Structural requirements for activity of propafenone-type modulators in P-glycoprotein-mediated multidrug resistance.
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.
Chiba
P
P
Department of Medical Chemistry, University of Vienna, Austria. peter.chiba@univie.ac.at
Ecker
G
G
Schmid
D
D
Drach
J
J
Tell
B
B
Goldenberg
S
S
Gekeler
V
V
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
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D011405:Propafenone