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Total Synthesis of Bioactive Lipids

par florent_r0s1 - publié le , mis à jour le

1. Research axes


  • Total synthesis of bioactive lipids, photoaffine probes (endocannabinoid analogues) and isoprostane analogues (Isoprostanes, Neuroprostanes or Phytoprostanes) or Isofuranes still.

 

2. Projects currently being developed


Synthesis of bioactive lipids

Free radicals play an important role in several diseases among which atherosclerosis, cancer, diabetes and neurodegenerative diseases.

A large family of molecules has been discovered : Iso-, Neuro- and Phytoprostanes, isomers of prostaglandins, formed in vivo by a non-enzymatic lipid peroxidation radicalar mechanism of polyunsaturated, free or esterified fatty acids in membranar phospholipids. The measurement of these molecules in biological fluids represents an excellent index of oxidising attacks, used in clinic.

We are developing new synthesis strategies of different cyclic lipidic compounds, so as to obtain the best biomarker and to study the interest of these molecules in human pathology and in the plants’ world.

We have synthesized F2-dihomo-isoprostanes (F2-dihomo-IsoP), peroxidation products from adrenic acid (C22:4 n-6, AdA,), a known component of myelin, and tested their potential value as a novel disease marker in Rett syndrome (RTT) and its relationship with clinical presentation, and disease progression. Dr Claudio de Felice (Neonatal Intensive Care Unit, AOUS, Siena, Italy) and coll. showed that average plasma F2-dihomo-IsoP levels in RTT were about 1 order of magnitude higher than in healthy controls, with a remarkable increase of about 2 orders of magnitude in patients at the earliest stage of the disease followed by a steady decrease during the natural clinical progression. These data indicate for the first time that quantification of F2-dihomo-IsoPs in plasma represents an early marker of the disease and may provide a better understanding of the pathogenic mechanisms behind the neurological regression in patients with RTT.

By analogy, dihomo-Isofuranes (dihomo-Isofs), oxygenated metabolites of AdA, and Isofs analogs deriving from arachidonic acid could be biomarkers of this syndrome. In order to confirm this hypothesis, we now develop a synthetic approach to dihomo-isofs, also applicable to reach Neurofuranes (NeuroFs), resulting of lipid peroxidation of docosahexaenoic acid (C22 : 6 n-3, DHA).

Simultaneously to our researches on isoprostanes, we deemed interesting to study other derivatives of arachidonic acid, i.e. endocannabinoids. The therapeutic issues are very significant since endocannabinoids are neurotransmitters implied in a large number of pathologies. However, their biosynthesis, their action and their metabolisation require more in-depth study, in order to clarify the significance of these endogenous compounds.

We are developing different total syntheses of photoactivable and fluorescent probes in order to :

  • 1) waive the current controversy regarding the existence of an anandamide transporter. Better knowledge of the desactivation of anandamide might, indeed, lead to the elaboration of inhibitors for re-capturing anandamide so as to maintain a significant anandamide concentration in its receptors.
  • 2) look for new anandamide receptors. Indeed, numerous studies on mice deprived of known cannabinoid receptors, CB1 and CB2, show the persistence of certain anandamide effects.
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