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 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.

• Authors: Marialessandra Contino, Stefano Guglielmo, Maria Grazia Perrone, Roberta Giampietro, Barbara Rolando, Antonio Carrieri, Daniele Zaccaria, Konstantin Chegaev, Vanessa Borio, Chiara Riganti, Katarzyna Zabielska-Koczywąs, Nicola A Colabufo, Roberta Fruttero
• Journal: MedChemComm (Medchemcomm) Vol. 9 Issue 5 Pg. 862-869 (May 01 2018) ISSN: 2040-2503 [Print] England
• PMID: 30108975 (Publication Type: Journal Article)