School of Pharmacy and ∥Department of Neurology, Institute of Clinical Medicine , University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.
J Med Chem. 2013 Sep 12;56(17):6681-95. doi: 10.1021/jm400438k. Epub 2013 Aug 22.
In the past few years sirtuins have gained growing attention for their involvement in many biological processes such as cellular metabolism, apoptosis, aging and inflammation. In this contribution, we report the synthesis of a library of thioacetylated pseudopeptides that were screened against human sirtuins 1-3 to reveal their in vitro inhibition activities. Molecular modeling studies were performed to acquire data about the binding modes of the inhibitors. Three sirtuin inhibitors were subjected to cellular studies, and all of them showed an increase in acetylation of Lys382 of p53 after DNA damage. Furthermore, two of the compounds were able to inhibit both A549 lung carcinoma and MCF-7 breast carcinoma cell growth in micromolar concentration with the ability to arrest cancer cell cycle in the G1 phase.
在过去的几年中，沉默调节蛋白因其参与许多生物学过程而受到越来越多的关注，如细胞代谢、细胞凋亡、衰老和炎症。在本研究中，我们报告了合成了一个硫代乙酰化假肽文库，并用其筛选人源沉默调节蛋白 1-3，以揭示其体外抑制活性。进行了分子建模研究以获取抑制剂结合模式的数据。对三种沉默调节蛋白抑制剂进行了细胞研究，它们都能在 DNA 损伤后增加 p53 赖氨酸 382 的乙酰化。此外，两种化合物能够以微摩尔浓度抑制 A549 肺癌和 MCF-7 乳腺癌细胞的生长，并能够将癌细胞周期阻滞在 G1 期。
