title: New phenothiazine-type multidrug resistance modifiers: anti-MDR activity versus membrane perturbing potency.
abstract: The phenothiazine multidrug resistance (MDR) modulators are chemically diversified but share the common feature to be hydrophobic cationic molecules. Molecular mechanisms of their action may involve interactions with either P-glycoprotein or membrane lipid matrix. In the present work we study the anti-MDR and biophysical membrane effects of new phenothiazine derivatives differing in the type of group substituting phenothiazine ring at position 2 (H-, Cl-, CF(3)-) and in the side chain group (NHCO(2)CH(3) or NHSO(2)CH(3)). Within each phenothiazine subset we found that anti-MDR activity (determined by P-glycoprotein inhibition assessed by flow cytometry) correlates with the theoretically calculated hydrophobicity value (logP) and experimental parameters (determined by calorimetry and fluorescence spectroscopy) of lipid bilayers. It is concluded that the biological and biophysical activity of phenothiazine derivatives depends more on the type of ring substitution than on the nature of the side chain group.
authors.affiliation: Department of Biophysics, Wrocław Medical University, ul. Chałubińskiego 10, 50-368, Wrocław, Poland. hendrich@biofiz.am.wroc.pl
authors.forename: Andrzej B
authors.initials: AB
authors.lastname: Hendrich
authors.forename: Olga
authors.initials: O
authors.lastname: Wesołowska
authors.forename: Noboru
authors.initials: N
authors.lastname: Motohashi
authors.forename: Joseph
authors.initials: J
authors.lastname: Molnár
authors.forename: Krystyna
authors.initials: K
authors.lastname: Michalak
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D002151:Calorimetry; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D057927:Hydrophobic and Hydrophilic Interactions; D008051:Lipid Bilayers / Q000737:chemistry; D008560:Membrane Fluidity; D051379:Mice; D010640:Phenothiazines / Q000737:chemistry* / Q000494:pharmacology*; D013050:Spectrometry, Fluorescence; D014407:Tumor Cells, Cultured
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D008051:Lipid Bilayers; D010640:Phenothiazines