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

• Published in: MedChemComm 2018-05, Vol.9 (5), p.862-869
• Main Authors: Contino, Marialessandra, Guglielmo, Stefano, Perrone, Maria Grazia, Giampietro, Roberta, Rolando, Barbara, Carrieri, Antonio, Zaccaria, Daniele, Chegaev, Konstantin, Borio, Vanessa, Riganti, Chiara, Zabielska-Koczywąs, Katarzyna, Colabufo, Nicola A, Fruttero, Roberta
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Biphenyl; Cancer; Central nervous system; Chemotherapy; Doxorubicin; Efflux; Glycoproteins; MDR1 protein; Modulators; Movement disorders; Neurodegenerative diseases; P-Glycoprotein; Parkinson's disease; Proteins; Substrates; Tetrahydroisoquinoline; Toxic substances; Toxicity
• ISSN: 2040-2503; 2040-2511
• DOI: 10.1039/c8md00075a

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.