Design and synthesis of benzo-lipoxin A4 analogs with enhanced stability and potent anti-inflammatory properties.

Abstract

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.

DOI: 10.1016/j.bmcl.2008.01.013

2 Figures and Tables

Cite this paper

@article{Petasis2008DesignAS, title={Design and synthesis of benzo-lipoxin A4 analogs with enhanced stability and potent anti-inflammatory properties.}, author={Nicos A Petasis and Raquel Keledjian and Yee-Ping Sun and Kalyan C Nagulapalli and Eric Tjonahen and Rong Yang and Charles N Serhan}, journal={Bioorganic & medicinal chemistry letters}, year={2008}, volume={18 4}, pages={1382-7} }