INBIOTEC   24408
INSTITUTO DE INVESTIGACIONES EN BIODIVERSIDAD Y BIOTECNOLOGIA
Unidad Ejecutora - UE
artículos
Título:
Analogues of the Lignan Pinoresinol as Novel Lead Compounds for P-glycoprotein (P-gp) Inhibitors
Autor/es:
TOMASIC; T; LANZA P.A.; MAIč L.P.; VERA D.M.A.; GANCEDO, S.N.; LAIOLO J.; KIKELJ D.; GONZÁLEZ M.L.; HODNIK ; CARPINELLA M. C.
Revista:
ACS Medicinal Chemistry Letters
Editorial:
American Chemical Society
Referencias:
Lugar: Washigton; Año: 2018 vol. 9 p. 1186 - 1192
ISSN:
1948-5875
Resumen:
ABSTRACT: 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 μM, 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 µM and rendering Lucena 1 sensitive to DOX from 1.56 and 0.78 µM, 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.