title: Novel cyclized Pifithrin-alpha p53 inactivators: synthesis and biological studies.
abstract: Starting from various cyclic or bicyclic ketones, we have synthesized novel Pifithrin-alpha analogues bearing different methyl substituted phenyl ketone groups at the N3-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-alpha like 2f as well as the cyclic dehydrated 6b analogue were found to be one log more potent p53 inactivators than reference compound Pft-alpha, with EC50 values ranging around 30 nM. These results support the finding that p53 inactivation by Pft-alpha analogues could be also due to the presence of the cyclic dehydrated Pft-alpha forms, generated in situ in the biological assay incubation medium.
authors.affiliation: Unité INSERM U-623, Laboratoire de Chimie Biomoléculaire, IBDM, Faculté des Sciences de Luminy, Université de la Méditerranée, 13288 Marseille Cedex 9, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Pietrancosta
authors.forename: Flavio
authors.initials: F
authors.lastname: Maina
authors.forename: Rosanna
authors.initials: R
authors.lastname: Dono
authors.forename: Anice
authors.initials: A
authors.lastname: Moumen
authors.forename: Cédrik
authors.initials: C
authors.lastname: Garino
authors.forename: Younes
authors.initials: Y
authors.lastname: Laras
authors.forename: Stéphane
authors.initials: S
authors.lastname: Burlet
authors.forename: Gilles
authors.initials: G
authors.lastname: Quéléver
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Kraus
mesh_terms: D000818:Animals; D052160:Benzothiazoles; D002540:Cerebral Cortex / Q000166:cytology; D004355:Drug Stability; D005047:Etoposide / Q000494:pharmacology; D051379:Mice; D008956:Models, Chemical; D015394:Molecular Structure; D009474:Neurons / Q000187:drug effects; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D014050:Toluene / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors*
chemical_list: D052160:Benzothiazoles; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53; D014050:Toluene; D005047:Etoposide; C121565:pifithrin