Design, Biological Evaluation, and Molecular Modeling of Tetrahydroisoquinoline Derivatives: Discovery of A Potent P-Glycoprotein Ligand Overcoming Multidrug Resistance in Cancer Stem Cells

P-glycoprotein (P-gp) is a well-known membrane transporter responsible for the efflux of an ample spectrum of anticancer drugs. Its relevance in the management of cancer chemotherapy is increased in view of its high expression in cancer stem cells (CSCs), a population of cancer cells with strong tumour-promoting ability. In the present study, a series of compounds were synthesized through structure modulation of MC70 ([4'-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-ylmethyl)biphenyl-4-ol]), modifying the phenolic group of the lead compound. Among them compound 5b emerged for its activity against the transporter (EC50 = 15 nM) and was capable of restoring Doxorubicin anti-proliferative activity at non-toxic concentration. Its behaviour was rationalized through a molecular modelling study consisting of a well-tempered metadynamics simulation, that allowed to identify the most favourable binding pose, and of a subsequent molecular dynamics run which indicated a peculiar effect of the compound on the motion pattern of the transporter.