Analogues of the Lignan Pinoresinol as Novel Lead Compounds for P‑glycoprotein (P-gp) Inhibitors

LAIOLO J.; TOMASIC; T; VERA D.M.A.; GONZÁLEZ M.L.; LANZA P.A.; GANCEDO, S.N.; HODNIK ; MAIč L.P.; KIKELJ D.; CARPINELLA M. C.

ACS Medicinal Chemistry Letters

American Chemical Society (ACS)

Año: 2018 vol. 9 p. 1186 - 1192

1948-5875

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. Based on the Tan-imotoCombo 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 dox-orubicin (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.