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  • Analogs of the lignan pinoresinol as novel lead compounds for P-glycoprotein (P-gp) inhibitors
    Laiolo, Jeronimo ...
    To find novel P-gp-inhibitors, a library of pregnane X receptor (PXR) ligands and the ZINC DrugsNow library were superimposed on the P-gp inhibitor (+)-pinoresinol (1) used as a query for a 3D ... similarity search. After determining the TanimotoCombo index of similarity with 1, eight compounds from the PXR library and two ZINC compounds were selected for biological evaluation. The P-gp inhibition study showed that compounds 7, 8 and 9 successfully increased intracellular doxorubicin (DOX) accumulation in the P-gp overexpressed Lucena 1 cells from 25, 12.5 and 6.25 %M, respectively. Among a series of analogs of 9, compounds 26-30 were shown to be active, with 26 and 27 causing a significant increase in DOX accumulation from 1.56 %M and rendering Lucena 1 sensitive to DOX from 1.56 and 0.78 %M, respectively. Molecular modeling studies showed that both compounds bind to the P-gp at transmembrane helices (TMH) 4, 5 and 6, with 27 also showing contacts with TMH 3.
    Source: ACS Medicinal Chemistry Letters. - ISSN 1948-5875 (Vol. 9, iss. 12, 2018, str. 1186-1192)
    Type of material - article, component part
    Publish date - 2018
    Language - english
    COBISS.SI-ID - 4642161

    Link(s):

    https://pubs.acs.org/doi/10.1021/acsmedchemlett.8b00324
    DOI

source: ACS Medicinal Chemistry Letters. - ISSN 1948-5875 (Vol. 9, iss. 12, 2018, str. 1186-1192)
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