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Comparative Study on the MDR Reversal Effects of Selected Chalcones
A B Ivanova1, D I Batovska1, I T Todorova1
1Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Acad. G. Bonchev Street Bl. 9, Sofia 1113, Bulgaria.
Abstract:
Based on the structure of three previously established lead compounds, fifteen selected chalcones were synthesized and evaluated for their multidrug resistance (MDR) reversal activity on mouse lymphoma cells. The most active chalcones were stronger revertants than the positive control, verapamil. In the model of combination chemotherapy, the interactions between the anticancer drug doxorubicin and two of the most effective compounds were measured in vitro, on human MDR1 gene transfected mouse lymphoma cells, showing that the type of interaction for one of these compounds was indifferent while that for the other one was additive. Furthermore, two chalcones inhibited 50% of cell proliferation in concentration of around 0.4 μg/mL and were from 2- to 100-fold more active than the most chalcones. The structure-activity relationships were obtained and discussed in view of their usefulness for the design of chalcone-like P-gp modulators and drugs able to treat resistant cancers.
Insights
New chalcone compounds show potent multidrug resistance (MDR) reversal activity, outperforming verapamil. These compounds offer promise for combination chemotherapy against resistant cancers.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Cancer Biology
Background:
- Multidrug resistance (MDR) in cancer poses a significant challenge to chemotherapy efficacy.
- P-glycoprotein (P-gp) is a key transporter involved in MDR.
- Chalcones are a class of compounds with diverse biological activities, including potential anticancer properties.
Purpose of the Study:
- To synthesize and evaluate novel chalcone derivatives for their ability to reverse multidrug resistance.
- To investigate the in vitro interaction of potent chalcones with doxorubicin in combination chemotherapy.
- To establish structure-activity relationships for the design of new P-gp modulators.
Main Methods:
- Synthesis of fifteen chalcone derivatives based on established lead compounds.
- Assessment of MDR reversal activity in mouse lymphoma cells.
- In vitro evaluation of drug interactions using doxorubicin and human MDR1 gene-transfected mouse lymphoma cells.
- Determination of IC50 values for cell proliferation inhibition.
Main Results:
- Several synthesized chalcones exhibited significant MDR reversal activity, exceeding that of verapamil.
- Two chalcones demonstrated additive or indifferent interactions with doxorubicin in combination chemotherapy models.
- Two chalcone compounds showed potent inhibition of cell proliferation with IC50 values around 0.4 μg/mL.
- Structure-activity relationship analysis provided insights into the design of effective P-gp modulators.
Conclusions:
- Chalcone derivatives are promising candidates for overcoming multidrug resistance in cancer.
- These compounds can enhance the efficacy of existing anticancer drugs like doxorubicin.
- The structure-activity relationships identified can guide the development of novel therapeutic agents for resistant cancers.
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