title: Identification of key structural characteristics of Schisandra chinensis lignans involved in P-glycoprotein inhibition.
abstract: 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.
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Masaryk University , Kamenice 5, Building A16, 625 00 Brno, Czech Republic.
authors.forename: Jiří
authors.initials: J
authors.lastname: Slanina
authors.forename: Gabriela
authors.initials: G
authors.lastname: Páchniková
authors.forename: Martina
authors.initials: M
authors.lastname: Carnecká
authors.forename: Ludmila
authors.initials: L
authors.lastname: Porubová Koubíková
authors.forename: Lenka
authors.initials: L
authors.lastname: Adámková
authors.forename: Otakar
authors.initials: O
authors.lastname: Humpa
authors.forename: Karel
authors.initials: K
authors.lastname: Smejkal
authors.forename: Iva
authors.initials: I
authors.lastname: Slaninová
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors*; D034242:Cyclooctanes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D017705:Lignans / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D015394:Molecular Structure; D011083:Polycyclic Compounds / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D012426:Russia; D032141:Schisandra / Q000737:chemistry*; D012639:Seeds / Q000737:chemistry
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D034242:Cyclooctanes; D017705:Lignans; D011083:Polycyclic Compounds; C510994:dibenzocyclooctadiene lignan; C015499:schizandrin B; C034734:schizandrin A; D004317:Doxorubicin