Design and synthesis of benzo-lipoxin A4 analogs with enhanced stability and potent anti-inflammatory properties.
A new class of chemically and metabolically stable lipoxin analogs featuring a replacement of the tetraene unit of native LXA(4) with a substituted benzo-fused ring system have been designed and studied. These molecules were readily synthesized via a convergent synthetic route involving iterative palladium-mediated cross-coupling, and exhibit enhanced chemical stability, as well as resistance to metabolic inactivation via eicosanoid oxido-reductase. These new LX analogs were evaluated in a model of acute inflammation and were shown to exhibit potent anti-inflammatory properties, significantly decreasing neutrophil infiltration in vivo. The most potent among these was compound 9 (o-[9,12]-benzo-15-epi-LXA(4) methyl ester. Taken together, these findings help identify a new class of stable and easily prepared LX analogs that may serve as novel tools and as promising leads for new anti-inflammatory agents with improved therapeutic profile.
Petasis
Nicos A
NA
Department of Chemistry and Loker Hydrocarbon Research Institute, University of Southern California, Los Angeles, CA 90089, USA.
Keledjian
Raquel
R
Sun
Yee-Ping
YP
Nagulapalli
Kalyan C
KC
Tjonahen
Eric
E
Yang
Rong
R
Serhan
Charles N
CN
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001555:Benzene Derivatives / Q000138:chemical synthesis* / Q000494:pharmacology*; D015195:Drug Design; D004355:Drug Stability; D044045:Lipoxins / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D020556:Neutrophil Infiltration / Q000187:drug effects; D010088:Oxidoreductases / Q000737:chemistry / Q000378:metabolism; D010538:Peritonitis / Q000188:drug therapy
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001555:Benzene Derivatives; D044045:Lipoxins; C040527:lipoxin A4; D010088:Oxidoreductases