Heterocyclic Nitrogen Compounds as Potential PDE4B Inhibitors in Activated Macrophages
Source abstract
Abstract
Cyclic-nucleotide phosphodiesterases (PDEs) represent a superfamily of enzymes playing a pivotal role in cell signaling by controlling cAMP and cGMP levels in response to receptor activation. PDE activity and expression are linked to many diseases including inflammatory diseases. In light of their specific biochemical properties, PDE inhibition has attracted the interest of several researrs In this context, PDE4 inhibition induces anti-inflammatory effects. Piclamilast and rolipram, well-known PDE4 inhibitors, are endowed with common side effects. The selective phosphodiesterase 4B (PDE4B) inhibitors could be a promising approach to overcome these side effects. In the present study, six potential PDE4B inhibitors have been investigated. Through this study, we identified three PDE4B inhibitors in human macrophages activated by lipopolysaccharide. Interestingly, two of them reduced reactive oxygen species production in pro-inflammatory macrophages.
Source: crossref · Quality: baseline
Research context
OpenAlex topics: Phosphodiesterase function and regulation · Synthesis and Catalytic Reactions · Phenothiazines and Benzothiazines Synthesis and Activities
SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.
Affiliations
Department of Science, University of Basilicata, Viale dell’Ateneo Lucano 10, 85100 Potenza, Italy
Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende, Italy
Faculty of Science, Assiut University, Assiut 71516, Egypt
Faculty of Pharmacy, Sphinx University, New Assiut 71515, Egypt
U.O.C. Primary Care and Territorial Health, Social and Health Department, State Hospital, 47893 San Marino, San Marino
Spinoff TNcKILLERS s.r.l., University of Basilicata, 85100 Potenza, Italy
References (31)
Show source-provided references
1. Structures of the four subfamilies of phosphodiesterase-4 provide insight into the selectivity of their inhibitors10.1042/BJ20070970 ↗
2. Cyclic nucleotide phosphodiesterase (PDE) isozymes as targets of the intracellular signalling network: Benefits of PDE inhibitors in various diseases and perspectives for future therapeutic developments10.1111/j.1476-5381.2011.01729.x ↗
3. Molecular mechanisms that could contribute to prolonged effectiveness of PDE5 inhibitors to improve erectile function10.1038/ijir.2008.4 ↗
4. Phosphodiesterase 4 and its inhibitors in inflammatory diseases
5. Phosphodiesterase 4B gene transcription is activated by lipopolysaccharide and inhibited by interleukin-10 in human monocytes10.1124/mol.55.1.50 ↗
6. Specific role of phosphodiesterase 4B in lipopolysaccharide-induced signaling in mouse macrophages10.4049/jimmunol.175.3.1523 ↗
7. Phosphodiesterase 4B is required for NLRP3 inflammasome activation by positive feedback with Nrf2 in the early phase of LPS- induced acute lung injury10.1016/j.freeradbiomed.2021.10.007 ↗
8. Induction of the cyclic nucleotide phosphodiesterase PDE4B is essential for LPS-activated TNF-alpha responses10.1073/pnas.122041599 ↗
9. Iacobazzi, D., Convertini, P., Todisco, S., Santarsiero, A., Iacobazzi, V., and Infantino, V. (2023). New Insights into NF-κB Signaling in Innate Immunity: Focus on Immunometabolic Crosstalks. Biology, 12.10.3390/biology12060776 ↗
10. Macrophages, innate immunity and cancer: Balance, tolerance, and diversity10.1016/j.coi.2010.01.009 ↗
11. Differential requirement for the activation of the inflammasome for processing and release of IL-1beta in monocytes and macrophages10.1182/blood-2008-03-146720 ↗
