TY  - JOUR
A1  - Hellmuth, Nadine
A1  - Brat, Camilla Anethe Sandra
A1  - Awad, Omar
A1  - George, Sven
A1  - Kahnt, Astrid Stefanie
A1  - Bauer, Tom
A1  - Phuoc, Hai Phong Huynh
A1  - Steinhilber, Dieter
A1  - Angioni, Carlo
A1  - Hassan, Mohamed
A1  - Hock, Katharina Julia
A1  - Manolikakes, Georg
A1  - Zacharowski, Kai
A1  - Roos, Jessica
A1  - Maier, Thorsten Jürgen
T1  - Structural modifications yield novel insights into the intriguing pharmacodynamic potential of anti-inflammatory nitro-fatty acids
T2  - Frontiers in pharmacology
N2  - 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.
KW  - nitroalkene
KW  - michael acceptor
KW  - structure-function
KW  - NF-κB
KW  - oluble epoxide hydrolase
KW  - Nrf-2
KW  - 5-lipoxygenase
KW  - cyclooxygenase-2
Y1  - 2021
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/62059
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-620597
SN  - 1663-9812
N1  - This work was supported by the Deutsche Forschungsgemeinschaft (DFG) MA-5825/1-2. This work did not receive any further specific grant(s) from funding agencies in the public, commercial, or not-for-profit sectors.
VL  - 12
IS  - art. 715076
SP  - 1
EP  - 16
PB  - Frontiers Media
CY  - Lausanne
ER  -