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

Journal article
Authors Tina Seifert
Marcus Malo
Tarja Kokkola
Karin Engen
Maria Fridén-Saxin
Erik A A Wallén
Maija Lahtela-Kakkonen
Elina Jarho
Kristina Luthman
Published in Journal of Medicinal Chemistry
Volume 57
Issue 23
Pages 9870-9888
ISSN 0022-2623
Publication year 2014
Published at Department of Chemistry and Molecular Biology
Pages 9870-9888
Language en
Subject categories Chemical Sciences


Sirtuins (SIRTs) catalyze the NAD+-dependent deacetylation of Nε-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 α-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.

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