Discovery of 5-Benzylidene-2-phenyl-1,3-dioxane-4,6-diones as Highly Potent and Selective SIRT1 Inhibitors,ACS Medicinal Chemistry Letters

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Discovery of 5-Benzylidene-2-phenyl-1,3-dioxane-4,6-diones as Highly Potent and Selective SIRT1 Inhibitors
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2021-03-01 , DOI: 10.1021/acsmedchemlett.0c00559
Chunpu Li _{1,

1,

2} , Sha-Sha Hu _{1,

3} , Lisheng Yang _{1,

1} , Min Wang ₁ , Jian-Dong Long ₁ , Bing Wang _{1,

3} , Haozhen Han _{1,

3} , Haoran Zhu _{1,

1,

3} , Sen Zhao _{1,

1} , Jing-Gen Liu ₁ , Dongxiang Liu _{1,

3} , Hong Liu _{1,

1,

2,

3}

Affiliation

SIRT1, a member of the sirtuin family, catalyzes the deacetylation of proteins with the transformation of NAD⁺ into nicotinamide and 2′-O-acetyl-ADP-ribose. Selective SIRT1/2 inhibitors have potential application in the chemotherapy of colorectal carcinoma, prostate cancer, and myelogenous leukemia. Here we identified novel SIRT1 inhibitors with the scaffold of 5-benzylidene-2-phenyl-1,3-dioxane-4,6-dione. The most potent inhibitor 12n displayed an IC₅₀ of 460 nM and a selectivity for SIRT1 over SIRT2, SIRT3, and SIRT5 of 113.5-, 254.3-, and 10.83-fold, respectively. It did not affect the activity of SIRT6. To elucidate the inhibitory mechanism, we determined the inhibition type of the inhibitor by enzyme kinetic analysis, showing that the inhibitor was competitive to the acetyl peptide and noncompetitive to NAD⁺. Further, the interaction of the inhibitor in SIRT1 was studied by using molecular docking, which was validated by the structure–activity relationship analysis of the inhibitors and the site-directed mutagenesis of SIRT1. Consistent with the in vitro assays, the inhibitors increased the acetylation level of p53 in a concentration-dependent manner in cells.

中文翻译：

发现 5-Benzylidene-2-phenyl-1,3-dioxane-4,6-diones 作为高效和选择性 SIRT1 抑制剂

SIRT1 是 sirtuin 家族的成员，通过将 NAD ⁺转化为烟酰胺和 2' - O-乙酰基-ADP-核糖来催化蛋白质的去乙酰化。选择性 SIRT1/2 抑制剂在结直肠癌、前列腺癌和骨髓性白血病的化疗中具有潜在应用。在这里，我们确定了具有 5-benzylidene-2-phenyl-1,3-dioxane-4,6-dione 支架的新型 SIRT1 抑制剂。最有效的抑制剂12n显示出 IC ₅₀460 nM 和 SIRT1 对 SIRT2、SIRT3 和 SIRT5 的选择性分别为 113.5、254.3 和 10.83 倍。它不影响 SIRT6 的活性。为了阐明抑制机制，我们通过酶动力学分析确定了抑制剂的抑制类型，表明该抑制剂与乙酰肽具有竞争性，与NAD ⁺没有竞争性。此外，通过分子对接研究了抑制剂在 SIRT1 中的相互作用，并通过抑制剂的构效关系分析和 SIRT1 的定点诱变进行了验证。与体外试验一致，抑制剂以浓度依赖性方式增加细胞中 p53 的乙酰化水平。

更新日期：2021-03-11

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