Topic

Inspired by natural plant or marine products, the team designs, synthesizes and studies the physico-chemical and biological properties of functionalized phenol derivatives, beta-dicarbonyl and substituted endoperoxides and marine alkaloids. The targeted diseases are cancers, cardiovascular diseases, tuberculosis and malaria.

Research focus and main results

This research work is divided into three main axes:
  • Phenol, cinnamic and macrocyclic derivatives
Since oxidative stress plays a key role in the development of atherosclerosis, the team uses its expertise in phenol derivatives chemistry to design and synthesize innovative linear or macrocyclic biaryl antioxidants with dual properties (cytoprotection, carbonyl scavengers, anti-inflammatory drugs). ..)
 
Structure-activity relationships studies (antiradical, antioxidant and cytoprotective against oxidized LDL toxicity) have shown the significance of para-hydroxyl and the nature of functionalization. In particular, the BVH (regimen) studied in vivo on apo E - / - mice reduces the formation of atheroma plaque by 55%.
  •  Antitubercular agents
Cinnamic systems have been differently subsumed and functionalized. Among the molecules synthesized, many have promising antitubercular activities (MIC in the range of μM on H37Rv cells), a selectivity index up to 560 for the best compound and an approriate druggability (PSA = 50-80A2) .
  • Antimalarial agents
In the search for new molecules with antimalarial activity, we are interested in natural endoperoxides from Eucalyptus grandis or Myrtaceae, called G factors (G1, G2, G3) acting as phytohormones and growth regulators in the plant. These compounds with a cyclic peroxide bridge can be compared with artemisinin, a natural compound from the Chinese pharmacopoeia or its derivatives and analogs containing trioxane or trioxolane.
The synthesis of the factors is based on an autoxidation reaction of the precursors in the dienol form, themselves obtained during a Knoevenagel-type reaction between syncarpic acid and an aldehyde allowing the variation of the substituents R1, R2.
 
Many analogs have been synthesized and evaluated for malaria; hybrid endoperoxide / 4-aminoquinoline molecules have proved to be particularly interesting.

Study of the autoxidation by a combined approach "spin trapping / EPR" and mass spectrometry (collaboration with B. Tuccio)

A radical mechanism involving the pathway B could be proposed on the basis of both the obtained EPR spectra and the tandem mass base (MS / MS) by electrospray ionization in positive and negative mode. of the characterization of spin adducts by mass spectrometry.
   

Paths in the singlet and triplet state are calculated (at B3LYP / 6-311 + G (d, p))

a spin crossing is actually possible on the geometry of a biradical having the same geometry and same energy level in the triplet state and singlet open layer.
 
  • Marine alkaloids and N-heteroaromatic systems
The team is focused on the total synthesis and  the analogs synthesis  of 2 alkaloids families in order to discover new anticancer agents. In the case of pyrroloquinolines including wakayine and tsitsikammamine, we are studying potential inhibitors of IDO (indoleamine dioxygenase) that may have application in immunotherapy field.
 
In the family of granulatimide and isogranulatimide, the developed derivatives aim to inhibit Chk1, an enzyme involved in checkpoint G2 itself constituting a key element of cell cycle regulation.

Major publications