title: A comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) of anthranilamide derivatives that are multidrug resistance modulators.
abstract: In a continuing effort to develop potent and selective modulators of P-glycoprotein (P-gp) activity overcoming the chemoresistance acquired by tumor cells during cancer chemotherapy, we developed 3D quantitative structure-activity relationship (3D QSAR) models using CoMFA and CoMSIA analyses. This study correlates the P-glycoprotein inhibitory activities of 49 structurally related anthranilamide derivatives to several physicochemical parameters representing steric, electrostatic, acceptor, donor, and hydrophobic fields. Both CoMFA and CoMSIA models using three different alignment conformations gave good internal predictions, and their cross-validated r2 values are between 0.503 and 0.644. These most comprehensive CoMFA and CoMSIA models are useful in understanding the structure-activity relationships of anthranilamide derivatives as well as aid in the design of novel derivatives with enhanced modulation of P-gp activity.
authors.affiliation: Unité des Biotechnologies et de Bioingénierie, Hôpital Saint-François d'Assise, Quebec City, Québec G1L 3L5, Canada. plabrie16@hotmail.com
authors.forename: Philippe
authors.initials: P
authors.lastname: Labrie
authors.forename: Shawn P
authors.initials: SP
authors.lastname: Maddaford
authors.forename: Sebastien
authors.initials: S
authors.lastname: Fortin
authors.forename: Suman
authors.initials: S
authors.lastname: Rakhit
authors.forename: Lakshmi P
authors.initials: LP
authors.lastname: Kotra
authors.forename: René C
authors.initials: RC
authors.lastname: Gaudreault
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D003630:Daunorubicin / Q000378:metabolism; D015195:Drug Design; D018432:Drug Resistance, Multiple; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D062367:ortho-Aminobenzoates / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D062367:ortho-Aminobenzoates; C000219:anthranilamide; D003630:Daunorubicin