Identification of Tri- and Tetracyclic Pyrimidinediones as Sirtuin Inhibitors

(Chemical Equation Presented) Sirtuins are deacetylase proteins that regulate transcription, genome maintenance, longevity, and metabolism. Eight compounds were identified as a novel class of sirtuin inhibitors, with 5, 7, and 9 being the most effective as SIRT1-selective inhibitors. In U937 cells 5 induced apoptosis and displayed antiproliferative effects in Raji, DLD1, and HeLa cancer cells, suggesting potential utility in cancer treatment. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA.