Novel cyclized Pifithrin-α p53 inactivators: synthesis and biological studies

• Published in: Bioorganic & medicinal chemistry letters 2005-03, Vol.15 (6), p.1561-1564
• Main Authors: Pietrancosta, Nicolas, Maina, Flavio, Dono, Rosanna, Moumen, Anice, Garino, Cédrik, Laras, Younes, Burlet, Stéphane, Quéléver, Gilles, Kraus, Jean-Louis
• Format: Article
• Language: English
• Subjects: Animals; Benzothiazoles; Biological and medical sciences; Cerebral Cortex - cytology; Chemical Sciences; Cortical neuron survival; Dehydration reaction; Drug Stability; Etoposide - pharmacology; Medical sciences; Mice; Miscellaneous; Models, Chemical; Molecular Structure; Neurons - drug effects; Neuropharmacology; Neuroprotective agent; Organic chemistry; p53 Inactivators; Pft-α; Pharmacology. Drug treatments; Structure-Activity Relationship; Thiazoles - chemical synthesis; Thiazoles - chemistry; Thiazoles - pharmacology; Toluene - analogs & derivatives; Toluene - chemical synthesis; Toluene - chemistry; Toluene - pharmacology; Tumor Suppressor Protein p53 - antagonists & inhibitors
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2005.01.075

[Display omitted] Starting from various cyclic or bicyclic ketones, we have synthesized novel Pifithrin-α analogues bearing different methyl substituted phenyl ketone groups at the N 3-position of the 2-iminothiazole heterocycle. From stability studies in a biological medium as well as under specific chemical conditions, we have shown by NMR techniques that through a dehydration process, some derivatives can generate their corresponding cyclized analogues. All of the new analogues, Pifithrin-like and polycyclic dehydrated derivatives were assessed for their p53 inactivation potency by measuring survival of cortical neurons, whose death was induced by the DNA-damaging agent etoposide. Pifithrin-α like 2f as well as the cyclic dehydrated 6b analogue were found to be one log more potent p53 inactivators than reference compound Pft-α, with EC 50 values ranging around 30 nM. These results support the finding that p53 inactivation by Pft-α analogues could be also due to the presence of the cyclic dehydrated Pft-α forms, generated in situ in the biological assay incubation medium.