Chroman-4-one- and chromone-based sirtuin 2 inhibitors with antiproliferative properties in cancer cells.
Sirtuins (SIRTs) catalyze the NAD(+)-dependent deacetylation of N(ε)-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.
Department of Chemistry and Molecular Biology, Medicinal Chemistry, University of Gothenburg , Kemivagen 10, SE-412 96 Göteborg, Sweden.
Tina
T
Seifert
Marcus
M
Malo
Tarja
T
Kokkola
Karin
K
Engen
Maria
M
Fridén-Saxin
Erik A A
EA
Wallén
Maija
M
Lahtela-Kakkonen
Elina M
EM
Jarho
Kristina
K
Luthman
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002839:Chromans / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002867:Chromones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors*; D014404:Tubulin / Q000378:metabolism
D000970:Antineoplastic Agents; D002839:Chromans; D002867:Chromones; D004791:Enzyme Inhibitors; D014404:Tubulin; D056565:Sirtuin 2