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 MC70 [4′-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-ylmethyl)biphenyl-4-ol], proved fairly selective towards P-gp, with a potency in the micromolar range. Compounds 5a, 5d and 12d proved capable of restoring doxorubicin toxicity in resistant cancer cells

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

Guglielmo, Stefano;Rolando, Barbara;Chegaev, Konstantin;Riganti, Chiara;Fruttero, Roberta
2018

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 MC70 [4′-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-ylmethyl)biphenyl-4-ol], proved fairly selective towards P-gp, with a potency in the micromolar range. Compounds 5a, 5d and 12d proved capable of restoring doxorubicin toxicity in resistant cancer cells
MEDCHEMCOMM
9
5
862
869
http://pubs.rsc.org/en/journals/journal/md
P-glycoprotein; tetrahydroisoquinoline ligands; drug-resistant cancer cells
Contino, Marialessandra; Guglielmo, Stefano*; Perrone, Maria Grazia; Giampietro, Roberta; Rolando, Barbara; Carrieri, Antonio; Zaccaria, Daniele; Chegaev, Konstantin; Borio, Vanessa; Riganti, Chiara; Zabielska-Koczywas, Katarzyna; Colabufo, Nicola A.; Fruttero, Roberta
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/1669830
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