Abstract
One of the principal reasons for the chemotherapy failure is the overexpression of drug efflux pumps, ABCB1 (also known as MDR1 or P-gp) and ABCC1 (also known as MRP1), whose inhibition remains a priority to circumvent drug resistance. We have recently shown a clear trend between lipophilicity and P-glycoprotein inhibitory activity for a class of galloyl-based modulators targeting P-glycoprotein and MRP1. Herein we report a new series of polymethoxy benzamides, whose lipophilicity was modulated through the establishment of an intramolecular hydrogen bond (IMHB) which allows reaching of P-gp inhibitory activity at the submicromolar IC50 level. The present study provides a strong rationale for candidates in the presence of IMHB as a key element for a high P-gp inhibitory activity.
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / chemistry
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
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Anilides / chemical synthesis
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Anilides / chemistry*
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Anilides / pharmacology
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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry*
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Antineoplastic Agents / pharmacology
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Caco-2 Cells
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Cell Line, Tumor
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Cell Membrane Permeability
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Dogs
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Doxorubicin / pharmacology
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Drug Resistance, Neoplasm
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Drug Screening Assays, Antitumor
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Drug Synergism
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Fluoresceins / metabolism
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Humans
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Hydrogen Bonding
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Hydrophobic and Hydrophilic Interactions
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Madin Darby Canine Kidney Cells
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Molecular Dynamics Simulation
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Structure-Activity Relationship
Substances
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Anilides
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Antineoplastic Agents
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Fluoresceins
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Doxorubicin
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fluorexon