title: Structural requirements for activity of propafenone-type modulators in P-glycoprotein-mediated multidrug resistance.
abstract: The sodium channel blocker propafenone and a series of analogs have been identified as effective modulators of P-glyco-protein-mediated multidrug resistance in human tumor cells. A series of closely related structural homologues showed a highly significant correlation between lipophilicity and pharmacological effect. Reduction of the carbonyl group as well as conversion to a methylether led to a remarkable decrease in activity, whereby lipophilicity lost its predictive character as the main determinant for modulator potency. Similarly, the relative positioning of the acyl- and propanolamine side chains also influences activity, so the distance between carbonyl group and nitrogen atom seems important.
authors.affiliation: Department of Medical Chemistry, University of Vienna, Austria. peter.chiba@univie.ac.at
authors.forename: P
authors.initials: P
authors.lastname: Chiba
authors.forename: G
authors.initials: G
authors.lastname: Ecker
authors.forename: D
authors.initials: D
authors.lastname: Schmid
authors.forename: J
authors.initials: J
authors.lastname: Drach
authors.forename: B
authors.initials: B
authors.lastname: Tell
authors.forename: S
authors.initials: S
authors.lastname: Goldenberg
authors.forename: V
authors.initials: V
authors.lastname: Gekeler
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000187:drug effects*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D006801:Humans; D051379:Mice; D011405:Propafenone / Q000494:pharmacology*; D012995:Solubility; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D011405:Propafenone