Asymmetric synthesis of aromatic lipoxin A 4 analogues with biological evaluation Lucy Byrne , Olivia Bracken, Derek Gilroy and Patrick J. Guiry University College Dublin, Ireland email: lucy.byrne3@ucdconnect.ie, p.guiry@ucd.ie Lipoxins are a class of bioactive compounds which play a vital role in the process and resolution of inflammation in the human body. They were first isolated in human leukocytes by Serhan and Samuelsson in 1984. 1 Lipoxins are enzymatically derived from arachidonic acid by a family of lipoxygenase enzymes and regulate components of both the innate and the adaptive immune systems. Their primary role is to initiate the resolution of inflammation by activating the FPR2/ALX receptor. 2 Lipoxins’ ability to resolve inflammation is essential to the restoration of heathy immune function.
This work focuses on the synthesis of a library of LXA 4 analogues, specifically designed to overcome the rapid metabolic deactivation that arises in the natural Lipoxin mimetic. The series of molecules were designed through the molecular hybridisation of aromatic LXA 4 analogues and Resolvin (RvD1), another important endogenous mediator in the resolution of inflammation. 3 This work also explores the modification of the aromatic core of the RvD1-LXA 4 molecule to include imidazole/ triazole moieties, which are prevalent in many pharmaceutically relevant compounds. The asymmetric synthesis of these heteroaromatic-LXA 4 analogues will be presented, along with preliminary results of their biological evaluation.
Biological evaluation of these compounds was carried out in collaboration with Prof. Derek Gilroy of University College London and shows the success of these LXA 4 mimetics in the inhibition of key inflammatory cytokines. References 1. Serhan, C. N.; Hamberg, M.; Samuelsson, B. Proc. Natl. Acad. Sci. U. S. A. 1984 , 81 (17 I), 5335–5339. 2. O’Sullivan, T. P.; Vallin, K. S. A.; Shah, S. T. A.; Fakhry, J.; Maderna, P.; Scannell, M.; Sampaio, A. L. F.; Perretti, M.; Godson, C.; Guiry, P. J. J. Med. Chem. 2007 , 50 (24), 5894–5902. 3. Serhan, C. N.; Hong, S.; Gronert, K.; Colgan, S. P.; Devchand, P. R.; Mirick, G.; Moussignac, R. L.. J. Exp. Med. 2002 , 196 (8), 1025–1037.
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