Anti-calmodulin acridone derivatives modulate vinblastine resistance in multidrug resistant (MDR) cancer cells

Abstract

Multidrug resistance (MDR) is one of the main obstacles limiting the efficacy of chemotherapy treatment of tumors. Parent acridones 1A and 1B were prepared by the Ullmann reaction followed by cyclization and N-alkylation. N-(ω-Chloroalkyl) analogues were subjected to iodide catalyzed nucleophilic substitution reaction with secondary amines to get the compounds 3A–13A and 3B–13B, which enhanced the uptake of vinblastine in KBCh R-8-5 cells to a greater extent (2.6–13.1-fold relative to control) than verapamil. The study on the structure–activity relationship revealed that substitution of –H at position C-4 in acridone nucleus by –OCH 3 increased the cytotoxic and anti-MDR activities. The ability of acridones to inhibit calmodulin dependent cyclic AMP phosphodiesterase has been determined and the results have shown a strong positive correlation between anti-calmodulin activity and cytotoxicity in KBCh R-8-5 cells or anti-MDR activity.