Tetramethylpiperidine-substitution increases the antitumor activity of theriminophenazines for an acquired multidrug-resistant cell line

The multidrug resistance (MDR)-neutralizing and cytotoxic properties of fiv e tetramethylpiperidine (TMP)-substituted phenazines were compared with tho se of their corresponding isopropyl-substituted analogues using a P-glycopr otein (P-gp)-expressing small cell lung cancer cell line (H69/LX4). All of the TMP-substituted phenazines tested outperformed their isopropyl analogue s with respect to both cytotoxic and chemosensitizing properties, indicatin g the importance of TMP-substitution when designing novel riminophenazines with increased activity against MDR cancer cell lines. Of the TMP-substitut ed phenazines tested, B4112, chlorinated at position 3 of the phenyl- and a nilino-rings, had the most potent anti-cancer activity in vitro, making thi s agent a potential candidate for evaluation in experimental and clinical o ncology.