Cyclic peptide-based potent and selective SIRT1/2 dual inhibitors harboring N^ε-thioacetyl-lysine

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• 作者：Di Chen ; Weiping Zheng ; ^{wzheng@ujs.edu.cn" class="auth_mail" title="E-mail the corresponding author}
• 关键词：β-NAD+ ; β-nicotinamide adenine dinucleotide ; MBHA ; 4-methylbenzhydrylamine ; SPPS ; solid phase peptide synthesis ; DMF ; N ; N-dimethylformamide ; TFA ; trifluoroacetic acid ; DCM ; dichloromethane ; HBTU ; 2-(1H-benzotriazole-1-yl)-1 ; 1 ; 3 ; 3-tetramethylaminium hexafluorophosphate ; NMM ; N-methylmorpholine ; RP-HPLC ; reversed-phase high performance liquid chromatography ; HRMS ; high-resolution mass spectrometry ; IC50 ; the inhibitor concentration at which an enzymatic reaction velocity is reduced by 50%
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：1 November 2016
• 年：2016
• 卷：26
• 期：21
• 页码：5234-5239
• 全文大小：803 K

文摘

In the current study, we discovered that several N-terminus-to-side chain cyclic tripeptides harboring the catalytic mechanism-based SIRT1/2/3 inhibitory warhead N^ε-thioacetyl-lysine at their central positions exhibited a comparably strong inhibition (nM level) against the SIRT1/2-catalyzed N^ε-acetyl-lysine deacetylation reactions. Their dual SIRT1/2 inhibitory action was also found to be stronger than that against SIRT3/5/6. Considering the previous demonstration that a SIRT1/2 dual inhibition could be instrumental in achieving an anti-cancer effect on those cancers retaining the wild-type tumor suppresser p53 protein, these compounds could be employed as leads for developing novel anti-cancer agents.