Structural Modifications Yield Novel Insights Into the Intriguing Pharmacodynamic Potential of Anti-inflammatory Nitro-Fatty Acids

Abstract

Endogenous nitro-fatty acids (NFA) are potent electrophilic lipid mediators that exert biological effects in vitro and in vivo via selective covalent modification of thiol-containing target proteins. The cytoprotective, anti-inflammatory, and anti-tumorigenic effects of NFA in animal models of disease caused by targeted protein nitroalkylation are a valuable basis for the development of future anti-phlogistic and anti-neoplastic drugs. Considering the complexity of diseases and accompanying comorbidities there is an urgent need for clinically effective multifunctional drugs. NFA are composed of a fatty acid backbone containing a nitroalkene moiety triggering Michael addition reactions. However, less is known about the target-specific structure–activity relationships and selectivities comparing different NFA targets. Therefore, we analyzed 15 NFA derivatives and compared them with the lead structure 9-nitro-oleic acid (9NOA) in terms of their effect on NF-κB (nuclear factor kappa B) signaling inhibition, induction of Nrf-2 (nuclear factor erythroid 2-related factor 2) gene expression, sEH (soluble epoxide hydrolase), LO (lipoxygenase), and COX-2 (cyclooxygenase-2) inhibition, and their cytotoxic effects on colorectal cancer cells. Minor modifications of the Michael acceptor position and variation of the chain length led to drugs showing increased target preference or enhanced multi-targeting, partly with higher potency than 9NOA. This study is a significant step forward to better understanding the biology of NFA and their enormous potential as scaffolds for designing future anti-inflammatory drugs.

Nitro Fatty Acids (NO2-FAs): An Emerging Class of Bioactive Fatty Acids

“…All of the tested NO 2 -FAs induced Nrf2, as it was demonstrated by Western blot and ELISA [34]. The majority of the tested compounds with a carbon chain length greater than sixteen, led to a significant Nrf2 gene expression.…”

“…12-LO was not inhibited at all, while 15-LO showed a weaker inhibition effect in comparison to 5-LO. The tested NO 2 -FAs showed an average inhibition of sEH and failed to inhibit COX-2 [34].…”

“…The SAR study against LOs showed that compound 23 exhibited significant inhibition of 5-LO with an IC 50 value of 0.3 ± 1.2 µM, while alternating the nitroalkene moiety position did not cause any significant result against 5-LO [34]. Compound 10 exhibited more potent inhibition of 5-LO (IC 50 0.4 ± 1.2 µM) in comparison to 9-NO 2 -OA (9) (IC 50 1.1 ± 1.2 µM).…”

“…Most recently, fifteen NO 2 -FAs have been studied for their effects on activation of Nrf2, and inhibition of NF-κB signaling pathway, cyclooxygenase-2 (COX-2), LO and soluble Epoxide Hydrolase (sEH), as well as for their cytotoxic activity on colorectal cancer cells [34]. All the new NO 2 -FAs were compared with the lead compound 9-NO 2 -OA (9) (Figure 5).…”

“…The carbon chain length varies between twelve to twenty-two total carbon atoms and the nitro group is inserted from position C4 to C11 each time, close or away from the carboxylic group. The inhibitory activity of these NO 2 -FAs against the NF-κB signaling pathway (p65 and p50) in colorectal cancer cells was studied in comparison with 9-NO 2 -OA [34]. The cytotoxic effect of the tested NO 2 -FAs against subunit p65 showed that compounds 22 and 23 demonstrated slightly worse activity than 9-NO 2 -OA.…”