Pietrancosta Nicolas, Maina Flavio, Dono Rosanna, Moumen Anice, Garino Cédrik, Laras Younes, Burlet Stéphane, Quéléver Gilles, Kraus Jean-Louis
Unité INSERM U-623, Laboratoire de Chimie Biomoléculaire, IBDM, Faculté des Sciences de Luminy, Université de la Méditerranée, 13288 Marseille Cedex 9, France.
Bioorg Med Chem Lett. 2005 Mar 15;15(6):1561-4. doi: 10.1016/j.bmcl.2005.01.075.
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.
我们从各种环状或双环酮出发，合成了新型的匹非尼酮-α类似物，这些类似物在2-亚氨基噻唑杂环的N3位带有不同的甲基取代苯酮基团。通过在生物介质以及特定化学条件下的稳定性研究，我们利用核磁共振技术表明，一些衍生物可通过脱水过程生成其相应的环化类似物。通过测量DNA损伤剂依托泊苷诱导死亡的皮质神经元的存活率，对所有新的类似物、匹非尼酮样和多环脱水衍生物的p53失活效力进行了评估。发现匹非尼酮-α样的2f以及环状脱水的6b类似物作为p53失活剂的效力比参考化合物Pft-α高一个对数级，其半数有效浓度（EC50）值约为30 nM。这些结果支持了以下发现：Pft-α类似物使p53失活也可能是由于在生物测定孵育介质中原位生成的环状脱水Pft-α形式的存在。
