Synthesis of dibenzocyclooctadiene lignans derivatives as P-glycoprotein inhibitors

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216224%3A14110%2F18%3A00104454" target="_blank" >RIV/00216224:14110/18:00104454 - isvavai.cz</a>

Výsledek na webu

—

DOI - Digital Object Identifier

—

Jazyk výsledku

angličtina

Název v původním jazyce

Synthesis of dibenzocyclooctadiene lignans derivatives as P-glycoprotein inhibitors

Popis výsledku v původním jazyce

In previous work, the structural requirements for P-glycoprotein inhibition by dibenzocyclooctadiene lignans were studied. P-Glycoprotein inhibition was quantified using flow cytometry doxorubicin accumulation assay in resistant human acute promyelocytic leukaemia cells overexpressing P-glycoprotein (HL60/MDR). 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. The five most effective dibenzocyclooctadiene lignans have met two of the three conditions; however, none of the 14 lignans tested fulfilled all three structural prerequisites.1 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 isolated from Schisandra chinensis extracts are modified to increase the effectiveness of P-glycoprotein inhibition. The 7-hydroxy group, which decreases the activity of lignans, was modified by acetylation, dehydration and methylation. The acetylated derivatives of schizandrin and gomisin A were prepared.

Název v anglickém jazyce

Synthesis of dibenzocyclooctadiene lignans derivatives as P-glycoprotein inhibitors

Popis výsledku anglicky

In previous work, the structural requirements for P-glycoprotein inhibition by dibenzocyclooctadiene lignans were studied. P-Glycoprotein inhibition was quantified using flow cytometry doxorubicin accumulation assay in resistant human acute promyelocytic leukaemia cells overexpressing P-glycoprotein (HL60/MDR). 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. The five most effective dibenzocyclooctadiene lignans have met two of the three conditions; however, none of the 14 lignans tested fulfilled all three structural prerequisites.1 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 isolated from Schisandra chinensis extracts are modified to increase the effectiveness of P-glycoprotein inhibition. The 7-hydroxy group, which decreases the activity of lignans, was modified by acetylation, dehydration and methylation. The acetylated derivatives of schizandrin and gomisin A were prepared.

Druh

O - Ostatní výsledky

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

<a href="/cs/project/LM2015043" target="_blank" >LM2015043: Česká infrastruktura pro integrativní strukturní biologii</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)<br>S - Specificky vyzkum na vysokych skolach

Rok uplatnění

2018

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů