Design, Synthesis, and Biological Evaluation of 8-Mercapto-3,7-Dihydro-1<i>H</i>-Purine-2,6-Diones as Potent Inhibitors of SIRT1, SIRT2, SIRT3, and SIRT5

• Main Authors: Haozhen Han, Chunpu Li, Man Li, Lisheng Yang, Sen Zhao, Zhifei Wang, Hong Liu, Dongxiang Liu
• Format: Article
• Language: English
• Published: MDPI AG 2020-06-01
• Series: Molecules
• Subjects: sirtuins; inhibitor; structure–activity relationship; deacetylase
• Online Access: https://www.mdpi.com/1420-3049/25/12/2755

Sirtuins (SIRT1-7) are a family of NAD⁺-dependent deacetylases. They regulate many physiological processes and play important roles in inflammation, diabetes, cancers, and neurodegeneration diseases. Sirtuin inhibitors have potential applications in the treatment of neurodegenerative diseases and various cancers. Herein, we identified new sirtuin inhibitors based on the scaffold of 8-mercapto-3,7-dihydro-1<i>H</i>-purine-2,6-dione. To elucidate the inhibitory mechanism, the binding modes of the inhibitors in SIRT3 were established by molecular docking, showing that the inhibitors occupy the acetyl lysine binding site and interact with SIRT3, mainly through hydrophobic interactions. The interactions were validated by site-directed mutagenesis of SIRT3 and structure–activity relationship analysis of the inhibitors. Consistently, enzyme kinetic assays and microscale thermophoresis showed that these compounds are competitive inhibitors to the acetyl substrate, and mix-type inhibitors to NAD⁺. Furthermore, we demonstrated that the compounds are potent SIRT1/2/3/5 pan-inhibitors. This study provides novel hits for developing more potent sirtuin inhibitors.