Développement préclinique de dérivés imidazo [1,2-a] quinoxaliniques à visée anticancéreuse : synthèse chimique, formulation galénique et validation de méthode de dosage en milieu biologique

Abstract : The project relates to heterocyclic molecules, low molecular weight, having cytotoxic activities similar to those presented by the best anticancer agents currently on the market. These molecules are originals, protected by an international patent and a selection patent filed in December 2014. The synthesis of the first molecules leader is under control and the exemplification of molecular diversity is underway. Studies to define their activity profile allow to identify quite original features. The project, in its academic preclinical development phase, enabled the identification of leader’s compounds with potential for development as anticancer. The exact mechanism of the molecules developed is still under study and will determine whether there is a single or multiple mode of action. Several series leads were identified with apparently different modes of action. Indeed, compounds EAPB0203 and EAPB0503 show a dose effect from 1 µM on tubulin polymerization but compound EAPB02303, the more active on A375 cell line (IC50 = 10 nM, ten times to hundred times more active than the preceding two), shows no binding to tubulin at a dose of 1 µM suggesting a different and original mechanism of action. The research topic presented concerns the preclinical development of these anticancer molecules. The first line of work was to develop a galenic formulation of EAPB0503 in the form of lipid nanocapsules. To optimize the bioavailability of the compounds, without losing their intrinsic activity, we achieved chemical modulation on the most active structure Imiqualines: EAPB02303. To improve the overall balance hydrophilic / lipophilic (HLB) of compounds derived from EAPB02303, we considered grafting amino acids on position 4. Finally, the development of a method for assaying EAPB02303 and EAPB02302 in plasma for a pharmacokinetic study has been the final focus of the thesis work.
Document type :
Theses
Liste complète des métadonnées

https://tel.archives-ouvertes.fr/tel-01947402
Contributor : Abes Star <>
Submitted on : Thursday, December 6, 2018 - 5:14:24 PM
Last modification on : Friday, December 7, 2018 - 1:18:39 AM
Document(s) archivé(s) le : Thursday, March 7, 2019 - 2:44:59 PM

File

2018_CHOUCHOU_archivage.pdf
Version validated by the jury (STAR)

Identifiers

  • HAL Id : tel-01947402, version 1

Collections

Citation

Adrien Chouchou. Développement préclinique de dérivés imidazo [1,2-a] quinoxaliniques à visée anticancéreuse : synthèse chimique, formulation galénique et validation de méthode de dosage en milieu biologique. Médecine humaine et pathologie. Université Montpellier, 2018. Français. ⟨NNT : 2018MONTT034⟩. ⟨tel-01947402⟩

Share

Metrics

Record views

85

Files downloads

56