Skip to Main content Skip to Navigation
New interface
Theses

Synthèse et évaluation d’inhibiteurs du transport de l’iode dans la thyroïde

Abstract : This work was intended to discover small organic molecules acting as iodide uptake inhibitors in thyroid cells. These compounds can indeed be derivatized into biochemical probes for further characterization of proteins involved in iodide transport mechanisms. On the long term, these inhibitors also appear as attractive drug candidates for treatment of thyroid pathologies or radioprotection against iodine isotopes. A similar strategy was adopted for both of the two inhibitor families. First, we synthesized a chemical library of around 100 analogues; we measured their IC50 against iodide uptake in FRTL-5 cells to get structure-activity relationships. Absolute configuration of stereogenic centers was also investigated, and a preferential stereochemistry was found to be responsible for activity. From this basis, around twenty « second-generation » analogues were synthesized by combining fragments contributing to biological activity. Biological evaluation indicated that nine were very potent inhibitors, with IC50 < 6 nM and satisfying physicochemical properties required for drug candidates. Finally, one photoactivatable biotinylated probe was developed in each family and used for photoaffinity labeling. Several specifically labeled proteins are still under identification and constitute new potential therapeutic targets.
Document type :
Theses
Complete list of metadata

Cited literature [87 references]  Display  Hide  Download

https://theses.hal.science/tel-00923159
Contributor : ABES STAR :  Contact
Submitted on : Thursday, January 2, 2014 - 1:47:26 AM
Last modification on : Monday, December 13, 2021 - 9:14:52 AM
Long-term archiving on: : Saturday, April 8, 2017 - 8:48:15 AM

File

VA_LACOTTE_PIERRE_18122012.pdf
Version validated by the jury (STAR)

Identifiers

  • HAL Id : tel-00923159, version 1

Citation

Pierre Lacotte. Synthèse et évaluation d’inhibiteurs du transport de l’iode dans la thyroïde. Autre. Université Paris Sud - Paris XI, 2012. Français. ⟨NNT : 2012PA112359⟩. ⟨tel-00923159⟩

Share

Metrics

Record views

337

Files downloads

2617