New tetrahydroisoquinoline-based P-glycoprotein modulators: decoration of the biphenyl core gives selective ligands

Abstract

P-glycoprotein (P-gp, MDR1) is a membrane transporter expressed in several regions of our body. It plays a crucial defense role as it mediates the efflux of hundreds of potentially toxic substances. However, P-gp is one of the main causes of failure in cancer chemotherapy, as a number of chemotherapeutic agents are P-gp substrates. Another interesting implication concerns the correlation between P-gp expression impairment and the onset of several central nervous system pathologies such as Alzheimer's and Parkinson's diseases. In view of these considerations, in the present study, a new series of P-gp modulators have been designed, synthesized and evaluated for their activity towards P-gp and two other sister proteins (BCRP and MRP1). The compounds, structurally correlated to the potent but non-selective P-gp inhibitor [4'-(6,7-dimethoxy-3,4-dihydro-1-isoquinolin-2-ylmethyl)biphenyl-4-ol], proved fairly selective towards P-gp, with a potency in the micromolar range. Compounds , and proved capable of restoring doxorubicin toxicity in resistant cancer cells.

Design, synthesis and biological evaluation of stereo- and regioisomers of amino aryl esters as multidrug resistance (MDR) reversers

“…The co-administration assay with doxorubicin was performed in MDCK-MDR1 cells at 48 h as reported with minor modification [71]. Details are reported in the Supplementary data.…”

The A‐B‐C of small‐molecule ABC transport protein modulators: From inhibition to activation—a case study of multidrug resistance‐associated protein 1 (ABCC1)

“…Primarily, pharmacological drugs such as verapamil or cyclosporine A were the first hits targeting P‐gp, affecting the persistence of cytotoxic agents in P‐gp‐overexpressing cancer cells . In the mid‐ and end‐90s of the last century, leading pharmaceutical companies started the development of highly potent and specific inhibitors of P‐gp, which was improved by working groups around the globe to elucidate the structure–activity relationship with respect to the inhibitory effect of the basic scaffolds as much as partial structures of these compounds …”

Optimization of 2-Amino-4,6-diarylpyrimidine-5-carbonitriles as Potent and Selective A1 Antagonists

“…Briefly, in MDCK-MDR1 cells, the pro-fluorescent Calcein-AM is not able to enter the cell membrane as effluxed by P-gp; in the presence of an agent able to interact with the pump (as a substrate), Calcein-AM enters the cell membrane and it is hydrolyzed, by the cytosol esterases, to the fluorescent Calcein (responsible for the fluorescence signal). 53 − 55 The results of this study are presented in Table 4 . As observed, any of the tested compounds showed a significant interaction in MDCK-MDR1 cells with the Calcein-AM transport with respect to the P-gp reference substrate verapamil (EC 50 = 0.50 μM).…”