Novel 3-arylideneindolin-2-ones as inhibitors of NAD+ -dependent histone deacetylases (sirtuins).
Class III histone deacetylases (sirtuins) play pivotal roles in many cellular processes. They are linked to extended lifespan and to the pathogenesis of cancer and neuronal disorders. We present novel sirtuin inhibitors based on a 6,7-dichloro-2-oxindole scaffold with low micromolar activity. In vitro activity was rationalized by docking studies, and hyperacetylation of sirtuin targets could be demonstrated in cell culture.
Huber
Kilian
K
Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians-Universität München, Butenandtstrasse 5-13, 81377 Munich, Germany.
Schemies
Jörg
J
Uciechowska
Urszula
U
Wagner
Julia M
JM
Rumpf
Tobias
T
Lewrick
Felicitas
F
Süss
Regine
R
Sippl
Wolfgang
W
Jung
Manfred
M
Bracher
Franz
F
D000107:Acetylation; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D009243:NAD / Q000378:metabolism; D037761:Sirtuins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D056572:Histone Deacetylase Inhibitors; D007211:Indoles; D009243:NAD; D037761:Sirtuins