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Structure-activity relationship of verapamil analogs and reversal of multidrug resistance
G Toffoli1, F Simone, G Corona
1Division of Experimental Oncology 1, Centro di Riferimento Oncologico, Aviano, Italy.
Abstract:
We studied the relationship between the chemical structure and multidrug resistance (MDR) reversal activity of racemic verapamil (VER) and 14 VER analogs (VAs). The LoVo-R human colon carcinoma cell line was used as an experimental model. This cell line exhibited a typical MDR phenotype and overexpressed the MDR1 gene products. Key structural features were identified as being related to MDR reversal and cytotoxic activity. In particular, we demonstrated that the methoxy groups in the VER molecule structure [1.7-Bis-(3.4-dimethoxyphenyl)-3-methylaza-7-cyan-8-methyl-n onane] prevented cytotoxicity when the VAs were used alone, whereas the 7-cyan-8-methyl groups were important for MDR reversal activity and interaction with P-glycoprotein (P-gp). Among the VAs tested, the most active compounds were gallopamil, R-isomer of VER (R-VER), and nor-VER, which potentiated doxorubicin (DOX) cytotoxicity by 52.3 +/- 7.2 (n = 3 +/- SD), 38.9 +/- 6.4 (n = 4 +/- SD), and 35.4 +/- 4.3 (n = 3 +/- SD) times, respectively. The reversal activity of these compounds was similar to that of VER, which enhanced DOX cytotoxicity by 41.3 +/- 5.0 (n = 3 +/- SD) times. The potentiation of DOX cytotoxicity was associated with an increase in DOX uptake in LoVo-R cells and with an increased [3H]azidopine P-gp photolabeling inhibition. Some compounds that had a high reversal potency (i.e. R-VER and nor-VER) showed a lower calcium antagonist activity than VER, and seem useful candidates for the treatment of MDR in cancer patients.
Insights
Researchers explored how chemical structure affects multidrug resistance (MDR) reversal in cancer. Specific structural features, like 7-cyan-8-methyl groups, enhance MDR reversal by interacting with P-glycoprotein (P-gp).
Area of Science:
- Pharmacology
- Medicinal Chemistry
- Cancer Biology
Background:
- Multidrug resistance (MDR) is a major challenge in cancer chemotherapy, often mediated by P-glycoprotein (P-gp) efflux pumps.
- Verapamil (VER) and its analogs (VAs) are known to modulate P-gp activity, but structure-activity relationships for MDR reversal are not fully elucidated.
Purpose of the Study:
- To investigate the relationship between the chemical structure of verapamil analogs and their ability to reverse multidrug resistance in a human colon carcinoma cell line.
- To identify key structural features responsible for MDR reversal activity and cytotoxic effects.
Main Methods:
- Utilized the LoVo-R human colon carcinoma cell line, which overexpresses the MDR1 gene product, as an experimental model for MDR.
- Synthesized and tested 14 verapamil analogs for their ability to reverse doxorubicin resistance and their cytotoxic effects.
- Assessed P-glycoprotein interaction using [3H]azidopine photolabeling inhibition and measured drug uptake.
Main Results:
- Methoxy groups in verapamil analogs were found to prevent cytotoxicity when used alone.
- The 7-cyan-8-methyl groups were crucial for MDR reversal activity and P-gp interaction.
- Gallopamil, R-verapamil (R-VER), and nor-verapamil demonstrated significant potentiation of doxorubicin cytotoxicity, comparable to verapamil.
- High reversal potency was observed with R-VER and nor-VER, which also exhibited lower calcium antagonist activity than verapamil.
Conclusions:
- Specific structural modifications of verapamil can yield potent MDR reversal agents with potentially reduced side effects.
- R-verapamil and nor-verapamil are promising candidates for further investigation in the treatment of multidrug-resistant cancers.
- Understanding structure-activity relationships is key to designing effective MDR reversal therapies.