Synthesis of methyl (5S,6R,7E,9E,11Z,13E,15S)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-7,9,11,13-hexadecatetraenoate, an analogue of 15R-Lipoxin A4

Phillips, Eifion D.; Chang, Huifang; Holmquist, Christopher R.; McCauley, John P.

doi:10.1016/s0960-894x(03)00667-x

Cited by 20 publications

(6 citation statements)

References 26 publications

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“…The 3-oxa analogues 4 and 5 differ in that all of the carbon atoms in the chain are either unsaturated or substituted with oxygen. As in the reported synthesis of 2 , the retrosynthetic analysis of the lipoxin analogues is based on the Nicolaou synthesis of lipoxin A 4 ( 1 ) and is shown in Scheme . This convergent approach divides the molecule into three parts: an enyne Wittig reagent ( 13 ), an aldehyde ( 11 or 12 ), and a vinyl bromide unit ( 17 ).…”

Section: Chemistrymentioning

confidence: 99%

Novel 3-Oxa Lipoxin A₄ Analogues with Enhanced Chemical and Metabolic Stability Have Anti-inflammatory Activity in Vivo

Guilford¹,

Bauman²,

Skuballa³

et al. 2004

J. Med. Chem.

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Lipoxin A(4) (LXA(4)) is a structurally and functionally distinct natural product called an eicosanoid, which displays immunomodulatory and anti-inflammatory activity but is rapidly metabolized to inactive catabolites in vivo. A previously described analogue of LXA(4), methyl (5R,6R,7E,9E,11Z,13E,15S)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-7,9,11,13-hexadecatetraenoate (2, ATLa), was shown to have a poor pharmacokinetic profile after both oral and intravenous administration, as well as sensitivity to acid and light. The chemical stability of the corresponding E,E,E-trien-11-yne analogue, 3, was improved over 2 without loss of efficacy in the mouse air pouch model of inflammation. Careful analysis of the plasma samples from the pharmacokinetic assays for both 2 and 3 identified a previously undetected metabolite, which is consistent with metabolism by beta-oxidation. The formation of the oxidative metabolites was eliminated with the corresponding 3-oxatetraene, 4, and the 3-oxatrien-11-yne, 5, analogues of 2. Evaluation of 3-oxa analogues 4 and 5 in calcium ionophore-induced acute skin inflammation model demonstrated similar topical potency and efficacy compared to 2. The 3-oxatrien-11-yne analogue, 5, is equipotent to 2 in an animal model of inflammation but has enhanced metabolic and chemical stability and a greatly improved pharmacokinetic profile.

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Section: Chemistrymentioning

confidence: 99%

Novel 3-Oxa Lipoxin A₄ Analogues with Enhanced Chemical and Metabolic Stability Have Anti-inflammatory Activity in Vivo

Guilford¹,

Bauman²,

Skuballa³

et al. 2004

J. Med. Chem.

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“…Nevertheless, LXA 4 and ATL are both undergoing rapid dehydrogenation and inactivation in monocytes by the 15‐hydroxyprostaglandin dehydrogenase (33, 34). Therefore, stable analogs of LXs and ATL needed to be synthesized (35–38): 15(R/S)‐methyl LXA 4 ,16‐phenoxy‐LXA 4 , and 15‐epi‐16‐(parafluoro)‐phenoxy‐LXA 4 presented higher anti‐inflammatory properties than LXs and ATL.…”

Section: Lipoxin Isolation Structure and Synthesismentioning

confidence: 99%

Lipoxins in asthma: potential therapeutic mediators on bronchial inflammation?

Bonnans

Chanez

Chavis

2004

Allergy

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Arachidonic acid metabolism represents an important source of mediators with ambivalent actions. Among these, lipoxins (LXs) are the first agents identified and recognized as anti-inflammatory endogenous lipid mediators, which are involved in the resolution of inflammation and are present in the airways of asthmatic patients. Lipoxins result mainly from the interaction between 5 and 15-lipoxygenases (LO) and their levels are modulated by the degree of bronchial inflammation as well as by the long-term glucocorticoid treatments. In the airways, LX synthesis is higher in mild asthmatics than in severe asthmatics, whereas in vitro chemokine release inhibition by LXs is more effective in cells from severe asthmatics than from mild asthmatics. LipoxinA(4) effects on interleukin (IL)-8 released by blood mononuclear cells and on calcium influx in epithelial cells are mediated by the specific receptor ALX. Lipoxin generation by lung epithelial cells depends mainly on 15-LO activity. Mild asthmatics present higher 15-LOb expression at the epithelium level than severe patients, whereas the LX deficit in severe asthma is associated with an up-regulation of the 15-LOa expressions. Therefore, bronchial epithelial cells become a target for therapeutic intervention and LXs represent a potential therapeutic solution for bronchial inflammation resolution in asthma.

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“…The resulting analogs exhibited increased phagocytotic activity compared to the native LXA4 [ 6 ]. A number of other synthetic strategies have also been reported [ 14 – 21 ]. In this paper, we describe a different and potentially more flexible approach to the synthesis of aromatic lipoxin analogues in their lactone forms using simple and available starting materials and the classical Wittig olefination to craft the central double bond.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of aromatic lactone analogues of Lipoxin A4

2022

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Objective Synthesis of novel aromatic Lipoxin A4 lactone analogues. Results Novel para-substituted aromatic lactone analogues of Lipoxin A4 have been synthesized in a convergent manner with six steps in the longest linear sequence in 12–13% yields, employing 2-deoxy-d-ribose as a chiral pool starting material and the classical E-selective Wittig olefination.

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Synthesis of methyl (5S,6R,7E,9E,11Z,13E,15S)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-7,9,11,13-hexadecatetraenoate, an analogue of 15R-Lipoxin A4

Cited by 20 publications

References 26 publications

Novel 3-Oxa Lipoxin A₄ Analogues with Enhanced Chemical and Metabolic Stability Have Anti-inflammatory Activity in Vivo

Novel 3-Oxa Lipoxin A₄ Analogues with Enhanced Chemical and Metabolic Stability Have Anti-inflammatory Activity in Vivo

Lipoxins in asthma: potential therapeutic mediators on bronchial inflammation?

Synthesis of aromatic lactone analogues of Lipoxin A4

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Synthesis of methyl (5S,6R,7E,9E,11Z,13E,15S)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-7,9,11,13-hexadecatetraenoate, an analogue of 15R-Lipoxin A4

Cited by 20 publications

References 26 publications

Novel 3-Oxa Lipoxin A4 Analogues with Enhanced Chemical and Metabolic Stability Have Anti-inflammatory Activity in Vivo

Novel 3-Oxa Lipoxin A4 Analogues with Enhanced Chemical and Metabolic Stability Have Anti-inflammatory Activity in Vivo

Lipoxins in asthma: potential therapeutic mediators on bronchial inflammation?

Synthesis of aromatic lactone analogues of Lipoxin A4

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Product

Resources

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Novel 3-Oxa Lipoxin A₄ Analogues with Enhanced Chemical and Metabolic Stability Have Anti-inflammatory Activity in Vivo

Novel 3-Oxa Lipoxin A₄ Analogues with Enhanced Chemical and Metabolic Stability Have Anti-inflammatory Activity in Vivo