title: Effects of tetramethylpiperidine (TMP)-substituted phenazines on membrane stability and P-glycoprotein function.
abstract: The lipophilicity and membrane-destabilizing activities of clofazimine and three tetramethyl-piperidine (TMP)-substituted phenazines were compared with the anti-tumor and multiple drug resistance (MDR) neutralizing potential of these agents using a P-glycoprotein (P-gp)-expressing small cell lung cancer cell line (H69/LX4). Partition coefficients were measured as an index of lipophilicity, while membrane-destabilizing potential was measured using a conventional hemolytic assay. The membrane-destabilizing potential of the TMP-substituted phenazines was found to correlate positively with the degree of lipophilicity, as well as with MDR reversal activity. The presence of a TMP group, as well as chlorine atoms on the phenyl and anilino rings of these agents contributed to the enhancement of anti-tumor activity by potentiating membrane-destabilizing activity. TMP-substituted phenazines may be useful in the design of novel anti-cancer and MDR reversal agents.
authors.affiliation: Medical Research Council Unit for Inflammation and Immunity, Department of Immunology, Institute for Pathology, Faculty of Medicine, University of Pretoria, Pretoria 0001, Republic of South Africa.
authors.forename: C
authors.initials: C
authors.lastname: Durandt
authors.forename: C E
authors.initials: CE
authors.lastname: van Rensburg
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D052160:Benzothiazoles; D018288:Carcinoma, Small Cell / Q000188:drug therapy / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002991:Clofazimine / Q000031:analogs & derivatives / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism; D008560:Membrane Fluidity / Q000187:drug effects; D011804:Quinolines; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000378:metabolism; D014747:Vinblastine / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D052160:Benzothiazoles; D011804:Quinolines; D013844:Thiazoles; C051000:thiazole orange; D014747:Vinblastine; D002991:Clofazimine