Development of new organocatalytic pathways for the synthesis of all-cis isoprostanes and prostaglandins

Les isoprostanoïdes sont des métabolites non-enzymatiques des acides gras polyinsaturés (AGPI) et sont omniprésentes chez les espèces vertébrées. Elles sont produites par l'action de radicaux libres oxygénés sur les AGPI et sont donc considérées comme d'excellents biomarqueurs du stress oxydant dans les organismes. Afin de déterminer leurs potentiels de biomarqueurs du stress oxydant pour l’analyse LC-MS/MS, la synthèse totale de ces métabolites oxydés doit tout d'abord être réalisée. Les travaux exposés dans ce manuscrit ont donc pour but de développer de nouvelles voies de synthèses organocatalytiques de métabolites de stéréochimies tout-cis et cis-trans-trans (stéréochimie prostaglandine) provenant de l'acide docosahexaénoïque et de l'acide icosapentaénoïque.Isoprostanes are non-enzymatically generated metabolites of polyunsaturated fatty acids (PUFA), and are ubiquitous in vertebrate species. As they are produced by the action of free oxygenated radicals on PUFA, they are considered as excellent oxidative stress biomarkers in the organisms. The synthesis of isoprostanoids is necessary to determine their potential as biomarkers of oxidative stress by LC-MS/MS analysis. The aim of the work reported in this thesis is the development of organocatalytic synthesis pathways of new metabolites, possessing all-cis and cis-trans-trans (prostaglandins stereochemistries and derived from docosahexaenoic and eicosapentaenoic acids

Développement de nouvelles voies organocatalytiques pour la synthèse d'isoprostanes tout-cis et de prostaglandines

Isoprostanes are non-enzymatically generated metabolites of polyunsaturated fatty acids (PUFA), and are ubiquitous in vertebrate species. As they are produced by the action of free oxygenated radicals on PUFA, they are considered as excellent oxidative stress biomarkers in the organisms. The synthesis of isoprostanoids is necessary to determine their potential as biomarkers of oxidative stress by LC-MS/MS analysis. The aim of the work reported in this thesis is the development of organocatalytic synthesis pathways of new metabolites, possessing all-cis and cis-trans-trans (prostaglandins stereochemistries and derived from docosahexaenoic and eicosapentaenoic acids.Les isoprostanoïdes sont des métabolites non-enzymatiques des acides gras polyinsaturés (AGPI) et sont omniprésentes chez les espèces vertébrées. Elles sont produites par l'action de radicaux libres oxygénés sur les AGPI et sont donc considérées comme d'excellents biomarqueurs du stress oxydant dans les organismes. Afin de déterminer leurs potentiels de biomarqueurs du stress oxydant pour l’analyse LC-MS/MS, la synthèse totale de ces métabolites oxydés doit tout d'abord être réalisée. Les travaux exposés dans ce manuscrit ont donc pour but de développer de nouvelles voies de synthèses organocatalytiques de métabolites de stéréochimies tout-cis et cis-trans-trans (stéréochimie prostaglandine) provenant de l'acide docosahexaénoïque et de l'acide icosapentaénoïque

Total Synthesis of a Docosahexaenoic Acid Prostanoid Using an Intramolecular Organocatalytic Michael Reaction of a Formyl-Enal Derivative

International audienc

Moving forward with isoprostanes, neuroprostanes and phytoprostanes: where are we now?

International audienc

Development of a chiral SFC-MS/MS and reversed-phase LC-MS/MS platform for the quantitative metabolic profiling of octadecanoid oxylipins

Octadecanoids are broadly defined as oxylipins (i.e., lipid mediators) derived from 18-carbon fatty acids. In contrast to the well-studied eicosanoids, there is a lack of analytical methods for octadecanoids, hampering further investigations in the field. We developed an integrated workflow combining chiral separation by supercritical fluid chromatography (SFC) and reversed-phase liquid chromatography (LC) coupled to tandem-MS detection for quantification of a broad panel of octadecanoids. The platform included 70 custom-synthesized analytical and internal standards to extend the coverage of the octadecanoid synthetic pathways. A total of 103 octadecanoids could be separated by chiral SFC and complex enantioseparations could be performed in 0.995) and LLOQ ranged from 0.03-6.00 ng/mL for SFC and 0.01-1.25 ng/mL for LC. The average accuracy in solvent and surrogate matrix ranged from 89-109% in SFC and from 106-220% in LC, whereas coefficients of variation (CV) were <14% (at medium and high concentration) and 26% (at low concentration). Validation in surrogate matrix showed negligible matrix effects (<16% for all analytes) and average recoveries ranged from 71-83%. The combined methods provide a platform to investigate the biological activity of octadecanoids and expand our understanding of these little studied compounds