1. Imino-tetrahydro-benzothiazole Derivatives as p53 Inhibitors: Discovery of a Highly Potent in Vivo Inhibitor and Its Action Mechanism
- Author
-
Pietrancosta, Nicolas, Moumen, Anice, Dono, Rosanna, Lingor, Paul, Planchamp, Veronique, Lamballe, Fabienne, Bähr, Mathias, Kraus, Jean-Louis, and Maina, Flavio
- Abstract
Several neurological disorders manifest symptoms that result from the degeneration and death of specific neurons. p53 is an important modulator of cell death, and its inhibition could be a therapeutic approach to several neuropathologies. Here, we report the design, synthesis, and biological evaluation of novel p53 inhibitors based on the imino-tetrahydrobenzothiazole scaffold. By performing studies on their mechanism of action, we find that cyclic analogue 6 and its open precursor 2b are more potent than pifithrin-α (PFT-α), which is known to block p53 pro-apoptotic activity in vitro and in vivo without acting on other pro-apoptotic pathways. Using spectroscopic methods, we also demonstrate that open form 2b is more stable than 6 in biological media. Compound 2b is converted into its corresponding active cyclic form through an intramolecular dehydration process and was found two log values more active in vivo than PFT-α. Thus, 2b can be considered as a new prodrug prototype that prevents in vivo p53-triggered cell death in several neuropathologies and possibly reduces cancer therapy side effects.
- Published
- 2006