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

by 1,2,†, 3,†, 4, 3, 3, 4,*, 3,* and 1,2,*
1
Department of Pharmacology III, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu-Chong-Zhi Road, Shanghai 201203, China
2
College of Pharmacy, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
3
Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu-Chong-Zhi Road, Shanghai 201203, China
4
School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
*
Authors to whom correspondence should be addressed.
These authors contribute equally to this work.
Academic Editor: Loredana Cappellacci
Molecules 2020, 25(12), 2755; https://doi.org/10.3390/molecules25122755
Received: 6 May 2020 / Revised: 5 June 2020 / Accepted: 6 June 2020 / Published: 15 June 2020
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-1H-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. View Full-Text
Keywords: sirtuins; inhibitor; structure–activity relationship; deacetylase sirtuins; inhibitor; structure–activity relationship; deacetylase
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MDPI and ACS Style

Han, H.; Li, C.; Li, M.; Yang, L.; Zhao, S.; Wang, Z.; Liu, H.; Liu, D. Design, Synthesis, and Biological Evaluation of 8-Mercapto-3,7-Dihydro-1H-Purine-2,6-Diones as Potent Inhibitors of SIRT1, SIRT2, SIRT3, and SIRT5. Molecules 2020, 25, 2755. https://doi.org/10.3390/molecules25122755

AMA Style

Han H, Li C, Li M, Yang L, Zhao S, Wang Z, Liu H, Liu D. Design, Synthesis, and Biological Evaluation of 8-Mercapto-3,7-Dihydro-1H-Purine-2,6-Diones as Potent Inhibitors of SIRT1, SIRT2, SIRT3, and SIRT5. Molecules. 2020; 25(12):2755. https://doi.org/10.3390/molecules25122755

Chicago/Turabian Style

Han, Haozhen, Chunpu Li, Man Li, Lisheng Yang, Sen Zhao, Zhifei Wang, Hong Liu, and Dongxiang Liu. 2020. "Design, Synthesis, and Biological Evaluation of 8-Mercapto-3,7-Dihydro-1H-Purine-2,6-Diones as Potent Inhibitors of SIRT1, SIRT2, SIRT3, and SIRT5" Molecules 25, no. 12: 2755. https://doi.org/10.3390/molecules25122755

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