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Updated: Aug 7, 2026
Development and Standardization of an Ex Vivo Micromethod for Intracellular Quantification of Vincristine in Primary ALL Cells by LC-MS/MS
Published on: January 23, 2026
Sensitization of multidrug resistant (MDR) cancer cells to vinblastine by novel acridones: correlation between
Y C Mayur1, T Padma, B H Parimala
1Department of Chemistry, Western Illinois University, 1 University Circle, Currens Hall, Macomb, IL 61455, USA.
Abstract:
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.
Insights
New acridone derivatives were synthesized to combat multidrug resistance (MDR) in cancer cells. These compounds effectively reversed MDR by inhibiting P-glycoprotein (P-gp) and enhancing chemotherapy drug efficacy.
Area of Science:
- Medicinal Chemistry
- Cancer Biology
- Pharmacology
Background:
- Multidrug resistance (MDR) in cancer cells is a major obstacle to successful chemotherapy.
- Developing novel MDR reversal agents is crucial for improving patient outcomes.
Purpose of the Study:
- To synthesize and evaluate novel N(10)-substituted-2-bromoacridones as potential modulators of MDR.
- To investigate the mechanism of action and structure-activity relationships of these compounds.
Main Methods:
- Synthesis of 19 N(10)-substituted-2-bromoacridone derivatives.
- Assay of vinblastine (VLB) uptake in MDR KBCh(R)-8-5 cells.
- VLB efflux inhibition studies.
- Competition assays with [(3)H] azidopine for P-glycoprotein (P-gp) binding.
- Evaluation of cytotoxicity modulation of VLB.
- Structure-activity relationship (SAR) analysis.
- Assessment of anti-calmodulin activity.
Main Results:
- Synthesized compounds enhanced VLB uptake in MDR cells (1.25 to 1.9-fold) compared to verapamil.
- Compounds significantly inhibited VLB efflux, indicating P-gp interaction.
- All compounds competed with [(3)H] azidopine for P-gp binding, confirming P-gp as the target.
- Cytotoxicity of VLB was enhanced by 3.8 to 34-fold in the presence of the modulators.
- Bromine substitution at C-2 position of the acridone nucleus increased anti-MDR and cytotoxic activities.
- A positive correlation was observed between anti-calmodulin activity and anti-MDR effects.
Conclusions:
- N(10)-substituted-2-bromoacridones are effective MDR modulators with potential clinical applications.
- These compounds act by inhibiting P-gp and potentially calmodulin.
- The bromine atom at C-2 and anti-calmodulin activity are important for enhanced efficacy.
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