Sensitization of multidrug resistant (MDR) cancer cells to vinblastine by novel acridones: correlation between anti-calmodulin activity and anti-MDR activity.
Multidrug resistance (MDR) of cancer cells remains to be an important cause of chemotherapy failure. Search for the new MDR reversal agents is still an unceasing challenge for the scientists. In an attempt to find clinically useful modulators of MDR, a series of 19 N(10)-substituted-2-bromoacridones has been synthesized. Parent compound 1, prepared by the Ullmann condensation of o-chlorobenzoic acid and p-bromoaniline, undergoes N-alkylation in the presence of a phase transfer catalyst. N-(omega-Chloroalkyl) analogues were subjected to iodide catalyzed nucleophilic substitution reaction with various secondary amines to get the products 3-10 and 12-19, which increased the uptake of vinblastine (VLB) in MDR KBCh(R)-8-5 cells to a greater extent (1.25 to 1.9-fold) than did a similar concentration of the standard modulator, verapamil (VRP). Results of the efflux experiment showed that each modulator significantly inhibited the efflux of VLB, suggesting that they may be competitors for P-gp. All the compounds effectively compete with [(3)H] azidopine for binding to P-gp, pointed out this transport membrane protein as their likely site of action. Compounds at IC(10) were evaluated for their efficacy to modulate the cytotoxicity of VLB in KBCh(R)-8-5 cells and found that the modulators enhanced the cytotoxicity of VLB by 3.8 to 34-fold. The study on the structure-activity relationship revealed that substitution of hydrogen atom at position C-2 in acridone nucleus by a bromine atom 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.