Hydrogen Sulfide (H2S)-Donating Formyl Peptide Receptor 2 (FPR2) Agonists: Design, Synthesis, and Biological Evaluation in Primary Mouse Microglia Culture
Abstract
1. Introduction
2. Materials and Methods
2.1. Chemistry
2.1.1. General Procedure for the Synthesis of Compounds 4b, 5a–c, 6b
2.1.2. General Procedure for the Synthesis of the Target Compounds 7a,b and 8b
2.2. Cell-Free H2S Release Studies
2.2.1. Fluorescence Assay
2.2.2. MTT-Based Assay
2.3. Biological Methods
2.3.1. Ca2+ Mobilization Assay
2.3.2. Cell Viability Assays
2.3.3. Intracellular H2S Release Studies
2.4. Mouse Primary Microglial Cell Cultures
2.4.1. Animals
2.4.2. Cell Culture
2.4.3. Cell Treatment
2.4.4. NO Release Assay
2.4.5. Lactate Dehydrogenase (LDH) Release Assay
2.4.6. Enzyme-Linked Immunosorbent Assay (ELISA)
2.4.7. Statistical Analysis
3. Results and Discussion
3.1. Chemistry
3.2. Agonist Activity at FPR2
Ca2+ Mobilization | |||||||
---|---|---|---|---|---|---|---|
HL60-FPR2 | HL60-FPR1 | ||||||
EC50, μM (Efficacy, %) | IC50, μM | EC50, μM (Efficacy, %) | IC50, μM | ||||
Compd | X | R | |||||
3a | F | a | 3.9 a | N.T. b | 5.2 a | N.T. | |
3b | F | b | 0.026 c | 0.01 c | 0.32 c | 17.6 c | |
3c | F | c | 0.16 c | 0.21 c | 4.8 c | N.A. d | |
4b | Br | b | 0.10 ± 0.04 (120) | 0.35 | 4.8 ± 1.2 (120) | N.A. c | |
5a | F | a | N.A. | N.A. | N.A. | N.A. | |
5b | F | b | 2.2 ± 0.7 (65) | N.A. | N.A. | N.A. | |
5c | F | c | 12.0 ± 32 (105) | N.A. | N.A. | N.A. | |
6b | Br | b | 1.7 ± 0.7 (65) | 2.2 ± 0.4 | N.A. | N.A. | |
7a | F | a | 2.3 ± 0.8 (145) | 0.3 ± 0.10 | N.A. | N.A. | |
7b | F | b | 0.6 ± 0.2 (170) | 0.06 ± 0.02 | N.A. | N.A. | |
8b | Br | b | 0.04 ± 0.02 (150) | 0.007 ± 0.003 | N.A. | N.A. | |
3.3. Quantification of H2S Release by Target Compounds
3.4. Effect of Compounds 8b and 7b on NO and Cell Death in Mouse Primary Microglial Cells
3.5. Effect of Compounds 8b and 7b on the Levels of Pro- and Anti-Inflammatory Factors in Mouse Primary Microglial Cells
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Brunetti, L.; Francavilla, F.; Niso, M.; Frydrych, J.K.; Trojan, E.; Schepetkin, I.A.; Kirpotina, L.N.; Grygier, B.; Łukowicz, K.; Quinn, M.T.; et al. Hydrogen Sulfide (H2S)-Donating Formyl Peptide Receptor 2 (FPR2) Agonists: Design, Synthesis, and Biological Evaluation in Primary Mouse Microglia Culture. Antioxidants 2025, 14, 827. https://doi.org/10.3390/antiox14070827
Brunetti L, Francavilla F, Niso M, Frydrych JK, Trojan E, Schepetkin IA, Kirpotina LN, Grygier B, Łukowicz K, Quinn MT, et al. Hydrogen Sulfide (H2S)-Donating Formyl Peptide Receptor 2 (FPR2) Agonists: Design, Synthesis, and Biological Evaluation in Primary Mouse Microglia Culture. Antioxidants. 2025; 14(7):827. https://doi.org/10.3390/antiox14070827
Chicago/Turabian StyleBrunetti, Leonardo, Fabio Francavilla, Mauro Niso, Jakub Kosma Frydrych, Ewa Trojan, Igor A. Schepetkin, Liliya N. Kirpotina, Beata Grygier, Krzysztof Łukowicz, Mark T. Quinn, and et al. 2025. "Hydrogen Sulfide (H2S)-Donating Formyl Peptide Receptor 2 (FPR2) Agonists: Design, Synthesis, and Biological Evaluation in Primary Mouse Microglia Culture" Antioxidants 14, no. 7: 827. https://doi.org/10.3390/antiox14070827
APA StyleBrunetti, L., Francavilla, F., Niso, M., Frydrych, J. K., Trojan, E., Schepetkin, I. A., Kirpotina, L. N., Grygier, B., Łukowicz, K., Quinn, M. T., Basta-Kaim, A., Lacivita, E., & Leopoldo, M. (2025). Hydrogen Sulfide (H2S)-Donating Formyl Peptide Receptor 2 (FPR2) Agonists: Design, Synthesis, and Biological Evaluation in Primary Mouse Microglia Culture. Antioxidants, 14(7), 827. https://doi.org/10.3390/antiox14070827