Design, Biological Evaluation, and Molecular Modeling of Tetrahydroisoquinoline Derivatives: Discovery of A Potent P-Glycoprotein Ligand Overcoming Multidrug Resistance in Cancer Stem Cells
Autor: | Marialessandra Contino, Francesco Leonetti, Stefano Guglielmo, Maria Grazia Perrone, Barbara Rolando, Loretta Lazzarato, Roberta Fruttero, Iris Chiara Salaroglio, Vladan Milosevic, Nicola Antonio Colabufo, Roberta Giampietro, Chiara Riganti |
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Jazyk: | angličtina |
Rok vydání: | 2019 |
Předmět: |
Cell Survival
Population Antineoplastic Agents Molecular Dynamics Simulation Ligands 01 natural sciences Permeability Madin Darby Canine Kidney Cells 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship Dogs Cancer stem cell Cell Line Tumor Tetrahydroisoquinolines Drug Discovery Structure–activity relationship Animals Humans ATP Binding Cassette Transporter Subfamily B Member 1 education 030304 developmental biology P-glycoprotein Gene Editing 0303 health sciences education.field_of_study Binding Sites biology Chemistry Drug Discovery3003 Pharmaceutical Science Molecular medicine 0104 chemical sciences 010404 medicinal & biomolecular chemistry Biochemistry Doxorubicin Drug Resistance Neoplasm Molecular Medicine Drug Design Cancer cell biology.protein Neoplastic Stem Cells Efflux Lead compound |
Popis: | P-Glycoprotein 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, a population of cancer cells with strong tumor-promoting ability. In the present study, a series of compounds were synthesized through structure modulation of [4′-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-ylmethyl)biphenyl-4-ol] (MC70), 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 antiproliferative activity at nontoxic concentration. Its behavior was rationalized through a molecular modeling study consisting of a well-tempered metadynamics simulation, which allowed one to identify the most favorable binding pose, and of a subsequent molecular dynamics run, which indicated a peculiar effect of the compound on the motion pattern of the... |
Databáze: | OpenAIRE |
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