Anti-inflammatory and pro-resolving properties of benzo-lipoxin A(4) analogs.
Lipoxins (LXs) are potent endogenous counter-regulatory lipid mediators that dampen acute inflammation and promote its resolution. Here, we present our investigation of a new class of thermally and metabolically stable benzo-LXA(4) analogs that are potently anti-inflammatory and easier to synthesize. Replacement of the tetraene unit of native LXA(4) with a benzo-fused ring system not only increases the thermal stability but also enables highly convergent and efficient syntheses of these analogs. In addition, they resist rapid catalysis and inactivation by eicosanoid oxidoreductase. Like native LXs, o-[9, 12]-benzo-omega6-epi-LXA(4), o-[9, 12]-benzo-deoxy-LXA(4), m-[9, 12]-benzo-omega6-epi-LXA(4) and [9, 14]-benzo-omega6-(R/S)-LXA(4) demonstrated potent time-dependent reduction, at nanogram dosages, of PMN infiltration and pro-inflammatory cytokine generation in vivo in murine peritonitis and were organ protective in hind limb ischemia-reperfusion injury of the lung. The o-[9, 12]-benzo-omega6-epi-LXA(4) and m-[9, 12]-benzo-omega6-epi-LXA(4) were most potent in nanogram doses; both decreased PMN infiltration by approximately 32%, while o-[9, 12]-benzo-deoxy-LXA(4) and [9, 15]-omega6-(R/S)-LXA(4) were less potent. The [9,12]-benzo-omega6-epi-LXA(4) also activated a lipoxin A(4) GPCR and increased macrophage phagocytic activity. Taken together, these findings demonstrate a new generation of LXA(4) stable analogs that are easy to synthesize and anti-inflammatory. These benzo-LXA(4) analogs are promising tools for new therapeutic approaches as well as assessing endogenous mechanisms in anti-inflammation and resolution.
Sun
Yee-Ping
YP
Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Tjonahen
Eric
E
Keledjian
Raquel
R
Zhu
Min
M
Yang
Rong
R
Recchiuti
Antonio
A
Pillai
Padmini S
PS
Petasis
Nicos A
NA
Serhan
Charles N
CN
D000208:Acute Disease; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D015777:Eicosanoids / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D007249:Inflammation / Q000188:drug therapy* / Q000517:prevention & control*; D044045:Lipoxins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use*; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008954:Models, Biological; D010538:Peritonitis / Q000188:drug therapy / Q000473:pathology; D044042:Receptors, Formyl Peptide / Q000378:metabolism; D012074:Remission Induction
D000893:Anti-Inflammatory Agents; D015777:Eicosanoids; C469988:Fpr1 protein, mouse; D044045:Lipoxins; D044042:Receptors, Formyl Peptide; C040527:lipoxin A4