12. Wang, L., Wang, D., Zhang, T., Ma, Y., Tong, X., and Fan, H. (2023). The role of immunometabolism in macrophage polarization and its impact on acute lung injury/acute respiratory distress syndrome. Front. Immunol., 14.10.3389/fimmu.2023.1117548 ↗
13. Metabolic Routes in Inflammation: The Citrate Pathway and its Potential as Therapeutic Target10.2174/0929867325666180510124558 ↗
14. ACLY as a modulator of liver cell functions and its role in Metabolic Dysfunction-Associated Steatohepatitis10.1186/s12967-023-04431-w ↗
15. Master and commander: Epigenetic regulation of macrophages10.1038/cr.2016.5 ↗
16. Hydrosol: Untargeted Metabolomic Analysis and Anti-Inflammatory Activity Mediated by NF-κB and the Citrate Pathway10.1155/2020/4264815 ↗
17. Santarsiero, A., Convertini, P., Todisco, S., Pierri, C.L., De Grassi, A., Williams, N.C., Iacobazzi, D., De Stefano, G., O’Neill, L.A.J., and Infantino, V. (2021). ACLY Nuclear Translocation in Human Macrophages Drives Proinflammatory Gene Expression by NF-κB Acetylation. Cells, 10.10.3390/cells10112962 ↗
18. Inhibition of Human Topoisomerase II by N,N,N-Trimethylethanammonium Iodide Alkylcarbazole Derivatives10.1002/cmdc.201800546 ↗
19. Caruso, A., Ceramella, J., Iacopetta, D., Saturnino, C., Mauro, M.V., Bruno, R., Aquaro, S., and Sinicropi, M.S. (2019). Carbazole Derivatives as Antiviral Agents: An Overview. Molecules, 24.10.3390/molecules24101912 ↗
20. Giuzio, F., Bonomo, M.G., Catalano, A., Infantino, V., Salzano, G., Monné, M., Geronikaki, A., Petrou, A., Aquaro, S., and Sinicropi, M.S. (2023). Potential PDE4B inhibitors as promising candidates against SARS-CoV-2 infection. Biomol. Concepts, 14.10.1515/bmc-2022-0033 ↗
21. N-alkyl carbazole derivatives as new tools for Alzheimer’s disease: Preliminary studies10.3390/molecules19079307 ↗
22. Saturnino, C., Grande, F., Aquaro, S., Caruso, A., Iacopetta, D., Bonomo, M.G., Longo, P., Schols, D., and Sinicropi, M.S. (2018). Chloro-1,4-dimethyl-9H-carbazole Derivatives Displaying Anti-HIV Activity. Molecules, 23.10.3390/molecules23020286 ↗
23. Expedient synthesis of eumelanin-inspired 5,6-dihydroxyindole-2-carboxylate ethyl ester derivatives10.1039/C8RA06148C ↗
24. Synthesis and Agonistic Activity at the GPR35 of 5,6-Dihydroxyindole-2-carboxylic Acid Analogues10.1021/ml300076u ↗
25. C-H Amination of Purine Derivatives via Radical Oxidative Coupling10.1021/acs.joc.8b00066 ↗
26. Marsico, M., Santarsiero, A., Pappalardo, I., Convertini, P., Chiummiento, L., Sardone, A., Di Noia, M.A., Infantino, V., and Todisco, S. (2021). Mitochondria-Mediated Apoptosis of HCC Cells Triggered by Knockdown of Glutamate Dehydrogenase 1: Perspective for Its Inhibition through Quercetin and Permethylated Anigopreissin A. Biomedicines, 9.10.3390/biomedicines9111664 ↗
27. Su, Y., Ding, J., Yang, F., He, C., Xu, Y., Zhu, X., Zhou, H., and Li, H. (2022). The regulatory role of PDE4B in the progression of inflammatory function study. Front. Pharmacol., 13.10.3389/fphar.2022.982130 ↗
28. Canton, M., Sánchez-Rodríguez, R., Spera, I., Venegas, F.C., Favia, M., Viola, A., and Castegna, A. (2021). Reactive Oxygen Species in Macrophages: Sources and Targets. Front. Immunol., 12.10.3389/fimmu.2021.734229 ↗
29. The role of NOX inhibitors in neurodegenerative diseases10.1016/j.ibror.2019.07.1721 ↗
30. Therapeutic potential of NOX inhibitors in neuropsychiatric disorders10.1007/s00213-023-06424-5 ↗
31. Picchianti-Diamanti, A., Spinelli, F.R., Rosado, M.M., Conti, F., and Laganà, B. (2021). Inhibition of Phosphodiesterase-4 in Psoriatic Arthritis and Inflammatory Bowel Diseases. Int. J. Mol. Sci., 22.10.3390/ijms22052638 ↗