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
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