Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 23, Issue 18, Pages -Publisher
MDPI
DOI: 10.3390/ijms231810710
Keywords
soluble epoxide hydrolase; inhibitor; adamantane; selenourea; anti-inflammatory
Funding
- Russian Fund for Basic Research [20-03-00298]
- Russian Science Foundation [22-14-00124]
- Ministry of Science and Higher Education of the Russian Federation [075-15-2019-1672, FWNR-2022-0017]
- NIEHS [R35 ES030443]
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The newly synthesized inhibitor compounds showed effective inhibitory activity against inflammation and exhibited low cytotoxicity in cell assays.
The inhibitory potency of the series of inhibitors of the soluble epoxide hydrolase (sEH) based on the selenourea moiety and containing adamantane and aromatic lipophilic groups ranges from 34.3 nM to 1.2 mu M. The most active compound 5d possesses aliphatic spacers between the selenourea group and lipophilic fragments. Synthesized compounds were tested against the LPS-induced activation of primary murine macrophages. The most prominent anti-inflammatory activity, defined as a suppression of nitric oxide synthesis by LPS-stimulated macrophages, was demonstrated for compounds 4a and 5b. The cytotoxicity of the obtained substances was studied using human neuroblastoma and fibroblast cell cultures. Using these cell assays, the cytotoxic concentration for 4a was 4.7-18.4 times higher than the effective anti-inflammatory concentration. The genotoxicity and the ability to induce oxidative stress was studied using bacterial lux-biosensors. Substance 4a does not exhibit genotoxic properties, but it can cause oxidative stress at concentrations above 50 mu M. Put together, the data showed the efficacy and safety of compound 4a.
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