effect of doxorubicin in HL60/MDR cells and when combined with a subtoxic concentration of this compound increased the proportion of G2/M cells significantly, which is a usual response to treatment with this anticancer drug.
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