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

Abstract

It has recently been demonstrated that replacement of the triene system, present in native LXA₄ and LXB₄ with benzene, increases the 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, and examine the effect this substitution has on the biological potency of the compound. This substitution is a classical example of the bioisoterism concept in medicinal chemistry [5, 6]. Thiophene is an excellent bioisostere for benzene, as the diameter of the sulphur atom is the same length of the replaced C=C double bond [7]. It also offers the possibility of accessing three positional isomers of the analogue which can assist in probing the compounds bioactivity. This particular drug design approach is common and accounts for a large proportion of the successful examples of bioisosteric replacement which can be seen in the literature [8–10].