1,2,3,4-Tetrahydroisoquinoline/2H-chromen-2-one conjugates as nanomolar P-glycoprotein inhibitors: Molecular determinants for affinity and selectivity over multidrug resistance associated protein 1

2019 ◽  
Vol 161 ◽  
pp. 433-444 ◽  
Author(s):  
Mariagrazia Rullo ◽  
Mauro Niso ◽  
Leonardo Pisani ◽  
Antonio Carrieri ◽  
Nicola Antonio Colabufo ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
P Glycoprotein ◽  
Molecular Determinants ◽  
Glycoprotein Inhibitors

scholarly journals Molecular Mimics of Classic P-Glycoprotein Inhibitors as Multidrug Resistance Suppressors and Their Synergistic Effect on Paclitaxel

PLoS ONE ◽  
2017 ◽  
Vol 12 (1) ◽  
pp. e0168938 ◽  
Author(s):  
Moustafa E. El-Araby ◽  
Abdelsattar M. Omar ◽  
Maan T. Khayat ◽  
Hanan A. Assiri ◽  
Ahmed M. Al-Abd
Keyword(s):  
Multidrug Resistance ◽  
Synergistic Effect ◽  
P Glycoprotein ◽  
Glycoprotein Inhibitors

scholarly journals Screening of Natural Compounds as P-Glycoprotein Inhibitors against Multidrug Resistance

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 357
Author(s):  
Sérgio M. Marques ◽  
Lucie Šupolíková ◽  
Lenka Molčanová ◽  
Karel Šmejkal ◽  
David Bednar ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Three Dimensional ◽  
Dimensional Structure ◽  
Cancer Drug ◽  
Binding Modes ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Anti Cancer ◽  
Theoretical Predictions ◽  
Glycoprotein Inhibitors

Multidrug resistance (MDR) is a common problem when fighting cancer with chemotherapy. P-glycoprotein (P-gp, or MDR1) is an active pump responsible for the efflux of xenobiotics out of the cell, including anti-cancer drugs. It is a validated target against MDR. No crystal structure of the human P-gp is available to date, and only recently several cryo-EM structures have been solved. In this paper, we present a comprehensive computational approach that includes constructing the full-length three-dimensional structure of the human P-gp and its refinement using molecular dynamics. We assessed its flexibility and conformational diversity, compiling a dynamical ensemble that was used to dock a set of lignan compounds, previously reported as active P-gp inhibitors, and disclose their binding modes. Based on the statistical analysis of the docking results, we selected a system for performing the structure-based virtual screening of new potential P-gp inhibitors. We tested the method on a library of 87 natural flavonoids described in the literature, and 10 of those were experimentally assayed. The results reproduced the theoretical predictions only partially due to various possible factors. However, at least two of the predicted natural flavonoids were demonstrated to be effective P-gp inhibitors. They were able to increase the accumulation of doxorubicin inside the human promyelocytic leukemia HL60/MDR cells overexpressing P-gp and potentiate the antiproliferative activity of this anti-cancer drug.

Synthesis and bioevaluation of novel benzodipyranone derivatives as P-glycoprotein inhibitors for multidrug resistance reversal agents

2016 ◽  
Vol 118 ◽  
pp. 219-229 ◽  
Author(s):  
Chien-Yu Chen ◽  
Nai-Yu Liu ◽  
Hui-Chang Lin ◽  
Chih-Yu Lee ◽  
Chin-Chuan Hung ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Reversal Agents ◽  
P Glycoprotein ◽  
Resistance Reversal ◽  
Glycoprotein Inhibitors

3-benzazecine-based cyclic allene derivatives as highly potent P-glycoprotein inhibitors overcoming doxorubicin multidrug resistance

2019 ◽  
Vol 11 (16) ◽  
pp. 2095-2106 ◽  
Author(s):  
Alexander A Titov ◽  
Mauro Niso ◽  
Modesto de Candia ◽  
Maxim S Kobzev ◽  
Alexey V Varlamov ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Multidrug Resistant ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Uptake Assay ◽  
Calcein Am ◽  
Inhibition Potency ◽  
Glycoprotein Inhibitors ◽  
Allene System

Aim: Enamino 3-benzazecine compounds, incorporating the C6-C8 allene system, were synthesized and evaluated in vitro as inhibitors of P-glycoprotein (P-gp) and/or multidrug resistance-associated protein 1 (MRP1), two efflux pumps mainly connected with multidrug resistance (MDR) in cancer cells. Results & methodology: Most of the synthesized compounds were selective P-gp inhibitors in Calcein-AM uptake assay. Structure–activity relationships (SARs) pointed out that CO2Me derivatives are more potent than acetyl derivatives, and 10,11-dimethoxy compounds are five to tenfold more potent inhibitors than the respective unsubstituted compounds, and that the P-gp inhibition potency is mainly related to volume parameters. Conclusion: Nanomolar P-gp inhibitors, such as 23 (IC50 = 4.2 nM), restored the antiproliferative activity of doxorubicin in multidrug-resistant cells. The observed activities showed that 3-benzazecine-based compounds may be promising MDR reversers.

Transfection with Protein Kinase Cα Confers Increased Multidrug Resistance to MCF-7 Cells Expressing P-Glycoprotein

1991 ◽  
Vol 3 (6) ◽  
pp. 181-189 ◽  
Author(s):  
Gang Yu ◽  
Shakeel Ahmad ◽  
Angelo Aquino ◽  
Craig R. Fairchild ◽  
Jane B. Trepel ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Protein Kinase ◽  
P Glycoprotein ◽  
Protein Kinase Cα ◽  
Mcf 7
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