Effects of tetramethylpiperidine (TMP)-substituted phenazines on membrane stability and P-glycoprotein function

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.