Scaffold Identification of a New Class of Potent and Selective BCRP Inhibitors

Abstract

We recently reported the synthesis and quantitative structure-activity relationships of a new breast cancer resistance protein (BCRP) inhibitor class. In the study presented herein, we investigated the possibility to better define the scaffold of this compound class by removing or modifying the aromatic ring A with various substituents selected on the basis of their electronic and lipophilic properties. The results show that this aromatic ring is important, but not essential, for activity. Many of the selected substituents led to compounds with low activity, but in some cases activity was retained. Among these, a phenolic hydroxy group proved to impart as much potency to the molecule as a hydroxyethyl side chain, initially considered necessary for activity. This derivative is one of the most active compounds in this class, maintaining an inhibitory activity similar to that of the reference compound; it is also selective for BCRP.

Acryloylphenylcarboxamides: A New Class of Breast Cancer Resistance Protein (ABCG2) Modulators

“…Mitochondrial dehydrogenases of viable cells reduced MTT to the purple formazan, which was quantified spectrophotometrically. The assay was performed as described earlier with minor modifications . Cells were harvested and seeded into 96‐well tissue‐culture treated plates (Starlab GmbH, Hamburg, Germany) at a density of approximately 3000 cells per well in a total volume of 180 μL.…”

“…MTT assay for determining cytotoxicity:T he intrinsic cytotoxicity of selected compounds in MDCK II BCRP and MDCK II wild-type cells was determined by using the MTT colorimetric assay.M itochondrial dehydrogenases of viable cells reduced MTT to the purple formazan, which was quantified spectrophotometrically.T he assay was performed as described earlier with minor modifications. [25,26,31,36,37] Cells were harvested and seeded into 96-well tissue-culture treated plates (Starlab GmbH, Hamburg, Germany) at ad ensity of approximately 3000 cells per well in at otal volume of 180 mL. The plates were kept under 5% CO 2 atmosphere and 37 8Cf or 6h for attachment of cells.…”

Recent advances in the search of BCRP- and dual P-gp/BCRP-based multidrug resistance modulators

“…The deletion of the tetrahydroisoquinoline group of tariquidar (59) led to compounds that were shown to be selective BCRP inhibitors [152][153][154] [ Figure 11]. In 2015, Marighetti et al [155] reported a quantitative structureactivity relationship (QSAR) study of this class of BCRP inhibitors. The inhibitory activities against BCRP and P-gp were determined on BCRP-overexpressing MCF-7 MX cells, by a Hoechst 33342 assay, and on A2780 adr cells by a calcein AM assay, respectively.…”

“…Compound 60 showed high and selective activity for BCRP (IC 50 = 0.94 M) since no P-gp inhibitory activity was observed. Otherwise, compound 61 was active also on P-gp despite with lower potency (IC 50 = 0.56 M on BCRP and 6.07 M on P-gp) [ 155 ] .…”

“…Compounds 60 [ 155 ] and 64 [ 157 ] have been used as leads by Gujarati et al [ 160 ] to synthesize several benzamide and phenyltetrazole derivatives with amide and urea linkers between rings B and C [Figure 13] . Various substituents were introduced on rings A and C to explore the consequences of steric, electronic and solubility characteristics on BCRP activity.…”