Inhibice P-glykoproteinu dibenzocyklooktadienovými lignany z rostliny Schizandra chinensis
| Title in English | P-glycoprotein inhibiton by dibenzocyclooctadiene lignans from plant Schizandra chinensis |
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| Authors | |
| Year of publication | 2018 |
| Type | Conference abstract |
| MU Faculty or unit | |
| Citation | |
| Description | Dibenzocyclooctadiene lignans are compounds occuring in plant Schisandra chinensis (Turcz.) Baill and latety their pharmacological acitivity is in the spotlight because of their potential therapeutical use. One of this activities is Pglycoprotein inhibition, P—glycoprotein is an ABC transporter often causing multidrug resistance of cancer cells. The structural requirements for P-glycoprotein inhibition by dibenzocyclooctadiene lignans were studied. Altogether 15 structurally related lignans isolated from Schisandra chinensis or prepared by their modification were investigated, including three pairs of enantiomers. P-Glycoprotein inhibition was quantified using a doxorubicin accumulation assay in human promyelocytic 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 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. The five most effective dibenzocyclooctadiene lignans found so far have met two of the three conditions; however, none of the lignans tested met all three structural prerequisites. The final structure-to-MDR reversing activity relationship has not been established due to a limited number of lignans. Our current work is directed towards a greater number of suitable lignans to gain a deeper insight into the structure-to-activity relationship and to obtain more effective inhibitors. The lignans are isolated from Schisandra chinensis extracts in accordance with the effectiveness of P- glycoprotein inhibition by semi-preparative HPLC. A semisynthetic way of modification of the lignans is applied in order to enhance P- glycoprotein inhibitory activity and discover another principal structure leading to the more effective inhibition. |
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