Chroman-4-one- and Chromone-Based Sirtuin 2 Inhibitors with Antiproliferative Properties in Cancer Cells

被引：113

作者：

Seifert, Tina ^{[1
]}

Malo, Marcus ^{[1
]}

Kokkola, Tarja ^{[2
]}

Engen, Karin ^{[1
]}

Friden-Saxin, Maria ^{[1
]}

Wallen, Erik A. A. ^{[3
]}

Lahtela-Kakkonen, Maija ^{[2
]}

Jarho, Elina M. ^{[2
]}

Luthman, Kristina ^{[1
]}

机构：

[1] Univ Gothenburg, Dept Chem & Mol Biol, SE-41296 Gothenburg, Sweden

[2] Univ Eastern Finland, Sch Pharm, Kuopio 70211, Finland

[3] Univ Helsinki, Fac Pharm, Div Pharmaceut Chem & Technol, FIN-00014 Helsinki, Finland

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2014年 / 57卷 / 23期

基金：

芬兰科学院; 瑞典研究理事会;

关键词：

HISTONE DEACETYLASE SIRT2; SMALL-MOLECULE INHIBITOR; CRYSTAL-STRUCTURE; STRUCTURAL BASIS; HISTONE/PROTEIN DEACETYLASES; ADP-RIBOSYLTRANSFERASE; STACKING INTERACTIONS; HUNTINGTONS-DISEASE; BINDING MODE; MECHANISM;

D O I：

10.1021/jm500930h

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Sirtuins (SIRTs) catalyze the NAD(+)-dependent deacetylation of N-e-acetyl lysines on various protein substrates. SIRTs are interesting drug targets as they are considered to be related to important pathologies such as inflammation and aging-associated diseases. We have previously shown that chroman-4-ones act as potent and selective inhibitors of SIRT2. Herein we report novel chroman-4-one and chromone-based SIRT2 inhibitors containing various heterofunctionalities to improve pharmacokinetic properties. The compounds retained both high SIRT2 selectivity and potent inhibitory activity. Two compounds were tested for their antiproliferative effects in breast cancer (MCF-7) and lung carcinoma (A549) cell lines. Both compounds showed antiproliferative effects correlating with their SIRT2 inhibition potency. They also increased the acetylation level of a-tubulin, indicating that SIRT2 is likely to be the target in cancer cells. A binding mode of the inhibitors that is consistent with the SAR data was proposed based on a homology model of SIRT2.

引用

页码：9870 / 9888

页数：19

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