Analogs of the lignan pinoresinol as novel P-glycoprotein (P-gp) inhibitors

JERÓNIMO LAIOLO; TIHOMIR TOMAIč; D. MARIANO A. VERA; MARÍA LAURA GONZÁLEZ; PRISCILA A. LANZA; SAMANTA GANCEDO; IGA HODNIK; LUCIJA PETERLIN MAIč; DANIJEL KIKELJ; MARÍA C. CARPINELLA

ACS Medicinal Chemistry Letters

American Chemical Society (ACS)

Año: 2018 p. 1 - 11

1948-5875

Tofind novel P-gp-inhibitors, a library of pregnane X receptor (PXR)ligands and the ZINC DrugsNow library were superimposed on the P-gpinhibitor (+)-pinoresinol (1) used as a query for a 3Dsimilarity search. After determining the TanimotoCombo index ofsimilarity with 1, eight compounds from the PXR libraryand two ZINC compounds were selected for biological evaluation. TheP-gp inhibition study showed that compounds 7, 8 and 9successfully increased intracellular doxorubicin (DOX) accumulationin the P-gp overexpressed Lucena 1 cells from 25, 12.5 and 6.25 μM,respectively. Among a series of analogs of 9, compounds 26-30were shown to be active, with 26 and 27 causing asignificant increase in DOX accumulation from 1.56 µMand rendering Lucena 1 sensitive to DOX from 1.56 and 0.78 µM,respectively. Molecular modeling studies showed that both compoundsbind to the P-gp at transmembrane helices (TMH) 4, 5 and 6, with 27also showing contacts with TMH 3.p { margin-bottom: 0.35cm; direction: ltr; color: rgb(0, 0, 0); text-align: center; }p.western { font-family: "Times", serif; font-size: 20pt; font-weight: bold; }p.cjk { font-family: "Times New Roman"; font-size: 20pt; font-weight: bold; }p.ctl { font-family: "Times New Roman"; font-size: 10pt; }a:link { color: rgb(0, 0, 255); }a.sdendnotesym-western { font-family: "Times", serif; font-size: 9pt; }a.sdendnotesym-cjk { font-size: 9pt; }