Regio- and Stereoselective Synthesis of Nitro-fatty Acids as NRF2 Pathway Activators Working under Ambient or Hypoxic Conditions
Year: 2025
Type: article
Abstract: High Resolution Image Download MS PowerPoint Slide Nitro-fatty acids (NO 2 FAs) are endogenously produced electrophiles and NRF2 activators with therapeutic potential. We developed a synthetic protocol combining a Henry reaction and base-promoted β-elimination, yielding ultrapure regio/stereoisomers of nitro-stearic (NO 2 SA), nitro-oleic (NO 2 OA), and conjugated/ bis -allylic nitro-linoleic (NO 2 LA) acids. These were tested for NRF2 pathway activation in bone marrow cells under different oxygen conditions. We observed that 9- and 10-NO 2 OA, and 10-NO 2 LA increased NRF2 stabilization under hypoxia, while 9- and 10-NO 2 OA significantly upregulated Hmox1 and Gclm at all oxygen levels. 9- and 10-NO 2 OA enhanced HO-1 and GCLM proteins independently of oxygen, while 10-NO 2 LA was oxygen-dependent, boosting HO-1 under hypoxia and GCLM under ambient conditions. Moreover, 10-NO 2 OA and 10-NO 2 LA induced NRF2 nuclear translocation. In contrast, the saturated 10-NO 2 SA, which has lower electron-acceptor ability, was inactive. In summary, these findings suggest the biological activity of NO 2 FAs is dependent on oxygen level, which could be used in future research of other oxidative stress-dependent pathways.
Source: Journal of Medicinal Chemistry
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,500
OpenAlex ID: W4410735330