1. Analogues of the Lignan Pinoresinol as Novel Lead Compounds for P-glycoprotein (P-gp) Inhibitors.
- Author
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Laiolo J, Tomašič T, Vera DMA, González ML, Lanza PA, Gancedo SN, Hodnik Ž, Peterlin Mašič L, Kikelj D, and Carpinella MC
- 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 three-dimensional 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 analogues 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., Competing Interests: The authors declare no competing financial interest.
- Published
- 2018
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