jm500930h_si_001.pdf (1.16 MB)
Chroman-4-one- and Chromone-Based Sirtuin 2 Inhibitors with Antiproliferative Properties in Cancer Cells
journal contribution
posted on 2015-12-17, 06:21 authored by Tina Seifert, Marcus Malo, Tarja Kokkola, Karin Engen, Maria Fridén-Saxin, Erik A. A. Wallén, Maija Lahtela-Kakkonen, Elina M. Jarho, Kristina LuthmanSirtuins
(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.