Novel cyclized Pifithrin-alpha p53 inactivators: synthesis and biological studies |
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Authors: | Pietrancosta Nicolas Maina Flavio Dono Rosanna Moumen Anice Garino Cédrik Laras Younes Burlet Stéphane Quéléver Gilles Kraus Jean-Louis |
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Institution: | Unité INSERM U-623, Laboratoire de Chimie Biomoléculaire, IBDM, Faculté des Sciences de Luminy, Université de la Méditerranée, 13288 Marseille Cedex 9, France. |
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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. |
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