Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 25, Issue 9, Pages 2545-2568Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2017.03.033
Keywords
Ischemia/reperfusion injury; Anti-inflammation activity; Oxidative damage; Indole-TEMPO conjugates; Mitochondrial function
Funding
- NIH [GM088795-01]
- NSF [1048655]
- NASA [MSGC R85197]
- MIIE [1204010]
- VPR-SI fund [R01386]
- National Science Foundation of China [81370419]
- Natural Science Foundation of HeBei, China [062761266]
- Administration of Traditional Chinese Medicine of HeBei Province [2007134]
- [R01121]
- [R01323]
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Mitochondrial oxidative damage contributes to a wide range of pathologies including ischemia/reperfusion injury. Accordingly, protecting mitochondria from oxidative damage should possess therapeutic relevance. In the present study, we have designed and synthesized a series of novel indole-TEMPO conjugates that manifested good anti-inflammatory properties in a murine model of xylene-induced ear edema. We have demonstrated that these compounds can protect cells from simulated ischemia/reperfusion (s-I/R)-induced reactive oxygen species (ROS) overproduction and mitochondrial dysfunction. Furthermore, we have demonstrated that indole-TEMPO conjugates can attenuate organ damage induced in rodents via intestinal I/R injury. We therefore propose that the pharmacological profile and mechanism of action of these indole-TEMPO conjugates involve convergent roles, including the ability to decrease free radical production via lipid peroxidation which couples to an associated decrease in ROS-mediated activation of the inflammatory process. We further hypothesize that the protective effects of indole-TEMPO conjugates partially reside in maintaining optimal mitochondrial function. (C) 2017 Published by Elsevier Ltd.
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