New tetrahydroisoquinoline based P-glycoprotein modulators: decoration of the biphenyl core gives selective ligands.
Marialessandra Contino, stefano guglielmo, Maria Grazia Perrone, Roberta Giampietro , Barbara Rolando, Antonio Carrieri, daniele zaccaria, Konstantin Chegaev, Vanessa Borio, Chiara Riganti, Katarzyna Agnieszka Zabielska-Koczywąs, Antonio Nicola Colabufo, Roberta Fruttero
P-glycoprotein (P-gp, MDR1) is a membrane transporter expressed in several districts of our body. It exerts a crucial defense role as it effluxes hundreds of potentially toxic substances. Hovewer, P-gp is one of the main causes of the failure in cancer chemotherapy, as a number of chemotherapeutic agents are P-gp substrates. Another interesting implication regards 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 has been designed, synthesized and evaluated for their activity towards P-gp and other two 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 to restore doxorubicin toxicity in resistant cancer cells.