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

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.

Accelerated degradation of cFLIPL and sensitization of the TRAIL DISC-mediated apoptotic cascade by pinoresinol, a lignan isolated from Rubia philippinensis

“…34), suggesting that down regulation of survivin by pinoresinol might be relevant in limiting cell division, especially in G2-M phase rather than apoptosis. In addition, it has recently been reported that pinoresinol suppresses the efflux of chemotherapeutic drugs outside by interacting with P-glycoprotein (P-gp) encoded by multidrug resistant-1 (MDR-1) gene 53,54 . Since P-gp efflux function was shown to contribute to TRAIL resistance via controlling the endogenous level of TRAIL in certain types of cancer cells 55,56 , such an anti-Pgp activity of pinoresinol might constitute another mechanism in enhancing TRAIL efficacy in TRAIL-resistant cancers including glioblastoma.…”

Quinolin-2-one-pyrimidine Hybrids Acting as Potent Reversal Agents on the P-gp-mediated Multidrug Resistance: Insights into Structure-activity Relationships and the Binding Mode

“…More important is the fact that most of these contacts, such as Ala229 and Trp232 from TMH 4, Phe303 and Ile306 from TMH 5, Ile340, Phe343 and Gln347 from TMH 6, and Phe983 and Met986 from TMH 12, among others, were proposed to play a key role in the binding to P-gp on both computational and experimental bases 5,8,25,29 . Compound 5c (Fig.…”

“…The sensitive chronic myelogenous leukemia cell line K562 and its resistant derivative, Lucena 1, were cultured in supplemented RPMI-1640 medium (Invitrogen Life Technologies, Carlsbad, CA, USA) with 10% fetal bovine serum, 2 mM L-glutamine, 100 U/mL penicillin and 100 µg/mL streptomycin (Invitrogen Life Technologies) at 37°C in a 5% CO 2 humidi ed atmosphere. Lucena 1 selectively overexpressed P-gp 37 and its MDR was maintained by once weekly exposure to the anticancer drug, Dox at 60 nM till 4 days before the experiments 29 . Dox displayed a weak toxic effect against Lucena 1 cells, which showed 35.8-fold resistance to this drug compared to its parental K562 (IC 50 to Dox = 22.97 ± 5.41 and 0.64 ± 0.13 µM, respectively).…”

“…Based on the results obtained in the accumulation assays, the effects of the most effective compounds 5c and 7b on reversing Dox resistance in Lucena 1 cells were evaluated as previously described 5,8,29 . Brie y, 5 x 10 4 Lucena 1 and K562 cells were seeded in 96-well plates containing RPMI-1640 medium with the anticancer drug Dox (3.4-431 or 0.3-34.5 µM, respectively) in the absence or presence of 0.02 to 1.25 µM of compounds 5c and 7b.…”

“…IC 50 values of Dox were then obtained. The FR values were calculated as the ratio of the IC 50 obtained with Dox / IC 50 value for Dox in combination with the different concentrations of each tested compound 8,29 .…”