title: 1,2,3-Triazole-Dithiocarbamate Hybrids, a Group of Novel Cell Active SIRT1 Inhibitors.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China; Co-innovation Center of Henan Province for New drug R &amp; D and Preclinical Safety; Institute of Drug Discovery and Development, Zhengzhou University, Zhengzhou, China.
authors.forename: Yi-Chao
authors.initials: YC
authors.lastname: Zheng
authors.forename: Long-Zhen
authors.initials: LZ
authors.lastname: Wang
authors.forename: Li-Jie
authors.initials: LJ
authors.lastname: Zhao
authors.forename: Li-Juan
authors.initials: LJ
authors.lastname: Zhao
authors.forename: Qian-Na
authors.initials: QN
authors.lastname: Zhan
authors.forename: Jin-Lian
authors.initials: JL
authors.lastname: Ma
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: Meng-Meng
authors.initials: MM
authors.lastname: Wang
authors.forename: Zhi-Ru
authors.initials: ZR
authors.lastname: Wang
authors.forename: Jin-Feng
authors.initials: JF
authors.lastname: Li
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Zhe-Sheng
authors.initials: ZS
authors.lastname: Chen
authors.forename: Dan-Dan
authors.initials: DD
authors.lastname: Shen
authors.forename: Xue-Qi
authors.initials: XQ
authors.lastname: Liu
authors.forename: Meng
authors.initials: M
authors.lastname: Ren
authors.forename: Wen-Lei
authors.initials: WL
authors.lastname: Lv
authors.forename: Wen
authors.initials: W
authors.lastname: Zhao
authors.forename: Ying-Chao
authors.initials: YC
authors.lastname: Duan
authors.forename: Hong-Min
authors.initials: HM
authors.lastname: Liu
mesh_terms: D000107:Acetylation / Q000187:drug effects; D001665:Binding Sites; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D062105:Molecular Docking Simulation; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D013859:Thiocarbamates / Q000737:chemistry / Q000494:pharmacology*; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D013859:Thiocarbamates; D014230:Triazoles; D016159:Tumor Suppressor Protein p53; D056564:Sirtuin 1; D056565:Sirtuin 2