A Combined Hansch/Free-Wilson Approach as Predictive Tool in QSAR Studies on Propafenone-Type Modulators of Multidrug Resistance

A series of 48 propafenone‐type modulators of multidrug resistance was synthesized and their P‐glycoprotein inhibitory activity was measured using the daunomycin efflux assay. Both a Free‐Wilson and a combined Hansch/Free‐Wilson analysis were performed using log P, partial log P and molar refraction...

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Bibliographic Details
Published in:Archiv der Pharmazie (Weinheim) 1998-07, Vol.331 (7-8), p.233-240
Main Authors: Tmej, Claudia, Chiba, Peter, Huber, Mario, Richter, Elisabeth, Hitzler, Manuela, Schaper, Klaus-Jürgen, Ecker, Gerhard
Format: Article
Language:English
Subjects:
Antibiotics, Antineoplastic - metabolism
Antineoplastic agents
ATP Binding Cassette Transporter, Subfamily B, Member 1 - antagonists & inhibitors
Biological and medical sciences
Cell Line
Daunorubicin - metabolism
Drug Resistance, Multiple - physiology
Drug Resistance, Neoplasm
Free-Wilson analysis
General aspects
Humans
Medical sciences
Multidrug resistance
P-glycoprotein
Pharmacology. Drug treatments
Propafenone
Propafenone - analogs & derivatives
Propafenone - chemistry
Propafenone - pharmacology
QSAR
Structure-Activity Relationship
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Summary:A series of 48 propafenone‐type modulators of multidrug resistance was synthesized and their P‐glycoprotein inhibitory activity was measured using the daunomycin efflux assay. Both a Free‐Wilson and a combined Hansch/Free‐Wilson analysis were performed using log P, partial log P and molar refraction values as Hansch descriptors. The results of the Free‐Wilson analysis show that modifications on the central aromatic ring generally influence pharmacological activity, whereby in almost all cases a decrease in MDR‐modulating potency is observed (Q2cv = 0.66). The combined approach results in equations with remarkably higher predictive power (Q2cv = 0.83), specifically molar refractivity shows high significance in all equations derived. This indicates that polar interactions also contribute to protein binding.
ISSN:0365-6233
1521-4184
DOI:10.1002/(SICI)1521-4184(199807)331:7/8<233::AID-ARDP233>3.0.CO;2-2