Identification of tri- and tetracyclic pyrimidinediones as sirtuin inhibitors.

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.