Abstract
The drug efflux pump P-glycoprotein (P-gp) has been shown to promote multidrug resistance (MDR) in tumors as well as to influence ADME properties of drug candidates. Here we synthesized and tested a series of benzophenone derivatives structurally analogous to propafenone-type inhibitors of P-gp. Some of the compounds showed ligand efficiency and lipophilic efficiency (LipE) values in the range of compounds which entered clinical trials as MDR modulators. Interestingly, although lipophilicity plays a dominant role for P-gp inhibitors, all compounds investigated showed LipE values below the threshold for promising drug candidates. Docking studies of selected analogues into a homology model of P-glycoprotein suggest that benzophenones show an interaction pattern similar to that previously identified for propafenone-type inhibitors.
© 2012 American Chemical Society
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
-
ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
-
Benzophenones / chemical synthesis*
-
Benzophenones / chemistry
-
Benzophenones / pharmacology
-
Binding Sites
-
Cell Line, Tumor
-
Crystallography, X-Ray
-
Drug Resistance, Multiple / drug effects*
-
Drug Resistance, Neoplasm / drug effects
-
Drug Screening Assays, Antitumor
-
ERG1 Potassium Channel
-
Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
-
Ether-A-Go-Go Potassium Channels / metabolism
-
Humans
-
Ligands
-
Models, Molecular
-
Molecular Conformation
-
Propafenone / analogs & derivatives
-
Propafenone / chemical synthesis
-
Propafenone / chemistry
-
Propafenone / pharmacology
-
Quantitative Structure-Activity Relationship
-
Serotonin Plasma Membrane Transport Proteins / metabolism
-
Structure-Activity Relationship
Substances
-
ATP Binding Cassette Transporter, Subfamily B, Member 1
-
Benzophenones
-
ERG1 Potassium Channel
-
Ether-A-Go-Go Potassium Channels
-
Ligands
-
Serotonin Plasma Membrane Transport Proteins
-
Propafenone