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Published on: February 9, 2021
1,2,3-Triazole-Dithiocarbamate Hybrids, a Group of Novel Cell Active SIRT1 Inhibitors
Yi-Chao Zheng1, Long-Zhen Wang, Li-Jie Zhao
1Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China; Co-innovation Center of Henan Province for New drug R & D and Preclinical Safety; Institute of Drug Discovery and Development, Zhengzhou University, Zhengzhou, China.
Background/Aims:
Human SIRT1 is reported to be involved in tumorgenesis, mainly due to its modulating effect on p53 by deacetylation on lysine382. A large quantity of SIRT1 inhibitors was applied in chemotherapeutic study, but few of them were applied into clinical trials.
Methods And Results:
In the current study, a novel series of compounds with 1,4-bispiperazinecarbodithioic acid methyl esters scaffold were characterized to have inhibitory potency to SIRT1 by molecular docking and biochemical evaluation. Further cell level study revealed that one of the most potent SIRT1 inhibitors, compound 3a, is cell active. It can upregulate the amount of p53 by accumulating the K382 acetylation of p53, which lead to the stabilization of p53 in human gastric cancer cell line MGC-803 cells. Meanwhile, we also found compound 3a can inactivate SIRT2 in cells, which suggests the compound as a non-selective SIRT inhibitor.
Conclusion:
All these findings indicate that compound 3a is a potent, reversible and cell active SIRT1 inhibitor and deserves further investigation as an anticancer agent or a biological tool.
Insights
A novel compound, 3a, effectively inhibits SIRT1 and stabilizes p53 in gastric cancer cells. This potent SIRT1 inhibitor shows promise as an anticancer agent and research tool.
Area of Science:
- Biochemistry
- Molecular Biology
- Medicinal Chemistry
Background:
- Sirtuin 1 (SIRT1) plays a role in tumorigenesis through p53 deacetylation.
- Existing SIRT1 inhibitors have limited clinical application.
Purpose of the Study:
- To develop and characterize novel SIRT1 inhibitors.
- To evaluate the anticancer potential of a new compound, 3a.
Main Methods:
- Molecular docking and biochemical assays to identify SIRT1 inhibitors.
- Cell-based studies using human gastric cancer cells (MGC-803).
- Assessment of p53 acetylation and stabilization.
Main Results:
- A novel series of 1,4-bispiperazinecarbodithioic acid methyl esters were synthesized and evaluated.
- Compound 3a demonstrated potent SIRT1 inhibition and cell activity.
- Compound 3a upregulated p53 by increasing K382 acetylation, leading to p53 stabilization in MGC-803 cells.
- Compound 3a also inhibited SIRT2, indicating non-selective activity.
Conclusions:
- Compound 3a is a potent, reversible, and cell-active SIRT1 inhibitor.
- Compound 3a warrants further investigation as a potential anticancer therapeutic or biological probe.
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