Mai Antonello, Valente Sergio, Meade Sarah, Carafa Vincenzo, Tardugno Maria, Nebbioso Angela, Galmozzi Andrea, Mitro Nico, De Fabiani Emma, Altucci Lucia, Kazantsev Aleksey
Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Università degli Studi di Roma La Sapienza, Roma, Italy.
J Med Chem. 2009 Sep 10;52(17):5496-504. doi: 10.1021/jm9008289.
NAD(+)-dependent sirtuin deacetylases have emerged as potential therapeutic targets for treatment of human illnesses such as cancer, metabolic, cardiovascular, and neurodegenerative diseases. The benefits of sirtuin modulation by small molecules have been demonstrated for these diseases. In contrast to the discovery of inhibitors of SIRT1, -2, and -3, only activators for SIRT1 are known. Here, we rationalized the potential of the previously unexplored dihydropyridine scaffold in developing sirtuin ligands, thus we prepared a series of 1,4-dihydropyridine-based derivatives 1-3. Assessment of their SIRT1-3 deacetylase activities revealed the importance of the substituent at the N1 position of the dihydropyridine structure on sirtuin activity. Placement of cyclopropyl, phenyl, or phenylethyl groups at N1 conferred nonselective SIRT1 and SIRT2 inhibition activity, while a benzyl group at N1 conferred potent SIRT1, -2, and -3 activation. Senescence assays performed on hMSC and mitochondrial function studies conducted with murine C2C12 myoblasts confirmed the compounds' novel and unique SIRT-activating properties.
烟酰胺腺嘌呤二核苷酸（NAD(+)）依赖性的沉默调节蛋白去乙酰化酶已成为治疗人类疾病（如癌症、代谢性疾病、心血管疾病和神经退行性疾病）的潜在治疗靶点。小分子调节沉默调节蛋白对这些疾病的益处已得到证实。与SIRT1、-2和-3抑制剂的发现不同，目前已知的只有SIRT1的激活剂。在这里，我们阐述了以前未被探索的二氢吡啶支架在开发沉默调节蛋白配体方面的潜力，因此我们制备了一系列基于1,4-二氢吡啶的衍生物1-3。对它们的SIRT1-3去乙酰化酶活性的评估揭示了二氢吡啶结构N1位上的取代基对沉默调节蛋白活性的重要性。在N1位上放置环丙基、苯基或苯乙基会赋予非选择性的SIRT1和SIRT2抑制活性，而在N1位上的苄基会赋予强效的SIRT1、-2和-3激活活性。对人骨髓间充质干细胞（hMSC）进行的衰老测定以及用小鼠C2C12成肌细胞进行的线粒体功能研究证实了这些化合物具有新颖独特的SIRT激活特性。
