Synthesis and Biological Evaluation of Pyridine Containing Lipoxin A4 Analogues

The development of stable LXA4 and LXB4 analogues which show resistance to enzymatic degradation is an on-going research goal in drug development. Efforts directed towards derivatisation of the triene system in particular have been inspired by the encouraging results obtained from the biological evaluation of our novel aromatic analogues 1 , along with those of Petasis et al. 2, 3 . Rational replacement of this triene system has previously led to more stable derivatives, where enzymatic...

Synthesis of Heck Coupling Partner for the Preparation of Heteroaromatic Lipoxin A4 Analogues

Our research group recently developed a short and efficient synthetic route for the preparation of novel stable benzene-containing Lipoxin A4 and Lipoxin B4 analogues, reviewed in Chap. 2 1 . One of the key synthetic steps relies on the construction of a trans double bond via a palladium-catalysed Heck reaction, a reliable and powerful method for the assembly of this class of alkene, Scheme 3.1 2, 3 . Scheme 3.1 Reterosynthesis of benzene-containing LXA4 Compound 1 is a key intermediate in the...

Towards the Synthesis of Various Heteroaromatic Lipoxin A4 Analogues

Our research group has successfully demonstrated that the introduction of benzene, pyridine and thiophene rings into the core Lipoxin structure has contributed to an enhancement of the biological profile of this class of eicos-anoid 1, 2 . There is an on-going effort in the pharmaceutical industry to design and synthesise new drugs to combat existing inflammatory disorders. These novel stable LXA4 analogues possess the ability to aid the inflammation process and are therefore showing potential...

Thiophene Containing Lipoxin A4 Analogues Synthesis and Their Effect on the Production of Key Cytokines

It has recently been demonstrated that replacement of the triene system, present in native LXA4 and LXB4 with benzene, increases the stability of these eicosanoids to enzymatic metabolism 1-3 . In Chap. 4, we demonstrated that the addition of a heteroatom can also enhance the bioactivity. This pyridine-containing analogue displayed an impressive ability to resolve the inflammation process 4 . In an extension to this work, we sought to replace the triene system with a thiophene ring, Fig. 5.1,...

Secondary Metabolites from Humans

An alternative strategy to drug design and discovery stems from investigating the secondary metabolites produced by humans instead of plants, animals or microorganisms. This rationale is inspired from the beneficial effects that the plant and microbial metabolites have on the host organism. Prostaglandins are a group of lipid mediators derived from the oxidation of C20 essential fatty acids 9 . They are produced on demand within the cell from arachidonic acid. These short lived messenger...

Discovery and Isolation of Lipoxins

Another important class of secondary metabolites, oxygenated derivatives of arachidonic acid, were discovered and identified from human leukocytes by Serhan and Samuelsson in 1984 13, 14 . Lipoxin A4 (LXA4) and Lipoxin B4 (LXB4), Fig. 1.5, are trihydroxytetraene-containing eicosanoids. They are produced by the sequential actions of lipoxygenases (LO) during a series of complex cellular interactions 13 . LO are a family of iron-containing enzymes, which are known to catalyse the oxygenation of...