Institute of Organic Chemistry, Department of Chemistry and Pharmacy , University of Regensburg , D-93040 , Regensburg , Germany.
Institute of Pharmaceutical Sciences , University of Freiburg , D-79104 Freiburg , Germany.
J Org Chem. 2018 Aug 3;83(15):7919-7927. doi: 10.1021/acs.joc.8b00795. Epub 2018 Jun 12.
Sirtuins are involved in epigenetic regulation, the pathogenesis of cancer, and several metabolic and neurodegenerative diseases. Despite being a promising drug target, only one small molecule passed class II clinical trials to date. Deriving a better mechanistic understanding is hence crucial to find new modulators. We previously reported on a series of dithienyl maleimides as photochromic tool compounds. However, their photochromic behavior was limited. To improve the interconversion and stability of both photoisomers, we replaced the dithienyl maleimide with a fulgimide as a photochromic core to result in biologically active compounds reversibly addressable with purple and orange light. We characterize the obtained compounds regarding their spectroscopic properties, their photostability, and binding characteristics toward sirtuins resulting in a fully remote-controllable Sirtuin modulator using visible light as the external stimulant.
Sirtuins 参与表观遗传调控、癌症的发病机制以及多种代谢和神经退行性疾病。尽管 Sirtuins 是一个很有前途的药物靶点，但迄今为止，只有一种小分子通过了 II 期临床试验。因此，深入了解其作用机制对于寻找新的调节剂至关重要。我们之前曾报道过一系列二噻吩基马来酰亚胺作为光致变色工具化合物。然而，它们的光致变色行为有限。为了改善两种光异构体的互变和稳定性，我们用富勒烯亚胺代替二噻吩基马来酰亚胺作为光致变色核心，得到了具有生物活性的化合物，可以用紫光和橙光可逆地寻址。我们对所得到的化合物的光谱性质、光稳定性以及对 Sirtuins 的结合特性进行了表征，结果得到了一种完全可以通过可见光远程控制的 Sirtuins 调节剂，将可见光作为外部刺激。
