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. 2022 Aug 19;24(32):6049-6053.
doi: 10.1021/acs.orglett.2c02345. Epub 2022 Aug 8.

Synthesis and Biological Evaluation of Bicyclo[1.1.1]pentane-Containing Aromatic Lipoxin A4 Analogues

Benjamin Owen  1 , Monica de Gaetano  2 , Andrew Gaffney  3 , Catherine Godson  3 , Patrick J Guiry  1
Affiliations

Synthesis and Biological Evaluation of Bicyclo[1.1.1]pentane-Containing Aromatic Lipoxin A4 Analogues

Benjamin Owen et al. Org Lett. .

Abstract

Lipoxins are important drivers of inflammation resolution, suggesting a potential therapeutic benefit. Bicyclo[1.1.1]pentanes (BCPs) are potential isosteric replacements for arenes and/or alkyl groups within drug candidates. We carried out an asymmetric synthesis of four BCP-containing synthetic lipoxin A4 mimetics (BCP-sLXms) in which the key steps were a Suzuki coupling, an asymmetric ketone reduction, and a triethylborane-initiated radical bicyclopentylation. These mimetics were screened for their impact on inflammatory responses, and one imidazolo-BCP-sLXm (6a) was found to possess high anti-inflammatory activity.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Lipoxin A4 (1) and examples of aromatic synthetic LXA4 mimetics (2–4).
Scheme 1
Scheme 1. Retrosynthetic Analysis of Target BCP-Containing Aromatic LXA4 Mimetics 5 and 6
Scheme 2
Scheme 2. Asymmetric Synthesis of BCP-Containing Benzo-LXA4 Mimetics 5a and 5b
Scheme 3
Scheme 3. Asymmetric Synthesis of BCP-Containing Imidazole Coupling Partners (S)-11 and (R)-11
Scheme 4
Scheme 4. Synthesis of BCP-Containing Imidazolo-LXA4 Mimetics 6a and 6b
Figure 2
Figure 2
Effect of BCP-sLXms on (a) LPS-induced NFκB-driven luciferase activity in monocytes and (b) pro-inflammatory cytokine release.
See this image and copyright information in PMC

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