5-Arylidenerhodanines as P-gp Modulators: An Interesting Effect of the Carboxyl Group on ABCB1 Function in Multidrug-Resistant Cancer Cells
Abstract
:1. Introduction
2. Results and Discussion
2.1. Synthesis
2.2. Biological Screening
2.2.1. The Rhodamine 123 Accumulation Assay
2.2.2. Cytotoxicity and Antiproliferative Assays
2.2.3. Drug Combination Assay
2.3. X-ray Studies of Compounds 3, 7, and 11
2.4. Molecular Modeling
2.5. Lipophilicity
3. Materials and Methods
3.1. Chemistry
3.1.1. General Method for the Synthesis of Compounds 1–8 and 10–12 [24]
3.1.2. Preparation of Compound 9 [44]
3.2. Biological Assays
3.2.1. Cell Lines
3.2.2. Modulation of P-gp: Rhodamine 123 Accumulation Assay
3.2.3. Cytotoxicity and Antiproliferative Assays
3.2.4. Drug Combination Assay
3.3. Crystallographic Study
Crystallographic Data
3.4. Molecular Docking
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Cmpd. | R1 | R2 |
---|---|---|
1 | -H | -Ph |
2 | -CH2COOH | -Ph |
3 | -(CH2)2COOH | -Ph |
4 | -(CH2)3COOH | -Ph |
5 | -H | -OCH2Ph |
6 | -CH2COOH | -OCH2Ph |
7 | -(CH2)2COOH | -OCH2Ph |
8 | -(CH2)3COOH | -OCH2Ph |
9 | -H | -N(Ph)2 |
10 | -CH2COOH | -N(Ph)2 |
11 | -(CH2)2COOH | -N(Ph)2 |
12 | -(CH2)3COOH | -N(Ph)2 |
Cmpd. | FAR 1 2 μM | FAR 1 20 μM |
---|---|---|
1 | <1 | 12.704 |
2 | <1 | <1 |
3 | <1 | <1 |
4 | <1 | <1 |
5 | <1 | 15.366 |
6 | <1 | <1 |
7 | <1 | <1 |
8 | <1 | <1 |
9 | 21.658 | 32.184 |
10 | 27.501 | 75.107 |
11 | 35.245 | 76.226 |
12 | 35.547 | 78.491 |
Verapamil | nd | 4.380 |
IC50 ± SD (μM) | ||||
---|---|---|---|---|
Cmpd. | Cytotoxic Effect | Antiproliferative Effect | ||
PAR | MDR | PAR | MDR | |
1 | 48.28 ± 1.54 | 56.09 ± 1.72 | 35.84 ± 0 | 39.26 ± 1.05 |
2 | >100 | >100 | 43.10 ± 0.66 | 55.17 ± 1.89 |
3 | 13.88 ± 0.49 | 17.02 ± 1.05 | 28.60 ± 0.72 | 36.75 ± 1.72 |
4 | >100 | >100 | 8.12 ± 0.89 | 4.30 ± 0.21 |
5 | 45.31 ± 0.94 | 49.57 ± 0.29 | 28.13 ± 0.43 | 50.08 ± 1.44 |
6 | >100 | >100 | 36.14 ± 1.49 | 63.48 ± 2.80 |
7 | 63.26 ± 2.61 | >100 | 36.12 ± 1.11 | 47.16 ± 0.54 |
8 | 47.01 ± 1.99 | 20.99 ± 0.95 | 7.45 ± 0.57 | 8.37 ± 0.61 |
9 * | nd | nd | nd | nd |
10 | >25 | >25 | 7.31 ± 0.70 | 9.28 ± 0.22 |
11 | >25 | >25 | 8.92 ± 1.35 | 42.10 ± 0.73 |
12 | >25 | >25 | 15.30 ± 2.24 | 11.16 ± 1.48 |
Cmpd. | Ratio 1 | CI | Interaction |
---|---|---|---|
1 | 69.6:1 | 1.50 (18) | Antagonism |
3 | 11.6:1 | 2.33 (83) | Antagonism |
5 | 34.8:1 | 1.60 (18) | Antagonism |
8 | 27.8:1 | 0.92 (8) | Nearly additive |
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Żesławska, E.; Tejchman, W.; Kincses, A.; Spengler, G.; Nitek, W.; Żuchowski, G.; Szymańska, E. 5-Arylidenerhodanines as P-gp Modulators: An Interesting Effect of the Carboxyl Group on ABCB1 Function in Multidrug-Resistant Cancer Cells. Int. J. Mol. Sci. 2022, 23, 10812. https://doi.org/10.3390/ijms231810812
Żesławska E, Tejchman W, Kincses A, Spengler G, Nitek W, Żuchowski G, Szymańska E. 5-Arylidenerhodanines as P-gp Modulators: An Interesting Effect of the Carboxyl Group on ABCB1 Function in Multidrug-Resistant Cancer Cells. International Journal of Molecular Sciences. 2022; 23(18):10812. https://doi.org/10.3390/ijms231810812
Chicago/Turabian StyleŻesławska, Ewa, Waldemar Tejchman, Annamária Kincses, Gabriella Spengler, Wojciech Nitek, Grzegorz Żuchowski, and Ewa Szymańska. 2022. "5-Arylidenerhodanines as P-gp Modulators: An Interesting Effect of the Carboxyl Group on ABCB1 Function in Multidrug-Resistant Cancer Cells" International Journal of Molecular Sciences 23, no. 18: 10812. https://doi.org/10.3390/ijms231810812