title: Inhibitors of Sir2: evaluation of splitomicin analogues.
abstract: Splitomicin (1) and 41 analogues were prepared and evaluated in cell-based Sir2 inhibition and toxicity assays and an in vitro Sir2 inhibition assay. Lactone ring or naphthalene (positions 7-9) substituents decrease activity, but other naphthalene substitutions (positions 5 and 6) are well-tolerated. The hydrolytically unstable aromatic lactone is important for activity. Lactone hydrolysis rates were used as a measure of reactivity; hydrolysis rates correlate with inhibitory activity. The most potent Sir2 inhibitors were structurally similar to and had hydrolysis rates similar to 1.
authors.affiliation: Clinical Research and Human Biology Divisions, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, Washington 98109, USA.
authors.forename: Jeff
authors.initials: J
authors.lastname: Posakony
authors.forename: Maki
authors.initials: M
authors.lastname: Hirao
authors.forename: Sam
authors.initials: S
authors.lastname: Stevens
authors.forename: Julian A
authors.initials: JA
authors.lastname: Simon
authors.forename: Antonio
authors.initials: A
authors.lastname: Bedalov
mesh_terms: D056572:Histone Deacetylase Inhibitors; D007783:Lactones / Q000737:chemistry; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011753:Pyrones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000201:enzymology; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae / Q000037:antagonists & inhibitors; D056565:Sirtuin 2; D037761:Sirtuins / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D056572:Histone Deacetylase Inhibitors; D007783:Lactones; D009281:Naphthalenes; D011753:Pyrones; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae; C031721:naphthalene; C444426:splitomicin; C087778:SIR2 protein, S cerevisiae; D056565:Sirtuin 2; D037761:Sirtuins